A Placebo-Controlled, Double-Blind, Randomized Phase 3 Study to Evaluate the Effect of 10mg Obicetrapib in Participants With HeFH and/or ASCVD Who Are Not Adequately Controlled by Their Lipid Modifying Therapies
Phase: PHASE3
Conditions: Dyslipidemias, High Cholesterol, Hypercholesterolemia, Familial Hypercholesterolemia, Atherosclerotic Cardiovascular Disease
Sponsor: NewAmsterdam Pharma

 
 
 
CLINICAL STUDY PROTOCOL 
 
Obicetrapib on Top of Maximum Tolerated Lipid-Modifying 
Therapies (BROADWAY): A Placebo-Controlled, Double-Blind, 
Randomized Phase 3 Study to Evaluate the Effect of 10 mg 
Obicetrapib in Participants With Underlying HeFH and/or 
Atherosclerotic Cardiovascular Disease (ASCVD) Who are Not 
Adequately Controlled by Their Lipid-Modifying Therapies 
Investigational Product: Obicetrapib 
Protocol Number: TA-8995-302 
EudraCT Number: 2021-005065-40 
 
 
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: 6.0 
Original Protocol: 29 November 2021  
Amendment 1: 20 December 2021 
Amendment 2: 11 January 2022 
Amendment 3: 15 July 2022 
Amendment 4: 19 August 2022 
Amendment 5: 22 December 2022 
 
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 or Independent Ethics Committee 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.
NCT number: NCT05142722
This NCT number has been applied to the document for the purposes of posting on clinicaltrials.gov

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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 product 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 full accordance with Ethics Committee Regulations and 
International Council for Harmonisation Guidelines for Good Clinical Practices. 
 
 
 
 
 
 
______________________________________________  
____________________ 
Investigator’s Signature 
 
 
 
 
 
Date 
 
 
 
______________________________________________ 
Investigator’s Printed Name 
 

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SYNOPSIS 
TITLE: 
Obicetrapib 
on 
Top 
of 
Maximum 
Tolerated 
Lipid-Modifying 
Therapies 
(BROADWAY): A Placebo-Controlled, Double-Blind, Randomized Phase 3 Study to Evaluate 
the Effect of 10 mg Obicetrapib in Participants With Underlying HeFH and/or Atherosclerotic 
Cardiovascular Disease (ASCVD) Who are Not Adequately Controlled by Their Lipid-Modifying 
Therapies 
PROTOCOL NUMBER: TA-8995-302 
INVESTIGATIONAL PRODUCT: Obicetrapib 
PHASE: 3 
INDICATION: As an adjunct to diet and maximally tolerated lipid-modifying therapy for the 
treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or a history of 
atherosclerotic cardiovascular (CV) disease (ASCVD) 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 on LDL-C levels at 
Day 84. 
The secondary objectives of this study include the following: 

To evaluate the effect of obicetrapib on LDL-C levels at Days 180 and 365;

To evaluate the effect of obicetrapib on apolipoprotein B (ApoB), non-high-density lipoprotein
cholesterol (non-HDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol
(TC), and triglycerides (TG) at Days 84, 180, and 365;

To evaluate the effect of obicetrapib on lipoprotein (a) (Lp[a]) and apolipoprotein A1 (ApoA1)
at Day 84; and

To evaluate the safety and tolerability profile of obicetrapib in a representative population of
adult males and females with HeFH and/or ASCVD of all ages, assessed by adverse events
(AEs), events of special interest (ESIs), vital signs (including blood pressure),
electrocardiogram (ECG) measurements, and clinical laboratory values.
The exploratory objectives of this study include the following:  

To evaluate the effect of obicetrapib on the following:
o
Proportion of participants achieving prespecified LDL-C levels at Days 84, 180, and 365;
and
o
Biomarkers, including glycosylated hemoglobin (HbA1c), homeostatic model assessment
of insulin resistance (HOMA-IR), and blood glucose at Day 365.

To evaluate trough levels of obicetrapib from Baseline to Day 365 in the obicetrapib group;

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 To evaluate the effect of obicetrapib on CV death, non-fatal myocardial infarction (MI), 
non-fatal stroke, or non-elective coronary revascularization; and 
 To evaluate the effect of obicetrapib on hospitalization for unstable angina and/or chest pain, 
hospitalization for heart failure (HF), and transient ischemic attack (TIA). 
POPULATION: 
The population for this study will comprise participants with underlying HeFH and/or a history of 
ASCVD who are not adequately controlled by their maximally tolerated lipid-modifying therapy. 
At least 70% of the participants enrolled into this study must be taking high-intensity statins (HIS). 
HIS include atorvastatin 40 and 80 mg and rosuvastatin 20 and 40 mg. Participants with underlying 
HeFH but without a history of ASCVD will comprise up to a maximum of 20% of the total 
participants enrolled into the study. The study aims to enroll adult males and females 18 years of 
age. 
STUDY DESIGN AND DURATION: 
This study will be a multisite, placebo-controlled, double-blind, randomized Phase 3 study in 
approximately 2400 participants with underlying HeFH and/or a history of ASCVD who are not 
adequately controlled by their lipid-modifying therapy to evaluate the efficacy, safety, and 
tolerability of obicetrapib. Informed consent will be obtained from participants before the 
initiation of any study-specific procedures. 
Approximately 2400 eligible participants will be randomized in a 2:1 ratio, respectively, to the 
following treatment groups: 
 Obicetrapib group: One 10 mg obicetrapib tablet once daily; or 
 Placebo group: 1 placebo tablet once daily. 
Treatment allocation will be stratified based on CV risk (HeFH or non-HeFH) and Baseline statin 
dose (HIS or non-HIS). At least 70% of the participants enrolled into this study must be taking 
HIS. Participants with underlying HeFH but without a history of ASCVD will comprise up to a 
maximum of 20% of the total participants enrolled into the study. Starting on Day 1, each 
participant will self-administer their assigned study drug once daily until Day 365. During the 
Treatment Period, participants will return to the study site for efficacy and safety assessments. 
Blood samples for pharmacokinetic (PK) assessment will be collected at specified visits 
throughout the study. An onsite End of Study Visit will be conducted 35 days after the participant’s 
last dose of study drug, during which an assessment of vital signs, concomitant medications, CV 
events, and AEs will be completed and documented in the participant’s record. 
A subset of approximately 200 participants from selected study sites who consent to participate 
will be enrolled in an ambulatory blood pressure monitoring (ABPM) substudy. These participants 
will have a 24-hour ABPM assessment conducted at Screening (Visit 1) and Visit 6 (Day 270). In 
order to participate in the substudy, participants must provide written informed consent in a 
substudy-specific informed consent form (ICF) and must be able to provide an acceptable 24-hour 
ABPM data collection at Screening (Visit 1). Additional details surrounding this substudy, 
including the definition of an acceptable 24-hour ABPM data collection, are included in a separate 
study manual. 

