A Placebo-Controlled, Double-Blind, Randomized, Phase 3 Study to Evaluate the Effect of Obicetrapib 10 mg and Ezetimibe 10 mg Fixed Dose Combination Daily on Top of Maximally Tolerated Lipid-Modifying Therapy in Participants With Heterozygous Familial Hypercholesterolemia (HeFH) and/or Atherosclerotic Cardiovascular Disease (ASCVD) or Multiple ASCVD Risk Factors
Phase: PHASE3
Conditions: Dyslipidemias, Hypercholesterolemia, Familial Hypercholesterolemia, ASCVD, High Cholesterol
Sponsor: NewAmsterdam Pharma

 
CLINICAL STUDY PROTOCOL 
 
A Placebo-Controlled, Double-Blind, Randomized, Phase 3 Study to 
Evaluate the Effect of Obicetrapib 10 mg and Ezetimibe 10 mg 
Fixed Dose Combination Daily on Top of Maximally Tolerated 
Lipid-Modifying Therapy in Participants With Heterozygous 
Familial Hypercholesterolemia (HeFH) and/or Atherosclerotic 
Cardiovascular Disease (ASCVD) or Multiple ASCVD Risk Factors 
 
Investigational Product: Obicetrapib 10 mg  ezetimibe 10 mg fixed dose combination (FDC) 
Protocol Number: OBEZ-301 
 
Sponsor: 
NewAmsterdam Pharma B.V. 
Gooimeer 2-35 
1411 DC 
Naarden  
The Netherlands 
Telephone: +31 35 699 30 00 
Fax: +31 20 240 07 79 
 
Version Number: 4.0 
Original Protocol: 14 December 2022 
Amendment 1: 10 August 2023 
Amendment 2: 08 November 2023 
Amendment 3: 09 October 2024 
 
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the written 
consent of NewAmsterdam Pharma B.V. except to the extent that disclosure would be required 
by law and for the purpose of evaluating and/or conducting a clinical study for NewAmsterdam 
Pharma B.V. You are allowed to disclose the contents of this document only to your Institutional 
Review Board 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 NewAmsterdam Pharma B.V. and that it may not be further disclosed to third 
parties. 

NewAmsterdam Pharma B.V. 
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Sponsor’s Medical Expert: 
 
 NewAmsterdam Pharma B.V. 
Gooimeer 2-35 
1411 DC 
Naarden 
The Netherlands 
 
 
 

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NewAmsterdam Pharma B.V. 
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INVESTIGATOR AGREEMENT 
By signing below I agree that: 
I have read this protocol. I approve this document and I agree that it contains all necessary details 
for carrying out the study as described. I will conduct this study in accordance with the design and 
specific provision of this protocol and will make a reasonable effort to complete the study within 
the time designated. I will provide copies of this protocol and access to all information furnished 
by NewAmsterdam Pharma B.V. to study personnel under my supervision. I will discuss this 
material with them to ensure they are fully informed about the study drugs and study procedures. 
I will let them know that this information is confidential and proprietary to NewAmsterdam 
Pharma B.V. 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 NewAmsterdam Pharma B.V., with or 
without cause, or by me if it becomes necessary to protect the best interests of the study 
participants. 
I agree to conduct this study in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki, the International Council for Harmonisation guidelines for Good Clinical 
Practice, and applicable regional regulations. 
 
 
 
 
 
 
______________________________________________  
____________________ 
Investigator’s Signature 
 
 
 
 
 
Date 
 
 
 
______________________________________________ 
Investigator’s Printed Name 
 

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SYNOPSIS 
TITLE: A Placebo-Controlled, Double-Blind, Randomized, Phase 3 Study to Evaluate the Effect 
of Obicetrapib 10 mg and Ezetimibe 10 mg Fixed Dose Combination Daily on Top of Maximally 
Tolerated 
Lipid-Modifying 
Therapy 
in 
Participants 
With 
Heterozygous 
Familial 
Hypercholesterolemia (HeFH) and/or Atherosclerotic Cardiovascular Disease (ASCVD) or 
Multiple ASCVD Risk Factors 
PROTOCOL NUMBER: OBEZ-301 
INVESTIGATIONAL PRODUCT: Obicetrapib 10 mg  ezetimibe 10 mg fixed dose 
combination (FDC) 
PHASE: 3 
INDICATION: As an adjunct to diet and maximally tolerated lipid-modifying therapy for the 
treatment of adults with heterozygous familial hypercholesterolemia (HeFH) and/or a history of 
atherosclerotic cardiovascular disease (ASCVD) or multiple ASCVD risk factors who require 
additional lowering of low-density lipoprotein cholesterol (LDL-C) 
OBJECTIVES: 
The 
primary 
objective 
of 
this 
study 
is 
to 
evaluate 
the 
effect 
of 
obicetrapib 10 mg  ezetimibe 10 mg FDC therapy on LDL-C at Day 84, compared with each of 
the following: 
 Placebo; 
 Ezetimibe 10 mg monotherapy; and 
 Obicetrapib 10 mg monotherapy, 
And to evaluate the effect of obicetrapib 10 mg monotherapy on LDL-C at Day 84 compared with 
placebo. 
The secondary objectives of this study include the following, in hierarchical order: 
 To evaluate the effect of obicetrapib 10 mg  ezetimibe 10 mg FDC therapy compared with 
placebo on non-high-density lipoprotein cholesterol (non-HDL-C) at Day 84; 
 To evaluate the effect of obicetrapib 10 mg  ezetimibe 10 mg FDC therapy compared with 
placebo on apolipoprotein B (ApoB) at Day 84; 
 To evaluate the effect of obicetrapib 10 mg monotherapy compared with placebo on 
non-HDL-C at Day 84; 
 To evaluate the effect of obicetrapib 10 mg monotherapy compared with placebo on ApoB at 
Day 84; 
 To evaluate the effect of obicetrapib 10 mg  ezetimibe 10 mg FDC therapy compared with 
ezetimibe 10 mg on non-HDL-C at Day 84; 

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 To evaluate the effect of obicetrapib 10 mg  ezetimibe 10 mg FDC therapy compared with 
ezetimibe 10 mg on ApoB at Day 84; 
 To evaluate the effect of obicetrapib 10 mg  ezetimibe 10 mg FDC therapy compared with 
obicetrapib 10 mg monotherapy on non-HDL-C at Day 84; and 
 To evaluate the effect of obicetrapib 10 mg  ezetimibe 10 mg FDC therapy compared with 
obicetrapib 10 mg monotherapy on ApoB at Day 84. 
The exploratory objectives of this study include the following: 
 To evaluate the effect of obicetrapib 10 mg  ezetimibe 10 mg FDC therapy compared with 
placebo, ezetimibe 10 mg monotherapy, and obicetrapib 10 mg monotherapy and the effect of 
obicetrapib 10 mg monotherapy compared with placebo on very low-density lipoprotein 
cholesterol (VLDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), 
lipoprotein (a) (Lp(a)), and small dense low-density lipoprotein cholesterol (sdLDL-C) at 
Day 84; 
 To evaluate the effect of obicetrapib 10 mg  ezetimibe 10 mg FDC therapy compared with 
placebo, ezetimibe 10 mg monotherapy, and obicetrapib 10 mg monotherapy and the effect of 
obicetrapib 10 mg monotherapy compared with placebo on LDL-C, HDL-C, and VLDL-C 
particle numbers and size, as measured by nuclear magnetic resonance (NMR) analysis, at 
Day 84; 
 To evaluate the effect of obicetrapib 10 mg  ezetimibe 10 mg FDC therapy compared with 
placebo, ezetimibe 10 mg monotherapy, and obicetrapib 10 mg monotherapy and the effect of 
obicetrapib 10 mg monotherapy compared with placebo on the proportion of participants 
achieving predefined LDL-C targets at Day 84; 
 To evaluate the effect of obicetrapib 10 mg + ezetimibe 10 mg FDC therapy compared with 
placebo, ezetimibe 10 mg monotherapy, and obicetrapib 10 mg monotherapy and the effect of 
obicetrapib 10 mg monotherapy compared with placebo on LDL-C at Day 28; 
 To evaluate the safety of obicetrapib 10 mg  ezetimibe 10 mg FDC therapy, obicetrapib 
10 mg monotherapy, and ezetimibe 10 mg monotherapy, assessed by clinical laboratory values 
and incidence of adverse events (AEs); and  
 To assess the mean trough plasma levels of obicetrapib and/or ezetimibe after 
obicetrapib 10 mg  ezetimibe 10 mg FDC therapy, obicetrapib 10 mg monotherapy, and 
ezetimibe 10 mg monotherapy on Days 28 and 84. 
POPULATION: 
The population for this study will comprise participants 18 years of age with underlying HeFH 
and/or a history of ASCVD or multiple ASCVD risk factors on maximally tolerated 
lipid-modifying therapy. Participants must have a fasting serum LDL-C 70 mg/dL 
(1.8 mmol/L). 
Approximately 70% of the participants enrolled into this study should be taking high-intensity 
statins (HIS). HIS include atorvastatin 40 and 80 mg and rosuvastatin 20 and 40 mg. No more than 
approximately 10% of participants in this study will be completely statin intolerant.  

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Participants without underlying HeFH or a history of ASCVD but with multiple ASCVD risk 
factors will comprise a maximum of 30% of the total participants enrolled into the study. 
Participants with only HeFH will comprise a maximum of 20% of the total participants enrolled 
into the study.  
STUDY DESIGN AND DURATION: 
This study will be a placebo-controlled, double-blind, randomized, Phase 3 study to evaluate the 
efficacy, safety, and tolerability of obicetrapib 10 mg, both as an FDC with ezetimibe 10 mg and 
as monotherapy, on top of maximally tolerated lipid-modifying therapy. This study will take place 
at approximately 60 sites.  
Screening Period 
At Screening (Visit 1), participants will be required to sign an informed consent form (ICF) before 
any study-related procedures are performed. After signing the ICF, participants will be assessed 
for study eligibility. 
Treatment Period 
Up to 2 weeks after Screening (Visit 1), participants will return to the site on Visit 2 (Day 1) and 
confirm study eligibility before being randomized and beginning treatment. Approximately 
400 eligible participants (100 participants per treatment group) will be randomized in a 
1:1:1:1 ratio to 1 of the following treatment groups: 
 FDC therapy: Obicetrapib 10 mg  ezetimibe 10 mg; 
 Obicetrapib monotherapy: Obicetrapib 10 mg; 
 Ezetimibe monotherapy: Ezetimibe 10 mg; or 
 Placebo. 
Approximately 70% of the participants enrolled into this study should be taking HIS. No more 
than approximately 10% of participants in this study will be completely statin intolerant.  
Participants without underlying HeFH or a history of ASCVD but with multiple ASCVD risk 
factors will comprise a maximum of 30% of the total participants enrolled into the study. 
Participants with only HeFH will comprise a maximum of 20% of the total participants enrolled 
into the study. 
During the 12-week Treatment Period, the assigned study drugs will be administered by the 
participants orally with water, with or without food, once daily on Day 1 to Day 84 at 
approximately the same time each morning. Participants will return to the site on Visit 3 (Day 28) 
(7 days) and Visit 4 (Day 84) (7 days) for efficacy and safety assessments. Participants, 
Investigators, the Clinical Research Organization, and the Sponsor will be blinded to all lipid 
results from Day 1 (Visit 2) for the first participant until the database is locked in order to protect 
blinding to treatment assignment. 
Safety Follow-Up Period 
Participants will return to the site for a Safety Follow-up Visit (Visit 5 [Day 112]) approximately 
4 weeks after the end of the Treatment Period for safety assessments.  

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DOSAGE FORMS AND ROUTE OF ADMINISTRATION: 
Participants will be randomized in a 1:1:1:1 ratio to 1 of the following treatment groups: 
 FDC 
therapy: 
Obicetrapib 
10 mg 
 
ezetimibe 
10 mg 
(administered 
as 
1 obicetrapib 10 mg  ezetimibe 10 mg FDC tablet, 1 obicetrapib-matched placebo tablet, and 
1 ezetimibe-matched placebo capsule); 
 Obicetrapib monotherapy: Obicetrapib 10 mg (administered as 1 FDC-matched placebo 
tablet, 1 obicetrapib 10 mg tablet, and 1 ezetimibe-matched placebo capsule); 
 Ezetimibe monotherapy: Ezetimibe 10 mg (administered as 1 FDC-matched placebo tablet, 
1 obicetrapib-matched placebo tablet, and 1 ezetimibe 10 mg capsule [over-encapsulated 
10 mg tablet]); or 
 Placebo (administered as 1 FDC-matched placebo tablet, 1 obicetrapib-matched placebo 
tablet, and 1 ezetimibe-matched placebo capsule). 
Study drugs (2 tablets and 1 capsule) will be administered by the participant orally with water, 
with or without food, once daily on Day 1 to Day 84 at approximately the same time each morning. 
EFFICACY ASSESSMENTS:  
The primary efficacy endpoint is the percent change from Day 1 to Day 84 in LDL-C. Co-primary 
endpoints include the percent change from Day 1 to Day 84 in LDL-C for the 
obicetrapib 10 mg  ezetimibe 10 mg FDC treatment group as follows: 
 Compared with the placebo group;  
 Compared with the ezetimibe 10 mg monotherapy treatment group; and 
 Compared with the obicetrapib 10 mg monotherapy treatment group, 
And the percent change from Day 1 to Day 84 in LDL-C for the obicetrapib 10 mg monotherapy 
treatment group compared with the placebo group. 
The secondary efficacy endpoints include the following, in hierarchical order: 
 Percent 
change 
from 
Day 
1 
to 
Day 
84 
in 
non-HDL-C 
for 
the 
obicetrapib 10 mg  ezetimibe 10 mg FDC treatment group compared with the placebo group; 
 Percent change from Day 1 to Day 84 in ApoB for the obicetrapib 10 mg  ezetimibe 10 mg 
FDC treatment group compared with the placebo group; 
 Percent change from Day 1 to Day 84 in non-HDL-C for the obicetrapib 10 mg monotherapy 
treatment group compared with the placebo group; 
 Percent change from Day 1 to Day 84 in ApoB for the obicetrapib 10 mg monotherapy 
treatment group compared with the placebo group; 
 Percent 
change 
from 
Day 
1 
to 
Day 
84 
in 
non-HDL-C 
for 
the 
obicetrapib 10 mg  ezetimibe 10 mg FDC treatment group compared with the ezetimibe 
10 mg monotherapy treatment group; 

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 Percent change from Day 1 to Day 84 in ApoB for the obicetrapib 10 mg  ezetimibe 10 mg 
FDC treatment group compared with the ezetimibe 10 mg monotherapy treatment group; 
 Percent 
change 
from 
Day 
1 
to 
Day 
84 
in 
non-HDL-C 
for 
the 
obicetrapib 10 mg  ezetimibe 10 mg FDC treatment group compared with the obicetrapib 
10 mg monotherapy treatment group; and 
 Percent change from Day 1 to Day 84 in ApoB for the obicetrapib 10 mg  ezetimibe 10 mg 
FDC treatment group compared with the obicetrapib 10 mg monotherapy treatment group. 
The exploratory efficacy endpoints include the following: 
 Percent change from Day 1 to Day 84 in VLDL-C, HDL-C, TG, Lp(a), and sdLDL-C for the 
obicetrapib 10 mg  ezetimibe 10 mg FDC treatment group compared with the placebo group, 
ezetimibe 10 mg monotherapy treatment group, and obicetrapib 10 mg monotherapy 
treatment group, and for the obicetrapib 10 mg monotherapy treatment group compared with 
the placebo group; 
 Percent change from Day 1 to Day 84 in particle numbers and size, as measured by NMR 
analysis, of LDL-C, HDL-C, and VLDL-C for the obicetrapib 10 mg  ezetimibe 10 mg FDC 
treatment group compared with the placebo group, ezetimibe 10 mg monotherapy treatment 
group, and obicetrapib 10 mg monotherapy treatment group, and for the obicetrapib 10 mg 
monotherapy treatment group compared with the placebo group; 
 Proportion of participants at Day 84 that achieve LDL-C <100 mg/dL (<2.6 mmol/L), LDL-C 
<70 mg/dL (<1.8 mmol/L), and LDL-C <55 mg/dL (<1.4 mmol/L) for the 
obicetrapib 10 mg  ezetimibe 10 mg FDC treatment group compared with the placebo group, 
ezetimibe 10 mg monotherapy treatment group, and obicetrapib 10 mg monotherapy 
treatment group, and for the obicetrapib 10 mg monotherapy treatment group compared with 
the placebo group; and 
 Percent change from Day 1 to Day 28 in LDL-C for the obicetrapib 10 mg + ezetimibe 10 mg 
FDC treatment group compared with the placebo group, ezetimibe 10 mg monotherapy 
treatment group, and obicetrapib 10 mg monotherapy treatment group, and for the obicetrapib 
10 mg monotherapy treatment group compared with the placebo group. 
PHARMACOKINETIC ASSESSMENTS: 
Plasma obicetrapib and ezetimibe concentrations, both in combination and each as monotherapy, 
will be assessed at the scheduled pharmacokinetic collection times. 
SAFETY ASSESSMENTS: 
The safety and tolerability profile of obicetrapib 10 mg  ezetimibe 10 mg FDC therapy, 
obicetrapib 10 mg as monotherapy, and ezetimibe 10 mg as monotherapy will be assessed by 
clinical laboratory assessments (chemistry, hematology, and coagulation), vital signs, physical 
examinations, and the incidence of AEs and events of special interest. 
STATISTICAL ANALYSES: 
A Statistical Analysis Plan (SAP) will be finalized before database lock. Any changes to the 
methods described in the SAP will be described and justified as needed in the Clinical Study 

