A Phase 2, Multi-Center, Double-Blind, Randomized, Placebo Controlled Study of MGL-3196 in Patients With Heterozygous Familial Hypercholesterolemia
Phase: PHASE2
Conditions: Heterozygous Familial Hypercholesterolemia
Sponsor: Madrigal Pharmaceuticals, Inc.

Protocol 
Official title: 
A Phase 2, Multi-Center, Double-Blind, Randomized, Placebo-Controlled 
Study of MGL-3196 in Patients With Heterozygous Familial 
Hypercholesterolemia 
NCT Number: 
NCT03038022 
Document Date: 
14 November 2016 
 

 
 
CLINICAL STUDY PROTOCOL 
 
A Phase 2, Multi-Center, Double-Blind, Randomized, 
Placebo-Controlled Study of MGL-3196 in Patients With 
Heterozygous Familial Hypercholesterolemia 
Investigational Product: MGL-3196 
Protocol Number: MGL-3196-06 
 
 
Sponsor: 
Madrigal Pharmaceuticals, Inc. 
Four Tower Bridge, 200 Barr Harbor Drive, Suite 400 
West Conshohocken, PA 19428 
USA 
Telephone: 610-220-7260 
 
 
Version Number: 2.0 
Date: 14 November 2016 
 
Original Protocol: 12 July 2016 
Amendment 1:  14 November 2016 
 
 
 
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) or Independent Ethics Committee (IEC) 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. 

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
3
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/IEC regulations and International Conference on Harmonisation (ICH) Guidelines for Good 
Clinical Practices. 
 
 
 
 
 
 
______________________________________________  
____________________ 
Investigator’s Signature 
 
 
 
 
 
Date 
 
 
 
______________________________________________ 
Investigator’s Printed Name 
 
  

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
6
SYNOPSIS 
TITLE:  A Phase 2, Multi-Center, Double-Blind, Randomized, Placebo-Controlled Study of 
MGL-3196 in Patients With Heterozygous Familial Hypercholesterolemia 
PROTOCOL NUMBER:  MGL-3196-06 
INVESTIGATIONAL PRODUCT:  MGL-3196 
PHASE:  2 
INDICATION:  Heterozygous familial hypercholesterolemia (HeFH) 
OBJECTIVES: 
The primary objective of this study is to determine the effect of each of two separate treatment 
groups (the “100 mg group” and the “60 mg group”) of once-daily oral dose of MGL-3196 and 
matching placebo on the percent change from baseline in low-density lipoprotein cholesterol 
(LDL-C) in patients with HeFH. 
The secondary objectives of this study are the following: 
• To evaluate the safety profile, including any changes in thyroid axis hormones, and 
tolerability of once-daily oral dosing regimen of MGL-3196 versus placebo after 12 weeks 
in patients with HeFH; 
• To determine the effect of once-daily oral dosing regimen of MGL-3196 versus placebo for 
12 weeks on the percent change from baseline on the following assessments in patients with 
HeFH: 
o Non-high-density lipoprotein cholesterol (non-HDL-C), 
o Apolipoprotein B (ApoB), 
o Total cholesterol (TC)/high-density lipoprotein cholesterol (HDL-C) ratio, 
o Triglycerides, 
o Lipoprotein(a), 
o Apolipoprotein A1 (ApoA1)/ApoB ratio, and 
o Lipoprotein particle assessment; and 
• To determine the effect of once-daily oral dose of MGL-3196 versus placebo for 12 weeks 
on the absolute change from baseline in LDL-C in patients with HeFH. 
• To determine the effect of all patients (100 and 60 mg groups) on per cent change from 
baseline in LDL-C 
• To determine the effect of  exposure to MGL-3196 on LDL-C lowering 

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
7
POPULATION: 
The population for this study is male and female patients ≥18 years of age who have met the 
diagnostic criteria for HeFH outlined by the Simon Broome Register Group (Appendix C) or 
World Health Organization (WHO)/Dutch Lipid Network (score >8; Appendix D).  
Inclusion Criteria: 
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) test 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 either 
be 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. Must have a diagnosis of HeFH by genetic testing or by having met the diagnostic criteria 
for definite familial hypercholesterolemia outlined by the Simon Broome Register Group 
(Appendix C) or WHO/Dutch Lipid Network (score >8; Appendix D); 
5. Must have a fasting LDL-C ≥2.6 mmol/L (100 mg/dL); and 
6. Must be on a stable or maximally tolerated dose (≥4 weeks prior to screening) of an 
approved statin (rosuvastatin ≤20 mg daily, atorvastatin ≤80 mg daily), with or without 
ezetimibe. 
 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from participation in the 
study: 
1. Homozygous familial hypercholesterolemia; 
2. Low-density lipoprotein (LDL) or plasma apheresis within 2 months prior to 
randomization; 
3. New York Heart Association class III or IV heart failure, or known left ventricular ejection 
fraction <30%; 

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
8
 
 
4. 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;  
5. Myocardial infarction, unstable angina, percutaneous coronary intervention, coronary 
artery bypass graft, or stroke within 3 months prior to randomization; 
6. Type 1 diabetes, or newly diagnosed or uncontrolled type 2 diabetes (hemoglobin A1c 
[HbA1c] >8%); 
7. 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;  
8. Hyperthyroidism; 
9. Thyroid replacement therapy 
10. 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; 
11. Evidence of chronic liver disease; 
12. Hepatitis B, as defined by the presence of hepatitis B surface antigen; 
13. Hepatitis C, as defined by the presence of hepatitis C 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; 
14. Serum alanine aminotransferase (ALT) >1.5 × ULN (one repeat allowed); 
15. Estimated glomerular filtration rate <60 mL/min; 
16. Creatine kinase >3 × ULN (one repeat allowed); 
17. History of biliary diversion; 
18. Positive for human immunodeficiency virus infection; 
19. History of malignant hypertension;  
20. Systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg at screening 
or randomization and confirmed at an unscheduled visit; 
21. Triglycerides >5.7 mmol/L (500 mg/dL) at screening and confirmed by repeat assessment; 

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
9
22. Active, serious medical disease with likely life expectancy <2 years; 
23. Active substance abuse, including inhaled or injection drugs within the year prior to 
screening; 
24. Use of any excluded medications or procedures listed in Section 5.6.1; 
25. Participation in an investigational new drug trial within the 30 days prior to randomization; 
or 
26. Any other condition which, in the opinion of the Investigator, would impede compliance, 
hinder completion of the study, or compromise the well-being of the patient. 
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 HeFH. Patients who qualify for study 
inclusion will be randomized to receive one of two 12-week treatments: a once daily oral 
dosing regimen of MGL-3196, or placebo (randomized 2:1) given orally once daily. Patients 
will self-administer MGL-3196 once daily each morning, and their statin medication each 
evening, during the 12-week treatment period. 
Screening Period 
To participate in the study, patients must be diagnosed with HeFH using standard accepted 
procedures and meet the study criteria. Patients must first provide written, informed consent 
and then undergo screening procedures within 14 days prior to randomization. Patients will 
begin taking their statin and other lipid lowering therapy at night at least 2 weeks before 
randomization, and will continue this practice for the duration of the study. 
Treatment Period 
On the morning of Day 1, patients will be randomized in 2:1 fashion to receive either MGL-
3196 100 mg or matching placebo. Following randomization, patients will undergo a 12-week 
treatment period and will periodically return to the study site (visits are planned at Weeks 2, 4, 
8, 12 and 16) for assessment of  drug exposure, safety laboratories, AEs, vital signs (oral 
temperature, pulse rate, respiratory rate, and seated blood pressure).  
At the week 2 visit, in addition to other labs described below, a PK assessment will be made, 
that will include a pre-dose fasting MGL-3196 determination. Based on their randomization, 
patients will then be administered one dose of study drug (100 mg MGL-3196 or placebo) and 
a 4 hour postdose MGL-3196 PK assessment will be made, while patients are fasting. A 12-
lead ECG will be measured at 4 hours postdose after the 4 h blood draw. Patients randomized 
to MGL-3196 100 mg will receive MGL-3196 60 mg between the week 2 and 4 visits, while 
patients receiving placebo will continue to receive placebo. At the week 4 visit, patients 
receiving MGL-3196 will either continue to receive 60 mg or be placed back on 100 mg 
depending on their week 2 MGL-3196 level 4 h postdose. (Patients with week 2 postdose 
MGL-3196 blood levels < 1,500 ng/mL will be placed on MGL-3196 100 mg, while patients 
with MGL-3196 blood levels ≥ 1,500 ng/mL will continue to receive 60 mg. 
Chemistry (including calcium and phosphorus) and hematology will be assessed at all study 
visits; a 12-lead electrocardiogram (ECG) will be performed at all study visits; and 
coagulation and urinalysis will be performed at baseline and end of study. At all study site 

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
10 
visits, blood samples will be collected for the assessment of thyroid hormone parameters 
including thyroid stimulating hormone (TSH), total triiodothyronine (T3) and thyroxine (T4), 
and free T3 (FT3) and free T4 (FT4). Lipids (as described in the secondary objectives) will be 
assessed at all study visits except for low density lipoprotein (LDL) particle analyses, which 
will be assessed at baseline, Week 12, and Week 16; LDL-C will be determined by 
ultracentrifugation at baseline and Week 12. Other biomarker assessments will include 
 
and 
, assessed 
at all study visits. Follicle-stimulating hormone (FSH), total and free testosterone, luteinizing 
hormone (LH), creatine kinase MB isoenzyme (CKMB), troponin I, reverse T3, fibrinogen, 
alkaline phosphatase (ALP) isoenzymes, procollagen type 1 N-terminal propeptide (P1NP), 
and C-terminal telopeptide (CTX) will be assessed at baseline, Week 12, and Week 16; free 
testosterone will be calculated from total testosterone, 
, and serum albumin. Patients 
will be evaluated for adverse events throughout the study.  
Following the first dose of MGL-3196 and thereafter, the dose of MGL-3196 will be down-
titrated if TSH is below the lower limit of normal (LLN) with a >50% change from baseline 
confirmed on 2 consecutive assessments. Down-titrations will be as follows: the 100 mg dose 
would be decreased to 80 mg, and an 80 mg dose would be decreased to 60 mg. Following 
down-titration, TSH testing will resume according to the schedule of procedures. A second 
down-titration is permitted (i.e. to 40 mg). 
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 alanine aminotransferase [ALT], aspartate aminotransferase [AST], and bilirubin), 
and other efficacy (lipid parameters) and safety data as needed. The DSMB will perform 
regularly scheduled reviews as well as an additional review if necessary. 
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 
100 mg  or placebo given orally once daily in the morning for 12 weeks. Each patient will 
receive 2 bottles labeled as A and B. The patient 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. After the week 2 visit, all patients receiving MGL-3196 
100 mg will receive MGL-3196 60 mg between the week 2 and 4 visits. Based on week 2 PK 
assessment, at the week 4 visit some patients will be placed back on MGL-3196 100 mg. The 
patient, study personnel, and Sponsor will remain blinded throughout the study. 
EFFICACY VARIABLES:  
The primary efficacy parameter is mean percent change from baseline in LDL-C.  
The secondary efficacy parameters include the following: 
• Mean percent change from baseline in non-HDL-C, ApoB, TC/HDL-C ratio, triglycerides, 
lipoprotein(a), ApoA1/ApoB ratio, and lipoprotein particle assessment; and 
• Absolute percent change from baseline in LDL-C. 