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The study will be governed by a Steering Committee. A Data and Safety Monitoring Board will 
provide independent oversight of participant safety. An independent Clinical Events Committee 
(CEC) will adjudicate all events of death and all potential or suspected CV events. 
The responsibilities, procedures, and workflow for these committees will be defined in separate 
charters outside of the protocol. 
INCLUSION AND EXCLUSION CRITERIA: 
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 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 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 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; 
Diagnosis of HeFH: 
Diagnosis must be made by either prior historical genotyping or by clinical assessment using 
either the World Health Organization Criteria/Dutch Lipid Clinic Network Criteria with a 
score that is 3 points or the Simon Broome Register Diagnostic Criteria with an assessment 

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of “Possible HeFH” or “Definite HeFH.” LDL-C values are required to assess the Dutch Lipid 
Clinic Network Criteria and/or Simon Broome Register Diagnostic Criteria. In some cases, 
historical lipid values may not be obtainable, as participants may have initiated 
lipid-modifying therapies years prior. In these instances, the Investigator will need to estimate 
an “off-treatment” LDL-C value to calculate whether the participant qualifies for the study. 
For this purpose, the Protocol contains correction factors for a variety of statins and/or 
ezetimibe. The current LDL-C value obtained most recently and/or through the screening 
process can be converted using the appropriate correction factor. This value will be used to 
assess whether the participant meets either the Dutch Lipid Clinic Network Criteria or the 
Simon Broome Register Diagnostic Criteria. Participants with a diagnosis of HeFH may or 
may not have a history of ASCVD or ASCVD-risk equivalents; 
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); 
 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; or 
 Coronary calcium score >100 Agatston units within 6 months prior to Screening 
(Visit 1).  
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: 
 Prior documentation of a resting ankle-brachial index 0.85;  
 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. 
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 

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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 was 
statin intolerant, aware of the benefit of statins to reduce the risk of a major adverse 
CV event, 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. 
o Ezetimibe for at least 8 weeks with or without maximally tolerated statin prior to Screening 
(Visit 1); 
o Bempedoic acid for at least 8 weeks in combination with a maximally tolerated statin prior 
to Screening (Visit 1); and/or 
o A proprotein convertase subtilisin/kexin type 9-targeted therapy alone or in combination 
with other lipid-modifying therapy for at least 4 stable doses prior to Screening (Visit 1). 
Note: At least 70% of the participants enrolled into this study must be taking HIS. 
Documentation in the electronic case report form (eCRF) of the reason why a participant is 
unable to take HIS is required. HIS include the following: atorvastatin 40 and 80 mg and 
rosuvastatin 20 and 40 mg. 
5. Have a fasting serum LDL-C at Screening (Visit 1) as follows: 
o Have a fasting serum LDL-C 55 mg/dL (1.4 mmol/L) to <100 mg/dL (<2.6 mmol/L) 
OR non-HDL-C 85 mg/dL (2.2 mmol/L) to <130 mg/dL (<3.4 mmol/L) with at least 
1 of the following risk enhancers: 
 Recent MI (>3 and <12 months prior to Randomization [Visit 2]); 
 Type 2 diabetes mellitus; 
 Current daily cigarette smoking; 
 Age of >60 years; 
 High sensitivity C-reactive protein 2.0 mg/L (19.0 nmol/L) at Screening (Visit 1) or 
within 6 months prior to Screening (Visit 1); 
 Fasting TG >150 mg/dL (>1.7 mmol/L); 
 Fasting Lp(a) >30 mg/dL (>70 nmol/L); and/or 
 Fasting HDL-C <40 mg/dL (<1.0 mmol/L). 
OR 

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o Have a fasting serum LDL-C 100 mg/dL (2.6 mmol/L) OR non-HDL-C 130 mg/dL 
(3.4 mmol/L). 
Note: LDL-C at Screening (Visit 1) will be calculated using the Friedewald equation unless 
TG 400 mg/dL (4.5 mmol/L) or LDL-C 50 mg/dL (1.3 mmol/L). If TG 400 mg/dL 
(4.5 mmol/L) or LDL-C 50 mg/dL (1.3 mmol/L), then LDL-C level will be measured 
directly by preparative ultracentrifugation, also referred to as beta quantification. 
6. Have fasting TG <500 mg/dL (<5.7 mmol/L) at Screening (Visit 1); and 
7. Have an estimated glomerular filtration rate 30 mL/min/1.73 m2 calculated using the Chronic 
Kidney Disease Epidemiology Collaboration equation at Screening (Visit 1). 
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 HF or left 
ventricular ejection fraction <30%; 
2. Have been hospitalized for HF 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 prior to Randomization (Visit 2) 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 familial hypercholesterolemia; 
6. Have active liver disease, defined as any known current infectious, neoplastic, or metabolic 
pathology of the liver; 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 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 >3  ULN at Screening (Visit 1); 

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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); 
11. Have a known history of alcohol and/or drug abuse within 5 years prior to Randomization 
(Visit 2); 
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 Coronavirus Disease 2019 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); 
14. Have planned use of other investigational products or devices during the course of the study;  
15. Have participated in any clinical study evaluating obicetrapib; 
16. Have a known allergy or hypersensitivity to the study drug, placebo, or any of the excipients 
in the study drug or placebo; or 
17. 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. 
DOSAGE FORMS AND ROUTE OF ADMINISTRATION: 
The study drugs used in this study are as follows: 
 10 mg obicetrapib tablet; or 
 Placebo tablet. 
All study drugs will be administered by the participant orally, once daily at approximately the 
same time, from Visit 2 (Day 1) to the End of Treatment Visit (Day 365). Study drug should be 
administered with water and can be taken with or without food. 

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EFFICACY ENDPOINTS:  
The primary efficacy endpoint is the percent change from Baseline to Day 84 in LDL-C in the 
obicetrapib group compared to the placebo group. 
The secondary efficacy endpoints include the following: 
 Percent change from Baseline to Days 180 and 365 in LDL-C in the obicetrapib group 
compared to the placebo group; 
 Percent change from Baseline to Days 84, 180, and 365 in ApoB in the obicetrapib group 
compared to the placebo group; 
 Percent change from Baseline to Days 84, 180, and 365 in non-HDL-C in the obicetrapib group 
compared to the placebo group; 
 Percent change from Baseline to Days 84, 180, and 365 in HDL-C in the obicetrapib group 
compared to the placebo group; 
 Percent change from Baseline to Day 84 in Lp(a) and ApoA1 in the obicetrapib group 
compared to the placebo group; 
 Percent change from Baseline to Days 84, 180, and 365 in TC in the obicetrapib group 
compared to the placebo group; and 
 Percent change from Baseline to Days 84, 180, and 365 in TG in the obicetrapib group 
compared to the placebo group. 
The exploratory efficacy endpoints include the following: 
 Proportion of participants at Days 84, 180, and 365 who achieve LDL-C <70 mg/dL 
(<1.8 mmol/L) in the obicetrapib group compared to the placebo group; 
 Proportion of participants at Days 84, 180, and 365 who achieve LDL-C <55 mg/dL 
(<1.4 mmol/L) in the obicetrapib group compared to the placebo group; 
 Proportion of participants at Days 84, 180, and 365 who achieve LDL-C <40 mg/dL 
(<1.0 mmol/L) in the obicetrapib group compared to the placebo group; 
 Percent change from Baseline to Day 365 in HbA1c in the obicetrapib group compared to the 
placebo group; 
 Percent change from Baseline to Day 365 in HOMA-IR in the obicetrapib group compared to 
the placebo group;  
 Percent change from Baseline to Day 365 in blood glucose in the obicetrapib group compared 
to the placebo group; 
 Trough levels of obicetrapib from Baseline to Day 365 in the obicetrapib group; 
 The time from Randomization until the first confirmed occurrence of a composite of CV death, 
non-fatal MI, non-fatal stroke, or non-elective coronary revascularization;  

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 The time from Randomization until the first confirmed occurrence of a composite of CV death, 
non-fatal MI, or non-fatal stroke; and 
 The time from Randomization until the first confirmed occurrence of hospitalization for 
unstable angina and/or chest pain, hospitalization for HF, and TIA. 
SAFETY ENDPOINTS: 
The safety endpoints include the following: 
 Safety and tolerability profile of obicetrapib assessed by AEs, ESIs, vital signs (including 
blood pressure as assessed by office blood pressure measurements), ECGs, and clinical 
laboratory values; and 
 Assessment of ABPM measured at Screening (Visit 1) and at Day 270 (Visit 6). 
All potential or suspected CV events will be reviewed and adjudicated by an independent CEC 
and reported in the appropriate clinical endpoint eCRF. In addition, these events are subject to 
normal AE/serious AE reporting procedures.  
CLINICAL EVENTS COMMITTEE: 
An independent CEC will adjudicate all events of death and all potential or suspected CV events. 
A committee charter will be drafted to define the composition, roles, and responsibilities of the 
CEC. 
 
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 final 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, mean, standard deviation, median, minimum, and maximum 
values. Analyses 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 study drug. 
Analysis populations 
The Intent-to-Treat (ITT) Population will include all participants who are 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.  