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Report. All study-collected data will be summarized by treatment group using descriptive 
statistics, graphs, and/or raw data listings. Descriptive statistics for continuous variables will 
include number of participants (n), mean, standard deviation (SD), median, minimum, and 
maximum values. Analysis of categorical variables will include frequency and percentage. 
Analysis Populations 
The Intent-to-Treat (ITT) Population will include all participants randomized into the study. 
Treatment classification will be based on the randomized treatment.  
The Full Analysis Set (FAS) will include all participants who are randomized into the study, take 
any study drug, and have at least 1 post-treatment lipid data assessment. Treatment classification 
will be based on the randomized treatment. 
The Modified ITT (mITT) Population will include all randomized participants who receive at 
least 1 dose of any study drug and have data for both the Day 1 and Day 84 LDL-C assessments. 
Treatment classification will be based on the randomized treatment.  
The mITT On-Treatment Population will include all randomized participants who receive at 
least 1 dose of any study drug, have data for both the Day 1 and Day 84 LDL-C assessments, and 
have an obicetrapib plasma concentration at Visit 4 (Day 84) that was >100 ng/mL. Treatment 
classification will be based on the randomized treatment.  
The Per-Protocol (PP) Population will include all participants in the mITT Population who did not 
experience a major protocol deviation that potentially impacted the primary efficacy endpoint. 
The PP Population, along with the reason for exclusion, will be finalized prior to study unblinding. 
The Safety Population will include all participants who receive at least 1 dose of any study drug. 
Treatment classification will be based on the actual treatment received. The Safety Population will 
be the primary population used for the safety analyses. 
Analysis of Efficacy  
The ITT Population will be the primary population for the efficacy analyses. Efficacy will also be 
analyzed using the FAS, mITT Population, mITT On-Treatment Population, and PP Population 
as supportive analyses. 
The primary efficacy endpoint is the percent change from Day 1 to Day 84 in LDL-C. Co-primary 
endpoints include the percent change from Day 1 to Day 84 in LDL-C for the 
obicetrapib 10 mg  ezetimibe 10 mg FDC treatment group compared with each of the following: 
placebo, ezetimibe 10 mg monotherapy, and obicetrapib 10 mg monotherapy, and for the 
obicetrapib 10 mg monotherapy treatment group compared with placebo. The primary endpoint 
will be analyzed using an analysis of covariance (ANCOVA) model with a fixed effect for the 
treatment group and a covariate of baseline LDL-C. The least squares (LS) mean, standard errors, 
and 2-sided 95% confidence intervals for each treatment group and for the mean difference 
compared to placebo will be obtained. 
Each of the comparisons within the co-primary endpoint family will be conducted at a significance 
level of 0.05. If and only if all 4 testing achieve statistical significance, the study is claimed to 
meet its primary objective and the hypothesis testing will continue to secondary endpoints, 
otherwise all statistical comparisons for secondary endpoints are considered descriptive only. 

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The primary estimand will correspond to a treatment policy estimand. The target population will 
comprise participants who are randomized into the study. The primary summary measure to assess 
the treatment effect will be the LS mean difference for the primary endpoint between obicetrapib 
10 mg + ezetimibe 10 mg FDC treatment and placebo, ezetimibe 10 mg monotherapy, and 
obicetrapib 10 mg monotherapy based on the ANCOVA methodology. The primary estimand will 
be addressed using the in-study observation period (ie, including data collected post treatment 
discontinuation or post prohibited medication use).  
Missing data will be imputed for the primary efficacy analysis based on a pattern mixture model 
that uses a multiple imputation technique analyzed with ANCOVA with pre-specified fixed 
factors and covariates. If appropriate, based on the number of retrieved dropouts, missing 
measurements of non-retrieved dropouts will be modeled by known measurements from retrieved 
dropouts (ie, participants who remain in the study after treatment discontinuation) in the same 
treatment group. The imputation model will be further clarified in the SAP.  
Additional sensitivity analyses may be carried out under secondary estimands and/or various 
assumptions for missing data. Full details will be provided in the SAP.  
In order to control the Type I error rate, a fixed sequential testing procedure will be implemented. 
In a hierarchical step-down manner, the co-primary endpoints will be tested first, followed by the 
secondary efficacy endpoints in the order specified. Continuous secondary efficacy endpoints will 
be analyzed using similar methods as in the primary efficacy analysis. 
Analysis of Safety 
The Safety Population will be the primary population for the safety analyses. All safety endpoints 
will be summarized descriptively. No statistical inference will be applied to the safety endpoints. 
SAMPLE SIZE DETERMINATION: 
A sample size of at least 380 evaluable participants (ie, 95 participants per treatment group) will 
provide more than 90% power to detect a 30% difference in LDL-C reduction at Day 84 
(SD of 25%) for the obicetrapib 10 mg  ezetimibe 10 mg FDC treatment group compared with 
the placebo group at a 1-sided significance level of 0.025. 
The sample size for this study was determined in order to provide sufficient power (>90%) for the 
analyses of the co-primary endpoints described above. A sample size of at least 380 evaluable 
participants (ie, 95 participants per treatment group) will provide more than 90% power to detect 
a 20% difference in LDL-C reduction at Day 84 for the obicetrapib 10 mg + ezetimibe 10 mg FDC 
treatment group compared with the ezetimibe 10 mg monotherapy treatment group, and it will 
provide more than 90% power to detect a 12% difference in LDL-C reduction at Day 84 for the 
obicetrapib 10 mg + ezetimibe 10 mg FDC treatment group compared with the obicetrapib 10 mg 
monotherapy treatment group, assuming an SD of 25% at a 1-sided significance level of 0.025.  
In addition, the sample of 95 participants in the obicetrapib 10 mg monotherapy treatment group 
will provide more than 90% power to detect a 15% difference in LDL-C reduction at Day 84 
compared with the placebo treatment group. 
Therefore, assuming an approximately 5% dropout rate, enrollment of approximately 
400 participants (ie, 100 participants per treatment group) is planned for this study. This sample 
size will also contribute sufficient participant exposure and safety data. 

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SITES: Approximately 60 sites 
SPONSOR: 
NewAmsterdam Pharma B.V.  
Gooimeer 2-35 
1411 DC 
Naarden  
The Netherlands 
Telephone: +31 35 699 30 00 
Fax: +31 20 240 07 79 

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TABLE OF CONTENTS 
Signature Page ................................................................................................................................ 3 
Investigator Agreement ................................................................................................................... 4 
Synopsis .......................................................................................................................................... 5 
Table of Contents .......................................................................................................................... 13 
List of Abbreviations and Definition of Terms............................................................................. 17 
1 Introduction and Background Information ............................................................................. 19 
1.1 
Background on Cardiovascular Disease ........................................................................ 19 
1.2 
Cholesteryl Ester Transfer Protein Inhibitors ................................................................ 20 
1.3 
Obicetrapib (TA-8995) .................................................................................................. 21 
1.4 
Clinical Development of Obicetrapib ........................................................................... 21 
1.5 
Rationale ........................................................................................................................ 22 
1.5.1 Rationale for Obicetrapib and Ezetimibe Fixed Dose Combination Therapy .. 22 
1.5.2 Dose Selection Rationale .................................................................................. 23 
1.6 
Risk/Benefit ................................................................................................................... 23 
1.6.1 Coronavirus Disease 2019 Impacts ................................................................... 24 
2 Study Objectives ..................................................................................................................... 25 
2.1 
Primary Objective ......................................................................................................... 25 
2.2 
Secondary Objectives .................................................................................................... 25 
2.3 
Exploratory Objectives .................................................................................................. 25 
3 Study Description.................................................................................................................... 27 
3.1 
Summary of Study Design ............................................................................................ 27 
3.1.1 Screening Period ............................................................................................... 27 
3.1.2 Treatment Period ............................................................................................... 27 
3.1.3 Safety Follow-Up Period ................................................................................... 27 
3.1.4 Coronavirus Disease 2019 Contingency Measures ........................................... 28 
3.2 
Study Indication ............................................................................................................ 28 
4 Selection and Withdrawal of Participants ............................................................................... 29 
4.1 
Inclusion Criteria ........................................................................................................... 29 
4.2 
Exclusion Criteria .......................................................................................................... 32 
4.3 
Retesting ........................................................................................................................ 33 

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4.4 
Rescreening ................................................................................................................... 33 
4.5 
Withdrawal Criteria ....................................................................................................... 33 
5 Study Treatments .................................................................................................................... 35 
5.1 
Treatment Groups .......................................................................................................... 35 
5.2 
Rationale for Dosing ..................................................................................................... 35 
5.3 
Randomization and Blinding ......................................................................................... 35 
5.4 
Breaking the Blind ........................................................................................................ 36 
5.5 
Drug Supplies ................................................................................................................ 36 
5.5.1 Formulation and Packaging ............................................................................... 36 
5.5.2 Study Drug Preparation and Dispensing ........................................................... 37 
5.5.3 Study Drug Administration ............................................................................... 38 
5.5.4 Treatment Compliance ...................................................................................... 38 
5.5.5 Storage and Accountability ............................................................................... 38 
5.6 
Prior and Concomitant Medications and/or Procedures ................................................ 38 
5.6.1 Excluded Medications and/or Procedures ......................................................... 38 
5.6.2 Restricted Medications and/or Procedures ........................................................ 39 
5.6.3 Documentation of Prior and Concomitant Medication Use .............................. 39 
5.6.4 Dietary Guidelines ............................................................................................. 39 
6 Study Procedures .................................................................................................................... 40 
7 Efficacy and Pharmacokinetic Assessments ........................................................................... 41 
7.1 
Efficacy Assessments .................................................................................................... 41 
7.1.1 Efficacy Endpoints ............................................................................................ 41 
7.1.1.1 Primary efficacy endpoint ................................................................... 41 
7.1.1.2 Secondary efficacy endpoints ............................................................. 41 
7.1.1.3 Exploratory efficacy endpoints ........................................................... 42 
7.1.2 Lipid Profile/Biomarkers ................................................................................... 42 
7.1.3 Lipoprotein (a) ................................................................................................... 42 
7.1.4 Nuclear Magnetic Resonance Analysis of Lipids ............................................. 43 
7.1.5 Urine Albumin-Creatinine Ratio ....................................................................... 43 
7.1.6 Serum Archive Samples for Future Assessment ............................................... 43 
7.2 
Pharmacokinetic Assessments ....................................................................................... 43 
8 Safety Assessments ................................................................................................................. 44 

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8.1 
Adverse Events .............................................................................................................. 44 
8.1.1 Adverse Reaction .............................................................................................. 45 
8.1.2 Unexpected Adverse Drug Reaction ................................................................. 45 
8.1.3 Assessment of Adverse Events by the Investigator .......................................... 45 
8.1.4 Events of Special Interest .................................................................................. 46 
8.1.4.1 Guidelines for management of elevated liver enzymes ...................... 47 
8.1.4.2 Guidelines for monitoring and management of creatine kinase ......... 48 
8.1.4.3 Guidelines for monitoring and management of new-onset diabetes 
mellitus ................................................................................................ 49 
8.1.4.4 Guidelines for monitoring and management of significant changes in 
renal function ...................................................................................... 49 
8.1.4.5 Guidelines for monitoring and management of changes to 
antihypertensive medication(s) ........................................................... 49 
8.1.4.6 Guidelines for management of macular degeneration ........................ 49 
8.2 
Serious Adverse Events ................................................................................................. 50 
8.3 
Serious Adverse Event Reporting − Procedures for Investigators ................................ 50 
8.4 
Pregnancy Reporting ..................................................................................................... 51 
8.5 
Expedited Reporting ...................................................................................................... 51 
8.6 
Special Situation Reports .............................................................................................. 52 
8.7 
Clinical Laboratory Evaluations .................................................................................... 53 
8.7.1 Chemistry, Hematology, and Coagulation Assessments ................................... 53 
8.7.2 Endocrinology Assessments .............................................................................. 53 
8.8 
Vital Signs ..................................................................................................................... 53 
8.9 
Weight and Height ........................................................................................................ 53 
8.10 Demographics ................................................................................................................ 53 
8.11 Electrocardiograms ........................................................................................................ 53 
8.12 Physical Examinations .................................................................................................. 54 
9 Statistics .................................................................................................................................. 55 
9.1 
Analysis Populations ..................................................................................................... 55 
9.2 
Statistical Methods ........................................................................................................ 55 
9.2.1 Analysis of Efficacy .......................................................................................... 55 
9.2.1.1 Primary efficacy analysis .................................................................... 55 
9.2.1.2 Secondary efficacy analyses ............................................................... 56 

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9.2.1.3 Exploratory analyses ........................................................................... 56 
9.2.2 Analysis of Safety ............................................................................................. 56 
9.2.3 Interim Analysis ................................................................................................ 57 
9.2.4 Sample Size Determination ............................................................................... 57 
10 Data Management and Record Keeping ................................................................................. 58 
10.1 Data Management ......................................................................................................... 58 
10.1.1 Data Handling ................................................................................................... 58 
10.1.2 Computer Systems ............................................................................................. 58 
10.1.3 Data Entry ......................................................................................................... 58 
10.1.4 Medical Information Coding ............................................................................. 58 
10.1.5 Data Validation ................................................................................................. 58 
10.2 Record Keeping ............................................................................................................. 58 
10.3 End of Study .................................................................................................................. 59 
11 Investigator Requirements and Quality Control ..................................................................... 60 
11.1 Ethical Conduct of the Study ........................................................................................ 60 
11.2 Institutional Review Board ............................................................................................ 60 
11.3 Informed Consent Procedures ....................................................................................... 60 
11.4 Study Monitoring Requirements ................................................................................... 60 
11.5 Disclosure of Data ......................................................................................................... 61 
11.6 Retention of Records ..................................................................................................... 61 
11.7 Publication Policy ......................................................................................................... 61 
11.8 Financial Disclosure ...................................................................................................... 62 
12 Study Administrative Information .......................................................................................... 63 
12.1 Protocol Amendments ................................................................................................... 63 
13 References ............................................................................................................................... 64 
Appendix A: Schedule of Procedures ........................................................................................... 66 
Appendix B: Clinical Laboratory Analytes .................................................................................. 68 
Appendix C: Diagnostic Scoring Table for Familial Hypercholesterolemia (Constructed by the 
Dutch Lipid Clinic Network) .................................................................................................. 70 
Appendix D: Simon Broome Register Diagnostic Criteria for Familial Hypercholesterolemia .. 71 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
Abbreviation 
Definition 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
ApoA1 
Apolipoprotein A1 
ApoB 
Apolipoprotein B 
ApoE 
Apolipoprotein E 
ASCVD 
Atherosclerotic cardiovascular disease 
AST 
Aspartate aminotransferase 
CETP 
Cholesteryl ester transfer protein 
CI 
Confidence interval 
CK 
Creatine kinase 
COVID-19 
Coronavirus Disease 2019 
CRA 
Clinical Research Associate 
CT 
Computed tomography 
CV 
Cardiovascular 
CVD 
Cardiovascular disease 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
eGFR 
Estimated glomerular filtration rate 
EIU 
Exposure In Utero 
EOT 
End of Treatment 
ESI 
Event of special interest 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FDC 
Fixed dose combination  
FH 
Familial hypercholesterolemia  
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HbA1c 
Glycosylated hemoglobin 
HDL 
High-density lipoprotein 
HDL-C 
High-density lipoprotein cholesterol 
HeFH 
Heterozygous familial hypercholesterolemia 
HIS 
High-intensity statin(s) 
HMGCR 
3-hydroxy-3-methylglutaryl-coenzyme A reductase 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 

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Abbreviation 
Definition 
IMP 
Investigational medicinal product 
IRB 
Institutional Review Board 
IRT 
Interactive response technology 
ITT 
Intent-to-Treat 
LDL 
Low-density lipoprotein 
LDL-C 
Low-density lipoprotein cholesterol 
Lp(a) 
Lipoprotein (a) 
LS 
Least squares 
MACE 
Major adverse cardiovascular event(s) 
MI 
Myocardial infarction 
mITT 
Modified Intent-to-Treat 
NMR 
Nuclear magnetic resonance 
NODM 
New-onset diabetes mellitus 
non-HDL-C 
Non-high-density lipoprotein cholesterol 
PCSK9 
Proprotein convertase subtilisin kexin type 9 
PK 
Pharmacokinetic(s) 
PP 
Per-Protocol 
QTc 
Heart rate-corrected QT interval 
QTcF 
Heart rate-corrected QT interval using Fridericia’s formula 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
sdLDL-C 
Small dense low-density lipoprotein cholesterol 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TG 
Triglyceride(s) 
ULN 
Upper limit of normal 
VLDL-C 
Very low-density lipoprotein cholesterol 
WHO 
World Health Organization 