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
11 
• Mean percent change from baseline in LDL-C for all patients on study drug (60-100 mg). 
• Mean per cent change from baseline in LDL-C according to MGL-3196 exposure. 
 
SAFETY VARIABLES: 
Safety variables to be assessed include safety laboratory tests, vital signs, 12-lead ECG with 
rhythm strip, physical examinations, assessment of adverse events, and clinic assessments. 
PHARMACOKINETICS: 
Blood samples for PK assessments will be obtained pre-dose from patients at the Baseline Visit 
(Day 1), Weeks 2, 8, and 12, and the Early Termination Visit. Patients will be instructed not to 
take study drug prior to PK sampling at these visits. Blood samples for PK assessments will be 
obtained 4 hours post-dose from patients at Week 2. 
STATISTICAL ANALYSES: 
Study 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 medication. 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 LDL-C measurements and do not have any major protocol 
deviations. Patients who are <80% compliant over the course of the 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 medication 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 change in LDL-C 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 and baseline LDL-C as a covariate. Determinations for the 100 (and 60) mg groups 
will be based on all 12 weeks of the study, including the first two weeks (Week 0-2) in which 
all patients were on 100 mg and the second two weeks (Week 2-4) when all patients down-
titrated to 60 mg. The assigned group (60 or 100 mg) will be based on the dose at Week 4 to 
Week 12. For any patients in the ITT Population with a missing primary efficacy parameter, 
the last observation carried forward method will be used. The multiplicity (MGL-3196 100 mg 
versus placebo and MGL-3196 60 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, logarithm 
transformation may be performed prior to fitting the ANCOVA model. For the categorical 

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
12 
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 any 
potential 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), body mass index (≥30 kg/m2 or 
<30 kg/m2), age group (≥median or <median), and baseline thyroid status. 
Safety: 
The safety endpoints for this study include: safety laboratory tests, vital signs, 12-lead ECGs, 
physical examinations, assessment of adverse events, and clinic 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 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.  
SAMPLE SIZE DETERMINATION: 
Up to 105 patients in total will be randomized to 1 of 2 treatments (70 patient to MGL-3196, 
35 patients to placebo). It is estimated that the treatment difference of percent change in LDL-
C from baseline to Week 12 between any dose of the MGL-3196 group and the placebo group 
is about -20%. With a common standard deviation for the change in LDL-C at 20%, 27 
patients per group to complete the Week 12 visit will provide 90% power with a two-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 vs. placebo group. The enrollment size is designed to 
allow for dropouts before the 12 week visit, and as such, patients who drop out of the study 
will not be replaced. 
SITES:  Approximately 13 sites in Europe. 
SPONSOR: 
Madrigal Pharmaceuticals, Inc. 
Four Tower Bridge, 200 Barr Harbor Drive, Suite 400 
West Conshohocken, PA 19428 
USA 
Telephone: 610-220-7260 

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
13 
TABLE OF CONTENTS 
SIGNATURE PAGE ...................................................................................................................... 2 
INVESTIGATOR AGREEMENT .................................................................................................. 3 
SYNOPSIS ...................................................................................................................................... 4 
TABLE OF CONTENTS .............................................................................................................. 13 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................................. 17 
1 
INTRODUCTION AND BACKGROUND INFORMATION ........................................ 19 
1.1 
Background ................................................................................................................. 19 
1.2 
Rationale ..................................................................................................................... 23 
2 
STUDY OBJECTIVES ..................................................................................................... 27 
2.1 
Primary Objective ....................................................................................................... 27 
2.2 
Secondary Objectives .................................................................................................. 27 
3 
STUDY DESCRIPTION .................................................................................................. 28 
3.1 
Summary of Study Design .......................................................................................... 28 
3.2 
Study Indication .......................................................................................................... 29 
4 
SELECTION AND WITHDRAWAL OF PATIENTS .................................................... 30 
4.1 
Inclusion Criteria ........................................................................................................ 30 
4.2 
Exclusion Criteria ....................................................................................................... 30 
4.3 
Withdrawal Criteria .................................................................................................... 32 
5 
STUDY TREATMENTS .................................................................................................. 33 
5.1 
Treatment Groups ....................................................................................................... 33 
5.2 
Rationale for Dosing ................................................................................................... 33 
5.3 
Randomization and Blinding ...................................................................................... 33 
5.4 
Breaking the Blind ...................................................................................................... 33 
5.5 
Drug Supplies.............................................................................................................. 34 
5.5.1 Formulation and Packaging .................................................................................. 34 
5.5.2 Study Drug Preparation and Dispensing ............................................................... 34 
5.5.3 Study Drug Administration ................................................................................... 34 
5.5.4 Treatment Compliance .......................................................................................... 34 
5.5.5 Storage and Accountability ................................................................................... 34 
5.6 
Prior and Concomitant Medications and/or Procedures ............................................. 35 

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
14 
5.6.1 Excluded Medications and/or Procedures ............................................................. 35 
5.6.2 Documentation of Prior and Concomitant Medication Use .................................. 35 
6 
STUDY PROCEDURES .................................................................................................. 36 
6.1 
Informed Consent ........................................................................................................ 36 
6.2 
Screening Visit (Day -14 to Day -1) ........................................................................... 36 
6.3 
Randomization ............................................................................................................ 37 
6.4 
Treatment Period – Day 1 Through Day 84 ................................................................ 37 
6.4.1 Baseline Visit (Day 1) ........................................................................................... 37 
6.4.2 Week 2 (Day 14 [±3 days]) ................................................................................... 38 
6.4.3 Week 4 (Day 28 [±3 days]) ................................................................................... 38 
6.4.4 Week 8 (Day 56 [±3 days]) ................................................................................... 39 
6.4.5 Week 12 (Day 84 [±3 days]) or Early Termination Visit ..................................... 39 
6.5 
Follow-Up Visit at Week 16 (Day 112 [±3 days]) ..................................................... 40 
6.6 
Early Termination Visit and Withdrawal Procedures ................................................. 41 
7 
EFFICACY ASSESSMENTS .......................................................................................... 42 
8 
PHARMACOKINETIC ASSESSMENTS ....................................................................... 43 
9 
SAFETY ASSESSMENTS ............................................................................................... 44 
9.1 
Adverse Events ........................................................................................................... 44 
9.1.1 Adverse (Drug) Reaction ...................................................................................... 44 
9.1.2 Unexpected Adverse Drug Reaction ..................................................................... 44 
9.1.3 Assessment of Adverse Events by the Investigator .............................................. 45 
9.2 
Serious Adverse Events .............................................................................................. 46 
9.3 
Serious Adverse Event Reporting − Procedures for Investigators ............................. 46 
9.4 
Pregnancy Reporting ................................................................................................... 47 
9.5 
Expedited Reporting ................................................................................................... 47 
9.6 
Informed Consent ........................................................................................................ 48 
9.7 
Demographic Information ........................................................................................... 48 
9.8 
Clinical Laboratory Evaluations ................................................................................. 48 
9.9 
Vital Signs ................................................................................................................... 49 
9.10 
Electrocardiograms ..................................................................................................... 50 
9.11 
Physical Examinations ................................................................................................ 50 
9.12 
Diet and Lifestyle Counseling .................................................................................... 50 

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
15 
10 
STATISTICS .................................................................................................................... 52 
10.1 
Analysis Populations ................................................................................................... 52 
10.2 
Statistical Methods ...................................................................................................... 52 
10.2.1 Analysis of Efficacy .............................................................................................. 52 
10.2.1.1 
Primary efficacy analysis ................................................................................. 52 
10.2.1.2 
Secondary efficacy analysis ............................................................................. 52 
10.2.1.3 
Other efficacy analysis .................................................................................... 52 
10.2.1.4 
Subgroup analysis ............................................................................................ 53 
10.2.2 Analysis of Safety ................................................................................................. 53 
10.2.3 Data Safety Monitoring Board .............................................................................. 53 
10.2.4 Sample Size Determination ................................................................................... 53 
11 
DATA MANAGEMENT AND RECORD KEEPING ..................................................... 54 
11.1 
Data Management ....................................................................................................... 54 
11.1.1 Data Handling ....................................................................................................... 54 
11.1.2 Computer Systems ................................................................................................ 54 
11.1.3 Data Entry ............................................................................................................. 54 
11.1.4 Medical Information Coding ................................................................................. 54 
11.1.5 Data Validation ..................................................................................................... 54 
11.2 
Record Keeping .......................................................................................................... 55 
12 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL ............................. 56 
12.1 
Ethical Conduct of the Study ...................................................................................... 56 
12.2 
Institutional Review Board/Independent Ethics Committee ....................................... 56 
12.3 
Informed Consent ........................................................................................................ 56 
12.4 
Patient Card ................................................................................................................. 57 
12.5 
Study Monitoring Requirements ................................................................................. 57 
12.6 
Disclosure of Data ....................................................................................................... 57 
12.7 
Retention of Records ................................................................................................... 57 
12.8 
Publication Policy ....................................................................................................... 58 
12.9 
Financial Disclosure .................................................................................................... 58 
12.10 Insurance and Indemnity ............................................................................................. 58 
12.11 Legal Aspects .............................................................................................................. 58 
13 
STUDY ADMINISTRATIVE INFORMATION ............................................................. 59 

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
16 
13.1 
Protocol Amendments ................................................................................................. 59 
13.2 
Address List ................................................................................................................ 59 
13.2.1 Sponsor ................................................................................................................. 59 
13.2.2 Contract Research Organization ........................................................................... 59 
13.2.3 Drug Safety ........................................................................................................... 59 
13.2.4 Biological Specimens ............................................................................................ 60 
13.2.5 Biological Specimens ............................................................................................ 60 
14 
REFERENCES ................................................................................................................. 61 
APPENDIX A:  SCHEDULE OF PROCEDURES ...................................................................... 64 
APPENDIX B:  CLINICAL LABORATORY ANALYTES ....................................................... 64 
APPENDIX C:  SIMON BROOME REGISTER DIAGNOSTIC CRITERIA FOR 
HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA .................................. 68 
APPENDIX D:  WHO CRITERIA (DUTCH LIPID NETWORK CLINICAL CRITERIA) FOR 
DIAGNOSIS OF HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA ..... 69 

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
17 
 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance  
ANGPTL3 
Angiopoietin-like 3 
anti-HCV 
Hepatitis C antibody 
ApoA1 
Apolipoprotein A1 
ApoB 
Apolipoprotein B 
ApoCIII 
Apolipoprotein CIII 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
CKMB 
Creatine kinase MB isoenzyme 
CRA 
Clinical research associate 
CTA 
Clinical trial authorization 
CTX 
C-terminal telopeptide 
CV 
Cardiovascular 
CYP 
Cytochrome P450  
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
FT3 
Free triiodothyronine 
FT4 
Free thyroxine 
FH 
Familial hypercholesterolemia 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transpeptidase 
HbA1c 
Hemoglobin A1c 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HCVAb 
Hepatitis C virus antibody 
HDL-C 
High-density lipoprotein cholesterol 
HIV 
Human immunodeficiency virus 
HeFH 
Heterozygous familial hypercholesterolemia 
HoFH 
Homozygous familial hypercholesterolemia 
hsCRP 
High-sensitivity C-reactive protein 
ICF 
Informed consent form 