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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. 
Efficacy analysis 
The ITT Population will be the primary population for the efficacy analysis. Efficacy will also be 
analyzed using the FAS, mITT Population, and PP Population as supplementary analyses. 
The primary efficacy endpoint is the percent change from Baseline to Day 84 in LDL-C in the 
obicetrapib group compared to the placebo group. The primary endpoint will be analyzed using 
an analysis of covariance (ANCOVA) model with a fixed effect for the treatment group and 
covariates of Baseline LDL-C, CV risk (HeFH or non-HeFH), and Baseline statin therapy (HIS or 
non-HIS). 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. The model 
will be fit assuming unequal variances for each treatment group. 
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 
and placebo 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 primary endpoint will be tested first, followed by the 
secondary efficacy endpoints in a pre-specified order. The pre-specified order of the hypothesis 
testing for the secondary endpoints will be described in the SAP. No adjustment for multiple 
comparisons will be made for the exploratory efficacy endpoints.  
Continuous secondary efficacy endpoints will be analyzed using similar methods as in the primary 
efficacy analysis. 
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% confidence interval 
for LS means will be provided for continuous variables. Odds ratio and 95% confidence interval 
for the odds ratio will be provided for exploratory efficacy endpoints corresponding to binary 
variables. For time-to-event endpoints, the log-rank test, stratified by CV risk (HeFH or 

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non-HeFH) and Baseline statin therapy (HIS or non-HIS), will be used to compare differences in 
the time-to-event between obicetrapib and placebo. The hazard ratio and the associated 
95% confidence interval will be estimated using a stratified Cox proportional hazards model with 
treatment as an explanatory variable, stratified by CV risk (HeFH or non-HeFH) and Baseline 
statin therapy (HIS or non-HIS). Additionally, Kaplan-Meier estimates of the time-to-event will 
be determined and displayed graphically. The proportional hazard assumption will be evaluated, 
such as through the examination of complementary log-log (event times) versus log (time) plots, 
etc. If the proportional hazard assumption raises concerns, additional analyses will be considered 
and will be further detailed in the SAP. Nominal p-values will be provided when applicable. 
Descriptive and graphical summaries by treatment group will also be presented. A population PK 
analysis will be described in a separate document.  
Full details of the models and analyses to be performed will be provided in the SAP. 
Safety analysis 
The Safety Population will be the primary population for the safety analysis. All safety endpoints 
will be summarized descriptively. 
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). 
SAMPLE SIZE DETERMINATION: 
Enrollment of approximately 2400 participants globally is planned for this study. 
Assuming an approximate 5% drop out rate, approximately 2280 participants will be evaluable for 
efficacy. This sample size of at least 2280 evaluable participants will provide more than 
90% power to detect a 30% reduction of LDL-C (standard deviation 15%) levels in the obicetrapib 
group compared to the placebo group at a 1-sided significance level of 0.025. This sample size 
will also contribute to sufficient participant exposure and safety data. 
ABPM substudy 
This substudy is designed for a non-inferiority assessment in systolic blood pressure from 
Screening (Visit 1) to Day 270 (Visit 6) between obicetrapib and placebo. The non-inferiority 
margin was selected in accordance with the United States Food and Drug Administration 
guidelines (Assessment of Pressor Effects of Drugs, Guidance for Industry). The non-inferiority 
margin was chosen to assess if obicetrapib is not substantially inferior to placebo for elevations in 
systolic blood pressure. The assumption for the common standard deviation is determined by a 
literature review and the obicetrapib Phase 2 program. From the reference paper by Vollmer et al, 
the estimate of the standard deviation for the change in systolic blood pressure (mmHg) for 

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hypertensive participants based on 24-hour ABPM measurements was 8.0 (95% confidence 
interval: 6.9, 9.4).1 
A subset of approximately 200 participants from selected study sites who consent to participate 
will be enrolled in the ABPM substudy. For inclusion in the substudy analysis, participants must 
have an acceptable 24-hour ABPM data collection at Screening (Visit 1), as defined in a separate 
study manual. This sample size will allow for non-inferiority to be established between the 
obicetrapib group compared to the placebo group, with desired power of >80%, against a 
non-inferiority difference of 3 mmHg. This assumes a mean treatment difference of 0 mmHg for 
the obicetrapib group compared to the placebo group, with a standard deviation of 8 mmHg, at a 
1-sided significance level of 0.05. 
SITES: Approximately 180 study sites globally 
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 
 
1 Vollmer WM, Appel LJ, Svetkey LP, et al. Comparing office-based and ambulatory blood pressure monitoring in 
clinical trials. J Hum Hypertens. 2005;19(1):77-82. 

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TABLE OF CONTENTS 
Signature Page ................................................................................................................................ 2 
Investigator Agreement ................................................................................................................... 3 
Synopsis .......................................................................................................................................... 4 
Table of Contents .......................................................................................................................... 16 
List of Abbreviations and Definition of Terms............................................................................. 21 
1  Introduction and Background Information ............................................................................. 23 
1.1 
Background Information on the Disease to be Treated ................................................. 23 
1.2 
Background Information on Cholesteryl Ester Transfer Protein Inhibition .................. 24 
1.3 
Obicetrapib (TA-8995) .................................................................................................. 24 
1.4 
Clinical Development of Obicetrapib ........................................................................... 24 
1.4.1  Dose Selection Rationale .................................................................................. 25 
1.5 
Rationale ........................................................................................................................ 25 
1.6 
Risk/Benefit ................................................................................................................... 26 
1.6.1  Coronavirus Disease 2019 Impacts ................................................................... 26 
2  Study Objectives ..................................................................................................................... 28 
2.1 
Primary Objective ......................................................................................................... 28 
2.2 
Secondary Objectives .................................................................................................... 28 
2.3 
Exploratory Objectives .................................................................................................. 28 
3  Study Description.................................................................................................................... 29 
3.1 
Summary of Study Design ............................................................................................ 29 
3.1.1  COVID-19 Contingency Measures ................................................................... 29 
3.2 
Study Indication ............................................................................................................ 30 
4  Selection and Withdrawal of Participants ............................................................................... 31 
4.1 
Inclusion Criteria ........................................................................................................... 31 
4.2 
Exclusion Criteria .......................................................................................................... 34 
4.3 
Withdrawal Criteria ....................................................................................................... 35 
4.4 
Retesting ........................................................................................................................ 37 
4.5 
Rescreening ................................................................................................................... 37 
5  Study Treatments .................................................................................................................... 38 
5.1 
Treatment Groups .......................................................................................................... 38 

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5.2 
Rationale for Dosing ..................................................................................................... 38 
5.3 
Randomization and Blinding ......................................................................................... 38 
5.4 
Breaking the Blind ........................................................................................................ 38 
5.5 
Drug Supplies ................................................................................................................ 39 
5.5.1  Formulation and Packaging ............................................................................... 39 
5.5.2  Study Drug Preparation and Dispensing ........................................................... 39 
5.5.3  Study Drug Administration ............................................................................... 39 
5.5.4  Treatment Compliance ...................................................................................... 40 
5.5.5  Storage and Accountability ............................................................................... 40 
5.6 
Prior and Concomitant Medications and/or Procedures ................................................ 40 
5.6.1  Excluded Medications and/or Procedures ......................................................... 40 
5.6.2  Restricted Medications and/or Procedures ........................................................ 40 
5.6.3  Documentation of Prior and Concomitant Medication Use .............................. 41 
5.6.4  Dietary Guidelines ............................................................................................. 41 
6  Study Procedures .................................................................................................................... 42 
7  Efficacy Assessments .............................................................................................................. 43 
7.1 
Lipid Profile/Biomarkers ............................................................................................... 44 
7.2 
CV Event Endpoint Definitions .................................................................................... 44 
7.2.1  CV Death ........................................................................................................... 44 
7.2.2  Myocardial Infarction ........................................................................................ 45 
7.2.3  Stroke and TIA .................................................................................................. 45 
7.2.4  Non-Elective Coronary Revascularization ........................................................ 45 
7.2.5  Hospitalization for Unstable Angina ................................................................. 46 
7.2.6  Hospitalization for HF ....................................................................................... 46 
7.3 
HOMA-IR ..................................................................................................................... 47 
7.4 
PK Sampling ................................................................................................................. 47 
7.5 
Lp(a) and ApoA1 .......................................................................................................... 47 
7.6 
Serum Archive Samples for Future Assessment ........................................................... 47 
8  Safety Assessments ................................................................................................................. 48 
8.1 
Handling of CV Events ................................................................................................. 48 
8.2 
Adverse Events .............................................................................................................. 48 
8.2.1  Adverse (Drug) Reaction .................................................................................. 49 