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1 
INTRODUCTION AND BACKGROUND INFORMATION 
NewAmsterdam Pharma B.V. is developing obicetrapib (TA-8995) a selective cholesteryl ester 
transfer protein (CETP) inhibitor, as an adjunct to diet and maximally tolerated lipid-modifying 
therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) and/or 
a history of atherosclerotic cardiovascular disease (ASCVD) or multiple ASCVD risk factors who 
require additional lowering of low-density lipoprotein cholesterol (LDL-C). This study will be a 
placebo-controlled, double-blind, randomized, Phase 3 study to evaluate the efficacy, safety, and 
tolerability of obicetrapib 10 mg, both as a fixed dose combination (FDC) with ezetimibe 10 mg 
and as monotherapy, on top of maximally tolerated lipid-modifying therapy. 
1.1 
Background on Cardiovascular Disease 
Despite advances in treatment, cardiovascular disease (CVD) is the leading cause of death 
globally, resulting in over 17 million deaths annually.1 Elevated LDL-C is a major modifiable risk 
factor for the development of CVD.2,3 Lowering LDL-C has been shown to reduce the risk of death 
or myocardial infarction (MI), and the clinical risk reduction is linearly proportional to the absolute 
LDL-C reduction.4 Approximately 100 million people worldwide are treated with lipid-modifying 
therapies, predominantly statins, to reduce LDL-C and the associated risk of cardiovascular (CV) 
events. Patients with documented ASCVD are at very high risk for events and require intensive 
pharmacologic intervention.5,6 For a variety of reasons, many with ASCVD are unable to attain 
aggressive LDL-C treatment goals despite the addition of lipid-modifying agents to maximally 
tolerated statin therapy.7 
Familial hypercholesterolemia (FH) refers to individuals with extremely elevated LDL-C due to 
underlying genetic mutations of the low-density lipoprotein (LDL) receptor, apolipoprotein B 
(ApoB), and proprotein convertase subtilisin/kexin type 9 (PCSK9). In adult patients with HeFH, 
LDL-C usually exceeds 190 mg/dL (4.9 mmol/L) and can be as high as 400 mg/dL (10.4 mmol/L). 
HeFH is the most common form of the disease with a prevalence of approximately 1 in 300 to 
500 persons worldwide and as high as 1 in 100 persons in some populations. HeFH increases the 
risk of atherosclerosis leading to CV events. The mean age for the onset of CVD is relatively 
young, at 42 to 46 years in men and 51 to 52 years in women.8 The National Lipid Association 
recommends that adults with HeFH use statins to achieve 50% reduction in LDL-C. HeFH 
patients at an even higher risk for CVD (such as those with a history of ASCVD, diabetes, smoking, 
family history, and other risk factors) have a treatment goal of 70 mg/dL (1.8 mmol/L). Those 
unable to achieve these treatment goals with maximally tolerated statin therapy require additional 
lipid-modifying therapy and still may be unable to reach LDL-C treatment goals. 
Lowering LDL-C is the primary therapeutic lipid target in patients with HeFH and/or ASCVD. 
LDL-C is largely accepted as a valid surrogate endpoint of CV events by clinicians and regulatory 
authorities.9 Chronic LDL-C elevations lead to progressive accumulation of atherosclerotic lesions 
in the arteries that require long-term management. While lifestyle changes are the primary 
intervention, these measures seldom reduce plasma LDL-C by >15%. Particularly in patients with 
HeFH and/or ASCVD, pharmacologic treatments are required to adequately treat 
hyperlipidemia.10 Evidence supporting LDL-C as a therapeutic target and surrogate for CV 
outcomes comes from interventional studies with LDL-C-lowering therapies, epidemiological 
studies, and genetic variants (both gain of function and loss of function). Large randomized clinical 
studies aimed at lowering LDL-C show a consistent, logarithmic-linear relationship between 
LDL-C reduction and CV risk reduction, independent of the way LDL-C lowering was achieved 

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based on the mechanism of action.10 A published patient-level meta-analysis, including 26 studies 
and more than 160,000 participants, showed a consistent relationship between LDL-C reduction 
and CV outcomes.10 This analysis showed that each 1 mmol/L (38.61 mg/dL) reduction in LDL-C 
is associated with a 22% reduction in the 5-year incidence of major coronary events, 
revascularizations, and ischemic strokes. Intensive statin therapy relative to low- or 
moderate-intensity statin treatment confers a greater benefit in patients at high CV risk.10 
Non-statin therapies may provide additional lowering of CV risk as demonstrated in the 
IMPROVE-IT study adding ezetimibe to statin therapy.11,12 Unfortunately, despite being treated 
with maximally tolerated lipid-modifying therapy, a substantial number of patients still do not 
reach their target guideline goals.11 
Patients with HeFH and/or a history of ASCVD or multiple ASCVD risk factors who require 
additional lowering of LDL-C despite treatment with maximally tolerated lipid-modifying therapy, 
including 
maximally 
tolerated 
doses 
of 
statins, 
have 
an 
unmet 
medical 
need. 
Obicetrapib 10 mg  ezetimibe 10 mg FDC may offer a useful option for these patients. 
1.2 
Cholesteryl Ester Transfer Protein Inhibitors 
CETP is a plasma glycoprotein produced in the liver and adipose tissue. It circulates in the blood, 
bound primarily to high-density lipoprotein cholesterol (HDL-C), and is involved in the transfer 
of cholesteryl esters and triglycerides (TG) between lipoproteins. In particular, it mediates the 
transfer of cholesteryl esters from high-density lipoprotein (HDL) to ApoB-containing particles, 
eg, very low-density lipoprotein and LDL-C, in exchange for TG. As a result, cholesteryl ester 
from HDL can be taken up by the liver through scavenger receptor class B type 1; this action also 
leads to decreased HDL-C and ultimately to increased LDL-C.  
Inhibition of CETP activity reduces ApoB and LDL-C and increases HDL-C. CETP-inhibiting 
therapies were originally developed based on the premise that increasing HDL-C levels would 
prevent CV events. However, clinical study results and Mendelian randomization data have 
revealed that these effects are caused by changes in the concentration of ApoB containing particles 
(including LDL particles) rather than changes in the HDL-C levels.13,14 Therefore, the LDL-C and 
ApoB-lowering effects, which arise from CETP inhibition and occur through upregulation of the 
LDL receptor, will benefit patients with elevated LDL-C and increased CV risk. 
Ference and colleagues have investigated the association between changes in LDL-C levels (and 
other lipoproteins) and the risk of CV events related to variants in the CETP gene alone and in 
combination with variants in the 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) 
gene.13 The results of these Mendelian randomization analyses demonstrate that treatment with a 
CETP inhibitor has the potential to reduce the risk of CV events. Both genetic and therapeutic 
inhibition of CETP leads to quantitatively concordant changes in LDL-C and ApoB levels. A 
further Mendelian randomization analysis concluded that the clinical benefit of lower LDL-C 
levels per unit difference may specifically be related to the absolute reduction in ApoB-containing 
lipoprotein particles.15  
The REVEAL study was a randomized, placebo-controlled trial which compared anacetrapib, a 
CETP inhibitor, with matching placebo on a background of atorvastatin therapy over a median 
4.1-year period. Approximately 2 years after study completion, the relative reduction in major 
adverse CV events (MACE) in the anacetrapib group was nearly double (approximately 18%) in 
when compared with the reduction observed at the end of the 4-year treatment period 

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(approximately 9%). In addition, between-group differences in the risk of coronary death emerged 
in the later years of follow-up, and, importantly, no safety concerns were described for 
non-vascular mortality or morbidity.16 
1.3 
Obicetrapib (TA-8995) 
Obicetrapib (TA-8995) is a selective CETP inhibitor. Inhibition of CETP by obicetrapib blocks 
the transfer of cholesteryl ester from non-atherogenic HDL particles to particles in lipoprotein 
fractions (including LDL) that cause atherosclerosis, and reduces the concentration of cholesterol 
in LDL, as well as other atherogenic lipoproteins. Obicetrapib also has several additional 
compound-specific activities that are hypothesized to be beneficial in patients. In a recent study, 
obicetrapib treatment not only reduced the number of ApoB-containing particles that constitute 
LDL-C, it also increased apolipoprotein E (ApoE), which leads to the removal of cholesterol via 
the liver and also reduced lipoprotein (a) (Lp(a)).17 Finally, obicetrapib not only potently increases 
HDL-C and the concentration of apolipoprotein A1 (ApoA1)-containing lipoproteins but has been 
demonstrated to be a potent inducer of cholesterol efflux, which is the main driver of reverse 
cholesterol transport.18 This effect is considered important because it is expected to reduce 
established atheroma burden. 
1.4 
Clinical Development of Obicetrapib 
Both single-ascending dose (TA-8995-01) and multiple-ascending dose (TA-8995-02) studies of 
obicetrapib have been conducted in healthy volunteers. A formal, thorough QT/QTc study 
(TA-8995-04) demonstrated that obicetrapib has no effect on the QTcF. A drug-drug interaction 
study (TA-8995-05) showed no significant effect of obicetrapib on P-glycoprotein activity but 
showed that obicetrapib is a mild inducer of cytochrome P450 3A4. A mass balance study in 
healthy males concluded that obicetrapib is steadily absorbed, and the principal route of excretion 
was in the feces (TA-8995-07). Finally, obicetrapib capsule and tablet were determined to be 
bioequivalent in terms of the area under the concentration-time curve from time 0 to 72 hours, and 
in terms of maximum plasma concentration when wider confidence intervals (CIs) were used to 
due to high within-subject variability (TA-8995-08). 
The first patient study conducted was a Phase 2 clinical study (TA-8995-03) in Denmark and 
The Netherlands where the aim was to evaluate the optimal dose of obicetrapib alone and in 
combination with statins in patients with mild dyslipidemia. This study concluded that a 10 mg 
daily dose of obicetrapib therapy resulted in an LDL-C reduction of 45.3%, an HDL-C increase of 
179.0%, an ApoA1 increase of 63.4%, and a significant increase of HDL-C efflux capacity. 
Furthermore, given on top of atorvastatin 20 mg, obicetrapib 10 mg resulted in an additional 
50.3% reduction in LDL-C. A second patient study (TA-8995-06) showed a statistically significant 
reduction in Lp(a) levels following 12 weeks of obicetrapib treatment. 
The results of 2 additional Phase 2 studies of obicetrapib (TA-8995-303 and TA-8995-201) are 
available. The first study, TA-8995-303, evaluated the LDL-lowering effects of obicetrapib 5 mg 
in combination with ezetimibe 10 mg in participants with mild dyslipidemia. The second study, 
TA-8995-201, evaluated the LDL-lowering effects of obicetrapib (both 5 mg and 10 mg) as an 
adjunct to high-intensity statin (HIS) therapy in participants with dyslipidemia. In both studies, the 
primary efficacy endpoints were achieved. Another Phase 2 study, TA-8995-202, has also recently 
completed with pending results. This study evaluated the LDL-lowering effects of 

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obicetrapib 10 mg, in combination with ezetimibe 10 mg as a monotherapy, in participants on HIS 
therapy.  
Three Phase 3 studies (TA-8995-301, TA-8995-302, and TA-8995-304) are ongoing. Two of the 
Phase 3 studies are investigating the LDL-C-lowering effect of 10 mg obicetrapib in participants 
on maximally tolerated lipid-modifying therapy. Study TA-8995-301 includes participants with 
HeFH and an LDL-C 70 mg/dL (1.8 mmol/L). Study TA-8995-302 includes participants with 
HeFH and/or ASCVD. Together, these 2 pivotal studies will evaluate the effects of 
obicetrapib 10 mg in populations requiring further LDL-C reduction across a range of baseline 
LDL-C values relevant to contemporary clinical practice. A third Phase 3 study (TA-8995-304) is 
investigating the effect of obicetrapib 10 mg on clinical outcomes (ie, MACE, including CV death, 
non-fatal MI, non-fatal stroke, or non-elective coronary revascularization). 
1.5 
Rationale 
Chronic LDL-C elevation leads to progressive accumulation of arterial atherosclerotic lesions that 
require long-term management. While lifestyle changes are the primary intervention, these 
measures seldom reduce plasma LDL-C by more than 15%, and pharmacologic treatments are 
required to adequately treat hyperlipidemia.10 
Statins are considered as first-line therapy for reducing LDL-C levels. However, despite 
lipid-modifying therapy with statins, many patients are unable to achieve acceptable levels of 
LDL-C.  
An alternative to statin use is the use of PCSK9-targeted therapies. However, there are notable 
limitations with this line of therapy, including very high costs. Because PCSK9-targeted therapies 
are injectable, this poses a less attractive option for patients who prefer oral medications. 
Bempedoic acid, either as a single agent or in combination with ezetimibe, is another alternative 
therapy but offers only a modest reduction in LDL-C.  
Accordingly, there remains an unmet need for therapies to effectively reduce elevated LDL-C 
levels and CV risk at an acceptable cost, a convenient dosage form, and a favorable safety and 
tolerability profile to encourage long-term use and patient compliance. Obicetrapib, an oral CETP 
inhibitor, has demonstrated safety and efficacy in the reduction of LDL-C, in addition to other 
beneficial effects. The combination of obicetrapib and ezetimibe, an oral cholesterol absorption 
inhibitor, could be a valuable alternative to a PCSK9 inhibitor in patients who require additional 
LDL-C lowering despite maximally tolerated lipid-modifying therapy. 
1.5.1 
Rationale for Obicetrapib and Ezetimibe Fixed Dose Combination Therapy 
Ezetimibe selectively inhibits intestinal cholesterol absorption. Ezetimibe used as monotherapy 
for patients with hypercholesterolemia significantly reduces serum LDL-C levels, as evidenced by 
a meta-analysis of 8 randomized, double-blind, placebo-controlled studies, with a statistically 
significant mean reduction in LDL-C of 18.58% compared with placebo.19 Ezetimibe in 
combination with statin therapy further reduces LDL-C levels. A meta-analysis of 27 studies, 
including more than 21,000 patients, demonstrated a 15.1% greater reduction in LDL-C in patients 
treated with statin and ezetimibe in combination compared with statin alone.20 The IMPROVE-IT 
study,12 in which simvastatin 40 mg daily was compared with a combination of simvastatin 40 mg 
plus ezetimibe 10 mg in 18,144 patients with acute coronary syndrome, demonstrated a modest 
but statistically significant further reduction in future CV events (a 2% absolute risk reduction over 

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7 years) in the combination group compared with statins alone. These large long-term studies have 
also demonstrated an excellent safety profile for ezetimibe. Importantly, additional Mendelian 
randomization studies have revealed that the CETP inhibitor HMGCR inhibitor interaction does 
not occur when a CETP inhibitor is combined with ezetimibe. The Phase 2 study TA-8995-303, 
which evaluated the LDL-lowering effects of obicetrapib 5 mg in combination with 
ezetimibe 10 mg in participants with mild dyslipidemia, achieved its primary endpoint, 
demonstrating that the combination therapy of obicetrapib 5 mg + ezetimibe 10 mg markedly 
reduced LDL-C, non-high-density lipoprotein cholesterol (non-HDL-C), and ApoB, and increased 
HDL-C and ApoE. Similarly, the recently completed Phase 2 study TA-8995-202, which evaluated 
the LDL-lowering effects of obicetrapib 10 mg in combination with ezetimibe 10 mg in 
participants on HIS therapy, also achieved its primary endpoint, demonstrating that the 
combination therapy of obicetrapib 10 mg + ezetimibe 10 mg also markedly reduced LDL-C, 
non-HDL-C, ApoB, and Lp(a) and increased HDL-C and ApoE. 
This study will evaluate the effect of obicetrapib 10 mg ezetimibe 10 mg FDC in participants 
with HeFH and/or a history of ASCVD or multiple ASCVD risk factors on maximally tolerated 
lipid-modifying therapy. 
1.5.2 
Dose Selection Rationale 
In clinical studies in healthy volunteers, obicetrapib was generally well tolerated in single doses 
up to 150 mg and multiple doses up to 25 mg/day for 21 days. In clinical studies in patients, 
obicetrapib was also well tolerated after daily dosing of 10 mg for 12 weeks, both alone and in 
combination with 2 different statins. Near maximal effects were observed with the 10 mg 
obicetrapib dose. At this dose level, CETP activity was reduced, HDL-C levels were increased, 
and LDL-C levels were decreased. There were no dose-related adverse events (AEs) identified and 
no clinically significant changes in vital signs, electrocardiograms (ECGs), or hematology or 
biochemistry parameters in any clinical studies. A statistically significant reduction in Lp(a) levels 
from baseline was also observed at the 10 mg obicetrapib dose level. Therefore, the present study 
will utilize a dose of 10 mg obicetrapib in participants with HeFH and/or a history of ASCVD or 
multiple ASCVD risk factors who are not adequately controlled by their maximally tolerated 
lipid-modifying therapy. 
The ezetimibe dose of 10 mg is the current Food and Drug Administration (FDA)-approved dose.  
1.6 
Risk/Benefit 
The primary pharmacology in in vitro, ex vivo, and in vivo studies have demonstrated that 
obicetrapib has the ability to inhibit CETP, decrease LDL-C levels, increase HDL-C levels, and 
importantly, reduce the number of atherogenic ApoB-containing particles in a way that is useful 
in the treatment of dyslipidemia. 
The safety pharmacology studies have demonstrated that obicetrapib has no adverse effect on 
critical physiological systems (eg, central nervous system, respiratory system, gastric emptying, 
urinary tract, and steroidal hormonal production [including aldosterone levels]) at doses up to 
300 mg/kg in rats. 
In clinical studies in patients, obicetrapib was also well tolerated after daily dosing of 10 mg for 
12 weeks, both alone and in combination with 2 different statins. There were no dose-related AEs 

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identified and no clinically significant changes in vital signs, ECGs, or hematology or biochemistry 
parameters in any clinical studies. 
As obicetrapib is an experimental medicine, it is possible that unforeseen, unknown or 
unanticipated drug reactions and toxicities may occur. However, this clinical protocol is designed 
to mitigate risks to participants through a detailed plan for careful safety monitoring, systematic 
review of AEs, serious AEs (SAEs), pharmacokinetics (PK), and active pharmacovigilance review 
to assess for safety signals or trends. These considerations indicate the benefit/risk ratio for 
obicetrapib in this study to be favorable. 
1.6.1 
Coronavirus Disease 2019 Impacts 
In March 2020, Coronavirus Disease 2019 (COVID-19), caused by infection with severe acute 
respiratory syndrome coronavirus 2, was characterized as a pandemic by the World Health 
Organization (WHO). The COVID-19 pandemic has impacted clinical studies worldwide due to 
quarantines, site closures, travel limitations, diversion of resources, and/or general interruptions in 
study-related procedures. This study will be initiated during the ongoing COVID-19 pandemic. 
The Sponsor has reviewed guidance from regulatory authorities and reports from the literature 
while planning study start-up and conduct (ie, European Medicines Agency 2022, FDA 2021).21,22 
The Sponsor will communicate with sites before study initiation and during the conduct of the 
study concerning the potential impact of COVID-19 on study-related procedures and overall 
conduct. The Sponsor will continue to monitor COVID-19 activity in the geographic areas and 
institutions where the trial will be conducted and conduct an ongoing risk assessment throughout 
the study. The risk assessment will be documented on an ongoing basis in the Sponsor’s trial 
master file.  
This study protocol includes contingency measures to ensure participant safety while enabling sites 
to generate reliable data and maintain integrity of the study and study data (see Section 3.1.4). The 
impacts of these implemented contingency measures on the outcomes of this study, including any 
protocol deviations that result from COVID-19 illness and/or COVID-19 control measures, will 
be discussed in the Clinical Study Report. 
Treatment with standard of care and/or emergency use authorization medications, including 
vaccinations and boosters, for COVID-19 will be permitted during this study. There is no known 
negative impact of vaccination on obicetrapib efficacy and safety, nor any known negative impact 
of obicetrapib on vaccination efficacy and safety. 