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
18 
Abbreviation 
Definition 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ITT 
Intent-to-Treat 
IUD 
Intrauterine device 
LDL 
Low-density lipoprotein 
LDL-C 
Low-density lipoprotein cholesterol 
LH 
Luteinizing hormone 
LLN 
Lower limit of normal 
MedDRA 
Medical Dictionary for Regulatory Activities 
NASH 
Non-alcoholic steatohepatitis 
Non-HDL-C 
Non-high-density lipoprotein cholesterol 
OATP 
Organic anion-transporting polypeptide 
P1NP 
Procollagen type 1 N-terminal propeptide 
PCSK9 
Proprotein convertase subtilisin/kexin type 9 
PK 
Pharmacokinetic 
PT 
Prothrombin time 
QTcF 
QT interval corrected using Fridericia’s formula 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SHBG 
Sex hormone-binding globulin 
T3 
Triiodothyronine 
T4 
Thyroxine 
TC 
Total cholesterol 
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 
WHO 
World Health Organization 
 

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
19 
1 
INTRODUCTION AND BACKGROUND INFORMATION 
1.1 
Background 
Madrigal Pharmaceuticals is developing MGL-3196 for the treatment of HeFH in adults 
receiving maximally tolerated statin therapy who require additional lowering of low density 
lipoprotein cholesterol (LDL-C). Despite advances in treatment, approximately 70% of high-risk 
cardiovascular (CV) 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 CV disease, including myocardial infarctions and strokes, and drugs 
such as statins that lower LDL-C also reduce CV morbidity and mortality.  
Heterozygous 
familial 
hypercholesterolemia 
(HeFH) 
and 
homozygous 
familial 
hypercholesterolemia (HoFH) are genetic disorders characterized by severe debilitating 
dyslipidemia and early onset CV disease. Individuals with HeFH typically have LDL-C levels 
approximately double that of unaffected siblings. HeFH is most commonly caused by mutations 
of the LDLR gene. If untreated, early onset coronary artery disease will likely develop in HeFH 
patients. The prevalence of HeFH is estimated to be 1 in 500 and may be as high as 1 in 200. 
Despite treatment with newer therapies (ie, proprotein convertase subtilisin/kexin type 9 
[PCSK9] inhibitors) and standard care (which includes statins and ezetimibe), some HeFH 
patients are not achieving their LDL-C goal.3  A recent large registry study of HeFH patients 
revealed that patients receiving maximal therapy (i.e., statins with a potency of >45% LDL-C 
reduction plus at least another lipid-lowering agent) only 11.2% reach target LDL-C levels of 
<100 mg/dL.4  
Thyroxine (T4) via its active derivative, T3, provides beneficial metabolic effects on cholesterol, 
triglycerides, and liver triglyceride levels, primarily through action at the THR-β, the 
predominant hepatocyte THR.5,6,7,8,9  However, excessive levels of thyroid hormone can lead to 
adverse effects, particularly in the heart and bones that are primarily mediated by the THR-α 
receptor which is the major systemic thyroid hormone receptor.10,11  MGL-3196 is a selective 
THR-β agonist with actions in the liver that is designed to avoid those systemic actions mediated 
through THR-α and the central thyroid action suppression observed with previous analogues.  
There are several rationales for the use of MGL-3196 for the treatment of patients with genetic 
dyslipidemias, including HeFH and HoFH. Specifically, thyroid receptor ß agonists have the 
potential to reduce LDL cholesterol by both LDL-receptor dependent and independent 
mechanisms, which include reduction in circulating PCSK9,12  stimulation of hepatic cholesterol 
metabolism and excretion, potential reduction of ANGPTL3, and direct reduction of ApoB. The 
effect of thyroid ß receptor agonism to reduce cholesterol in familial hypercholesterolemia (FH) 
has been demonstrated in mouse LDL-receptor knockout mice13  and in humans with HeFH 
treated with an earlier thyroid agonist, eprotirome.14  Thyroid beta agonists are one of the few 
mechanisms that has the potential to reduce lipoprotein(a), an atherogenic lipoprotein particle 
that is frequently elevated in patients with FH. MGL-3196 potently reduces triglycerides, 
providing additional cardiovascular benefit. In addition, MGL-3196’s mechanism is 
complementary to statins and ezetimibe because thyroid ß receptor agonists do not affect 
cholesterol synthesis pathways or intestinal absorption of cholesterol. 
 

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
20 
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.15,16 However, 
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.17,18  MGL-3196 has shown absence of these safety issues in preclinical and in 
clinical studies, so far, as described below. 
 
1.1.1 
Profile of MGL-3196, Preclinical and Clinical Data 
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). MGL-3196 was selected for clinical development based 
on its enhanced THR-ß selectivity in functional THR assays and its greatly improved safety in 
preclinical animal models relative to other THR analogues and T3.19  Unlike previous clinical 
analogues which are, in fact, potent at the alpha receptor like thyroid hormone, MGL-3196 is 
highly THR-ß selective in a functional coactivator recruitment assay and has virtually no THR-α 
activity.19   Liver uptake is mediated by hepatic transporters and, systemic exposure is limited by 
high protein binding and low tissue penetration outside the liver. In preclinical animal studies, 
MGL-3196 showed rapid and robust lowering of non-HDL cholesterol, triglycerides, and liver 
triglycerides, differentiating MGL-3196 from statins and other lipid-lowering agents. In a rabbit 
model, MGL-3196 showed excellent lipid lowering, including cholesterol and triglycerides when 
administered alone, and an additive effect of MGL-3196 was observed when administered in 
combination with atorvastatin.  
Preclinical studies, including acute, subchonic, reproductive and chronic animal toxicology 
studies support the Phase 2 studies.  The toxicities observed in both toxicological animal species, 
rats and dogs,  were generally reversible, reflective of pharmacology on the drug target, and were 
not serious or life-threatening.  Between the range of possible clinical doses (80-120 mg per day) 
a dose of 80 mg is 11,13 fold, and 120 mg is 5,6 fold below the NOAEL in the rat and dog, 
respectively (Investigator Brochure) and 29-49 fold below the maximum dose that was generally 
well tolerated, and, while not the NOAEL, in rat was due to monitorable HPT suppression, and 
in dog, generally monitorable biliary hyperplasia which was associated with elevated ALP. In 
rats or dogs, no histologic effects on cartilage (or bone) were observed at any dose (NOEL in 
dogs 62 fold relative to expected clinical exposure at 80 mg), clearly differentiating MGL-3196 
from eprotirome. 
To date, a total of 129 healthy volunteers have received oral doses of MGL-3196 ranging from 
single doses of 0.25 to 200 mg, to multiple once-daily oral doses from 5 to 200 mg for up to14 
days. The single and multiple ascending dose studies were placebo controlled.  
 
A two-week multiple dose study (VIA-3196-02, NCT01519531) was conducted at doses of 
•
5, 20, 50, 80, 100, and 200 mg per day in healthy subjects with mildly elevated low density 
lipoprotein (LDL) cholesterol (> 110 mg/dL).  

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
21 
- 
MGL-3196 was well tolerated at all doses with no dose-related adverse events or liver 
enzyme, ECG or vital-sign changes, except for a trend in diastolic BP reduction at the 
highest doses.  There were no changes in standard laboratory safety tests including liver 
enzymes. 
- 
Doses ranging from 50−200 mg demonstrated highly statistically significant reductions 
relative to placebo of up to: 30% for LDL cholesterol (range, p = .05-<.0001); 28% for 
non- high density lipoprotein (HDL) cholesterol (range, p = .027-.0001); 24% for 
Apolipoprotein B (range, p = .008-.0004), and statistical trends of up to 60% reduction in 
triglycerides (TG) (range, p = .13-.016).  The near maximal lipid effects were observed at 
a dose of 80 mg daily.  
- 
Lipid lowering effects were confirmed in two Phase 1 clinical drug interaction studies in 
which either 100 or 200 mg of MGL-3196 was dosed in healthy volunteers for 9-11 days 
and on one or more day received a single dose of 20 mg simvastatin, 10 mg rosuvastatin 
or 20 mg atorvastatin. In these studies, the lipid lowering effects were even more 
pronounced than in the MAD, including a very significant reduction of 45% in TGs in 
subjects with elevated TGs, Lp(a) lowering of up to 40% in patients with measurable 
Lp(a), and up to 42% LDL-C lowering, the LDL-C result suggesting the potential for 
complementarity with statins. 
- 
Overall, in the Phase 1 studies, there were no TEAEs including dose-related AEs 
consistently associated with MGL-3196 dosing and no laboratory abnormalities including 
liver enzyme abnormalities.  
- 
In the multiple ascending dose study, subjects receiving the highest dose (200mg) 
experienced small reversible reductions in prohormone T4 levels, without an effect on 
active hormone T3, or TSH, that is considered most likely due to increased hepatic T4 
deiodination and conversion to the active hormone T3. Importantly, no evidence of 
central thyroid axis suppression was observed in the MAD. The Phase 1 safety profile for 
MGL-3196 clearly differentiates it from previous thyroid analogues tested in Phase 1 
studies,15  and confirms its selective pharmacologic action at the liver THR-β receptor. 
 
1.1.2 
Comparative Liver Enzyme Effects 
In the MGL-3196 SAD and MAD studies, the clinical laboratory values were considered 
unremarkable and none of the values outside of the reference range with the exception of lipid 
markers and T4 levels that were considered attributable to the pharmacology.  There were no 
mean changes of note in hematology, chemistry, including liver and renal function, or in 
urinalysis.  There were no effects on vital signs.  
Because other thyroid agonists (eprotirome, Metabasis, MB-7811/ Viking, VK-2809) have 
reported liver enzyme abnormalities in Phase 1, 2, and 3 studies, a comparative analysis was 
made of MGL-3196 to other analogues, particularly to results from a recent report of 
eprotirome’s Phase 3 study in HeFH patients.14,18,20,21  In Phase 1 studies, MB-7811 (now VK-
2809) reported ALT and AST elevations peaking at about 1.5x ULN on day 14 of the study22  
KB-2115 (eprotirome) in 14 day Phase 1 described: “the most frequent drug-related adverse 
events observed were mild increases in transaminase [alanine aminotransferase (ALT) and 

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
22 
aspartate aminotransferase] levels, and one subject, who had elevated ALT before dosing with 
KB2115 developed a transient increase in ALT of 3-fold the upper level for normal.”20   In a 
Phase 3 study of eprotirome in HeFH patients, statistically significant increases in AST, ALT, 
bilirubin and GGT were observed that were evident at week 2 and increased at week 6.  The 
ALT elevations were on average 144-183% and AST 60-114 % increased over baseline.  A 
comparative table showing the two week change in ALT and AST for MGL-3196 from the MAD 
study and eprotirome in the Phase 3 study is shown (Table 1).  Approximately 50% of HeFH 
patients demonstrate > 1XULN elevation of ALT/AST after two weeks of dosing with 
eprotirome, whilst none of the subjects treated with clinically relevant doses of MGL-3196 
showed AST or ALT elevations in 2 weeks.  The results of the comparison must be viewed 
cautiously because the subjects treated with MGL-3196 as compared with eprotirome are 
different, HeFH patients typically taking several concomitant medications.  In recent data 
submitted for publication (personal communication, J. Kastelein) the effect of thyroid hormone 
on liver enzymes (ALT, AST, bilirubin) in normal volunteers given at roughly 5X the 
replacement thyroxine dose was investigated.  The study demonstrated no evidence of ALT/AST 
elevations in any subjects treated with high clinical doses of thyroxine for 2 weeks.  The authors 
suggest that liver enzyme effects of eprotirome may be off-target, compound-specific or 
secondary to drug interactions rather than due to thyroid hormone receptor agonism. 
 