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8.2.2  Unexpected Adverse Drug Reaction ................................................................. 49 
8.2.3  Assessment of AEs by the Investigator ............................................................. 49 
8.2.4  CV Events ......................................................................................................... 50 
8.2.5  Events of Special Interest .................................................................................. 50 
8.2.5.1  Guidelines for management of elevated liver enzymes ...................... 51 
8.2.5.2  Guidelines for monitoring and management of CK ............................ 52 
8.2.5.3  Guidelines for monitoring and management of NODM ..................... 53 
8.2.5.4  Guidelines for monitoring and management of significant changes in 
renal function ...................................................................................... 53 
8.2.5.5  Guidelines for monitoring and management of changes to 
antihypertensive medication(s) ........................................................... 53 
8.2.5.6  Guidelines for management of macular degeneration ........................ 54 
8.3 
Serious Adverse Events ................................................................................................. 54 
8.4 
SAE Reporting − Procedures for Investigators ............................................................. 55 
8.5 
Pregnancy Reporting ..................................................................................................... 55 
8.6 
Expedited Reporting ...................................................................................................... 56 
8.6.1  Project Specific Exemption From SAE Immediate Reporting to Health 
Authorities and IRBs ......................................................................................... 56 
8.7 
Special Situation Reports .............................................................................................. 57 
8.8 
Clinical Laboratory Evaluations .................................................................................... 58 
8.8.1  Urine Albumin-Creatinine Ratio and Urine Protein-Creatinine Ratio .............. 58 
8.8.2  Aldosterone and hsCRP .................................................................................... 58 
8.8.3  Efficacy Endpoint Laboratory Assessments ..................................................... 58 
8.8.4  Managing Abnormal and Critical Laboratory Values ....................................... 59 
8.9 
Vital Signs ..................................................................................................................... 59 
8.9.1  Blood Pressure Monitoring ............................................................................... 60 
8.9.1.1  24-hour ABPM.................................................................................... 60 
8.10  Electrocardiograms ........................................................................................................ 60 
8.11  Physical Examinations .................................................................................................. 61 
9  Statistics .................................................................................................................................. 62 
9.1 
Analysis Populations ..................................................................................................... 62 
9.2 
Statistical Methods ........................................................................................................ 62 
9.2.1  Analysis of Efficacy .......................................................................................... 62 

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9.2.1.1  Primary efficacy analysis .................................................................... 62 
9.2.1.2  Secondary and exploratory efficacy analysis ...................................... 63 
9.2.2  Analysis of Safety ............................................................................................. 63 
9.2.2.1  Analysis of ESIs .................................................................................. 64 
9.2.3  Interim Analysis ................................................................................................ 64 
9.2.4  Clinical Events Committee ................................................................................ 64 
9.2.5  Data and Safety Monitoring Board ................................................................... 65 
9.2.6  Sample Size Determination ............................................................................... 65 
9.2.6.1  ABPM substudy .................................................................................. 65 
10  Data Management and Record Keeping ................................................................................. 66 
10.1  Data Management ......................................................................................................... 66 
10.1.1  Data Handling ................................................................................................... 66 
10.1.2  Computer Systems ............................................................................................. 66 
10.1.3  Data Entry ......................................................................................................... 66 
10.1.4  Medical Information Coding ............................................................................. 66 
10.1.5  Data Validation ................................................................................................. 66 
10.2  Record Keeping ............................................................................................................. 66 
10.3  End of Study .................................................................................................................. 67 
11  Investigator Requirements and Quality Control ..................................................................... 68 
11.1  Ethical Conduct of the Study ........................................................................................ 68 
11.2  IRB/IEC ......................................................................................................................... 68 
11.3  Informed Consent .......................................................................................................... 68 
11.4  Subject Card .................................................................................................................. 69 
11.5  Study Monitoring Requirements ................................................................................... 69 
11.6  Disclosure of Data ......................................................................................................... 69 
11.7  Retention of Records ..................................................................................................... 69 
11.8  Publication Policy ......................................................................................................... 70 
11.9  Financial Disclosure ...................................................................................................... 70 
11.10 Insurance and Indemnity ............................................................................................... 70 
11.11 Legal Aspects ................................................................................................................ 70 
12  Study Administrative Information .......................................................................................... 71 
12.1  Protocol Amendments ................................................................................................... 71 

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13  References ............................................................................................................................... 72 
Appendix A: Schedule of Procedures ........................................................................................... 74 
Appendix B: Clinical Laboratory Analytes .................................................................................. 77 
Appendix C: Diagnostic Scoring Table for Familial Hypercholesterolemia (Constructed by the 
Dutch Lipid Clinic Network) .................................................................................................. 79 
Appendix D: Simon Broome Register Diagnostic Criteria for Familial Hypercholesterolemia .. 80 
Appendix E: Correction Factors for Lipid-Modifying Drugs ....................................................... 81 
Appendix F: Endpoint Definitions Per the 2017 Cardiovascular and Stroke Endpoint 
Definitions for Clinical Trials ................................................................................................. 82 
Appendix G: Universal Definitions of Myocardial Injury and Myocardial Infarction: Summary 
From the Fourth Universal Definition of Myocardial Infarction (2018) .............................. 105 
 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
Abbreviation 
Definition 
ABPM 
Ambulatory blood pressure monitoring 
AE 
Adverse event 
ALT  
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
ApoA1 
Apolipoprotein A1 
ApoB 
Apolipoprotein B 
ASCVD 
Atherosclerotic cardiovascular disease 
AST 
Aspartate aminotransferase 
CABG 
Coronary artery bypass grafting 
CD 
Calendar day 
CEC 
Clinical Events Committee 
CETP 
Cholesteryl ester transfer protein 
CFR 
Code of Federal Regulations 
CHMP 
Committee for Medicinal Products for Human Use 
CK 
Creatine kinase 
COVID-19 
Coronavirus Disease 2019 
CRA 
Clinical Research Associate 
CT 
Computed tomography 
CTA 
Clinical trial authorisation 
CV 
Cardiovascular 
CVD 
Cardiovascular disease 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
eGFR 
Estimated glomerular filtration rate 
EIU 
Exposure In Utero 
EOS 
End of Study 
EOT 
End of Treatment 
ESI 
Event of special interest  
ET  
Early Termination 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FH 
Familial hypercholesterolemia 
GCP 
Good Clinical Practice 
HA 
Health Authorities 
HbA1c 
Glycosylated hemoglobin 

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Abbreviation 
Definition 
HDL 
High-density lipoprotein 
HDL-C 
High-density lipoprotein cholesterol  
HeFH 
Heterozygous familial hypercholesterolemia 
HF 
Heart failure 
HIS 
High-intensity statin(s) 
HOMA-IR 
Homeostatic model assessment of insulin resistance 
hsCRP 
High sensitivity C-reactive protein 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation  
IEC 
Independent Ethics Committee 
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 
MI 
Myocardial infarction  
mITT 
Modified Intent-to-Treat 
NODM 
New-onset diabetes mellitus 
Non-HDL-C 
Non-high-density lipoprotein cholesterol 
PCI  
Percutaneous coronary intervention 
PCSK9 
Proprotein convertase subtilisin/kexin type 9 
PK 
Pharmacokinetic(s) 
PP 
Per-Protocol 
SAE 
Serious adverse event 
 
SAP 
Statistical Analysis Plan 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TC 
Total cholesterol 
TG 
Triglycerides 
TIA 
Transient ischemic attack 
ULN 
Upper limit of normal 
VLDL 
Very low-density lipoprotein 
WHO 
World Health Organization 
 