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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The 
primary 
objective 
of 
this 
study 
is 
to 
evaluate 
the 
effect 
of 
obicetrapib 10 mg  ezetimibe 10 mg FDC therapy on LDL-C at Day 84, compared with each of 
the following: 
 Placebo; 
 Ezetimibe 10 mg monotherapy; and 
 Obicetrapib 10 mg monotherapy, 
And to evaluate the effect of obicetrapib 10 mg monotherapy on LDL-C at Day 84 compared with 
placebo. 
2.2 
Secondary Objectives 
The secondary objectives of this study include the following, in hierarchical order: 
 To evaluate the effect of obicetrapib 10 mg  ezetimibe 10 mg FDC therapy compared with 
placebo on non-HDL-C at Day 84; 
 To evaluate the effect of obicetrapib 10 mg  ezetimibe 10 mg FDC therapy compared with 
placebo on ApoB at Day 84; 
 To evaluate the effect of obicetrapib 10 mg monotherapy compared with placebo on 
non-HDL-C at Day 84; 
 To evaluate the effect of obicetrapib 10 mg monotherapy compared with placebo on ApoB at 
Day 84; 
 To evaluate the effect of obicetrapib 10 mg  ezetimibe 10 mg FDC therapy compared with 
ezetimibe 10 mg on non-HDL-C at Day 84; 
 To evaluate the effect of obicetrapib 10 mg  ezetimibe 10 mg FDC therapy compared with 
ezetimibe 10 mg on ApoB at Day 84; 
 To evaluate the effect of obicetrapib 10 mg  ezetimibe 10 mg FDC therapy compared with 
obicetrapib 10 mg monotherapy on non-HDL-C at Day 84; and 
 To evaluate the effect of obicetrapib 10 mg  ezetimibe 10 mg FDC therapy compared with 
obicetrapib 10 mg monotherapy on ApoB at Day 84. 
2.3 
Exploratory Objectives 
The exploratory objectives of this study include the following: 
 To evaluate the effect of obicetrapib 10 mg  ezetimibe 10 mg FDC therapy compared with 
placebo, ezetimibe 10 mg monotherapy, and obicetrapib 10 mg monotherapy and the effect of 
obicetrapib 10 mg monotherapy compared with placebo on very low-density lipoprotein 
cholesterol (VLDL-C), HDL-C, TG, Lp(a), and small dense low-density lipoprotein 
cholesterol (sdLDL-C) at Day 84; 

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 To evaluate the effect of obicetrapib 10 mg  ezetimibe 10 mg FDC therapy compared with 
placebo, ezetimibe 10 mg monotherapy, and obicetrapib 10 mg monotherapy and the effect of 
obicetrapib 10 mg monotherapy compared with placebo on LDL-C, HDL-C, and VLDL-C 
particle numbers and size, as measured by nuclear magnetic resonance (NMR) analysis, at 
Day 84; 
 To evaluate the effect of obicetrapib 10 mg  ezetimibe 10 mg FDC therapy compared with 
placebo, ezetimibe 10 mg monotherapy, and obicetrapib 10 mg monotherapy and the effect of 
obicetrapib 10 mg monotherapy compared with placebo on the proportion of participants 
achieving predefined LDL-C targets at Day 84; 
 To evaluate the effect of obicetrapib 10 mg + ezetimibe 10 mg FDC therapy compared with 
placebo, ezetimibe 10 mg monotherapy, and obicetrapib 10 mg monotherapy and the effect of 
obicetrapib 10 mg monotherapy compared with placebo on LDL-C at Day 28; 
 To evaluate the safety of obicetrapib 10 mg  ezetimibe 10 mg FDC therapy, obicetrapib 
10 mg monotherapy, and ezetimibe 10 mg monotherapy, assessed by clinical laboratory values 
and incidence of AEs; and  
 To assess the mean trough plasma levels of obicetrapib and/or ezetimibe after 
obicetrapib 10 mg  ezetimibe 10 mg FDC therapy, obicetrapib 10 mg monotherapy, and 
ezetimibe 10 mg monotherapy on Days 28 and 84. 

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3 
STUDY DESCRIPTION 
3.1 
Summary of Study Design 
This study will be a placebo-controlled, double-blind, randomized, Phase 3 study to evaluate the 
efficacy, safety, and tolerability of obicetrapib 10 mg, both as an FDC with ezetimibe 10 mg and 
as monotherapy, on top of maximally tolerated lipid-modifying therapy. This study will take place 
at approximately 60 sites. 
3.1.1 
Screening Period 
At Screening (Visit 1), participants will be required to sign an informed consent form (ICF) before 
any study-related procedures are performed. After signing the ICF, participants will be assessed 
for study eligibility. 
3.1.2 
Treatment Period 
Up to 2 weeks after Screening (Visit 1), participants will return to the site on Visit 2 (Day 1) and 
confirm study eligibility before being randomized and beginning treatment. Approximately 
400 eligible participants (100 participants per treatment group) will be randomized in a 
1:1:1:1 ratio to 1 of the following treatment groups: 
 FDC therapy: Obicetrapib 10 mg  ezetimibe 10 mg; 
 Obicetrapib monotherapy: Obicetrapib 10 mg; 
 Ezetimibe monotherapy: Ezetimibe 10 mg; or 
 Placebo. 
Approximately 70% of the participants enrolled into this study should be taking HIS. No more 
than approximately 10% of participants in this study will be completely statin intolerant.  
Participants without underlying HeFH or a history of ASCVD but with multiple ASCVD risk 
factors will comprise a maximum of 30% of the total participants enrolled into the study. 
Participants with only HeFH will comprise a maximum of 20% of the total participants enrolled 
into the study. 
During the 12-week Treatment Period, the assigned study drugs will be administered by the 
participants orally with water, with or without food, once daily on Day 1 to Day 84 at 
approximately the same time each morning. Participants will return to the site on Visit 3 (Day 28) 
(7 days) and Visit 4 (Day 84) (7 days) for efficacy and safety assessments. Participants, 
Investigators, the Clinical Research Organization, and the Sponsor will be blinded to all lipid 
results from Day 1 (Visit 2) for the first participant until the database is locked in order to protect 
blinding to treatment assignment. 
3.1.3 
Safety Follow-Up Period 
Participants will return to the site for a Safety Follow-up Visit (Visit 5 [Day 112]) approximately 
4 weeks after the end of the Treatment Period for safety assessments.  

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3.1.4 
Coronavirus Disease 2019 Contingency Measures 
In cases of COVID-19 limitations, it is the Investigator’s responsibility to assure the safety of 
participants. If necessary, the Sponsor will implement and document mitigation strategies. At the 
Investigator’s discretion, the study visit(s) can be conducted in-clinic or virtually. If conducted 
virtually, the visit will include alternative methods for safety, efficacy, and distribution/collection 
of study drugs, including but not limited to phone/video contact, alternative location for biologic 
sample collection, alternative secure delivery of study drugs, home health care (if available), and 
a secured way of transferring participant data from and to home health services and the site. 
If these contingency measures occur, the Sponsor will document the changes made, communicate 
recommendations about such changes in a timely fashion to minimize or prevent disruptions to the 
study, and support sites in implementing these changes. Documentation of these cases and the 
site’s management of participants should be recorded in the Investigator study files. In the absence 
of a COVID-19 impact, it is expected that Investigators and participants follow the protocol 
requirements as set forth. 
3.2 
Study Indication 
Obicetrapib 10 mg  ezetimibe 10 mg FDC is being developed as an adjunct to diet and maximally 
tolerated lipid-modifying therapy for the treatment of adults with HeFH and/or a history of 
ASCVD or multiple ASCVD risk factors who require additional lowering of LDL-C. 

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4 
SELECTION AND WITHDRAWAL OF PARTICIPANTS  
4.1 
Inclusion Criteria 
Participants who meet all of the following criteria will be eligible to participate in the study: 
1. Are willing and able to give written informed consent before initiation of any study-related 
procedures and willing to comply with all required study procedures; 
2. Are male or female and 18 years of age at Screening (Visit 1);  
o Females may be enrolled if all 3 of the following criteria are met: 
 They are not pregnant; 
 They are not breastfeeding; and 
 They do not plan on becoming pregnant during the study. 
o Females of childbearing potential must have a negative urine pregnancy test at Screening 
(Visit 1);  
Note: Females are not considered to be of childbearing potential if they meet 1 of the 
following criteria as documented by the Investigator:  
 They have had a hysterectomy or tubal ligation at a minimum of 1 cycle prior to signing 
the ICF; or  
 They are postmenopausal, defined as 1 year since their last menstrual period for 
females 55 years of age or 1 year since their last menstrual period and have a 
follicle-stimulating hormone (FSH) level in the postmenopausal range at Screening 
(Visit 1) for females <55 years of age. 
o Females of childbearing potential must agree to use an effective method of avoiding 
pregnancy from Screening (Visit 1) until 35 days after the last dose of a study drug. Males 
whose partners are of childbearing potential must agree to use an effective method of 
avoiding pregnancy from Screening (Visit 1) until 35 days after the last dose of a study 
drug. Effective methods of avoiding pregnancy are contraceptive methods used 
consistently and correctly (including implantable contraceptives, injectable contraceptives, 
oral contraceptives, transdermal contraceptives, intrauterine devices, and barrier methods) 
or a sterile sexual partner. 
3. Have underlying HeFH and/or a history of ASCVD or multiple ASCVD risk factors; 
Diagnosis of HeFH: 
Diagnosis must be made by either prior historical genotyping or by clinical assessment using 
either the WHO Criteria/Dutch Lipid Clinical Network Criteria with a score that is 3 points, 
as specified in Appendix C or the Simon Broome Register Diagnostic Criteria with an 
assessment of “Possible HeFH” or “Definite HeFH,” as specified in Appendix D.23,24 
Participants with a diagnosis of HeFH may or may not have a history of ASCVD or 
ASCVD-risk equivalents; 

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History of ASCVD, defined by at least 1 of the following conditions: 
o Coronary artery disease: 
 MI;  
 Prior coronary revascularization (percutaneous coronary intervention or coronary 
artery bypass grafting); or 
 Angiographic or computed tomography (CT) imaging (eg, multidetector CT or CT 
angiography) evidence of coronary atherosclerosis with >70% stenosis in at least 
1 major epicardial coronary artery. 
o Cerebrovascular disease: 
 Prior ischemic stroke confirmed by a brain imaging study (CT or magnetic resonance 
imaging), considered not to be caused by atrial fibrillation, valvular heart disease, or 
mural thrombus;  
 Carotid artery stenosis >70% on prior angiography or ultrasound; or 
 History of percutaneous or surgical carotid artery revascularization. 
o Peripheral arterial disease: 
 History of percutaneous or surgical revascularization of an iliac, femoral, or popliteal 
artery; or 
 Prior non-traumatic amputation of a lower extremity due to peripheral artery disease. 
Multiple risk factors for ASCVD, defined as follows: 
o Type 2 diabetes plus 1 of the following risk factors or 3 of the following ASCVD risk 
factors:  
 Age >45 years (males) or >55 years (females);  
 Recent MI (>3 and <12 months prior to Randomization [Visit 2 (Day 1)]); 
 Family history of coronary heart disease (first degree relative with clinical coronary 
heart disease [males <55 years or females <65 years]); 
 Increased waist circumference (80 cm [women], 94 cm [men of non-Asian descent], 
or 90 cm [men of Asian descent]);  
 Current cigarette smoking; 
 Hypertension on active medical therapy; 
 High-sensitivity C-reactive protein 2.0 mg/L (19.0 nmol/L); 
 Lp(a) 50 mg/dL (125 nmol/L); 
 Low HDL-C (<40 mg/dL); 
 Coronary calcium score >100 Agatston units; 
 TG >175 mg/dL (>1.98 mmol/L); or 
 Ankle brachial index <0.9. 

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4. Are on maximally tolerated lipid-modifying therapy as an adjunct to a lipid-lowering diet and 
other lifestyle modifications, defined as follows: 
o A statin at a maximally tolerated stable dose;  
 A participant’s maximally tolerated stable statin dose will be determined by the 
Investigator using his/her medical judgment and available sources, including the 
participant’s self-reported history of lipid-modifying therapy for at least 8 weeks prior 
to Screening (Visit 1); and 
 For any participant not taking statin therapy due to statin intolerance, including those 
participants taking bempedoic acid or fibrate monotherapy, written confirmation will 
be required of both the participant and the Investigator stating that the participant is 
statin intolerant, aware of the benefit of statins to reduce the risk of a MACE, and aware 
that many other patients who are unable to tolerate a statin were actually able to tolerate 
a different statin or dose. 
Note: Statin intolerance will be defined as intolerance due to an adverse safety effect 
that started or increased during statin therapy and resolved or improved when statin 
therapy was discontinued, resulting in an inability to tolerate either 1) two or more 
statins at any dose, or 2) one statin at any dose and either an unwillingness to attempt 
a second statin or advice by a physician not to attempt a second statin.25 
o Bempedoic acid for at least 8 weeks in combination with a maximally tolerated statin prior 
to Screening (Visit 1); and/or 
o A PCSK9-targeted therapy alone or in combination with other lipid-modifying therapy for 
at least 4 doses prior to Screening (Visit 1). 
Note: Patients taking inclisiran must have received at least 2 stable doses prior to 
Screening.  
Note: Approximately 70% of the participants enrolled into this study should be taking HIS. No 
more than approximately 10% of participants in this study will be completely statin intolerant. 
Documentation in the electronic case report form (eCRF) of the reason why a participant is 
unable to take HIS is required. HIS include atorvastatin 40 and 80 mg and rosuvastatin 20 and 
40 mg. 
5. Have a fasting serum LDL-C at Screening (Visit 1) 70 mg/dL (1.8 mmol/L); 
Note: For eligibility purposes, LDL-C at Screening (Visit 1) will be calculated using the 
Martin-Hopkins equation unless TG 400 mg/dL (4.5 mmol/L) or LDL-C 50 mg/dL 
(1.3 mmol/L); in both cases, LDL-C level will be measured directly by preparative 
ultracentrifugation, also referred to as beta quantification.26 
6. Have fasting TG <500 mg/dL (<5.7 mmol/L) at Screening (Visit 1); and 
7. Have an estimated glomerular filtration rate (eGFR) 15 mL/min/1.73 m2 calculated using the 
Chronic Kidney Disease Epidemiology Collaboration equation27 at Screening (Visit 1). 