Table 1 
ALT, AST After Two Weeks of Clinical Dosing; MGL-3196, eprotirome  
 
 
  
Level 
ALT 
AST 
 
 
Baseline 
2 weeks 
Baseline 
2 weeks 
Placebo 
 
 
NL 
12 (100*) 
12 (100) 
12 (100) 
12 (100) 
>ULN 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
MGL-3196 
 
5mg 
NL 
6 (100) 
6 (100) 
6 (100) 
6 (100) 
>ULN 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
20mg NL 
6 (100) 
5 (83) 
6 (100) 
6 (100) 
>ULN 
0 (0) 
1 (17) 
0 (0) 
0 (0) 
50mg NL 
4 (66.6) 
5 (83) 
5 (83) 
6 (100) 
>ULN 
2 (33.3) 
1 (17) 
1 (17) 
0 (0) 
80mg NL 
5 (83) 
6 (100) 
5 (83) 
6 (100) 
>ULN 
1 (17) 
0 (0) 
1 (17) 
0 (0) 
100mg NL 
6 (100) 
6 (100) 
6 (100) 
6 (100) 
>ULN 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
200mg NL 
6 (100) 
6 (100) 
6 (100) 
6 (100) 
>ULN 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
* percentage 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
23 
 
Table 1 
ALT, AST After Two Weeks of Clinical Dosing; MGL-3196, eprotirome 
(Continued) 
  
 
 
Level 
ALT 
AST 
 
 
Baseline 
2 weeks 
6 weeks 
Baseline 
2 weeks 
6 weeks 
Placebo 
 
 
NL  
20 (87*) 
23 (100) 
21 (91) 
20 (87*) 
23 (100) 
19 (83) 
ULN-2ULN 
3 (13) 
 
2 (9) 
3 (13) 
 
4(17) 
 
50 µg NL  
18 (75) 
7 (29) 
5 (21) 
21 (88) 
8 (33) 
8 (33) 
 
 
ULN-2ULN 
6 (25) 
10 (42) 
14 (58) 
3 (13) 
12 (50) 
13 (54) 
 
 
2ULN-3ULN 
 
5 (21) 
3 (13) 
 
4 (17) 
3 (13) 
 
 
3ULN-4ULN 
 
2 (8) 
2 (8) 
 
 
 
Eprotirome 100 µg NL 
20 (91) 
9 (41) 
4 (18) 
20 (91) 
11 (50) 
5 (23) 
 
 
ULN-2ULN 
2 (9) 
7 (32) 
11 (50) 
2 (9) 
8 (36) 
12 (55) 
 
 
2ULN-3ULN 
 
4 (18) 
3 (14) 
 
3 (14) 
3 (14) 
 
 
3ULN-4ULN 
 
2 (9) 
3 (14) 
 
 
2(9) 
 
 
4ULN-5ULN  
 
 
1 (5) 
 
 
 
*percentage  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.2 
Rationale for Phase 2 HeFH Study Design 
Doses of 80-200 mg per day of MGL-3196 appeared to have similar effects on lipids after 14 
days of dosing in a modest number of otherwise-healthy volunteers with mildly elevated LDL-C; 
effects in patients with HeFH or in individuals dosed for longer periods may differ.  Results of 
the completed clinical studies, including robust lipid changes observed in the MAD and MGL-
3196-03, suggest that MGL-3196 is suitable for once-daily dosing, and that it can be dosed with 
or without food.  Based on the dose-related lipid effects, the doses of MGL-3196 planned for the 
Phase 2 study in HeFH patients is 100 mg/day (range of projected mean exposure ~4000−9000 
ng*hr/ml), to be given once-daily without regard to food.   
Patients with HeFH typically take high dose statins, particularly atorvastatin and rosuvastatin 
with ezetimibe21,23 to achieve therapeutic targets. MGL-3196’s mechanism of cholesterol 
lowering is complementary to statins.5 MGL-3196 provides additional benefits, potently 
lowering triglycerides and, like other thyroid agonists appears to reduce Lp(a), a particularly 
atherogenic particle frequently elevated in HeFH, including severe HeFH. 
1.2.1 
Drug Interaction Studies with Statins 
A Phase 1 clinical drug interaction study (MGL-3196-03) was conducted between MGL-3196 
200 mg per day (steady-state) and rosuvastatin (10 mg) that indicated that there was an increase 
in rosuvastatin exposure (1.8x) felt to be mediated by the effect of high gut levels of MGL-3196 
dosed at 200 mg to inhibit the intestinal transporter BCRP (IC50=22 uM), thereby increasing the 
absorption of rosuvastatin. This interaction is predicted to be less at a dose of 100 mg per day 
(~1.6x). Notably, a gut interaction will not diminish the lipid lowering effects of rosuvastatin. 
Rather as observed in Asians who frequently have BCRP polymorphisms that increase the 

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
24 
exposure to rosuvastatin, a lower rosuvastatin dose will be effective.24  Therefore as discussed 
below, the maximal dose of rosuvastatin used in this Phase 2 study will be 20 mg, a two-fold 
reduction relative to the maximal rosuvastatin dose of 40 mg. To further mitigate an interaction, 
doses will be staggered with MGL-3196 (dosed in AM) and up to 20 mg rosuvatatin (dosed at 
night).  
 
A drug interaction study was conducted (MGL-3196-04) between MGL-3196 100 mg per day (at 
steady-state) and atorvastatin (20 mg) that indicated that there was a mild increase in atorvastatin 
exposure (1.35x) also felt to be mediated by interactions in the intestine (mild BCRP 
(IC50=22uM) and weak CYP3A4 inhibition (IC50=200uM)). This mild gut interaction will be 
mitigated by staggered dosing of MGL-3196 (dosed in AM) with up to 80-mg atorvastatin dosed 
at night. 
 
In summary, once-daily doses of 100mg (or 60mg after dose adjustment) MGL-3196 and the 
proposed statin dosing regimens in this 12 week randomized blinded placebo controlled clinical 
trial are as follows: 
• Statins will be dosed at night, MGL-3196 in the morning 
• Rosuvastatin, up to 20 mg will be allowed 
• Atorvastatin, up to 80 mg will be allowed 
• Simvastatin, fluvastatin and other statins will be excluded 
 
Ezetimibe will be allowed in MGL-3196-06. Ezetimibe is commonly used in HeFH patients, 
given at low dose and has few drug interactions.25  Given data suggesting that MGL-3196 may 
increase cholesterol excretion from the liver (increased ABCG5/8 liver gene expression, 
preclinical data),26  an agent, ezetimibe, that decreases intestinal absorption of cholesterol may be 
mechanistically complementary to MGL-3196. 
 
1.2.2 
Dose Selection for Phase 2 
MGL-3196-06 employs a simple adaptive design, that will optimize dose for individuals 
randomized to MGL-3196. Based on studies in 129 individuals safely dosed for up to two weeks 
with MGL-3196, at doses ranging from 50- 200 mg per day, MGL-3196 drug exposure shows 
variability in exposure between individuals and higher exposure in some individuals, particularly 
at the 200 mg dose, which will not be used in the Phase 2 HeFH study. This is similar to statins, 
which are also liver-directed drugs that interact with liver and gut uptake transporters. MGL-
3196 exposures are less variable at the lower doses, including 60-100 mg, that will be studied in 
this Phase 2 study. There are no studies that suggest that exposure to MGL-3196 will be different 
in patients with HeFH or that HeFH patients have consistent alterations in drug metabolizing 
enzymes or transporters which may be involved in MGL-3196 uptake by the gut or liver.  Unlike 
statins, there has been no myopathy associated with higher drug exposures of MGL-3196 in 
humans or animal studies; nonetheless, the design of the HeFH Phase 2 trial is adaptive in that 

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
25 
dose adjustments of MGL-3196 will be made after 2 weeks of dosing to optimize exposure for 
the individual patient. 
MGL-3106 exposure variability, which may relate to polymorphisms in drug metabolizing 
enzymes and transporters, may occur in some (~25-30%) patients in the HeFH study who may 
have higher than the target exposure (4000-9000 ng*hr/ml) to MGL-3196 at the 100 mg dose. A 
few patients (10%) (likely to be non-LDL responders) may have drug levels lower than the target 
exposure. Therefore, the trial design is adaptive to optimize both safety and efficacy. 
Randomization will be 2:1, 100 mg MGL-3196 to placebo. The drug level of MGL-3196 reaches 
steady state in a few days. At the Week 2 clinic visit, an assessment of MGL-3196 PK will be 
performed, including measurement of the pre-dose and Tmax (4 h) levels of MGL-3196. These 
two assessments will allow an accurate assessment of MGL-3196’s total exposure. Between 
weeks 2-4, pending results of the PK measurements, all patients randomized to drug will be 
treated with 60 mg of MGL-3196. Based on the Cmax value of MGL-3196 at Week 2, an 
unblinded clinical pharmacologist will assign MGL-3196 dose to the time period, Weeks 4-12. 
At Week 4, patients who had a Week 2 Cmax≥1500 ng/ml will continue on 60 mg of MGL-3196 
and those with Cmax<1500 ng/ml will be placed back on 100 mg/day. 
The primary endpoint will be determined as change from baseline LDL-C for all patients on 100 
mg MGL-3196 from week 4-12 relative to placebo the “100 mg group” (a similar calculation 
will be made for those who continue from Week 4-12 on the 60 mg dose, the “60 mg group”); 
secondary endpoints will include LDL-C lowering in all patients on MGL-3196 relative to 
placebo (for 12 weeks), and LDL-C lowering according to exposure to MGL-3196. Additional 
secondary endpoints will include change from baseline in other lipids including ApoB, nonHDL-
C, Lp(a), and TGs. 
The exposure levels of statins will also be assessed at baseline and Week 2 (two time points) and 
pre-dose PK samples will be collected throughout the study. Patients will record the exact time 
they took the statin the evening before the clinic visit. This will allow the unblinded clinical 
pharmacologist to determine if there is any unexpected effect on statin exposure related to MGL-
3196 dosing. Any changes in statin levels will be monitored by the DSMB and medical monitors. 
 
1.2.3 
Safety Monitoring 
Careful safety monitoring will be performed including assessment of safety labs, vital signs, 
ECGs, drug levels to help assure patient safety during this Phase 2 study, particularly during the 
first few weeks when drug levels will be established. As discussed, a DSMB (including lipid, 
thyroid, liver and statistical experts) 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), muscle and cardiovascular effects, and other efficacy (lipid parameters) and 
safety data as needed. The DSMB will perform regularly scheduled reviews. 
Biomarkers of thyroid action, 
 TSH, free T4 and free T3 levels will be assessed at study 
visits. TSH levels will be monitored in the Phase 2 studies as described in the protocol, and 
downward dose adjustments will be made in any patients who show significant reduction of TSH 
on two occasions of at least 50% and below the normal range. However, such a reduction in TSH 
is extremely unlikely. The target exposures at the clinical doses to be used in the Phase 2 studies 

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
26 
are in the range of 4-9000 ng*hr/ml, at least 10 fold lower than exposures where modest, 
reversible TSH suppression might be anticipated (IB).  Small decreases in TSH within the 
normal range might be observed in HeFH patients treated with MGL-3196 because we anticipate 
that hepatic T3 production may increase with MGL-3196 treatment, and T3 (the active thyroid 
hormone) is the key regulator of TSH.   
 