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1 
INTRODUCTION AND BACKGROUND INFORMATION  
1.1 
Background Information on the Disease to be Treated 
Despite advances in treatment, cardiovascular (CV) disease (CVD) is the leading cause of death 
globally, resulting in over 17 million deaths annually.1 Elevated low-density lipoprotein (LDL) 
cholesterol (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 CV events. Patients with documented atherosclerotic 
CVD (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 LDL receptor, apolipoprotein B (ApoB), and proprotein 
convertase subtilisin/kexin type 9 (PCSK9). In adult patients with heterozygous FH (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 ASCVD and HeFH patients. 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 ASCVD and 
HeFH patients, 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 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 (38.67 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 

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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 ASCVD and HeFH who require additional lipid lowering despite treatment with 
maximally tolerated lipid-modifying therapy, including maximally tolerated doses of statins, have 
an unmet medical need. Obicetrapib may offer a useful option for these patients. Obicetrapib has 
been well tolerated to date and its Phase 2 data demonstrate significant LDL-C lowering, thus 
prompting further evaluation in Phase 3 clinical studies. 
1.2 
Background Information on Cholesteryl Ester Transfer Protein Inhibition 
Cholesteryl ester transfer protein (CETP) is a plasma glycoprotein produced in the liver and 
adipose tissue. It circulates in the blood bound primarily to high-density lipoprotein (HDL) 
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 HDL to the 
ApoB-containing particles, VLDL, and LDL-C, in exchange for TG. 
Inhibition of CETP activity reduces LDL-C levels and increases HDL-C levels. These effects are 
not only caused by inhibition of CETP-mediated cholesterol transfer from HDL to LDL, but also 
by a decrease in the number of ApoB-containing lipoproteins and an increase in apolipoprotein A1 
(ApoA1)-containing lipoproteins. The LDL-C lowering effect, which arises from CETP inhibition, 
will benefit patients with elevated LDL-C and increased CV risk. 
The relative reduction in major adverse CV events (MACEs) 2 years after completion of the 
REVEAL study was nearly double (approximately 18%) than seen at the end of the 4-year 
treatment period with the CETP inhibitor, anacetrapib (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.13 
1.3 
Obicetrapib (TA-8995) 
Obicetrapib (TA-8995) has been shown to be a selective CETP inhibitor. Apart from preventing 
the shuttling of cholesterol esters from HDL-C to LDL-C particles, obicetrapib has several 
additional compound-specific activities that are hypothesized to be beneficial in patients. 
Obicetrapib treatment has recently been shown to reduce the number of ApoB-containing particles 
that constitute LDL-C. Obicetrapib also increases apolipoprotein E, which leads to removal of 
cholesterol via the liver and also reduces lipoprotein (a) (Lp[a]). Finally, obicetrapib not only 
potently increases HDL-C and the number of ApoA1-containing lipoproteins but has been 
demonstrated to be a potent inducer of cholesterol efflux, which is the main driver of reverse 
cholesterol transport.14 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 have 
been conducted in healthy volunteers. A formal thorough QT/heart rate-corrected QT interval 
study (TA-8995-04) has been completed and obicetrapib was shown to have no effect on the 
corrected QT interval by Fridericia. A drug-drug interaction study (TA-8995-05) has also been 
conducted; this study showed no significant effect of obicetrapib on P-glycoprotein activity, but 

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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, bioequivalence between obicetrapib capsule and tablet 
formulations was investigated (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 daily dose 
of 10 mg of obicetrapib therapy resulted in an LDL-C reduction of 45.4%, 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) was conducted where the effect 
of obicetrapib on Lp(a) was investigated following 12 weeks of treatment. There was a statistically 
significant reduction in Lp(a) levels following 12 weeks of treatment; however, the magnitude of 
the changes was not likely to be clinically relevant. 
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 
obicetrapib 10 mg, in combination with ezetimibe 10 mg as a monotherapy, in participants on HIS 
therapy. 
This study is a pivotal Phase 3 study to investigate the treatment of elevated LDL-C levels in 
participants with underlying HeFH and/or a history of ASCVD. This study will include 
participants on maximally tolerated lipid-modifying therapy, including maximally tolerated doses 
of statins. 
1.4.1 
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 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 underlying HeFH and/or a history of 
ASCVD who are not adequately controlled by their maximally tolerated lipid-modifying therapy. 
1.5 
Rationale 
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 and limited data regarding long-term 

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success relative to statins. Because PCSK9-targeted therapies are injectable, this poses a less 
attractive option for patients who prefer oral medications. 
Accordingly, there remains an unmet need for therapies to effectively reduce elevated LDL-C 
levels and CV risk at an acceptable cost and with a convenient dosage form and a favorable safety 
and tolerability profile to encourage long-term use and patient compliance. 
1.6 
Risk/Benefit 
The primary pharmacology in in vitro, ex vivo, and in vivo studies has 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 the 
critical physiological systems (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 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 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 underlying HeFH and/or a history of ASCVD who are not adequately 
controlled by their maximally tolerated lipid-modifying therapy. 
1.6.1 
Coronavirus Disease 2019 Impacts 
In March 2020, the 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, Food and Drug 
Administration [FDA] 2021).15,16 
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 study 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 3.1.1). The 

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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 on LDL-C levels at 
Day 84. 
2.2 
Secondary Objectives 
The secondary objectives of this study include the following: 
 To evaluate the effect of obicetrapib on LDL-C levels at Days 180 and 365; 
 To evaluate the effect of obicetrapib on ApoB, non-high-density lipoprotein cholesterol 
(non-HDL-C), HDL-C, total cholesterol (TC), and TG at Days 84, 180, and 365; 
 To evaluate the effect of obicetrapib on Lp(a) and ApoA1 at Day 84; and 
 To evaluate the safety and tolerability profile of obicetrapib in a representative population of 
adult males and females with HeFH and/or ASCVD of all ages, assessed by AEs, events of 
special interest (ESIs), vital signs (including blood pressure), ECG measurements, and clinical 
laboratory values.  
2.3 
Exploratory Objectives 
The exploratory objectives of this study include the following:  
 To evaluate the effect of obicetrapib on the following:  
o Proportion of participants achieving prespecified LDL-C levels at Days 84, 180, and 365; 
and  
o Biomarkers, including glycosylated hemoglobin (HbA1c), homeostatic model assessment 
of insulin resistance (HOMA-IR), and blood glucose at Day 365. 
 To evaluate trough levels of obicetrapib from Baseline to Day 365 in the obicetrapib group; 
 To evaluate the effect of obicetrapib on CV death, non-fatal MI, non-fatal stroke, or 
non-elective coronary revascularization; and 
 To evaluate the effect of obicetrapib on hospitalization for unstable angina and/or chest pain, 
hospitalization for heart failure (HF), and transient ischemic attack (TIA). 