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4.2 
Exclusion Criteria 
Participants who meet any of the following criteria will be excluded from participation in the study: 
1. Have current or any previous history of New York Heart Association class III or IV heart 
failure or left ventricular ejection fraction <30%; 
2. Have been hospitalized for heart failure within 5 years prior to Screening (Visit 1); 
3. Have had any of the following clinical events within 3 months prior to Screening (Visit 1): 
o Non-fatal MI; 
o Non-fatal stroke; 
o Non-elective coronary revascularization; and/or 
o Hospitalization for unstable angina and/or chest pain. 
4. Have uncontrolled severe hypertension, defined as either systolic blood pressure 160 mmHg 
or diastolic blood pressure 100 mmHg at both Screening (Visit 1) and Randomization (Visit 2 
[Day 1]) taken as the average of triplicate measurements. One triplicate retest will be allowed 
during the same visit, at which point if the retest result is no longer exclusionary, the participant 
may be randomized; 
5. Have a formal diagnosis of homozygous FH; 
6. Have active liver disease, defined as any known current infectious, neoplastic, or metabolic 
pathology of the liver; Child-Pugh score of 7 to 9 (Class B) or 10 to 15 (Class C); unexplained 
elevations in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3  upper 
limit of normal (ULN); or total bilirubin >2  ULN at Screening (Visit 1); 
Note: An abnormal ALT, AST, or total bilirubin must be confirmed by a repeat abnormal 
measurement at least 1 week apart. 
7. Have a glycosylated hemoglobin (HbA1c) 10.0% (0.100 hemoglobin fraction) or a fasting 
glucose 270 mg/dL (15.0 mmol/L) at Screening (Visit 1); 
8. Have thyroid-stimulating hormone >1.5  ULN at Screening (Visit 1); 
9. Have creatine kinase (CK) >3  ULN at Screening (Visit 1); 
10. Have a history of a malignancy that required surgery (excluding local and wide local excision), 
radiation therapy, and/or systemic therapy during the 3 years prior to Randomization (Visit 2 
[Day 1]); 
11. Have a known history of alcohol and/or drug abuse within 5 years prior to Randomization 
(Visit 2 [Day 1]); 
12. Have received treatment with other investigational products or devices within 30 days of 
Screening (Visit 1) or 5 half-lives of the previous investigational product, whichever is longer; 
Note: Participants who have received treatment for COVID-19 with standard of care and/or 
emergency use authorization medications, including vaccinations and boosters, within 30 days 
of Screening (Visit 1) or 5 half-lives of the previous investigational product will be permitted. 
13. Are taking gemfibrozil or have taken gemfibrozil within 30 days of Screening (Visit 1); 

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14. Are taking ezetimibe or have taken ezetimibe within 14 days of Screening (Visit 1);  
15. Have planned use of other investigational products or devices during the course of the study; 
16. Have participated in any clinical study evaluating obicetrapib; 
17. Have a known allergy or hypersensitivity to the study drugs, placebo, or any of the excipients 
in the study drugs or placebo; or 
18. Have any participant condition that, according to the Investigator, could interfere with the 
conduct of the study, such as, but not limited to, the following: 
o Are unable to communicate or to cooperate with the Investigator; 
o Are unable to understand the protocol requirements, instructions and study-related 
restrictions, and the nature, scope, and possible consequences of the study (including 
participants whose cooperation is doubtful due to drug abuse or alcohol dependency); 
o Are unlikely to comply with the protocol requirements, instructions, and study-related 
restrictions (eg, uncooperative attitude, inability to return for follow-up visits, and 
improbability of completing the study); 
o Have any medical or surgical condition which, in the opinion of the Investigator, would 
put the participant at increased risk from participating in the study; or 
o Are directly involved in the conduct of the study. 
4.3 
Retesting 
If laboratory abnormalities during the Screening Period are considered by the Investigator to be 
transient, then the laboratory tests may be repeated once during the Screening Period. The 
Investigator’s rationale for retesting should be documented. If the retest result is no longer 
exclusionary, the participant may be randomized. 
4.4 
Rescreening 
A participant who is screened and does not meet the study eligibility criteria may be considered 
for rescreening upon Sponsor and/or Medical Monitor consultation and approval. Rescreened 
participants will be assigned a new participant number. Rescreening should occur no less than 
5 days after the last screening visit. 
4.5 
Withdrawal Criteria 
A participant may prematurely discontinue study drug and/or withdraw from the study at any time. 
However, a distinction must be made between premature discontinuation of study drug and 
withdrawal from the study. All efforts should be made to ensure the participant continues in the 
study per protocol. If a participant discontinues study drug prior to completion of the study, all 
efforts will be made to continue to follow the participant and collect data for all visits.  
Only participants that request discontinuation from the study and withdraw consent will be 
considered withdrawn from the study. For safety reasons, it will be recommended that all 
participants who withdraw from the study complete an End of Treatment (EOT) Visit. Withdrawn 
participants will not be replaced. 

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Participants may need to discontinue study drug during the course of the study. All efforts will be 
made to restart the study drug; however, in the event of the following, participants may be 
permanently discontinued from study drug: 
 Occurrence of any medical condition or circumstance that exposes the participant to substantial 
risk and/or does not allow the participant to adhere to the protocol-specified study drug 
treatment regimen; 
 Any SAE, clinically significant AE, severe laboratory abnormality, intercurrent illness, or 
other medical condition, which indicates to the Investigator that continued treatment with study 
drug is not in the best interest of the participant; 
 Pregnancy; or 
 Requirement of prohibited concomitant medication. 
If a participant permanently discontinues study drug, he/she will continue to participate in study 
visits as described below: 
 If a participant discontinues study drug between Visit 2 (Day 1) and Visit 3 (Day 28) or at 
Visit 3 (Day 28), he/she should complete an EOT Visit at Day 28, return to complete Visit 4 
(Day 84), and return to complete the Safety Follow-up Visit (Day 112); or 
 If a participant discontinues study drug between Visit 3 (Day 28) and Visit 4 (Day 84), he/she 
should return for Visit 4 (Day 84) and the Safety Follow-up Visit (Day 112) as scheduled.  
If a participant who discontinues study drug will not or does not return for 1 or all future visits, 
efforts should be made to collect as much information as possible via a telephone call, conducted 
at the same time as the planned study visit(s). The efforts to follow-up via telephone at each 
planned visit day should continue through the day of the planned Safety Follow-up Visit 
(Day 112). 
When participants enter the study, contact information and alternative methods of contact will be 
collected in the event that the site loses contact with the participant. In the case of a participant lost 
to follow-up, attempts to contact the participant must be made and documented in the participant’s 
medical records. 
The Sponsor or regulatory agency can terminate the study at any time for any reason. 

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5 
STUDY TREATMENTS 
5.1 
Treatment Groups 
Participants will be randomized in a 1:1:1:1 ratio to 1 of the following treatment groups: 
 FDC 
therapy: 
Obicetrapib 
10 mg 
 
ezetimibe 
10 
mg 
(administered 
as 
1 obicetrapib 10 mg  ezetimibe 10 mg FDC tablet, 1 obicetrapib-matched placebo tablet, and 
1 ezetimibe-matched placebo capsule); 
 Obicetrapib monotherapy: Obicetrapib 10 mg (administered as 1 FDC-matched placebo tablet, 
1 obicetrapib 10 mg tablet, and 1 ezetimibe-matched placebo capsule); 
 Ezetimibe monotherapy: Ezetimibe 10 mg (administered as 1 FDC-matched placebo tablet, 
1 obicetrapib-matched placebo tablet, and 1 ezetimibe 10 mg capsule [over-encapsulated 
10 mg tablet]); or 
 Placebo (administered as 1 FDC-matched placebo tablet, 1 obicetrapib-matched placebo tablet, 
and 1 ezetimibe-matched placebo capsule). 
5.2 
Rationale for Dosing 
In clinical studies in healthy volunteers, obicetrapib was generally well tolerated in single doses 
up to 150 mg and multiple doses up to 25 mg/day for 21 days. In clinical studies in patients, 
obicetrapib was also well tolerated after daily dosing of 10 mg for 12 weeks, both alone and in 
combination with 2 different statins. Near maximal effects were observed with the 10 mg 
obicetrapib dose. At this dose level, CETP activity was reduced, HDL-C levels were increased, 
and LDL-C levels were decreased. There were no dose-related AEs identified and no clinically 
significant changes in vital signs, ECGs, or hematology or biochemistry parameters in any clinical 
studies. A statistically significant reduction in Lp(a) levels from baseline was also observed at the 
10 mg obicetrapib dose level. Therefore, the present study will utilize a dose of 10 mg obicetrapib 
in participants with HeFH and/or a history of ASCVD or multiple ASCVD risk factors who are 
not adequately controlled by their maximally tolerated lipid-modifying therapy. 
The ezetimibe dose of 10 mg is the current FDA-approved dose.  
5.3 
Randomization and Blinding 
Participants who meet all inclusion criteria and none of the exclusion criteria will be randomized 
at Visit 2 (Day 1) via the 
 Interactive Response technology (IRT) system a 1:1:1:1 ratio 
to receive FDC therapy, obicetrapib monotherapy, ezetimibe monotherapy, or placebo as described 
in Section 5.1. 
Approximately 70% of the participants enrolled into this study should be taking HIS. No more 
than approximately 10% of participants in this study will be completely statin intolerant.  
Participants without underlying HeFH or a history of ASCVD but with multiple ASCVD risk 
factors will comprise a maximum of 30% of the total participants enrolled into the study. 
Participants with only HeFH will comprise a maximum of 20% of the total participants enrolled 
into the study. 
Participants, the Sponsor, Investigators, and all study site personnel involved in the study, 
including personnel carrying out study procedures, evaluating participants, entering study data, 

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5.5.3 
Study Drug Administration 
Study drugs (2 tablets and 1 capsule) will be administered by the participant orally with water, 
with or without food, once daily on Day 1 to Day 84 at approximately the same time each morning. 
On days with visits scheduled, participants should not take the study drugs prior to the visit but 
should bring the study drugs with them to the site. The study drugs will be administered with water 
following all fasted blood samples. At Visit 3 (Day 28) and Visit 4 (Day 84), participants will dose 
from the kit received at the previous visit (Visit 2 [Day 1] and Visit 3 [Day 28], respectively).  
If a participant forgets to take the study drugs on a given day, he/she should take the next dose as 
normal and should not take a double dose to make up for the forgotten dose. 
5.5.4 
Treatment Compliance 
Compliance with the study drug regimen will be evaluated by counting unused tablets and 
capsules. Participants will be instructed to bring all unused study drugs to the site at Visit 3 
(Day 28) and at Visit 4 (Day 84) (or at an EOT Visit, in cases of early discontinuation of study 
drug or study). During the Treatment Period, if compliance is not between 80% and 120%, 
inclusive, the participant will be counselled about the importance of compliance with the regimen. 
5.5.5 
Storage and Accountability 
All study drugs must be stored at room temperature, no higher than 77°F (25°C), and protected 
from moisture in a secure area with access limited to the Investigator and authorized site personnel. 
In accordance with regulatory requirements, the Investigator or designated site personnel must 
document the amount of study drugs dispensed and/or administered to participants, the amount 
returned by participants, and the amount received from and returned to the Sponsor (or 
representative) when applicable. Study drug accountability records must be maintained throughout 
the course of the study. The accountability unit for this study is a tablet or capsule. Discrepancies 
are to be reconciled or resolved. At the end of the study, a final reconciliation must be made 
between the amount of study drug supplied, dispensed, and subsequently returned to the Sponsor 
(or representative) or destroyed with the written permission of the Sponsor, in accordance with 
applicable laws and study site’s procedures. Procedures for final disposition of unused study drugs 
will be provided in the appropriate study manual. 
5.6 
Prior and Concomitant Medications and/or Procedures 
5.6.1 
Excluded Medications and/or Procedures 
Participants must not take any other investigational products or use any investigational devices 
within 30 days of Screening (Visit 1) or 5 half-lives of the previous investigational product, 
whichever is longer, or during the course of the study or they will be excluded from study 
participation.  
Participants must not take gemfibrozil within 30 days of Screening (Visit 1) or during study 
participation. Participants must not take additional ezetimibe within 14 days of Screening (Visit 1) 
or during study participation. Participants must agree not to donate blood during study 
participation. 

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5.6.2 
Restricted Medications and/or Procedures 
Participants receiving maximally tolerated lipid-modifying therapy (other than PCSK9-targeted 
therapies) as described in Section 4.1 should be on a stable dose for at least 8 weeks prior to 
Screening (Visit 1). Participants taking PCSK9-targeted therapies (except for inclisiran) should 
have received at least 4 doses prior to Screening (Visit 1). Participants taking inclisiran must have 
received at least 2 stable doses prior to Screening (Visit 1). There should be no planned medication 
or dose changes of lipid-modifying therapy during study participation. Participants must agree not 
to initiate any new lipid-modifying medications (including supplements) and not to change the 
dose of the existing lipid-modifying medications (including supplements) during study 
participation. However, if there are changes to lipid-modifying therapy during the study, these data 
will be recorded and reported as a protocol deviation. 
Participants are not required to be taking statins. Reasons for not using statin therapy must be 
documented as described in Section 5.6.3.  
5.6.3 
Documentation of Prior and Concomitant Medication Use 
Any prior lipid-modifying therapies, administered at any time, must be recorded. Any 
non-lipid-modifying medications administered within 90 days prior to the first dose of study drug 
must be recorded. All prior and concomitant medications must be documented in the source 
documents and applicable eCRFs. Concomitant medications will continue to be assessed and 
recorded at every study visit from the time of informed consent until study participation is 
complete. 
Data from all participants regarding lipid-modifying medications taken throughout the study will 
be recorded. The number of participants taking a statin or PCSK9-targeted therapy during the study 
and the number of participants who discontinue background statin therapy, along with the reasons 
for discontinuation of background statin therapy, will be recorded in the applicable eCRFs. 
A participant’s maximally tolerated stable statin dose will be determined by the Investigator using 
his/her medical judgment and available sources, including the participant’s self-reported history 
of lipid-modifying therapy, for at least 8 weeks prior to Screening (Visit 1), and recorded in the 
applicable eCRFs. 
No more than approximately 10% of participants in this study will be completely statin intolerant. 
For any participant not taking statin therapy due to statin intolerance (as defined in Inclusion 
Criterion 4), including those participants taking bempedoic acid or fibrate monotherapy, written 
confirmation will be required of both the participant and the Investigator stating that the participant 
is statin intolerant, aware of the benefit of statins to reduce the risk of a MACE, and aware that 
many other patients who are unable to tolerate a statin were actually able to tolerate a different 
statin or dose. Statin intolerance should be recorded as intolerance to any dose of any statin as 
historical events attributed to the statin in question, in the source documentation and eCRF as part 
of the medical history to confirm intolerance to statins.25  
Documentation in the eCRF of the reason why a participant is unable to take HIS is required. 
5.6.4 
Dietary Guidelines  
Participants will be instructed to follow a lipid-lowering diet as per local or regional guidelines 
throughout the study. 

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6 
STUDY PROCEDURES 
Study procedures will follow the Schedule of Procedures (Appendix A).  
Unscheduled visits may be scheduled as needed per the judgment of the Investigator. Procedures 
will be determined based on the reason for the visit. 

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7 
EFFICACY AND PHARMACOKINETIC ASSESSMENTS 
7.1 
Efficacy Assessments 
7.1.1 
Efficacy Endpoints 
7.1.1.1 
Primary efficacy endpoint 
The primary efficacy endpoint is the percent change from Day 1 to Day 84 in LDL-C. Co-primary 
endpoints include the percent change from Day 1 to Day 84 in LDL-C for the 
obicetrapib 10 mg  ezetimibe 10 mg FDC treatment group as follows: 
 Compared with the placebo group;  
 Compared with the ezetimibe 10 mg monotherapy treatment group; and 
 Compared with the obicetrapib 10 mg monotherapy treatment group, 
And the percent change from Day 1 to Day 84 in LDL-C for the obicetrapib 10 mg monotherapy 
treatment group compared with the placebo group. 
7.1.1.2 
Secondary efficacy endpoints 
The secondary efficacy endpoints include the following, in hierarchical order: 
 Percent 
change 
from 
Day 
1 
to 
Day 
84 
in 
non-HDL-C 
for 
the 
obicetrapib 10 mg  ezetimibe 10 mg FDC treatment group compared with the placebo group; 
 Percent change from Day 1 to Day 84 in ApoB for the obicetrapib 10 mg  ezetimibe 10 mg 
FDC treatment group compared with the placebo group; 
 Percent change from Day 1 to Day 84 in non-HDL-C for the obicetrapib 10 mg monotherapy 
treatment group compared with the placebo group; 
 Percent change from Day 1 to Day 84 in ApoB for the obicetrapib 10 mg monotherapy 
treatment group compared with the placebo group; 
 Percent 
change 
from 
Day 
1 
to 
Day 
84 
in 
non-HDL-C 
for 
the 
obicetrapib 10 mg  ezetimibe 10 mg FDC treatment group compared with the ezetimibe 
10 mg monotherapy treatment group; 
 Percent change from Day 1 to Day 84 in ApoB for the obicetrapib 10 mg  ezetimibe 10 mg 
FDC treatment group compared with the ezetimibe 10 mg monotherapy treatment group; 
 Percent 
change 
from 
Day 
1 
to 
Day 
84 
in 
non-HDL-C 
for 
the 
obicetrapib 10 mg  ezetimibe 10 mg FDC treatment group compared with the obicetrapib 
10 mg monotherapy treatment group; and 
 Percent change from Day 1 to Day 84 in ApoB for the obicetrapib 10 mg  ezetimibe 10 mg 
FDC treatment group compared with the obicetrapib 10 mg monotherapy treatment group. 