Small decreases in prohormone FT4 of 20% but remaining within the reference range such as 
observed in MGL-3196 Phase 1 studies are not considered to be clinically meaningful.  Most 
recent human data suggest that maintaining a normal level of active hormone FT3 may be 
sufficient to establish euthyroidism.27  In the Phase 1 MAD study, a single subject on the 200 mg 
dose with the highest drug exposure in the study had a FT4 below the standard reference range 
(0.7 ng/dL), and in MGL-3196-03, a few subjects had levels of 0.7 ng/dL; in MGL-3196-04, a 
few subjects, 0.9 ng/dL.  After two weeks of dosing in the MAD study, most FT4 levels 
appeared to reach steady state.  Per thyroid expert advice, given the short duration of the HeFH 
study (12 weeks), and normal TSH and FT3, dose adjustments will not be made to maintain FT4 
levels  above 0.7 ng/dL. 
 
 

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
28 
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 HeFH. Patients who qualify for study inclusion will 
be randomized to receive one of two 12-week treatments: once daily oral dosing regimen of 
MGL-3196, or placebo (randomized 2:1) given orally once daily. Patients will self-administer 
MGL-3196 once daily each morning, and their statin medication each evening, during the 12-
week treatment period. 
To participate in the study, patients must be diagnosed with HeFH using standard accepted 
procedures and meet the study criteria. Patients must first provide written, informed consent and 
then undergo screening procedures within 14 days prior to randomization. Patients will begin 
taking their statin and other lipid lowering therapy at night at least 2 weeks before 
randomization, and will continue this practice for the duration of the study. 
On the morning of Day 1, patients will be randomized in 2:1 fashion to receive either MGL-3196 
100 mg or matching placebo. Following randomization, patients will undergo a 12-week 
treatment period and will periodically return to the study site (visits are planned at Weeks 2, 4, 8, 
12 and 16) for assessment of drug exposure, safety laboratories, AEs, vital signs (oral 
temperature, pulse rate, respiratory rate, and seated blood pressure).  
At the week 2 visit, in addition to other labs described below, a PK assessment will be made, that 
will include a pre-dose fasting MGL-3196 determination. Based on their randomization, patients 
will then be administered one dose of study drug (100 mg MGL-3196 or placebo) and a 4 hour 
postdose MGL-3196 PK assessment will be made, while patients are fasting. A 12-lead ECG will 
be measured at 4 hours postdose after the 4 h blood draw. Patients randomized to MGL-3196 
100 mg will receive MGL-3196 60 mg between the week 2 and 4 visits, while patients receiving 
placebo will continue to receive placebo. At the week 4 visit, patients receiving MGL-3196 will 
either continue to receive 60 mg or be placed back on 100 mg depending on their week 2 MGL-
3196 level 4 h postdose. (Patients with week 2 postdose MGL-3196 blood levels < 1,500 ng/mL 
will be placed on MGL-3196 100 mg, while patients with MGL-3196 blood levels ≥ 1,500 
ng/mL will continue to receive 60 mg. 
Chemistry (including calcium and phosphorus) and hematology will be assessed at all study 
visits; a 12-lead electrocardiogram (ECG) will be performed at all study visits; and coagulation 
and urinalysis will be performed at baseline and end of study. At all study site visits, blood 
samples will be collected for the assessment of thyroid hormone parameters including thyroid 
stimulating hormone (TSH), total triiodothyronine T3 and thyroxine T4, and free T3 (FT3) and 
free T4 (FT4). Lipids (as described in the secondary objectives) will be assessed at all study 
visits except for low-density lipoprotein (LDL) particle analyses, which will be assessed at 
baseline, Week 12, and Week 16; LDL-C will be determined by ultracentrifugation at baseline 
and Week 12. Other biomarker assessments will include 
 
and high-sensitivity C-reactive protein (hsCRP), assessed at all study visits. Follicle-stimulating 
hormone (FSH), total and free testosterone, luteinizing hormone (LH), creatine kinase MB 
isoenzyme (CKMB), troponin I, reverse T3, fibrinogen, alkaline phosphatase (ALP) isoenzymes, 
procollagen type 1 N-terminal propeptide (P1NP), and C-terminal telopeptide (CTX) will be 
assessed at baseline, Week 12, and Week 16; free testosterone will be calculated from total 

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
29 
testosterone, 
, and serum albumin. Patients will be evaluated for adverse events 
throughout the study.  
Following the first dose of MGL-3196 and thereafter, the dose of MGL-3196 will be down-
titrated if TSH is below the lower limit of normal (LLN) with a >50% change from baseline 
confirmed on 2 consecutive assessments. Down-titrations will be as follows: the 100 mg dose 
would be decreased to 80 mg, and an 80 mg dose would be decreased to 60 mg. Following 
down-titration, TSH testing will resume according to the schedule of procedures. A second 
down-titration is permitted (i.e. to 40 mg). 
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 alanine aminotransferase [ALT], aspartate aminotransferase [AST], and bilirubin), and 
other efficacy (lipid parameters) and safety data as needed. The DSMB will perform regularly 
scheduled reviews as well as an additional review if necessary. 
3.2 
Study Indication 
The indication for this study is the reduction of LDL-C in patients with HeFH. 

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
30 
4 
SELECTION AND WITHDRAWAL OF PATIENTS 
4.1 
Inclusion Criteria 
The population for this study is male and female patients ≥18 years of age who have met the 
diagnostic criteria for HeFH outlined by the Simon Broome Register Group (Appendix C) World 
Health Organization (WHO)/Dutch Lipid Network (score >8; Appendix D). 
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) test 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 either be 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. Must have a diagnosis of HeFH by genetic testing or by having met the diagnostic criteria for 
definite familial hypercholesterolemia outlined by the Simon Broome Register Group 
(Appendix C) or WHO/Dutch Lipid Network (score >8; Appendix D); 
5. Must have a fasting LDL-C ≥2.6 mmol/L (100 mg/dL); and 
6. Must be on a stable or maximally tolerated dose (≥4 weeks prior to screening) of an approved 
statin (rosuvastatin ≤20 mg daily, atorvastatin ≤80 mg daily), with or without ezetimibe. 
4.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from participation in the study: 
1. Homozygous familial hypercholesterolemia; 
2. Low-density lipoprotein (LDL) or plasma apheresis within 2 months prior to randomization; 
3. New York Heart Association class III or IV heart failure, or known left ventricular ejection 
fraction <30%; 
4. 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;  

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
31 
5. Myocardial infarction, unstable angina, percutaneous coronary intervention, coronary artery 
bypass graft, or stroke within 3 months prior to randomization; 
6. Type 1 diabetes, or newly diagnosed or uncontrolled type 2 diabetes (hemoglobin A1c 
[HbA1c] >8%); 
7. 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;  
8. Hyperthyroidism; 
9. Thyroid replacement therapy 
10. 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; 
11. Evidence of chronic liver disease; 
12. Hepatitis B, as defined by the presence of hepatitis B surface antigen (HBsAg); 
13. Hepatitis C, as defined by the presence of hepatitis C 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; 
14. Serum ALT >1.5 × ULN (one repeat allowed); 
15. Estimated glomerular filtration rate <60 mL/min; 
16. Creatine kinase >3 × ULN (one repeat allowed); 
17. History of biliary diversion; 
18. Positive for human immunodeficiency virus (HIV) infection; 
19. History of malignant hypertension;  
20. Systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg at screening or 
randomization and confirmed at an unscheduled visit; 
21. Triglycerides >5.7 mmol/L (500 mg/dL) at screening and confirmed by repeat assessment; 
22. Active, serious medical disease with likely life expectancy <2 years; 
23. Active substance abuse, including inhaled or injection drugs within the year prior to 
screening; 
24. Use of any excluded medications or procedures listed in Section 5.6.1; 
25. Participation in an investigational new drug trial within the 30 days prior to randomization; 
or 

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
32 
26. Any other condition which, in the opinion of the Investigator, would impede compliance, 
hinder completion of the study, or compromise the well-being of the patient. 
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, or other medical condition which indicates to the 
Investigator that continued participation is not in the best interest of the patient; 
• 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 (Week 12). 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. 
 

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
34 
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.  
MGL-3196 capsules consist of MGL-3196 active ingredient, pregelatinized starch (Starch 1500), 
colloidal silicon dioxide (Cab-O-Sil), and magnesium stearate encapsulated in #2 Swedish-
orange hard gelatin capsules. MGL-3196 capsules are made in accordance with ICH and FDA 
guidelines.  
MGL-3196 capsules are packaged in high-density polyethylene plastic bottles with child-
resistant closures. MGL-3196 and matching placebo are available as hard gelatin capsules for 
oral administration in 40 mg and 60 mg strengths. Product labels will be identical except for a 
unique identifying code. Patients will receive 2 bottles with the additional labels of A and B. 
Each bottle will contain 32 capsules (64 capsules total). 
5.5.2 
Study Drug Preparation and Dispensing 
Study drug will be bottled and labeled by 
 using current Good Manufacturing Practice. 
Study drug will be assigned by Interactive Response Technology (IRT) to study site/patients. 
5.5.3 
Study Drug Administration 
Study drug will be administered in the morning at the Week 1, 4, 8, and 12 study visits. Each 
patient will receive 2 bottles labeled as A and B. The patient 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.  
5.5.4 
Treatment Compliance 
Patients will be assessed for study drug compliance at each visit. On Day 1, patients will receive 
a study drug journal in which to record study drug compliance. Site staff will record the number 
of capsules taken from each study drug bottle and record this information in the patient’s eCRF. 
If at any visit the patient is <80% compliant, the patient will be counseled on the importance of 
compliance to the study regimen. If at the end of study, the patient is <80% compliant over the 
course of the 12-week Treatment Period, the patient will not be included in the Per Protocol 
Population. 
5.5.5 
Storage and Accountability 
Adequate records on receipt, use, return, loss, or other disposition of medication must be 
maintained. Other required data includes relevant dates, quantities, unique bottle code, and 
patient identification for patients who receive study drug. Patients will be instructed to return all 
unused study medication to the Investigator, in the original bottles. At the end of the study, all 
unused products will be collected and destroyed according to institutional pharmacy policies and 
procedures. The study drug will be stored according to manufacturing guidelines (see 
Section 5.5.1).  

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
35 
5.6 
Prior and Concomitant Medications and/or Procedures 
5.6.1 
Excluded Medications and/or Procedures 
Excluded medications and/or procedures include:  
• Major inhibitors of OATP transporters such as gemfibrozil, cyclosporine A, or protease 
inhibitors; 
• Repaglinide or a glitazone such as rosiglitazone (substrates of CYP2C8) or gemfibrozil 
(inhibitor of CYP2C8); 
• Glipizide or tolbutamide treatment; 
• Warfarin treatment; 
• Fibrates, PCSK9 inhibitors (within 4 months prior to randomization), or niacin; 
• Prior or planned (during the study period) upper gastrointestinal surgery, including bariatric 
surgery (eg, gastroplasty, roux-en-Y gastric bypass); 
• GLP-1 analogue or complex oral antidiabetic regimen (3 or more oral antidiabetic drugs). 
Patients are allowed to be on insulin if there has been no change >10% in unit dose in the 
2 months prior to screening, and they are allowed to be on up to 2 oral antidiabetic drugs; and 
• Systemic steroids, herbal supplements (eg, kelp), or iodine supplements that can affect 
thyroid or weight loss medications.  
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.  
Patients taking bile acid sequestrants should take them approximately 4-6 hours after taking their 
MGL-3196 study drug or matching placebo and approximately 4-6 hours prior to their evening 
statin dose.  