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3 
STUDY DESCRIPTION 
3.1 
Summary of Study Design 
This study will be a multisite, placebo-controlled, double-blind, randomized Phase 3 study in 
approximately 2400 participants with underlying HeFH and/or a history of ASCVD who are not 
adequately controlled by their lipid-modifying therapy to evaluate the efficacy, safety, and 
tolerability of obicetrapib. Informed consent will be obtained from participants before the initiation 
of any study-specific procedures. 
Approximately 2400 eligible participants will be randomized in a 2:1 ratio, respectively, to the 
following treatment groups: 
 Obicetrapib group: One 10 mg obicetrapib tablet once daily; or 
 Placebo group: 1 placebo tablet once daily. 
Treatment allocation will be stratified based on CV risk (HeFH or non-HeFH) and Baseline statin 
dose (HIS or non-HIS). At least 70% of the participants enrolled into this study must be taking 
HIS. Participants with underlying HeFH but without a history of ASCVD will comprise up to a 
maximum of 20% of the total participants enrolled into the study. Starting on Day 1, each 
participant will self-administer their assigned study drug once daily until Day 365. During the 
Treatment Period, participants will return to the study site for efficacy and safety assessments. 
Blood samples for pharmacokinetic (PK) assessment will be collected at specified visits 
throughout the study. An onsite End of Study (EOS) Visit will be conducted 35 days after the 
participant’s last dose of study drug, during which an assessment of vital signs, concomitant 
medications, CV events, and AEs will be completed and documented in the participant’s record. 
A subset of approximately 200 participants from selected study sites who consent to participate 
will be enrolled in an ambulatory blood pressure monitoring (ABPM) substudy. These participants 
will have a 24-hour ABPM assessment conducted at Screening (Visit 1) and Visit 6 (Day 270). In 
order to participate in the substudy, participants must provide written informed consent in a 
substudy-specific informed consent form (ICF) and must be able to provide an acceptable 24-hour 
ABPM data collection at Screening (Visit 1). Additional details surrounding this substudy, 
including the definition of an acceptable 24-hour ABPM data collection, are included in a separate 
study manual. 
The study will be governed by a Steering Committee. A Data and Safety Monitoring Board 
(DSMB) will provide independent oversight of participant safety. An independent Clinical Events 
Committee (CEC) will adjudicate all events of death and all potential or suspected CV events.  
The responsibilities, procedures, and workflow for these committees will be defined in separate 
charters outside of the protocol. 
3.1.1 
COVID-19 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. It may 
be necessary to conduct some study visits virtually. 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 drug, including but 
not limited to phone/video contact, alternative location for biologic sample collection, alternative 

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secure delivery of study drug, 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 is being developed as an adjunct to diet and maximally tolerated lipid-modifying 
therapy for the treatment of adults with HeFH or a history of ASCVD 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 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 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 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; 
Diagnosis of HeFH: 
Diagnosis must be made by either prior historical genotyping or by clinical assessment using 
either the WHO Criteria/Dutch Lipid Clinic 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.17,18 LDL-C values are 
required to assess the Dutch Lipid Clinic Network Criteria and/or Simon Broome Register 
Diagnostic Criteria. In some cases, historical lipid values may not be obtainable, as participants 
may have initiated lipid-modifying therapies years prior. In these instances, the Investigator 
will need to estimate an “off-treatment” LDL-C value to calculate whether the participant 
qualifies for the study. For this purpose, Appendix E contains correction factors for a variety 

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of statins and/or ezetimibe. The current LDL-C value obtained most recently and/or through 
the screening process can be converted using the appropriate correction factor. This value will 
be used to assess whether the participant meets either the Dutch Lipid Clinic Network Criteria 
or the Simon Broome Register Diagnostic Criteria. Participants with a diagnosis of HeFH may 
or may not have a history of ASCVD or ASCVD-risk equivalents; 
History of ASCVD, defined by at least 1 of the following conditions: 
o Coronary artery disease: 
 MI;  
 Prior coronary revascularization (percutaneous coronary intervention [PCI] or coronary 
artery bypass grafting [CABG]); 
 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; or 
 Coronary calcium score >100 Agatston units within 6 months prior to Screening 
(Visit 1). 
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: 
 Prior documentation of a resting ankle-brachial index 0.85;  
 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. 
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 

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 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 was 
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.19 
o Ezetimibe for at least 8 weeks with or without maximally tolerated statin prior to Screening 
(Visit 1); 
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 stable doses prior to Screening (Visit 1). 
Note: At least 70% of the participants enrolled into this study must be taking HIS. 
Documentation in the electronic case report form (eCRF) of the reason why a participant is 
unable to take HIS is required. HIS include the following: atorvastatin 40 and 80 mg and 
rosuvastatin 20 and 40 mg. 
5. Have a fasting serum LDL-C at Screening (Visit 1) as follows: 
o Have a fasting serum LDL-C 55 mg/dL (1.4 mmol/L) to <100 mg/dL (<2.6 mmol/L) 
OR non-HDL-C 85 mg/dL (2.2 mmol/L) to <130 mg/dL (<3.4 mmol/L) with at least 
1 of the following risk enhancers: 
 Recent MI (>3 and <12 months prior to Randomization [Visit 2]);  
 Type 2 diabetes mellitus; 
 Current daily cigarette smoking; 
 Age of >60 years; 
 High sensitivity C-reactive protein (hsCRP) 2.0 mg/L (19.0 nmol/L) at Screening 
(Visit 1) or within 6 months prior to Screening (Visit 1); 
 Fasting TG >150 mg/dL (>1.7 mmol/L); 
 Fasting Lp(a) >30 mg/dL (>70 nmol/L); and/or 
 Fasting HDL-C <40 mg/dL (<1.0 mmol/L). 
OR 
o Have a fasting serum LDL-C 100 mg/dL (2.6 mmol/L) OR non-HDL-C 130 mg/dL 
(3.4 mmol/L). 

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Note: LDL-C at Screening (Visit 1) will be calculated using the Friedewald equation unless 
TG 400 mg/dL (4.5 mmol/L) or LDL-C 50 mg/dL (1.3 mmol/L). If TG 400 mg/dL 
(4.5 mmol/L) or LDL-C 50 mg/dL (1.3 mmol/L), then LDL-C level will be measured 
directly by preparative ultracentrifugation, also referred to as beta quantification. 
6. Have fasting TG <500 mg/dL (<5.7 mmol/L) at Screening (Visit 1); and 
7. Have an estimated glomerular filtration rate (eGFR) 30 mL/min/1.73 m2 calculated using the 
Chronic Kidney Disease Epidemiology Collaboration equation at Screening (Visit 1). 
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 HF or left 
ventricular ejection fraction <30%; 
2. Have been hospitalized for HF 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 prior to Randomization (Visit 2) 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; 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 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); 
11. Have a known history of alcohol and/or drug abuse within 5 years prior to Randomization 
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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); 
14. Have planned use of other investigational products or devices during the course of the study; 
15. Have participated in any clinical study evaluating obicetrapib; 
16. Have a known allergy or hypersensitivity to the study drug, placebo, or any of the excipients 
in the study drug or placebo; or 
17. 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 
Withdrawal Criteria 
Participation of a participant in this clinical study will be discontinued for any of the following 
reasons: 
 Withdrawal of consent; or 
 Termination of the study by the Sponsor or the regulatory authority.  
Study drug treatment may be discontinued either permanently or temporarily (although the 
participant should be encouraged to remain in the study and to follow-up for study visits) for any 
of the following reasons: 
 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 requirements of the protocol; 
 Any serious AE (SAE), clinically significant AE, severe laboratory abnormality, intercurrent 
illness, or other medical condition which indicates to the Investigator that continued 
participation is not in the best interest of the participant; 
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 Requirement of prohibited concomitant medication; or 
 Participant failure to comply with protocol requirements or study-related procedures. 
Participants are free to withdraw consent from the study (which means permanent discontinuation 
of study drug and all follow-up assessments) at any time without prejudice. Note that 
discontinuation of study drug in and of itself is not considered withdrawal of consent. 
An excessive rate of withdrawals (either discontinuation of study drug or study withdrawal) can 
render the study non-interpretable. Therefore, unnecessary withdrawal of participants should be 
avoided, and all efforts should be taken to motivate participants to comply with all of the 
study-specific procedures and to continue follow-up until the end of the study to detect the 
occurrence of CV events and assess vital status. 
Every attempt should be made to keep participants on study drug throughout the duration of the 
study. Before permanently discontinuing study drug (either participant- or Investigator-initiated), 
an interruption should be considered. Participants who temporarily discontinue study drug for any 
reason should restart as soon as it is medically justified in the opinion of the Investigator. In 
addition, participants should not be withdrawn from the study drug or from the study after 
experiencing a potential CV event. 
All participants who permanently discontinue study drug should continue scheduled study visits. 
If the participant declines continued onsite visits but is agreeable to telephone calls, he/she will be 
contacted by the Investigator periodically to assess occurrence of CV events until death, 
documented withdrawal of participant informed consent (in writing if allowed by local 
regulations), or the final closure of the study. 
The Investigator should show due diligence and explore all possible options to reach a participant 
who fails to return for a visit. In the case of participants lost to follow-up, attempts to contact the 
participant must be made and documented in the participant’s medical records and in source 
documents. Per routine, in order to avoid participants lost to follow-up, the Investigator should ask 
the participant at the study start for the contact details of a relative or friend who can be contacted 
for participant contact information in case the participant cannot be reached. 
Participants should not be withdrawn from follow-up unless they explicitly withdraw consent to 
be contacted. All efforts should therefore be made to minimize the number of participants who 
withdraw consent as, in general, no further information on CV events and survival status may be 
collected after that point. Participants who do not want regular in-person follow-up after cessation 
of study drug should be offered alternative methods of follow-up, including periodic telephone 
follow-up, contact at study closure, or assessment of health status via treating physicians or 
medical records. Such participants would then not be viewed as withdrawal of consent. The 
Investigator must explain to the participant all options for continued participation, and document 
which options were refused by the participant and the reason for refusal. Withdrawal of consent to 
all follow-up must be ascertained and documented in writing by the Investigator, who must inform 
the Sponsor and document the withdrawal of consent in the eCRF and medical records. 
For participants who permanently discontinue from study treatment and who decline continued 
study participation, an Early Termination (ET) Visit will be scheduled as soon as possible 
followed by an onsite EOS Visit 35 days later. The ET Visit procedures are identical to the End of 
Treatment (EOT) Visit procedures. If the discontinuation occurs at a specific onsite visit, this visit 
will become the ET Visit and EOT Visit procedures should be followed. Participants who 