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7.1.1.3 
Exploratory efficacy endpoints 
The exploratory efficacy endpoints include the following: 
 Percent change from Day 1 to Day 84 in VLDL-C, HDL-C, TG, Lp(a), and sdLDL-C for the 
obicetrapib 10 mg  ezetimibe 10 mg FDC treatment group compared with the placebo group, 
ezetimibe 10 mg monotherapy treatment group, and obicetrapib 10 mg monotherapy treatment 
group, and for the obicetrapib 10 mg monotherapy treatment group compared with the placebo 
group; 
 Percent change from Day 1 to Day 84 in particle numbers and size, as measured by NMR 
analysis, of LDL-C, HDL-C, and VLDL-C for the obicetrapib 10 mg  ezetimibe 10 mg FDC 
treatment group compared with the placebo group, ezetimibe 10 mg monotherapy treatment 
group, and obicetrapib 10 mg monotherapy treatment group, and for the obicetrapib 10 mg 
monotherapy treatment group compared with the placebo group; 
 Proportion of participants at Day 84 that achieve LDL-C <100 mg/dL (<2.6 mmol/L), LDL-C 
<70 mg/dL (<1.8 mmol/L), and LDL-C <55 mg/dL (<1.4 mmol/L) for the 
obicetrapib 10 mg  ezetimibe 10 mg FDC treatment group compared with the placebo group, 
ezetimibe 10 mg monotherapy treatment group, and obicetrapib 10 mg monotherapy treatment 
group, and for the obicetrapib 10 mg monotherapy treatment group compared with the placebo 
group; and 
 Percent change from Day 1 to Day 28 in LDL-C for the obicetrapib 10 mg + ezetimibe 10 mg 
FDC treatment group compared with the placebo group, ezetimibe 10 mg monotherapy 
treatment group, and obicetrapib 10 mg monotherapy treatment group, and for the obicetrapib 
10 mg monotherapy treatment group compared with the placebo group. 
7.1.2 
Lipid Profile/Biomarkers 
Blood samples for the lipid profile must be obtained under fasting conditions (ie, after the 
participant has fasted for a minimum of 8 hours) and before study drug administration. For the 
purposes of this study, fasting will be defined as nothing by mouth except water and any essential 
medications. If a participant is not fasting, the Investigator should reschedule the visit as soon as 
possible. 
LDL-C level will be calculated using the Martin-Hopkins and Friedewald equations unless TG 
400 mg/dL (4.5 mmol/L) or LDL-C 50 mg/dL (1.3 mmol/L); in both cases, LDL-C level will 
be measured directly by preparative ultracentrifugation, also referred to as beta quantification.26,28 
Additionally, LDL-C will be measured by preparative ultracentrifugation at Visit 2 (Day 1), Visit 4 
(Day 84), and, in cases of early discontinuation of study drug or study, at an EOT Visit, for all 
participants. 
7.1.3 
Lipoprotein (a) 
A plasma sample for Lp(a) will be collected at visits specified in the Schedule of Procedures 
(Appendix A). Samples should be collected prior to study drug administration and while the 
participant is fasting (a minimum of 8 hours). 

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7.1.4 
Nuclear Magnetic Resonance Analysis of Lipids 
A plasma sample for NMR analysis will be collected at visits specified in the Schedule of 
Procedures (Appendix A). Samples should be collected prior to study drug administration and 
while the participant is fasting (a minimum of 8 hours).  
7.1.5 
Urine Albumin-Creatinine Ratio 
A urine sample for urine albumin-creatinine ratio will be collected at visits specified in the 
Schedule of Procedures (Appendix A). 
7.1.6 
Serum Archive Samples for Future Assessment 
Serum archive samples will be collected prior to the first dose at Visit 2 (Day 1) and at Visit 4 
(Day 84) (or at an EOT Visit, in cases of early discontinuation of study drug or study) for potential 
future assessment of conditions associated with cholesterol metabolism. Samples should be 
collected prior to study drug administration and while the participant is fasting (a minimum of 
8 hours). If the samples are analyzed, it will be for non-genetic tests.  
7.2 
Pharmacokinetic Assessments 
Plasma obicetrapib and ezetimibe concentrations, both in combination and each as monotherapy, 
will be assessed at the scheduled PK collection times. 
A PK sample will be collected prior to study drug administration for trough measurements of 
obicetrapib and ezetimibe in plasma. At Visit 2 (Day 1), Visit 3 (Day 28), Visit 4 (Day 84), and 
the EOT Visit, in cases of early discontinuation of study drug or study, participants should take 
study drug after a trough PK sample has been collected. 

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8 
SAFETY ASSESSMENTS 
The safety and tolerability profile of obicetrapib 10 mg  ezetimibe 10 mg FDC therapy, 
obicetrapib 10 mg as monotherapy, and ezetimibe 10 mg as monotherapy will be assessed by 
clinical laboratory assessments (chemistry, hematology, and coagulation), vital signs, physical 
examinations, and the incidence of AEs and events of special interest (ESIs).  
8.1 
Adverse Events 
An AE is defined as any untoward medical occurrence in a clinical investigation participant 
administered a pharmaceutical product, which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and/or unintended sign (including a 
clinically significant abnormal laboratory finding), symptom, or disease temporally associated 
with the use of an investigational medicinal product (IMP), whether or not related to the IMP. All 
AEs, including observed or volunteered problems, complaints, or symptoms, are to be recorded on 
the appropriate eCRF. 
AEs, which include clinical laboratory assessment variables, will be monitored and documented 
from the time of first dose of study treatment until completion of Visit 5 (Day 112). Participants 
should be instructed to report any AE that they experience to the Investigator, whether or not they 
think the event is due to a study drug. Beginning at the date of the first dose of study treatment, 
Investigators should make an assessment for AEs at each visit and record the event on the 
appropriate AE 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 AE 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 AE, not the procedure itself.  
Any medical condition already present at the date of the first dose of study treatment should be 
recorded as medical history and not be reported as an AE unless the medical condition or signs or 
symptoms present at baseline changes in severity, frequency, or seriousness at any time during the 
study. In this case, it should be reported as an AE. 
Clinically significant abnormal laboratory or other examination findings (eg, ECG) that are 
detected during the study or are present at the date of the first dose of study treatment and 
significantly worsen during the study should be reported as AEs, as described below. 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 study will be followed until repeat 
tests return to normal, stabilize, or are no longer clinically significant. Abnormal test results that 
are determined to be an error should not be reported as an AE. Laboratory abnormalities or other 
abnormal clinical findings (eg, ECG abnormalities) should be reported as an AE if any of the 
following are applicable: 
 If an intervention is required as a result of the abnormality; 
 If action taken with a study drug is required as a result of the abnormality; or  

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 Based on the clinical judgment of the Investigator. 
8.1.1 
Adverse 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 AE is at least a reasonable possibility, ie, the 
relationship cannot be ruled out. 
8.1.2 
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. 
For the obicetrapib 10 mg  ezetimibe 10 mg FDC, the reference safety information is included in 
Section 6 of the Investigator’s Brochure currently in force. The reference safety information will 
be reviewed annually by the Sponsor and the periodicity of the review will be harmonized with 
the reporting period of the Development Safety Update Report, where possible. 
For ezetimibe, the reference safety information is included in the Summary of Product 
Characteristics.  
8.1.3 
Assessment of Adverse Events by the Investigator 
The Investigator will assess the severity (intensity) of each AE as mild, moderate, or severe, and 
will also categorize each AE as to its potential relationship to the study drugs using the categories 
of yes or 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 AE to the administration of the study drugs is to be assessed according to 
the following definitions: 
No (unrelated, not related, unlikely to be related) – The time course between the administration of 
study drugs and the occurrence or worsening of the AE is not consistent with a causal relationship 
and another cause (concomitant drugs, therapies, complications, etc) is suspected. 
Yes (possibly, probably, or definitely related) – The time course between the administration of 
study drugs and the occurrence or worsening of the AE 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 drugs. This means that there are facts (evidence) or arguments to suggest a causal 
relationship. 

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The following factors should also be considered: 
 The temporal sequence from a study drug administration- 
The event should occur after a 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- 
Each report should be evaluated in the context of the natural history and course of the disease 
being treated and any other disease the participant may have. 
 Concomitant drug- 
The other drugs the participant is taking or the treatment the participant 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- 
Clinical and/or preclinical data displayed in the Investigator’s Brochure may indicate whether 
a particular response is likely to be a class effect. 
 Exposure to physical and/or mental stresses- 
The exposure to stress might induce adverse changes in the recipient and provide a logical and 
better explanation for the event. 
 The pharmacology and PK of the study drugs- 
The known pharmacologic properties (absorption, distribution, metabolism, and excretion) of 
the study drugs should be considered. 
8.1.4 
Events of Special Interest  
ESIs will be monitored, regardless of whether these events were reported as AEs. Any events that 
qualify as an AE or SAE will be reported accordingly (see Sections 8.1, 8.2, and 8.3). 
ESIs will include the following hepatic abnormalities, muscle-related abnormalities, new-onset 
diabetes mellitus (NODM) and/or hyperglycemia, renal abnormalities, changes to antihypertensive 
medication(s) due to changes in blood pressure, and ophthalmic events (ie, macular degeneration), 
described as follows: 
 AST or ALT >3  ULN; 
 Total bilirubin >2  ULN; 
 CK >5  ULN; 
 NODM or worsening of glycemic control;  
Note: NODM is defined by 1 or more of the following criteria, based upon information from 
AE, medication, and laboratory data:  
o AE indicating new type 1 or type 2 diabetes; 
o Initiation of anti-diabetes medication with confirmation of the diagnosis of diabetes by 
blinded external review by experts in diabetology; 

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o HbA1c 6.5% (0.065 hemoglobin fraction); and/or 
o Two consecutive values of fasting plasma glucose that are 126 mg/dL (7.0 mmol/L). 
Note: Worsening of glycemic control will be defined as an HbA1c increase from baseline 
>0.5% (>0.005 hemoglobin fraction) and/or a new concomitant medication or increase in 
current antidiabetic therapy in a participant with a baseline HbA1c 6.5% (0.065 hemoglobin 
fraction). 
 A >25% decrease in eGFR from baseline or an eGFR <15 mL/min/1.73 m2, calculated using 
the Chronic Kidney Disease Epidemiology Collaboration equation, and/or an increase in serum 
creatinine of 0.3 mg/dL (26.5 mol/L) from baseline; 
 Changes to antihypertensive medication(s) due to changes in blood pressure in those 
participants receiving antihypertensive medication(s) treatment at baseline, and new 
antihypertensive medication prescriptions for participants not previously treated for 
hypertension; and  
 Macular degeneration.  
These ESIs will be monitored through review of the AE and laboratory databases. 
8.1.4.1 
Guidelines for management of elevated liver enzymes  
Participants with signs or symptoms consistent with liver injury (eg, nausea, vomiting, anorexia, 
fatigue, or right upper abdominal pain or discomfort) should undergo immediate testing of ALT, 
AST, gamma-glutamyl transferase, bilirubin, alkaline phosphatase, prothrombin time, and 
international normalized ratio.  
In the absence of clinical symptoms, participants with ALT or AST >3  ULN (if normal at 
baseline) or >2-fold change (if abnormal at baseline) should be retested within 48 to 72 hours for 
the usual serum measurements (ALT, AST, alkaline phosphatase, and bilirubin) to confirm the 
abnormalities and to determine if the associated values are increasing or decreasing. There should 
also be an inquiry about symptoms at the time of follow-up. 
If the above abnormalities are confirmed: 
 Repeat liver enzyme and serum bilirubin tests 2 or 3 times weekly. The frequency of retesting 
can decrease to once a week or less if abnormalities stabilize or the study drug has been 
discontinued and the participant is asymptomatic; 
 Obtain a more detailed history of symptoms and prior or concurrent diseases; 
 Obtain a history of concomitant drug use (including nonprescription medications and herbal 
and dietary supplement preparations), alcohol use, recreational drug use, and special diet; 
 Rule out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic hepatitis; 
nonalcoholic steatohepatitis; hypoxic/ischemic hepatopathy; and biliary tract disease; 
 Obtain a history of exposure to environmental chemical agents; 
 Obtain additional tests to evaluate liver function, as appropriate (eg, international normalized 
ratio, direct bilirubin); and 
 Consider gastroenterology or hepatology consultations. 

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Study drug discontinuation should occur if: 
 ALT or AST >8  ULN; 
 ALT or AST >5  ULN for more than 2 weeks; 
 ALT or AST >3  ULN and total bilirubin >2  ULN or international normalized ratio >1.5; 
or 
 ALT or AST >3  ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (>5%). 
8.1.4.2 
Guidelines for monitoring and management of creatine kinase  
If at any time after Randomization (Visit 2 [Day 1]) a participant experiences a CK elevation 
>5  ULN, the participant will undergo a repeat confirmatory assessment as soon as is reasonably 
possible, preferably within 3 to 7 days of the laboratory result becoming available. 
A repeat CK assessment will include query for related symptoms. 
If the repeat CK assessment confirms an unexplained (ie, not associated with recent trauma or 
physically strenuous activity) CK abnormality >5  ULN and the participant is asymptomatic, 
he/she should receive further assessment and investigation into the cause, assessment of whether 
there is renal injury, and measurement of CK approximately weekly, or more frequently if 
clinically indicated, until resolution. If CK levels continue to rise, the study drug should be 
discontinued. 
If the participant experiences a CK elevation >5  ULN and is symptomatic, the following should 
be completed: 
 Interruption of study drug;  
 Clarification of the nature, duration, and intensity of muscle symptoms; 
 Review of possible predisposing factors, such as unaccustomed exercise, heavy alcohol intake, 
and viral illness (consider performing serology); 
 Evaluation for additional diagnoses or other conditions which can cause myopathy, including 
muscle tenderness (by physical examination), weakness, rash, measurement of serum 
creatinine, and/or urine dipstick analysis with microscopy if indicated; 
 Measurement of clinical chemistries to assess the possibility of lactic acidosis; and 
 Follow-up of symptoms and CK until the abnormality has resolved. 
If, based on the above evaluation, an alternative explanation is suspected, consideration can be 
given to resuming study drug once CK returns to baseline levels. 
If no alternative explanation exists, consideration should be given to discontinuing study drug 
treatment. 
If the repeat CK assessment confirms an unexplained (ie, not associated with recent trauma or 
physically strenuous activity) CK >10  ULN, the participant should be discontinued from study 
drug, even in the absence of symptoms. The signs and symptoms and laboratory assessments as 
outlined above should also be evaluated. The participant should continue being followed in the 
study for safety. 

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Any event of rhabdomyolysis, regardless of CK level, should lead to study drug interruption or 
discontinuation until the contribution of obicetrapib has been excluded. 
8.1.4.3 
Guidelines for monitoring and management of new-onset diabetes mellitus 
Diabetes mellitus may be newly diagnosed during the study as described in Section 8.1.4. If a 
participant is newly diagnosed with diabetes mellitus during the course of the study, the 
Investigator will recommend referral for initial diabetes education and management by an 
appropriate healthcare provider (eg, diabetologist, endocrinologist, or primary care provider). 
Interventions for management may include diet and lifestyle counseling, self-monitoring of blood 
glucose, oral glucose-lowering medications, injectable medications, or insulin as deemed 
necessary by the treating physician based on the level of hyperglycemia and relevant symptoms. 
8.1.4.4 
Guidelines for monitoring and management of significant changes in renal function  
If at any time after Randomization (Visit 2 [Day 1]) a participant experiences ANY of the 
following, the participant will undergo a repeat confirmatory assessment as soon as is reasonably 
possible, preferably within 3 to 7 days of the laboratory result becoming available: 
 A >25% decrease in eGFR from baseline, calculated using the Chronic Kidney Disease 
Epidemiology Collaboration equation; 
 An eGFR <15 mL/min/1.73 m2, calculated using the Chronic Kidney Disease Epidemiology 
Collaboration equation; and/or 
 An increase in serum creatinine of 0.3 mg/dL (26.5 mol/L) from baseline. 
In consultation with the Medical Monitor and/or nephrologist, if no alternative etiology is 
determined, the study drug should be discontinued if participants experience an unexplained, 
confirmed increase in serum creatinine of 0.3 mg/dL (26.5 mol/L) from baseline or an 
unexplained, confirmed >25% decrease in eGFR from baseline. 
If any of these individual laboratory parameters are confirmed, such events of decline in renal 
function should be recorded as an ESI. 
8.1.4.5 
Guidelines for monitoring and management of changes to antihypertensive 
medication(s) 
Any changes to antihypertensive medication(s) due to changes in blood pressure in those 
participants receiving antihypertensive medication(s) treatment at baseline will be assessed by the 
Investigator, primary care physician, or other appropriate health care provider to assess for 
etiologies of blood pressure change, to confirm clinical safety of the participant, to assess the need 
for any AE or SAE reporting, and to arrange for appropriate medical follow-up. 
8.1.4.6 
Guidelines for management of macular degeneration 
In cases of suspected macular degeneration or acute vision loss, participants will be referred for 
an ophthalmological consultation.  

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The Sponsor/designee will also report any additional expedited safety reports required in 
accordance with the timelines outlined in country-specific legislation.  
The Sponsor/designee will also inform all Investigators as required per local regulation. 
The requirements above refer to the requirements relating to study drugs. 
8.6 
Special Situation Reports 
Special situation reports include reports of overdose, misuse, abuse, medication error, and reports 
of adverse reactions associated with product complaints. 
 Overdose: Refers to the administration of a quantity of a medicinal product given per 
administration or cumulatively (accidentally or intentionally), which is above the maximum 
recommended dose according to the protocol. Clinical judgement should always be applied. In 
cases of a discrepancy in the drug accountability, overdose will be established only when it is 
clear that the participant has taken additional dose(s) or the Investigator has reason to suspect 
that the participant has taken additional dose(s).  
 Misuse: Refers to situations where the medicinal product is intentionally and inappropriately 
used not in a way that is not in accordance with the protocol instructions or local prescribing 
information and may be accompanied by harmful physical and/or psychological effects.  
 Abuse: Is defined as persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects. 
 Medication error: Is any unintentional error in the prescribing, dispensing, or administration 
of a medicinal product by a healthcare professional, participant, or consumer, respectively. The 
administration or consumption of the unassigned treatment and administration of an expired 
product are always reportable as medication errors, cases of participants missing doses of 
investigational product are not considered reportable as medication error. 
 Product complaint: Is defined as any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug or device after it is released for distribution. A special situations form 
will only be completed if a complaint is associated with an adverse drug reaction.  
All special situation events as described above must be reported on the Special Situations Report 
form and faxed/emailed to 
 (contact information listed 
below) within 24 hours of knowledge of the event. All AEs associated with these Special Situation 
reports should be reported as AEs or SAEs as well as recorded on the AE eCRF and/or the SAE 
report form. Details of the symptoms and signs, clinical management, and outcome should be 
provided, when available. 