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
36 
6 
STUDY PROCEDURES 
6.1 
Informed Consent 
Informed consent will be obtained at the Screening Visit (Day -14 to Day -1) prior to performing 
any study-related procedures. 
6.2 
Screening Visit (Day -14 to Day -1) 
The following procedures will be performed at the Screening Visit: 
• Obtain informed consent; 
• Collect demographic information and review medical history; 
• Assess eligibility; 
• Collect vital signs; 
• Measure height and weight (calculate body mass index); 
• Perform 12-lead ECG; 
• Perform complete physical examination; 
• Collect blood samples for the following assessments: 
o Hematology and chemistry; 
o Serum pregnancy test (female patients only);  
o Coagulation panel; 
o Thyroid function test (except TBG); 
o Lipid panel, apolipoproteins, and lipoprotein(a); 
o 
 
o HbA1c; 
o Hepatitis panel, including hepatitis B, HBsAg, HCV, and HCV antibody (HCVAb); and 
o HIV;  
• Collect urine sample for the following assessments: 
o Urinalysis, and 
o Urine drug screen; 
• Provide diet and lifestyle counseling; and 
• Review concomitant medications. 
• Verify on stable maximally tolerated dose of atorvastatin or rosuvastatin (up to 20 mg) and 
adjust statin dosing to once daily in evenings 
 

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
37 
6.3 
Randomization 
Patients will be randomized at the Baseline Visit (Day 1). 
6.4 
Treatment Period – Day 1 Through Day 84 
Following randomization to study medication at the Baseline Visit, patients will return for visits 
and procedures to occur within ±3 days of the scheduled date. In all cases, the patient should 
arrive at the clinic in the morning after at least 10 hours of fasting, and record the time they took 
their statin the night before. 
6.4.1 
Baseline Visit (Day 1) 
The following procedures will be performed at the Baseline Visit: 
• Assess eligibility;  
• Randomize patients;  
• Collect vital signs; 
• Measure weight; 
• Perform 12-lead ECG; 
• Perform targeted, symptom-directed physical examination; 
• Collect blood samples for the following assessments: 
o Hematology and chemistry; 
o Coagulation panel (prothrombin time [PT] and activated partial thromboplastin time 
[aPTT] only); 
o Thyroid function test; 
o Lipid panel, apolipoproteins, ApoCIII, and lipoprotein(a); 
o Lipoprotein particle analysis; 
o LDL-C by ultracentrifugation; 
o FSH, total and free (calculated) testosterone, LH, CKMB, troponin I, reverse T3, ALP 
isoenzymes, P1NP, CTX, and fibrinogen. Free testosterone will be calculated from total 
testosterone, 
, and serum albumin; 
o 
; 
o HbA1c;  
o Genomics;  
o Backup sample; 
o 
  
o 
; and 
o Pre-dose PK (measurement of statin level); 

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
38 
• Collect urine sample for the following assessments: 
o Urinalysis, and 
o Human chorionic gonadotropin (if applicable); 
• Assign study drug via IRT;  
• Dispense study drug for Weeks 1-2; and 
• Review concomitant medications and adverse events. 
6.4.2 
Week 2 (Day 14 [±3 days]) 
Patient arrives at the clinic in the morning fasting. The following procedures will be performed at 
Week 2: 
• Collect vital signs; 
• Measure height and weight (calculate body mass index); 
• Perform targeted, symptom-directed physical examination; 
• Collect blood samples for the following assessments: 
o Hematology and chemistry; 
o Serum pregnancy test (female patients only); 
o Thyroid function test; 
o Lipid panel, apolipoproteins, ApoCIII, and lipoprotein(a); 
o 
; and 
o Pre-dose and 4-hr post dose PK (for statins and MGL-3196); 
• Perform 12-lead ECG at 4 hours post dose (after second blood draw); 
• Assess study drug accountability;  
• Dispense study drug for weeks 3-4 via IRT; 
• Review concomitant medications and adverse events; and 
• Verify on statin dose and once daily in evenings. 
6.4.3 
Week 4 (Day 28 [±3 days]) 
Patients will arrive at the clinic fasting. The following procedures will be performed at Week 4: 
• Collect vital signs; 
• Measure height and weight (calculate body mass index); 
• Perform targeted, symptom-directed physical examination; 
• Collect blood samples for the following assessments: 
o Hematology and chemistry; 

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
39 
o Serum pregnancy test (female patients only); 
o Thyroid function test; 
o Lipid panel, apolipoproteins, ApoCIII, and lipoprotein(a); 
o 
 and 
o Pre-dose PK; 
• Perform 12-lead ECG (after 30 minutes of rest following blood draws);  
• Assess study drug accountability;  
• Dispense study drug for weeks 5-8 via IRT; and 
• Review concomitant medications and adverse events. 
6.4.4 
Week 8 (Day 56 [±3 days]) 
The following procedures will be performed at Week 8: 
• Collect vital signs; 
• Measure height and weight (calculate body mass index); 
• Perform 12-lead ECG; 
• Perform targeted, symptom-directed physical examination; 
• Collect blood samples for the following assessments: 
o Hematology and chemistry; 
o Serum pregnancy test (female patients only); 
o Thyroid function test; 
o Lipid panel, apolipoproteins, ApoCIII, and lipoprotein(a); 
o 
;  
o HbA1C; and 
o Pre-dose PK; 
• Assess study drug accountability;  
• Dispense study drug for weeks 9-12 via IRT; and 
• Review concomitant medications and adverse events. 
6.4.5 
Week 12 (Day 84 [±3 days]) or Early Termination Visit 
The following procedures will be performed at Week 12 or at the Early Termination Visit: 
• Collect vital signs; 
• Measure weight; 
• Perform 12-lead ECG; 

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
40 
• Perform targeted, symptom-directed physical examination; 
• Collect blood samples for the following assessments: 
o Hematology and chemistry; 
o Serum pregnancy test (female patients only); 
o Coagulation panel; 
o Thyroid function test; 
o Lipid panel, apolipoproteins, ApoCIII, and lipoprotein(a); 
o Lipoprotein particle analysis; 
o LDL-C by ultracentrifugation; 
o 
;  
o FSH, total and free (calculated) testosterone, LH, CKMB, troponin I, reverse T3, ALP 
isoenzymes, P1NP, CTX, and fibrinogen. Free testosterone will be calculated from total 
testosterone, 
, and serum albumin;  
o HbA1c;  
o Backup sample; 
o 
  
o 
; and 
o Pre-dose PK; 
• Collect urine sample for urinalysis; 
• Assess study drug accountability; and 
• Review concomitant medications and adverse events. 
6.5 
Follow-Up Visit at Week 16 (Day 112 [±3 days]) 
The following procedures will be performed at the Follow-Up Visit at Week 16: 
• Collect vital signs; 
• Measure weight; 
• Perform 12-lead ECG; 
• Perform targeted, symptom-directed physical examination; 
• Collect blood samples for the following assessments: 
o Hematology and chemistry; 
o Serum pregnancy test (female patients only); 
o Thyroid function test; 
o Lipid panel, apolipoproteins, ApoCIII, and lipoprotein(a); 

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
41 
o Lipoprotein particle analysis; 
o 
; and 
o FSH, total and free (calculated) testosterone, LH, CKMB, troponin I, reverse T3, ALP 
isoenzymes, P1NP, CTX, and fibrinogen. Free testosterone will be calculated from total 
testosterone, 
, and serum albumin; and 
• Review concomitant medications and adverse events. 
6.6 
Early Termination Visit and Withdrawal Procedures 
For patients who are withdrawn from the study prior to completion, the procedures described for 
the Week 12 Visit (Section 6.4.5) will be performed at an Early Termination Visit. 

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
43 
8 
PHARMACOKINETIC ASSESSMENTS 
Blood samples for PK assessments will be obtained fasting pre-dose from patients at the Baseline 
Visit (Day 1), Weeks 2, 4, 8, and 12, and the Early Termination Visit. Blood samples for PK 
assessment will also be obtained 4 hours post-dose from patients at Week 2 under fasting 
conditions. Statin PK will also be assessed at baseline and Week 2 visits and may be assessed at 
later visits. 

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
44 
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. 

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
45 
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. 
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. 
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 drug- 
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. 

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
49 
A lipid panel, apolipoproteins, and lipoprotein(a) will be measured at the Screening Visit (Day -
14 to Day -1). These lipids plus ApoCIII will be measured at Baseline Visit (Day 1), and Weeks 
2, 4, 8, 12, and 16. A lipoprotein particle analysis will be performed at the Baseline Visit (Day 
1), Week 12, and Week 16, and LDL-C will be determined by ultracentrifugation at the Baseline 
Visit (Day 1) and Week 12. 
Sex hormone binding globulin and 
 will be measured at the Screening Visit (Day -14 to 
Day -1), Baseline Visit (Day 1), and Weeks 2, 4, 8, 12, and 16. 
Follicle stimulating hormone, total and free testosterone, LH, CKMB, troponin I, reverse T3, 
ALP isoenzymes, P1NP, CTX, and fibrinogen will be measured at the Baseline Visit (Day 1), 
Week 12, and Week 16. Free testosterone will be calculated from total testosterone, 
, and 
serum albumin. 
Hemoglobin A1c will be measured at the Screening Visit (Day -14 to Day -1), Baseline Visit 
(Day 1), and Weeks 8 and 12. 
Genomic samples will be collected at the Baseline Visit (Day 1). 
Backup blood samples will be collected at Baseline Visit (Day 1) and Week 12 for use if a 
laboratory evaluation needs to be repeated. 
A urine drug screen will be performed at the Screening Visit (Day -14 to Day -1). 
Proprotein convertase subtilisin/kexin type 9 and 
 will be measured at the Baseline 
Visit (Day 1) and at Week 12. 
9.9 
Vital Signs  
Vital signs (oral temperature, pulse, respiratory rate, and seated blood pressure) will be measured 
at the Screening Visit (Day -14 to Day -1), the Baseline Visit (Day 1), and Weeks 2, 4, 8, 12, and 
16.  
Blood pressure will be measured using a standardized process:  
• Patient should 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; 
• Use of a mercury sphygmomanometer or automatic blood pressure device with an 
appropriately sized cuff with the bladder centered over the brachial artery;  
• Record the arm used for measurement and use the same arm throughout the study; and 
• Measure and record the blood pressure.  
Blood pressure should 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 should be repeated 1 to 
2 minutes later, and the second reading should also be recorded to the nearest 2 mmHg mark. 
Body weight will be measured at the Screening Visit (Day -14 to Day -1), the Baseline Visit 
(Day 1), and Weeks 2, 4, 8, 12, and 16. Height will be recorded at the Screening Visit and 
Weeks 2, 4, and 8. Body weight measurement should be performed with the patient dressed in 
indoor clothing, shoes removed, and bladder empty. Patients should be weighed on the same 
scale at all visits. Height measurement should be performed with the patient’s shoes removed; 
the patient’s knees should be straightened, head held erect, and eyes forward. 