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withdraw consent to all follow-up will be asked about the reason(s) and will be assessed for the 
presence of any AEs. 
For participants who completely withdraw consent, life status will be obtained at study end through 
public record information according to local guidelines and as allowed by local regulations. 
If premature withdrawal from the study occurs for any reason, the Investigator must determine the 
primary reason for a participant’s premature withdrawal from the study and record this information 
in the medical records and on the eCRF. 
Withdrawn participants will not be replaced. 
4.4 
Retesting 
If laboratory abnormalities during Screening (Visit 1) are considered by the Investigator to be 
transient, then the laboratory tests may be repeated once during Screening (Visit 1). Laboratory 
samples may also be repeated if samples are unable to be tested due to hemolysis, platelet 
clumping, or other processing errors. Retesting will be performed by the central laboratory. The 
Investigator’s rationale for retesting should be documented. If the retest result is no longer 
exclusionary, the participant may be randomized. 
4.5 
Rescreening 
Participants who have screen failed are permitted to rescreen, following consultation with the 
Medical Monitor. Rescreening may be scheduled after at least 5 days have elapsed from the 
previous study visit. Rescreened participants will be assigned a new participant number. 

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5 
STUDY TREATMENTS 
5.1 
Treatment Groups 
Approximately 2400 eligible participants will be randomized in a 2:1 ratio, respectively, to the 
following treatment groups: 
 Obicetrapib group: One 10 mg obicetrapib tablet once daily; or 
 Placebo group: 1 placebo tablet once daily. 
All study drugs will be administered by the participant orally from Visit 2 (Day 1) to the EOT 
Visit (Day 365). 
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 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 underlying HeFH and/or a history of ASCVD who are not adequately 
controlled by their maximally tolerated lipid-modifying therapy. 
5.3 
Randomization and Blinding 
Participants who meet all inclusion criteria and none of the exclusion criteria will be randomized 
on Day 1 (Visit 2) via the
 Interactive Response Technology (IRT) system in a 2:1 ratio 
to receive obicetrapib or placebo. 
Treatment allocation will be stratified based on CV risk (HeFH or non-HeFH) and Baseline statin 
dose (HIS or non-HIS). At least 70% of the participants enrolled into this study must be taking 
HIS. Participants with underlying HeFH but without a history of ASCVD will comprise up to a 
maximum of 20% of the total participants enrolled into the study.  
The study drug blind will be maintained through the EOS Visit (Visit 8). Participants, the Sponsor, 
Investigators, and all study site personnel involved in the study, including personnel carrying out 
study procedures, evaluating participants, entering study data, and/or evaluating study data, will 
remain blinded to treatment allocations until all participants have completed the EOS Visit 
assessments and the database has been locked for analysis. 
Active and placebo product will be identical. Medication bottles with a unique code will be 
assigned to participants at various points in the study by the IRT system. 
5.4 
Breaking the Blind 
Study drug will be managed using the IRT system. Each user will have a unique username and 
passcode to access the system. Investigators shall not break the study blind during the study, and 
Investigators should treat all participants as if they had received obicetrapib. However, in situations 

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5.5.4 
Treatment Compliance 
Participants will return used and unused bottles of study drug at Visits 3, 4, 5, 6, and 7. The number 
of tablets returned should be counted and documented in the source documentation and in the 
eCRF for compliance. Any discrepancies between the number of days and the number of tablets 
administered should be clarified and documented in the source. 
Compliance with study drug dosing will be assessed using the following formula: 
𝐶𝑜𝑚𝑝𝑙𝑖𝑎𝑛𝑐𝑒 ሺ%ሻൌ ሺ# 𝑡𝑎𝑏𝑙𝑒𝑡𝑠 𝑑𝑖𝑠𝑝𝑒𝑛𝑠𝑒𝑑െ# 𝑡𝑎𝑏𝑙𝑒𝑡𝑠 𝑟𝑒𝑡𝑢𝑟𝑛𝑒𝑑ሻ
# 𝑒𝑥𝑝𝑒𝑐𝑡𝑒𝑑 𝑑𝑜𝑠𝑖𝑛𝑔 𝑑𝑎𝑦𝑠
ൈ100 
5.5.5 
Storage and Accountability 
All study drug must be stored below 25°C (77°F) in a secure area with access limited to the 
Investigator and authorized study site personnel. Study drug should not be frozen or refrigerated. 
In accordance with regulatory requirements, the Investigator or designated study site personnel 
must document the amount of study drug 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. Discrepancies 
are to be reconciled or resolved. Procedures for final disposition of unused study drug 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 who 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) will be excluded from study participation. 
Participants with a known history of alcohol and/or drug abuse within 5 years prior to 
Randomization (Visit 2) will be excluded from study participation.  
Participants who plan to use other investigational products or devices during the course of the 
study will be excluded from study participation.  
Participants who are taking gemfibrozil or who have taken gemfibrozil within 30 days of Screening 
(Visit 1) will be excluded from study participation per Exclusion Criterion 13. 
5.6.2 
Restricted Medications and/or Procedures 
Participants receiving lipid-modifying therapies as described in Section 4.1 (Inclusion Criterion 4) 
should be on a stable dose for at least 8 weeks prior to Screening (Visit 1). Participants taking 
PCSK9-targeted therapies should have received 4 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. 

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Participants are not required to be taking statins. Reasons for not using statin therapy must be 
documented (eg, the participant is statin intolerant) as described in Section 5.6.3. If the participant 
is statin intolerant, written confirmation will be required of both the participant and the Investigator 
stating that the participant was 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, as defined in Inclusion Criterion 4, 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.19 
Participants must agree not to donate blood during study participation. 
5.6.3 
Documentation of Prior and Concomitant Medication Use 
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 10% of participants in this study will be 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 was 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.19 
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 
Please refer to Appendix A (Schedule of Procedures) for a complete list of procedures to be 
completed at each study visit.  