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8.12 
Physical Examinations 
A physical examination will be performed as indicated in Appendix A. The physical examination 
should comprise a focused examination, which includes general, respiratory, CV, abdominal, and 
extremities evaluations. 

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9 
STATISTICS 
9.1 
Analysis Populations 
The Intent-to-Treat (ITT) Population will include all participants randomized into the study. 
Treatment classification will be based on the randomized treatment.  
The Full Analysis Set (FAS) will include all participants who are randomized into the study, take 
any study drug, and have at least 1 post-treatment lipid data assessment. Treatment classification 
will be based on the randomized treatment. 
The Modified ITT (mITT) Population will include all randomized participants who receive at 
least 1 dose of any study drug and have data for both the Day 1 and Day 84 LDL-C assessments. 
Treatment classification will be based on the randomized treatment.  
The mITT On-Treatment Population will include all randomized participants who receive at 
least 1 dose of any study drug, have data for both the Day 1 and Day 84 LDL-C assessments, and 
have an obicetrapib plasma concentration at Visit 4 (Day 84) that was >100 ng/mL. Treatment 
classification will be based on the randomized treatment. 
The Per-Protocol (PP) Population will include all participants in the mITT Population who did not 
experience a major protocol deviation that potentially impacted the primary efficacy endpoint. The 
PP Population, along with the reason for exclusion, will be finalized prior to study unblinding. 
The Safety Population will include all participants who receive at least 1 dose of any study drug. 
Treatment classification will be based on the actual treatment received. The Safety Population will 
be the primary population used for the safety analyses. 
9.2 
Statistical Methods 
A Statistical Analysis Plan (SAP) will be finalized before database lock. Any changes to the 
methods described in the SAP will be described and justified as needed in the Clinical Study 
Report. All study-collected data will be summarized by treatment group using descriptive 
statistics, graphs, and/or raw data listings. Descriptive statistics for continuous variables will 
include number of participants (n), mean, standard deviation (SD), median, minimum, and 
maximum values. Analysis of categorical variables will include frequency and percentage. 
Unless otherwise stated, baseline values will be the last non-missing measurements taken prior to 
the participant receiving any study drug. 
9.2.1 
Analysis of Efficacy 
The ITT Population will be the primary population for the efficacy analyses. Efficacy will also be 
analyzed using the FAS, mITT Population, mITT On-Treatment Population, and PP Population as 
supportive analyses. 
9.2.1.1 
Primary efficacy analysis 
The primary efficacy endpoint is the percent change from Day 1 to Day 84 in LDL-C. Co-primary 
endpoints include the percent change from Day 1 to Day 84 in LDL-C for the 
obicetrapib 10 mg  ezetimibe 10 mg FDC treatment group compared with each of the following: 
placebo, ezetimibe 10 mg monotherapy, and obicetrapib 10 mg monotherapy, and for the 
obicetrapib 10 mg monotherapy treatment group compared with placebo. The primary endpoint 

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will be analyzed using an analysis of covariance (ANCOVA) model with a fixed effect for the 
treatment group and a covariate of baseline LDL-C. The least squares (LS) mean, standard errors, 
and 2-sided 95% confidence intervals for each treatment group and for the mean difference 
compared to placebo will be obtained. 
Each of the comparisons within the co-primary endpoint family will be conducted at a significance 
level of 0.05. If and only if all 4 testing achieve statistical significance, the study is claimed to 
meet its primary objective and the hypothesis testing will continue to secondary endpoints, 
otherwise all statistical comparisons for secondary endpoints are considered descriptive only. 
The primary estimand will correspond to a treatment policy estimand. The target population will 
comprise participants who are randomized into the study. The primary summary measure to assess 
the treatment effect will be the LS mean difference for the primary endpoint between obicetrapib 
10 mg + ezetimibe 10 mg FDC treatment and placebo, ezetimibe 10 mg monotherapy, and 
obicetrapib 10 mg monotherapy based on the ANCOVA methodology. The primary estimand will 
be addressed using the in-study observation period (ie, including data collected post treatment 
discontinuation or post prohibited medication use).  
Missing data will be imputed for the primary efficacy analysis based on a pattern mixture model 
that uses a multiple imputation technique analyzed with ANCOVA with pre-specified fixed factors 
and covariates. If appropriate, based on the number of retrieved dropouts, missing measurements 
of non-retrieved dropouts will be modeled by known measurements from retrieved dropouts 
(ie, participants who remain in the study after treatment discontinuation) in the same treatment 
group. The imputation model will be further clarified in the SAP.  
Additional sensitivity analyses may be carried out under secondary estimands and/or various 
assumptions for missing data. Full details will be provided in the SAP.  
9.2.1.2 
Secondary efficacy analyses 
In order to control the Type I error rate, a fixed sequential testing procedure will be implemented. 
In a hierarchical step-down manner, the co-primary endpoints will be tested first, followed by the 
secondary efficacy endpoints in the order specified. Continuous secondary efficacy endpoints will 
be analyzed using similar methods as in the primary efficacy analysis. 
9.2.1.3 
Exploratory analyses 
No adjustment for multiple comparisons will be made for the exploratory efficacy endpoints.  
Exploratory efficacy endpoints corresponding to continuous variables will be analyzed using a 
similar ANCOVA model as in the primary efficacy analysis. The 2-sided 95% CI for LS means 
will be provided for continuous variables. Odds ratio and 95% CI for the odds ratio will be 
provided for exploratory efficacy endpoints corresponding to binary variables. Descriptive and 
graphical summaries by treatment group will also be presented.  
Full details of the models and analyses to be performed will be provided in the SAP. 
9.2.2 
Analysis of Safety 
The Safety Population will be the primary population for the safety analyses. All safety endpoints 
will be summarized descriptively. No statistical inference will be applied to the safety endpoints. 

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AEs will be categorized by primary system organ class and preferred term as coded using the 
Medical Dictionary for Regulatory Activities category designations. Summaries of AEs, including 
the number and percentage of participants who experience an AE, will be provided. 
Laboratory values will be summarized descriptively, including the change from baseline, by 
treatment group, and overall. In addition, shift tables will be presented to describe the change in 
laboratory parameter values at post-baseline visits using normal range categories (low, normal, 
and high). 
9.2.3 
Interim Analysis 
No interim analysis is planned for this study. 
9.2.4 
Sample Size Determination 
A sample size of at least 380 evaluable participants (ie, 95 participants per treatment group) will 
provide more than 90% power to detect a 30% difference in LDL-C reduction at Day 84 (SD of 
25%) for the obicetrapib 10 mg  ezetimibe 10 mg FDC treatment group compared with the 
placebo group at a 1-sided significance level of 0.025. 
The sample size for this study was determined in order to provide sufficient power (>90%) for the 
analyses of the co-primary endpoints described above. A sample size of at least 380 evaluable 
participants (ie, 95 participants per treatment group) will provide more than 90% power to detect 
a 20% difference in LDL-C reduction at Day 84 for the obicetrapib 10 mg + ezetimibe 10 mg FDC 
treatment group compared with the ezetimibe 10 mg monotherapy treatment group, and it will 
provide more than 90% power to detect a 12% difference in LDL-C reduction at Day 84 for the 
obicetrapib 10 mg + ezetimibe 10 mg FDC treatment group compared with the obicetrapib 10 mg 
monotherapy treatment group, assuming an SD of 25% at a 1-sided significance level of 0.025. 
In addition, the sample of 95 participants in the obicetrapib 10 mg monotherapy treatment group 
will provide more than 90% power to detect a 15% difference in LDL-C reduction at Day 84 
compared with the placebo treatment group. 
Therefore, assuming an approximately 5% dropout rate, enrollment of approximately 
400 participants (ie, 100 participants per treatment group) is planned for this study. This sample 
size will also contribute sufficient participant exposure and safety data. 
 

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10 
DATA MANAGEMENT AND RECORD KEEPING 
10.1 
Data Management 
10.1.1 
Data Handling 
Data will be recorded at the site on eCRFs and reviewed, per the monitoring plan, 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. 
10.1.2 
Computer Systems 
Data will be processed using a validated computer system conforming to regulatory requirements. 
10.1.3 
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 username and password in order to enter, review, or correct 
study data. These procedures must comply with Title 21 of the Code of Federal Regulations Part 11 
and other appropriate international regulations. All passwords will be strictly confidential. 
10.1.4 
Medical Information Coding 
For medical information, the following thesauri will be used: 
 Medical Dictionary for Regulatory Activities (latest) for medical history and AEs; and  
 WHO Drug Dictionary for prior and concomitant medications. 
10.1.5 
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 site for resolution through data queries. 
The eCRFs must be reviewed and electronically signed by the Investigator. 
10.2 
Record Keeping 
Records of participants, source documents, monitoring visit logs, eCRFs, inventory of study drugs, 
regulatory documents, and other Sponsor correspondence pertaining to the study must be kept in 
the appropriate study files at the site. Source data are defined as all information in original records 
and certified copies of original records of clinical findings, observations, or other activities in a 
clinical study necessary for the evaluation and reconstruction of the clinical study. Source data are 
contained in source documents (original records or certified copies). These records will be retained 
in a secure file for the period as set forth in the Clinical Study Agreement. Prior to transfer or 
destruction of these records, the Sponsor must be notified in writing and be given the opportunity 
to further store such records.  

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10.3 
End of Study 
The end of the study (“study completion”) is defined as the date of the last protocol-specified 
visit/assessment (including telephone contact) for the last participant in the study.  

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11 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL 
11.1 
Ethical Conduct of the Study 
Good Clinical Practice (GCP) is an international ethical and scientific quality standard for 
designing, conducting, recording, and reporting studies that involve human participants. 
Compliance with this standard provides public assurance that the rights, safety, and wellbeing of 
study participants are protected, consistent with the principles that have their origin in the 
Declaration of Helsinki, and that the clinical study data are credible. 
11.2 
Institutional Review Board 
The IRB will review all appropriate study documentation in order to safeguard the rights, safety, 
and well-being of participants. The study will only be conducted at sites where IRB approval has 
been obtained. The protocol, Investigator’s Brochure, ICF, advertisements (if applicable), written 
information given to the participants, safety updates, annual progress reports, and any revisions to 
these documents will be provided to the IRB by the Investigator. 
Federal regulations and International Council for Harmonisation (ICH) Guidelines require that 
approval be obtained from an IRB prior to participation of participants in research studies. Prior 
to study onset, the protocol, any protocol amendments, ICFs, advertisements to be used for 
participant recruitment, and any other written information regarding this study to be provided to a 
participant or participant’s legal guardian must be approved by the IRB. 
No study drugs will be released to the site for dosing until written IRB authorization has been 
received by the Sponsor. 
11.3 
Informed Consent Procedures 
The ICF and any changes to the ICF made during the course of the study must be agreed to by the 
Sponsor or designee and the IRB prior to its use and must be in compliance with all ICH GCP, 
local regulatory requirements, and legal requirements.  
The Investigator must ensure that each study participant is fully informed about the nature and 
objectives of the study and possible risks associated with participation and must ensure that the 
participant has been informed of his/her rights to privacy. The Investigator will obtain written 
informed consent from each participant before any study-related activity is performed and should 
document in the source documentation that consent was obtained prior to enrollment in the study. 
The original signed copy of the ICF must be maintained by the Investigator and is subject to 
inspection by a representative of the Sponsor, their representatives, auditors, the IRB, and/or 
regulatory agencies. A copy of the signed ICF will be given to the participant. 
11.4 
Study Monitoring Requirements 
It is the responsibility of the Investigator to ensure that the study is conducted in accordance with 
the protocol, ICH GCP, applicable regulatory requirements, Declaration of Helsinki, and that valid 
data are entered into the eCRFs. 
To achieve this objective, the CRA’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 participant in this study, the Sponsor or their designee will review 
with the Investigator and site personnel the following documents: protocol, Investigator’s 

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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. Study 
monitoring may include onsite, remote, or a combination of both onsite and remote monitoring. 
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 Sponsor or 
their designee and provide any missing information, whenever possible. 
All monitoring activities will be reported and archived. 
11.5 
Disclosure of Data 
Data generated by this study must be available for inspection by the FDA, the Sponsor or their 
designee, regulatory authorities, and the IRB as appropriate. Participants or their legal 
representatives may request their medical information be given to their personal physician or other 
appropriate medical personnel responsible for their welfare. 
Participant medical information obtained during the study is confidential and disclosure to 
third parties other than those noted above is prohibited. 
11.6 
Retention of Records 
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator 
will keep records, including the identity of all participants (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 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.  
11.7 
Publication Policy 
Following completion of the study, the data may be considered for publication in a scientific 
journal or for reporting at a scientific meeting. Each Investigator is obligated to keep data 
pertaining to the study confidential. The Investigator must consult with the Sponsor before any 
study data are submitted for publication. The Sponsor reserves the right to deny publication rights 
until mutual agreement on the content, format, interpretation of data in the manuscript, and journal 
selected for publication are achieved. 

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11.8 
Financial Disclosure 
Investigators are required to provide financial disclosure information to the Sponsor to permit the 
Sponsor to fulfill its obligations under 21 Code of Federal Regulations Part 54. In addition, 
Investigators must commit to promptly updating this information if any relevant changes occur 
during the study and for a period of 1 year after the completion of the study. 
 

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12 
STUDY ADMINISTRATIVE INFORMATION 
12.1 
Protocol Amendments 
Any amendments to the study protocol will be communicated to the Investigators by 
 or 
the Sponsor. All protocol amendments will undergo the same review and approval process as the 
original protocol. A protocol amendment may be implemented after it has been approved by the 
IRB, unless immediate implementation of the change is necessary for participant safety. In this 
case, the situation must be documented and reported to the IRB within 5 working days. 

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13 
REFERENCES 
 
1. 
World 
Health 
Organization. 
Cardiovascular 
diseases 
(CVDs). 
http://www.who.int/mediacentre/factsheets/fs317/en/. Accessed 30 March 2021. 
 
2. 
Go AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke statistics--2014 update: 
a report from the American Heart Association. Circulation. 2014;129(3):e28-e292. 
 
3. 
Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the 
National Cholesterol Education Program Adult Treatment Panel III guidelines. J Am Coll 
Cardiol. 2004;44(3):720-732. 
4. 
Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering 
treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised 
trials of statins. Lancet. 2005;366(9493):1267-1278. 
5. 
Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA guideline on the primary 
prevention of cardiovascular disease: a report of the American College of 
Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. 
Circulation. 2019;140(11):e596-e646. 
6. 
Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS guidelines for the management of 
dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 
2020;41(1):111-188. 
7. 
Jacobson TA. NLA Task Force on Statin Safety--2014 update. J Clin Lipidol. 
2014;8(3 Suppl):S1-S4. 
8. 
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):139-149. 
9. 
Lansberg P, Lee A, Lee ZV, et al. Nonadherence to statins: individualized intervention 
strategies outside the pill box. Vasc Health Risk Manag. 2018;14:91-102. 
10. 
Cholesterol Treatment Trialists’ (CTT) Collaboration. Baigent C, Blackwell L, 
Emberson J, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a 
meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 
2010;376(9753):1670-1681. 
11. 
Banach M, Rizzo M, Toth PP, et al. Statin intolerance - an attempt at a unified definition. 
Position paper from an International Lipid Expert Panel. Arch Med Sci. 2015;11(1):1-23. 
12. 
Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute 
coronary syndromes. N Engl J Med. 2015;372(25):2387-2397. 
13. 
Ference BA, Kastelein JJP, Ginsberg HN, et al. Association of genetic variants related to 
CETP inhibitors and statins with lipoprotein levels and cardiovascular risk. JAMA. 
2017;318(10):947-956. 
14. 
Tall AR, Rader DJ. Trials and tribulations of CETP inhibitors. Circ Res. 
2018;122(1):106-112. 
15. 
Ference BA, Kastelein JJP, Ray KK, et al. Association of triglyceride-lowering LPL 
variants and LDL-C-lowering LDLR variants with risk of coronary heart disease. JAMA. 
2019;321(4):364-373. 
 