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
50 
9.10 
Electrocardiograms 
Twelve-lead ECGs with rhythm strip will be performed at the Screening Visit (Day -14 to Day -
1), the Baseline Visit (Day 1), and Weeks 2, 4, 8, 12, and 16. At the Week 2 visit, patients will 
rest for 30 minutes after the 4 h post-dose blood draw before the ECG is performed. 
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,  
• QTc 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 and 
will be performed at the Screening Visit (Day -14 to Day -1). Targeted, symptom-directed 
physical examinations will be performed at all other study visits. 
9.12 
Diet and Lifestyle Counseling 
Patients will be counseled on maintaining a consistent diet, exercise regimen, and lifestyle at the 
Screening Visit (Day -14 to Day -1).  
9.13 
Drug Induced Liver Injury Monitoring 
With any of the following liver function test elevations, patients should undergo repeat 
laboratory measurements as soon as possible, preferably within 72 hours (unless otherwise 
specified), and no later than 1 week. Local laboratory measurements may be used to facilitate 
follow-up: 
• ALT or AST >8 × ULN; 
• ALT or AST >3 × ULN and bilirubin >2 × ULN or International Normalized Ratio >1.5 
× ULN; 
• ALT or AST >3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever rash, and/or eosinophilia (>5%); and 
• ALT or AST >5 × ULN, regardless of symptoms should be followed up within 1 week. 

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
51 
 
Repeat evaluation should include AST, ALT, prothrombin time/International Normalized Ratio, 
total bilirubin, alkaline phosphatase, gamma-glutamyltransferase, creatinine, CK, and complete 
viral hepatitis screen. The patient should be questioned regarding symptoms, as well as potential 
causative factors. This information, including results and normal ranges of any laboratory 
parameters collected at a local laboratory, should be collected on the appropriate eCRF. 
Hepatobiliary ultrasonography and/or consultation with a hepatologist should be considered if 
clinically indicated. 
Abnormal laboratory parameters should be followed at least weekly (more frequently as 
clinically indicated) until they have returned to baseline or have stabilized. 

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
52 
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 LDL-C measurements, have ≥80% treatment compliance, and do not have any major 
protocol deviations. 
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. 
For patients randomized to MGL-3196, the assigned treatment group (60 or 100 mg group) will 
be based on the dose at Week 4 to Week 12. 
10.2 
Statistical Methods 
10.2.1 
Analysis of Efficacy 
10.2.1.1 
Primary efficacy analysis 
The primary efficacy variable will be the change in LDL-C 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 and baseline LDL-C 
as a covariate. Determinations for the 100 (and 60) mg groups will be based on all 12 weeks of 
the study, including the first two weeks (Week 0-2) in which all patients were on 100 mg and the 
second two weeks (Week 2-4) when all patients down-titrated to 60 mg. The assigned group (60 
or 100 mg) will be based on the dose at Week 4 to Week 12. For any patients in the ITT 
Population with a missing primary efficacy parameter, the last observation carried forward 
method will be used. The multiplicity (MGL-3196 100 mg versus placebo and MGL-3196 60 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, 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 any 
potential exploratory efficacy variables. 

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
53 
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), body mass index (≥30 kg/m2 or 
<30 kg/m2), age group (≥median or <median), and baseline thyroid status. 
10.2.2 
Analysis of Safety 
The safety endpoints for this study include: safety laboratory tests, vital signs, 12-lead ECGs, 
physical examinations, assessment of adverse events, and clinic 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 
Data Safety Monitoring Board 
A 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), and other 
efficacy (lipid parameters) and safety data as needed. The DSMB will perform regularly 
scheduled reviews as well as an additional review if necessary. 
10.2.4 
Sample Size Determination 
Up to 105 patients in total will be randomized to 1 of 2 treatments (70 patient to MGL-3196, 35 
patients to placebo). It is estimated that the treatment difference of percent change in LDL-C 
from baseline to Week 12 between any dose of the MGL-3196 group and the placebo group is 
about -20%. With a common standard deviation for the change in LDL-C at 20%, 27 patients per 
group to complete the Week 12 visit will provide 90% power with a two-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 vs. placebo group. The enrollment size is designed to allow for 
dropouts before the 12-week visit, and as such, patients who drop out of the study will not be 
replaced. 

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
54 
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 
• WHO 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. 

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
55 
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.  

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
57 
12.4 
Patient Card 
On enrollment in the study, European patients will receive a patient card to be carried at all 
times. The patient card will state that the patient is participating in a clinical research study, type 
of treatment, number of treatment packs received, and contact details in case of an SAE. 
12.5 
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, Directive 2001/20/EC, ICH GCP, and applicable 
regulatory requirements, and that valid data are entered into the eCRFs. 
To achieve this objective, the study 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, 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. 
12.6 
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/IEC, 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. 
12.7 
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, eCRFs and hospital records), all original signed ICFs, copies of all eCRFs, 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 

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
58 
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.  
12.8 
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. 
12.9 
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. 
12.10 
Insurance and Indemnity 
In accordance with the relevant national regulations, the Sponsor has taken out patient liability 
insurance for all patients who have given their consent to the clinical study. This cover is 
designed for the event that a fatality, physical injury, or damage to health occurs during the 
clinical study’s execution. 
12.11 
Legal Aspects 
The clinical study is submitted to the relevant national competent authorities in all participating 
countries to achieve a clinical trial authorization (CTA). 
The study will commence (ie, initiation of study centers) when the CTA and favorable Ethics 
opinions have been received.  

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
61 
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;120(1):28-34. 
2. 
Joy TR and Hegele RA. Narrative review: statin-related myopathy. Ann Intern Med. 
2009;150(12):858-868. 
3. 
Cuchel M, Bruckert E, Ginsberg HN, et al. Homozygous familial hypercholesterolaemia: 
new insights and guidance for clinicians to improve detection and clinical management. A 
position paper from the Consensus Panel on Familial Hypercholesterolaemia of the 
European Atherosclerosis Society. Eur Heart J. 2014;35(32):2146-2157. 
4. 
Perez de Isla L. at al. Attainment of LDL-Cholesterol Treatment Goals in Patients With 
Familial Hypercholesterolemia: 5-Year SAFEHEART Registry Follow-Up. JACC. 2016 
Mar:67(11):1278-85. 
5.  
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. 
6.  
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. 
7.  
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. 
8.  
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.  
9.  
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.  
10 . Gogakos AI, Duncan Bassett JH and Williams GR. Thyroid and bone. Arch Biochem 
Biophys. 2010 Nov 1;503(1): 129-136. 
 

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
62 
 
11. Klein I and Danzi S. Thyroid disease and the heart. Circulation. 2007 Oct 9;116(15):1725-
1735. 
12.  Bonde Y, Breuer O, Lütjohann D, Sjöberg S, Angelin B, Rudling M. Thyroid hormone 
reduces PCSK9 and stimulates bile acid synthesis in humans. J Lipid Res. 2014 Nov; 
55(11):2408-2415. 
13. Goldbert IJ, Huang LS, Huggins LA, et al. Thyroid hormone reduces cholesterol via a 
non-LDL receptor-mediated pathway. Endocrinology. 2012 Nov;153(11):5143-5149. 
14. Sjouke B, Langslet G, Ceska R, et al. Eprotirome in patients with familial 
hypercholesterolaemia (the AKKA trial): a randomized, double-blind, placebo-controlled 
phase 3 study. Lancet Diabetes Endocrinol. 2014 Jun;2(6):455-463. 
15. 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. 
16.  Dong BJ. How medications affect thyroid function. West J Med. 2000 Feb;172(2): 102-
106. 
17.  Bengsston, P. “Karo Bio terminates the Eprotirome Program” Karo Bio February 14, 2012 
http://www.karobio.com/investormedia/pressreleaser/pressrelease?pid=639535. 
18. Elbers LP, Kastelein JJ, Sjouke B Thyroid Hormone Mimetics: the Past, Current Status and 
Future Challenges. Curr Atheroscler Rep. 2016 Mar;18(3):14. doi: 10.1007/s11883-016-
0564-7 
19.  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. 
20. Berkenstam, A, Kristensen J, Mellstrom K, Carlsson B, Malm J, Rehnmark S, Garg N, 
Andersson CM, Rudling M, Sjoberg F, Angelin B and Baxter JD. The thyroid hormone 
mimetic compound KB2115 lowers plasma LDL cholesterol and stimulates bile acid 
synthesis without cardiac effects in humans. Proc Natl Acad Sci U S A. 105(2): 663-667, 
2008.  
21. Robinson, JG Management of familial hypercholesterolemia:a review of the 
recommendations from the National Lipid Association Expert Panel on Familial 
Hypercholesterolemia J Manag Care Pharm. 2013;19(2):139-49. 
 

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
63 
 
22.  Lian A, Hanley R, Schoenfeld S. Phase 1 Randomized, Double-Blind, Placebo-Controlled, 
Multiple Ascending Dose Study to Evaluate Safety, Tolerability and Pharmacokinetics of 
the Liver-Selective Tr-Beta Agonist Vk2809 (Mb07811) in Hypercholesterolemic Subjects. 
ACC 2016 J Am Coll Cardiol. 2016; 67(13_S):1932-1932. doi: 10.1016/S0735- 
1097(16)31933-7. 
23.  Santos RD et al. Defining severe familial hypercholesterolaemia and theimplications for 
clinical management: a consensus statement from the International Atherosclerosis Society 
Severe Familial Hypercholesterolemia Panel. Lancet Diabetes-Endocrinol 2016 
http://dx.doi.org/10.1016/S2213-8587(16)30041-9. 
24.  Allred AJ, Bowen CJ, Park JW, Peng B, Williams DD, Wire MB, et al. Eltrombopag 
increases plasma rosuvastatin exposure in healthy volunteers. Br J Clin Pharmacol. 72(2): 
321–9, 2011. 
25.  Simard C, Turgeon J. The pharmacokinetics of ezetimibe. Can J Clin Pharmacol. 2003 
Winter;10 Suppl A:13A-20A. 
26.  Pedrelli M, Pramfalk, C Parini, P. Thyroid hormones and thyroid hormone receptors: 
Effects of thyromimetics on reverse cholesterol transport World J Gastroenterol 2010 
December 21; 16(47): 5958-5964. 
27.  Jonklaas J, Bianco AC, Bauer AJ, et al. Guidelines for the Treatment of Hypothyroidism: 
Prepared by the American Thyroid Association Task Force on Thyroid Hormone 
Replacement. Thyroid. 2014;24(12):1670-1751. 
 
 

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
64 
APPENDIX A:  SCHEDULE OF PROCEDURES 
Footnotes on the next page.  
 
 
Visit 
Screening 
Baseline 
Week 2 
Week 4 
Week 8 
Week 12/ 
Early Term 
Week 16 
(Follow-Up) 
Study Day [Window (days)] 
-14 to -1 
1 
14 [±3] 
28 [±3] 
56 [±3] 
84 [±3] 
112 [±3] 
Informed consent 
X 
 
 
 
 
 
 
Demographics and medical history 
X 
 
 
 
 
 
 
Eligibility assessment 
X 
X 
 
 
 
 
 
Diet and lifestyle counseling 
X 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
Height (and BMI calculation) 
X 
 
X 
X 
X 
 
 
ECG 
X 
X 
X 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
X 
X 
X 
Physical examination [1] 
X 
X 
X 
X 
X 
X 
X 
Chemistry [2]  
X 
X 
X 
X 
X 
X 
X 
Pregnancy test (female patients only) 
X 
X [3] 
X 
X 
X 
X 
X 
Coagulation panel 
X 
X [4] 
 
 
 
X 
 
Urinalysis 
X 
X 
 
 
 
X 
 
Thyroid function test [5] 
X[6] 
X 
X 
X 
X 
X 
X 
Lipid panel, apolipoproteins, 
ApoCIII, lipoprotein(a) 
X[7] 
X 
X 
X 
X 
X 
X 
Lipoprotein particle analysis  
 
X 
 
 
 
X 
X 
LDL-C by ultracentrifugation 
 
X 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
FSH, total and free testosterone [8], 
LH, CKMB, troponin I, reverse T3, 
ALP isoenzymes, P1NP, CTX, 
fibrinogen  
 
X 
 
 
 
X 
X 
HbA1c 
X 
X 
 
 
X 
X 
 

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
65 
APPENDIX A: SCHEDULE OF PROCEDURES (CONTINUED) 
 
Visit 
Screening 
Baseline 
Week 2 
Week 4 
Week 8 
Week 12/ 
Early Term 
Week 16 
(Follow-Up) 
Study Day  [Window (days)] 
-14 to 1 
1 
14 [±3] 
28 [±3] 
56 [±3] 
84 [±3] 
112 [±3] 
Hepatitis panel [9] and HIV 
X 
 
 
 
 
 
 
Backup sample 
 
X 
 
 
 
X 
 
Genomic samples  
 
X 
 
 
 
 
 
PK sampling [10] 
 
X 
X[11] 
X 
X 
X 
 
Urine drug screen 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
Fasting prior to visit [12] and  
Record time of statin dose 
 
X 
X 
X 
X 
X 
 
Study drug dispensing and 
accountability by IRT[13] 
 
X 
X 
X 
X 
X 
 
Review adverse events 
 
X 
X 
X 
X 
X 
X 
Review concomitant medications 
X 
X 
X 
X 
X 
X 
X 
1. 
A complete physical examination will be performed at screening. Targeted, symptom-directed physical examinations will be performed at all other study visits.  
2. 
Includes calcium, phosphorus, GGT, CPK, and albumin. See Appendix B for a complete list of analytes. 
3. 
Urine test for human chorionic gonadotropin at randomization.  
4. 
Only PT and aPTT at baseline. 
5. 
Includes TBG, TSH, total T3 and T4, and free T3 and T4 except for Screening (see footnote 6). 
6. 
Exclude TBG. 
7. 
Exclude ApoCIII. 
8. 
Free testosterone will be calculated from total testosterone, 
, and serum albumin.  
9. 
Includes hepatitis B, HBsAg, HCV, and HCVAb 
10. Patients will be instructed not to take study drug prior to PK sampling except for Week 2 (see footnote 11). 
11. Patients will fast and arrive at the study site in the morning and following a predose PK blood draw, be administered study drug. All other assessments will be performed 
except for ECG. At 4 hours post dose, a second blood draw for PK will be taken. Following the blood draw, patients may discontinue fasting. Patients will then rest for 30 
minutes, after which an ECG will be performed. 
12. Patients should fast for at least 10 hours prior to the visit. 
13. Treatments include MGL-3196 100 mg, MGL-3196 60 mg, or placebo. 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 Week 12 or Early Termination. Study drug accountability will not be 
assessed at baseline. 
ALP = alkaline phosphatase; 
; ApoCIII = apolipoprotein CIII; aPTT = activated partial thromboplastin time; BMI = body mass index; 
CKMB = creatine kinase MB; CPK = creatine phosphokinase; CTX = C-terminal telopeptide; ECG = electrocardiogram; FSH = follicle-stimulating hormone; 
GGT = gamma-glutamyl transferase; HbA1c = hemoglobin A1c; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HCVAb = hepatitis C virus antibody; 
HIV = human immunodeficiency virus; 
; IRT = Interactive Response Technology; LDL-C = low-density lipoprotein cholesterol; 
LH = luteinizing hormone; P1NP = procollagen type 1 N-terminal propeptide; 
 PK = pharmacokinetic; PT = 
prothrombin time; 
; T3 = triiodothyronine; T4 = thyroxine; Term = termination; TSH = thyroid stimulating hormone. 
 

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
66 
APPENDIX B:  CLINICAL LABORATORY ANALYTES 
Standard Chemistry Panel 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Amylase 
Aspartate aminotransferase 
Bicarbonate 
Blood urea nitrogen 
Calcium 
Chloride 
Creatine kinase 
Creatinine 
Direct bilirubin 
Estimated glomerular filtration rate [1] 
Gamma-glutamyl transferase 
Glucose 
Inorganic phosphorus 
Lactate dehydrogenase 
Lipase 
Magnesium 
Potassium 
Sodium 
Total bilirubin 
Total protein 
Uric acid 
 
 
1. 
Calculated using Modification of Diet in Renal Disease (MDRD) formula. 
 
Standard Hematology Panel 
Hematocrit 
Hemoglobin 
Platelets 
Red blood cell count 
White blood cell count and differential 
 
 
Urinalysis 
Bilirubin 
Blood 
Glucose 
Ketones 
Leukocyte esterase 
Microscopy 
Nitrite 
pH 
Protein 
Specific gravity 
Urobilinogen 
 
 
Coagulation 
Activated partial thromboplastin time 
Prothrombin time 
International normalized ratio  
 
 
Serology 
Hepatitis B  
Hepatitis B surface antigen  
Hepatitis C 
Hepatitis C virus antibodies 
Human Immunodeficiency Virus 
Hepatitis C virus RNA (only if 
HCV Ab positive) 
 

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
67 
Lipid Panel 
Total cholesterol  
Triglycerides 
High-density lipoprotein cholesterol 
Non-high-density lipoprotein cholesterol 
Calculated low-density lipoprotein 
cholesterol 
Low-density lipoprotein cholesterol by 
preparative ultracentrifugation (Baseline 
and Week 12 only)  
 
Additional Parameters 
Apolipoprotein A1 
Apolipoprotein B 
Apolipoprotein CIII 
Total and free thyroxine 
Lipoprotein particle analysis 
Total and free triiodothyronine 
Sex hormone-binding globulin 
Thyroid stimulating hormone 
Follicle-stimulating hormone 
Thyroid Binding Globulin 
High-sensitivity C-reactive protein 
Luteinizing hormone 
Total testosterone 
Troponin I 
Creatine kinase MB 
Alkaline phosphatase isoenzymes 
Reverse triiodothyronine 
Angiopoietin-like 3 
Proprotein convertase subtilisin/kexin type 9 
C-terminal telopeptide 
Fibrinogen 
Calculated free testosterone 
Procollagen type 1 N-terminal propeptide 
Hemoglobin A1c 
 
 
Other assessments 
Serum pregnancy test (female patients only) 
Urine test for drugs of abuse 
Pharmacokinetic sample 
Backup samples 
Genomic sample 

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
68 
APPENDIX C:  SIMON BROOME REGISTER DIAGNOSTIC CRITERIA 
FOR HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA  
Definite familial hypercholesterolemia is defined as: 
• Total-C >6.7 mmol/L (260 mg/dL) or LDL cholesterol above 4.0 mmol/L (155 mg/dL) in a 
child <16 years or Total-C >7.5 mmol/L (290 mg/dL) or LDL cholesterol above 4.9 mmol/L 
(190 mg/dL) in an adult. (Levels either pre-treatment or highest on treatment); 
PLUS 
• Tendon xanthomas in patient, or in 1st degree relative (parent, sibling, child), or in 2nd 
degree relative (grandparent, uncle, aunt); 
OR 
• DNA-based evidence of an LDL receptor mutation or familial defective apo B-100, 
Possible familial hypercholesterolemia is defined as: 
• Total-C >6.7 mmol/L (260 mg/dL) or LDL cholesterol above 4.0 mmol/L (155 mg/dL) in a 
child <16 years or Total-C >7.5 mmol/L (290 mg/dL) or LDL cholesterol above 4.9 mmol/L 
(190 mg/dL) in an adult. (Levels either pre-treatment or highest on treatment), 
And at least one of the following: 
• Family history of myocardial infarction below 50 years of age in 2nd degree relative or 
below 60 years of age in 1st degree relative; or 
• Family history of raised cholesterols >7.5 mmol/L (290 mg/dL) in adult 1st or 2nd degree 
relative or >6.7 mmol/L (260 mg/dL) in child or sibling under 16 years of age. 
 
 
 
 
 
 
 
 
Reference: DeMott K, Nherera L, Shaw EJ, et al. Clinical guidelines and evidence review for familial 
hypercholesterolaemia: 
the 
identification 
and 
management 
of 
adults 
and 
children 
with 
familial 
hypercholesterolaemia. London: National Collaborating Centre for Primary Care and Royal College of General 
Practitioners; 2008. Available at: https://www.nice.org.uk/guidance/cg71/evidence/full-guideline-appendix-f-
241917811.  

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-06 
Confidential & Proprietary 
Version 2.0, 14 November 2016 
69 
APPENDIX D:  WHO CRITERIA (DUTCH LIPID NETWORK CLINICAL 
CRITERIA) FOR DIAGNOSIS OF HETEROZYGOUS FAMILIAL 
HYPERCHOLESTEROLEMIA 
 
Reference: Nordestgaard BG, Chapman MJ, Humphries SE, et al. Familial hypercholesterolaemia is underdiagnosed 
and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus 
statement of the European Atherosclerosis Society. Eur Heart J. 2013;34(45):3478-3490a. Available at: 
http://eurheartj.oxfordjournals.org/content/early/2013/08/15/eurheartj.eht273.  
Diagnostic Scoring for Heterozygous Familial Hypercholesterolemia 
Family history 
 
First-degree relative with known premature (men <55 yrs, women <60 yrs) coronary and 
vascular disease,  
OR   
First-degree relative with known LDL-C level above the 95th percentile 
1 
First-degree relative with tendinous xanthomata and/or arcus cornealis,  
OR  
Children aged less than 18 years with LDL-C level above the 95th percentile 
2 
Clinical history 
 
Patient with  premature (men <55 yrs, women <60 yrs) coronary artery disease 
2 
Patient with premature (men <55 yrs, women <60 yrs) cerebral or peripheral vascular 
disease 
1 
Physical examination 
 
Tendinous xanthomata 
6 
Arcus cornealis prior to age 45 years 
4 
Cholesterol levels  
 
LDL-C >= 330 mg/dL (≥8.5 mmol/L) 
8 
LDL-C 250 – 329 mg/dL (6.5–8.4 mmol/L) 
5 
LDL-C 190 – 249 mg/dL (5.0–6.4 mmol/L) 
3 
LDL-C 155 – 189 mg/dL (4.0–4.9 mmol/L) 
1 
DNA analysis 
 
Functional mutation in the LDLR, apo B or 
 gene 
8 
Diagnosis (diagnosis is based on the total number of points obtained) 
 
Definite Familial Hypercholesterolemia 
>8 
Probable Familial Hypercholesterolemia 
6-8 
Possible Familial Hypercholesterolemia 
3-5 
Unlikely Familial Hypercholesterolemia 
<3