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16. 
American Heart Association Scientific Sessions, 2019. MDP477. The effects of 
anacetrapib therapy on occlusive vascular events during post-trial follow-up of the 
REVEAL randomized trial. 
https://www.ctsu.ox.ac.uk/files/research/reveal_aha_ptfu_slides_2019_11_12.pdf. 
Accessed 22 November 2021. 
17. 
Hovingh GK, Kastelein JJP, van Deventer SJ, et al. Cholesterol ester transfer protein 
inhibition by TA-8995 in patients with mild dyslipidaemia (TULIP): a randomised, 
double-blind, placebo-controlled phase 2 trial. Lancet. 2015;386(9992):452-460. 
18. 
van Capelleveen JC, Kastelein JJP, Zwinderman AH, et al. Effects of the cholesteryl ester 
transfer protein inhibitor, TA-8995, on cholesterol efflux capacity and high-density 
lipoprotein particle subclasses. J Clin Lipidol. 2016;10(5):1137-1144.e3. 
19. 
Pandor A, Ara RM, Tumur I, et al. Ezetimibe monotherapy for cholesterol lowering in 
2,722 people: systematic review and meta-analysis of randomized controlled trials. J Intern 
Med. 2009;265(5):568-580.  
20. 
Morrone D, Weintraub WS, Toth PP, et al. Lipid-altering efficacy of ezetimibe plus statin 
and statin monotherapy and identification of factors associated with treatment response: a 
pooled analysis of over 21,000 subjects from 27 clinical trials. Atherosclerosis. 
2012;223(2):251-261. 
21. 
European Medicines Agency. Guidance on the management of clinical trials during the 
COVID-19 (coronavirus) pandemic. Version 5. 10 February 2022. Accessed 27 June 2022. 
https://health.ec.europa.eu/system/files/2022-
02/guidanceclinicaltrials_covid19_en_1.pdf. 
22. 
Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and 
Research (CBER), Center for Devices and Radiological Health (CDRH), et al. Conduct of 
clinical trials of medical products during the COVID-19 public health emergency. 
Guidance for industry, investigators, and institutional review boards. US Dept of Health 
and Human Services, Food and Drug Administration. 30 August 2021. Accessed 
03 December 2021. https://www.fda.gov/media/136238/download. 
23. 
World Health Organization. Familial hypercholesterolaemia (FH): report of a second 
WHO 
consultation. 
04 
September 
1998. 
http://whqlibdoc.who.int/hq/1999/WHO_HGN_FH_CONS_99.2.pdf. 
Accessed 
21 April 2022.  
24. 
Raal FJ, Kallend D, Ray KK, et al. Inclisiran for the treatment of heterozygous familial 
hypercholesterolemia. N Engl J Med. 2020;382(16):1520-1530. 
25. 
Nicholls SJ, Lincoff AM, Bays HE, et al. Rationale and design of the CLEAR-outcomes 
trial: evaluating the effect of bempedoic acid on cardiovascular events in patients with 
statin intolerance. Am Heart J. 2021;235:104-112.  
26. 
Martin SS, Blaha MJ, Elshazly MB, et al. LDL calculator. Johns Hopkins Medicine. 
https://ldlcalculator.com. Accessed 27 October 2023.  
27. 
Levey AS and Inker LA. CKD-EPI equations for glomerular filtration rate (GFR). 
MDCalc. 
https://www.mdcalc.com/ckd-epi-equations-glomerular-filtration-rate-gfr. 
Accessed 11 November 2022. 
28. 
Friedewald W. LDL calculated. MDCalc. https://www.mdcalc.com/ldl-calculated. 
Accessed 11 November 2022. 

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APPENDIX A: SCHEDULE OF PROCEDURES 
 
Screeninga,b 
Treatment Period 
Safety Follow-Up 
EOTc 
Visit 
1 
2 
3 
4  
5 
Week 
Up to -2 
0 
4 
12 
16 
Day (Visit Window) 
-14 to -1 
1 
28 (7) 
84 (7) 
112 (7) 
 
Informed consentd 
X 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
Xe 
 
 
 
 
Demographic information 
X 
 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
 
Prior/concomitant medications 
X 
X 
X 
X 
X 
X 
Weight and heightf 
X 
 
 
 
 
 
Physical examinationg 
X 
 
 
X 
 
X 
Vital signsh 
X 
X 
X 
X 
X 
X 
12-lead ECGi 
X 
 
 
 
 
 
Urine pregnancy testj 
X 
 
 
X 
 
X 
FSH testk 
X 
 
 
 
 
 
Fasting chemistry and hematologyl 
X 
X 
X 
X 
X 
X 
Coagulation parameters 
X 
 
 
X 
 
X 
Fasting lipid profilem 
X 
X 
X 
X 
 
X 
Fasting Lp(a)n  
 
X 
 
X 
 
X 
Urine sample for UACR 
X 
X 
X 
X 
X 
X 
Pharmacokineticso 
 
X 
X 
X 
 
X 
Serum archive samplep 
 
X 
 
Xq 
 
X 
Randomization 
 
X 
 
 
 
 
Dispense study drugsr 
 
X 
X 
 
 
 
Study drug administrations 
 
-----------------------------X--------------------------- 
 
 
Study drug compliance  
 
 
X 
Xq 
 
X 
Register visit in IRT 
X 
X 
X 
X 
 
X 
Adverse events 
 
X 
X 
X 
X 
X 
Note: When several assessments are required at the same visit, samples for clinical laboratory assessments should be collected after completing other assessments, such as physical 
examinations, vital signs, and 12-lead ECGs. 
Note: In cases of COVID-19 limitations, it is the Investigator’s responsibility to assure the safety of participants. If necessary, the Sponsor will implement and document mitigation 
strategies as described in Section 3.1.4. In the absence of a COVID-19 impact, it is expected that Investigators and participants follow the protocol requirements as set forth. 
Note: For the purposes of this study, fasting will be defined as nothing by mouth except water and any essential medications for a minimum of 8 hours.  
Note: Unscheduled visits may be scheduled as needed per the judgment of the Investigator. Procedures will be determined based on the reason for the visit.  

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a. 
If laboratory abnormalities during the Screening Period are considered by the Investigator to be transient, then the laboratory tests may be repeated once during the 
Screening Period. The Investigator’s rationale for retesting should be documented. If the retest result is no longer exclusionary, the participant may be randomized. 
b. 
A participant who is screened and does not meet the study eligibility criteria may be considered for rescreening upon Sponsor and/or Medical Monitor consultation and approval. 
Rescreened participants will be assigned a new participant number. Rescreening should occur no less than 5 days after the last screening visit. 
c. 
Participants who discontinue study drug between Visit 2 (Day 1) and Visit 3 (Day 28) or at Visit 3 (Day 28) should complete an EOT Visit at Day 28, return to complete Visit 4 
(Day 84), and return to complete the Safety Follow-up Visit (Day 112). In addition, participants who withdraw from the study should complete an EOT Visit. Participants who 
discontinue study drug between Visit 3 (Day 28) and Visit 4 (Day 84) will not undergo an EOT Visit but continue with study visits per protocol.  
d. 
Participants will be required to sign an ICF before any study-related procedures are performed. 
e. 
Confirm the participant continues to meet the inclusion and exclusion criteria and assess any updates since Screening (Visit 1). 
f. 
Weight and height will be measured at Screening (Visit 1) and will be used to calculate body mass index. Measurement of weight should be performed with the participant 
dressed in indoor clothing, with shoes removed. 
g. 
The physical examination should comprise a focused examination, which includes general, respiratory, CV, abdominal, and extremities evaluations. 
h. 
Vital signs will include body temperature, heart rate, and triplicate blood pressure (systolic and diastolic) measurements. Participants should be in the supine position after at 
least 10 minutes rest prior to the vital sign measurements. 
i. 
A single 12-lead ECG will be performed in the supine position after 10 minutes of rest. ECGs are to be assessed for clinical significance by a qualified medical designee at the 
study site. 
j. 
For women of childbearing potential only. 
k. 
FSH test will be performed in women <55 years of age for whom it has been 1 year since their last menstrual period. 
l. 
At Screening (Visit 1), Visit 4 (Day 84), and EOT, chemistry panel will include HbA1c. 
m. LDL-C, HDL-C, and VLDL-C will also be evaluated by NMR analysis for particle numbers and size. LDL-C level will be calculated using the Martin-Hopkins and Friedewald 
equations unless TG 400 mg/dL (4.5 mmol/L) or LDL-C 50 mg/dL (1.3 mmol/L); in both cases, LDL-C level will be measured directly by preparative ultracentrifugation, 
also referred to as beta quantification. Additionally, LDL-C will be measured by preparative ultracentrifugation at Visit 2 (Day 1), Visit 4 (Day 84), and EOT for all participants 
(Sources: Martin SS, Blaha MJ, Elshazly MB, et al. LDL calculator. Johns Hopkins Medicine. https://ldlcalculator.com. Accessed 27 October 2023; Friedewald W. LDL 
calculated. MDCalc. https://www.mdcalc.com/ldl-calculated. Accessed 11 November 2022).  
n. 
Samples should be collected prior to study drug administration. 
o. 
A PK sample will be collected prior to study drug administration for trough measurements of obicetrapib and ezetimibe in plasma. 
p. 
Serum archive samples will be collected prior to the first dose at Visit 2 (Day 1) and at Visit 4 (Day 84) (or at an EOT Visit, in cases of early discontinuation) for potential 
future assessment of conditions associated with cholesterol metabolism. Samples should be collected prior to study drug administration and while the participant is fasting (a 
minimum of 8 hours). If the samples are analyzed, it will be for non-genetic tests. 
q. 
This assessment does not need to be repeated if the participant discontinued study drug early and has already undergone an EOT Visit. 
r. 
At Visit 2 (Day 1), participants will receive 1 kit (containing 36 FDC tablets or matching placebo tablets, 36 obicetrapib tablets or matching placebo tablets, and 36 ezetimibe 
capsules or matching placebo capsules totaling 108 tablets/capsules per kit) with the study drugs appropriate for the participant’s treatment group. At Visit 3 (Day 28), 
participants will receive 2 kits as described above. The 2 kits provide sufficient supplies for 56 days of dosing, with enough for an extra 16 days of dosing in case the participant 
needs to postpone Visit 4 (Day 84). Each individual kit will provide a sufficient supply for 28 days of dosing, with enough for an extra 8 days of dosing. Participants will be 
instructed to take 3 units from the kit each day. The kit will be clearly labelled to indicate which tablets and capsule to use on each day. Participants will be instructed to bring 
all unused study drugs to the site at the next visit. 
s. 
Study drugs (2 tablets and 1 capsule) will be administered by the participant orally with water, with or without food, once daily on Day 1 to Day 84 at approximately the same 
time each morning. On days with visits scheduled, participants should not take the study drugs prior to the visit but should bring the study drugs with them to the site. The study 
drugs will be administered with water following all fasted blood samples. At Visits 3 and 4, participants will dose from the kit received at the previous visit (Visits 2 and 3, 
respectively). If a participant permanently discontinues study drug, he/she will continue to participate in study visits, as described in Section 4.5, but will no longer administer 
study drug.  
COVID-19 = Coronavirus Disease 2019; CV = cardiovascular; ECG = electrocardiogram; EOT = End of Treatment; FDC = fixed dose combination; FSH = follicle-stimulating 
hormone; HbA1c = glycosylated hemoglobin; HDL-C = high-density lipoprotein cholesterol; ICF = informed consent form; IRT = interactive response technology; 
LDL-C = low-density lipoprotein cholesterol; Lp(a) = lipoprotein (a); NMR = nuclear magnetic resonance; PK = pharmacokinetic(s); TG = triglyceride(s); UACR = urine 
albumin-creatinine ratio; VLDL-C = very low-density lipoprotein cholesterol. 

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APPENDIX B: CLINICAL LABORATORY ANALYTES 
Standard Safety Chemistry Panel 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Amylase 
Aspartate aminotransferase 
Bicarbonate 
Bilirubin (total, direct, and indirect) 
Blood urea nitrogen 
Calcium 
Chloride 
Creatine kinase 
Creatinine 
Estimated glomerular filtration rate [1] 
Gamma-glutamyl transferase 
Glucose (fasting) 
Glycosylated hemoglobin [2] 
High-sensitivity C-reactive protein 
Inorganic phosphorus 
Lactate dehydrogenase 
Lipase 
Potassium 
Sodium 
Total protein 
Uric acid 
1. 
Calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. (Source: Levey AS and Inker LA. 
CKD-EPI equations for glomerular filtration rate (GFR). MDCalc. https://www.mdcalc.com/ckd-epi-equations-
glomerular-filtration-rate-gfr. Accessed 11 November 2022). 
2. 
Screening (Visit 1), Visit 4 (Day 84), and EOT only. 
 
Coagulation Parameters 
International normalized ratio 
Prothrombin time  
 
Endocrinology 
Follicle-stimulating hormone [1] 
Urine pregnancy test [2] 
1. 
Follicle-stimulating hormone test will be performed in women <55 years of age for whom it has been 1 year since their 
last menstrual period. 
2. 
For women of childbearing potential only. 
 
Hematology 
Hematocrit 
Hemoglobin 
Platelets 
Red blood cell count 
White blood cell count and differential [1] 
 
1. 
Manual microscopic review is performed only if white blood cell count and/or differential values are out of reference 
range. 

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Lipid Profile 
Apolipoprotein B 
High-density lipoprotein cholesterol 
Low-density lipoprotein cholesterol [1] 
Non-high-density lipoprotein cholesterol 
Small dense low-density lipoprotein 
cholesterol 
Triglycerides 
Very low-density lipoprotein cholesterol 
 
1. 
LDL-C level will be calculated using the Martin-Hopkins and Friedewald equations unless TG 400 mg/dL 
(4.5 mmol/L) or LDL-C 50 mg/dL (1.3 mmol/L); in both cases, LDL-C level will be measured directly by 
preparative ultracentrifugation, also referred to as beta quantification. Additionally, LDL-C will be measured by 
preparative ultracentrifugation at Visit 2 (Day 1), Visit 4 (Day 84), and EOT for all participants (Sources: Martin SS, 
Blaha MJ, Elshazly MB, et al. LDL calculator. Johns Hopkins Medicine. https://ldlcalculator.com. Accessed 
27 October 2023; Friedewald W. LDL calculated. MDCalc. https://www.mdcalc.com/ldl-calculated. Accessed 
11 November 2022). 
 
Other Laboratory Analytes 
Lipoprotein (a) 
Urine albumin-creatinine ratio 

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APPENDIX C: DIAGNOSTIC SCORING TABLE FOR FAMILIAL 
HYPERCHOLESTEROLEMIA (CONSTRUCTED BY THE DUTCH LIPID 
CLINIC NETWORK) 
Criteria  
Score 
Family history  
a) First-degree relative known with premature (men <55 years, women <60 years) coronary 
and vascular disease; OR 
b) First-degree relative known with LDL-C >95th percentile; AND/OR 
1 
c) First-degree relative with tendon xanthomata and/or arcus cornealis; OR 
d) Children <18 years with LDL-C >95th percentile. 
2 
Clinical history 
a) Patient has premature (men <55 years, women <60 years) coronary artery disease 
2 
b) Patient has premature (men <55 years, women <60 years) cerebral or peripheral vascular 
disease 
1 
Physical examination  
a) Tendon xanthomata 
6 
b) Arcus cornealis below the age of 45 years 
4 
Laboratory analysis1 
a) LDL-C >330 mg/dL (>8.5 mmol/L) 
8 
b) LDL-C 250 to 329 mg/dL (6.5 to 8.5 mmol/L) 
5 
c) LDL-C 190 to 249 mg/dL (4.9 to 6.4 mmol/L) 
3 
d) LDL-C 155 to 189 mg/dL (4.0 to 4.9 mmol/L) 
1 
DNA analysis 
a) Presence of functional LDL-R mutation (in the LDL-R, ApoB, or PCSK9 gene) 
8 
Diagnosis of familial hypercholesterolemia is: 
Certain when 
>8 points 
Probable when 
6 to 8 points 
Possible when 
3 to 5 points  
1. 
High-density lipoprotein cholesterol and triglycerides are normal. 
ApoB = apolipoprotein B; DNA = deoxyribonucleic acid; LDL-C = low-density lipoprotein cholesterol; LDL-R = low-density 
lipoprotein receptor; PCSK9 = proprotein convertase subtilisin/kexin type 9. 
Sources:  
World Health Organization. Familial hypercholesterolaemia (FH): report of a second WHO consultation. 04 September 1998. 
http://whqlibdoc.who.int/hq/1999/WHO_HGN_FH_CONS_99.2.pdf. Accessed 11 November 2022 
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. Erratum in: Eur Heart J. 2020;41(47):4517 
McGowan MP, Hosseini Dehkordi SH, Moriarty PM, et al. Diagnosis and treatment of heterozygous familial 
hypercholesterolemia. J Am Heart Assoc. 2019;8(24):e013225 
 

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APPENDIX D: SIMON BROOME REGISTER DIAGNOSTIC CRITERIA 
FOR FAMILIAL HYPERCHOLESTEROLEMIA 
Definite Familial Hypercholesterolemia: 
Required laboratory = high cholesterol levels: 
 Adult = Total cholesterol (TC) levels >290 mg/dL (>7.5 mmol/L) or low-density lipoprotein 
(LDL) cholesterol (LDL-C) >190 mg/dL (>4.9 mmol/L). 
Note: Qualifying TC and LDL-C values for the Simon Broome Register Diagnostic Criteria 
for Familial Hypercholesterolemia may be fulfilled by historical values. 
Plus at least 1 of the 2: 
 Physical finding = tendon xanthomas, or tendon xanthomas in first- or second-degree relative; 
OR 
 DNA-based evidence of an LDL-receptor mutation, familial defective apolipoprotein B-100, 
or a proprotein convertase subtilisin/kexin type 9 mutation. 
Possible Familial Hypercholesterolemia: 
Laboratory = high cholesterol levels: 
 Adult = TC levels >290 mg/dL (>7.5 mmol/L) or LDL-C >190 mg/dL (>4.9 mmol/L). 
Note: Qualifying TC and LDL-C values for the Simon Broome Register Diagnostic Criteria 
for Familial Hypercholesterolemia may be fulfilled by historical values. 
Plus at least 1 of the 2: 
 Family history of at least 1 of the following: 
o Family history of myocardial infarction at: 
 Age 60 years or younger in first-degree relative; or 
 Age 50 years or younger in second-degree relative. 
OR 
 Family history of elevated TC: 
o >290 mg/dL (>7.5 mmol/L) in adult first- or second-degree relative; or 
o >260 mg/dL (>6.7 mmol/L) in child, brother, or sister aged younger than 16 years. 
 
Source: Raal FJ, Kallend D, Ray KK, et al. Inclisiran for the treatment of heterozygous familial hypercholesterolemia. N Engl J 
Med. 2020;382(16):1520-1530.