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7 
EFFICACY ASSESSMENTS 
The primary efficacy endpoint is the percent change from Baseline to Day 84 in LDL-C in the 
obicetrapib group compared to the placebo group. 
The secondary efficacy endpoints include the following: 
 Percent change from Baseline to Days 180 and 365 in LDL-C in the obicetrapib group 
compared to the placebo group; 
 Percent change from Baseline to Days 84, 180, and 365 in ApoB in the obicetrapib group 
compared to the placebo group; 
 Percent change from Baseline to Days 84, 180, and 365 in non-HDL-C in the obicetrapib group 
compared to the placebo group; 
 Percent change from Baseline to Days 84, 180, and 365 in HDL-C in the obicetrapib group 
compared to the placebo group; 
 Percent change from Baseline to Day 84 in Lp(a) and ApoA1 in the obicetrapib group 
compared to the placebo group; 
 Percent change from Baseline to Days 84, 180, and 365 in TC in the obicetrapib group 
compared to the placebo group; and 
 Percent change from Baseline to Days 84, 180, and 365 in TG in the obicetrapib group 
compared to the placebo group. 
The exploratory efficacy endpoints include the following: 
 Proportion of participants at Days 84, 180, and 365 who achieve LDL-C <70 mg/dL 
(<1.8 mmol/L) in the obicetrapib group compared to the placebo group; 
 Proportion of participants at Days 84, 180, and 365 who achieve LDL-C <55 mg/dL 
(<1.4 mmol/L) in the obicetrapib group compared to the placebo group; 
 Proportion of participants at Days 84, 180, and 365 who achieve LDL-C <40 mg/dL 
(<1.0 mmol/L) in the obicetrapib group compared to the placebo group;  
 Percent change from Baseline to Day 365 in HbA1c in the obicetrapib group compared to the 
placebo group; 
 Percent change from Baseline to Day 365 in HOMA-IR in the obicetrapib group compared to 
the placebo group;  
 Percent change from Baseline to Day 365 in blood glucose in the obicetrapib group compared 
to the placebo group; 
 Trough levels of obicetrapib from Baseline to Day 365 in the obicetrapib group; 
 The time from Randomization until the first confirmed occurrence of a composite of CV death, 
non-fatal MI, non-fatal stroke, or non-elective coronary revascularization; 

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 The time from Randomization until the first confirmed occurrence of a composite of CV death, 
non-fatal MI, or non-fatal stroke; and 
 The time from Randomization until the first confirmed occurrence of hospitalization for 
unstable angina and/or chest pain, hospitalization for HF, and TIA. 
7.1 
Lipid Profile/Biomarkers 
Samples will be collected for the lipid profile/biomarkers at visits specified in the Schedule of 
Procedures (Appendix A). The lipid profile/biomarker samples will be analyzed for ApoB, 
HDL-C, LDL-C, non-HDL-C, TC, and TG. Samples should be collected while the participant is 
fasting (a minimum of 8 hours). 
At Baseline (Visit 2), Day 84 (Visit 4), and Day 365 (Visit 7)/EOT/ET, LDL-C will be measured 
for all participants by preparative ultracentrifugation, also referred to as beta quantification. At all 
other scheduled visits, LDL-C will be calculated using the Friedewald equation unless 
TG 400 mg/dL (4.5 mmol/L) or LDL-C 50 mg/dL (1.3 mmol/L). If TG 400 mg/dL 
(4.5 mmol/L) or LDL-C 50 mg/dL (1.3 mmol/L), then LDL-C level will be measured directly 
by preparative ultracentrifugation.  
All lipid profile/biomarker values will be blinded during the study through the EOS Visit (Visit 8). 
Participants, the Sponsor, Investigators, and all study site personnel involved in the study, 
including personnel carrying out study procedures, evaluating participants, entering study data, 
and/or evaluating study data, will remain blinded to lipid profile/biomarker values until all 
participants have completed the EOS Visit and the database has been locked for analysis. 
7.2 
CV Event Endpoint Definitions 
CV death, stroke, TIA, non-elective coronary revascularization, hospitalization for unstable 
angina, and hospitalization for HF will be defined based on the 2017 Cardiovascular and Stroke 
Endpoint Definitions for Clinical Trials described in Appendix F.20 MI will be defined based on 
the Fourth Universal Definition of Myocardial Infarction described in Appendix G.21 
An independent CEC will adjudicate all events of death and all potential or suspected CV events.  
Additional details will be provided in the CEC Charter. 
7.2.1 
CV Death 
CV death is defined as death resulting from an acute MI, sudden cardiac death, death due to HF, 
death due to stroke, death due to CV procedures, death due to CV hemorrhage, or death due to 
other CV causes.20 
Death due to acute MI refers to death by any CV mechanism (eg, arrhythmia, sudden death, HF, 
stroke, pulmonary embolus, peripheral arterial disease) 30 days after an MI, related to the 
immediate consequences of the MI (eg, progressive HF or recalcitrant arrhythmia). Death resulting 
from a procedure to treat an MI (eg, PCI, CABG surgery), or to treat a complication resulting from 
an MI, should also be considered a death due to an acute MI. 
Sudden cardiac death refers to death that occurs unexpectedly and not within 30 days of an acute 
MI. Death due to HF refers to death in association with clinically worsening symptoms and/or 
signs of HF regardless of HF etiology. Death due to stroke refers to death after a stroke that is 

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either a direct consequence of the stroke or a complication of the stroke. Death due to CV 
procedures refers to death caused by the immediate complications of a cardiac procedure. Death 
resulting from an elective coronary procedure to treat myocardial ischemia or death due to an MI 
that occurs as a direct consequence of a CV investigation, procedure, or operation should be 
considered as a death due to CV procedure. Death due to CV hemorrhage refers to death related 
to hemorrhage such as a non-stroke intracranial hemorrhage (eg, subdural hematoma), 
non-procedural or non-traumatic vascular rupture (eg, aortic aneurysm), or hemorrhage causing 
cardiac tamponade.  
Death due to other CV causes refers to CV death not included in the above categories but with a 
specific, known cause (eg, pulmonary embolism or peripheral arterial disease).20 
7.2.2 
Myocardial Infarction  
The term acute MI should be used when there is acute myocardial injury with clinical evidence of 
acute myocardial ischemia and with detection of a rise and/or fall of cardiac troponin values with 
at least 1 value above the 99th percentile upper reference limit and at least 1 of the following:21 
 Symptoms of myocardial ischemia;  
 New ischemic ECG changes;  
 Development of pathological Q waves;  
 Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality 
in a pattern consistent with an ischemic etiology; or 
 Identification of a coronary thrombus by angiography or autopsy (not for types 2 or 3 MI).  
More details regarding the diagnosis of MI are provided in Appendix G. 
7.2.3 
Stroke and TIA 
Stroke is defined as an acute episode of focal or global neurological dysfunction caused by brain, 
spinal cord, or retinal vascular injury as a result of hemorrhage or infarction.20 A TIA, defined as 
a transient episode of focal neurological dysfunction caused by brain, spinal cord, or retinal 
ischemia without acute infarction, should not be classified as a stroke.20 
More details regarding the diagnosis of stroke and TIA are provided in Appendix F. 
7.2.4 
Non-Elective Coronary Revascularization 
Coronary revascularization includes any coronary arterial vascular intervention done to treat 
clinical or functional ischemia and/or prevent major ischemic events, including PCI or surgical 
intervention of the coronary arteries.  
A non-elective coronary revascularization includes “emergent” or “urgent” classification, as 
defined by the following:20  
 Emergency: The procedure should be performed as soon as possible because of substantial 
concerns that ongoing myocardial ischemia and/or MI could lead to death. “As soon as 
possible” refers to a participant who is of sufficient acuity that one would cancel a scheduled 
case to perform this procedure immediately in the next available room during business hours, 
or one would activate the on-call team were this to occur during off-hours; and  

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 Urgent: The procedure should be performed on an inpatient basis and prior to discharge 
because of significant concerns that there is risk of myocardial ischemia, MI, and/or death. 
Participants who are outpatients or in the emergency department at the time that the cardiac 
catheterization is requested would warrant hospital admission based on their clinical 
presentation. 
More details regarding the classification of coronary revascularization procedures are provided in 
Appendix F.  
7.2.5 
Hospitalization for Unstable Angina  
Unstable angina requiring hospitalization is defined as all of the following:20  
 Ischemic discomfort (angina or symptoms thought to be equivalent) 10 minutes in duration 
occurring either at rest or in an accelerating pattern with frequent episodes associated with 
progressively decreased exercise capacity; 
 Prompting an unscheduled hospitalization within 24 hours of the most recent symptoms, with 
hospitalization being defined as an admission to an inpatient unit or a visit to an emergency 
department that results in at least a 24-hour stay (or a change in calendar date if the hospital 
admission or discharge times are not available);  
 At least 1 of the following:  
o New or worsening ST or T wave changes on resting ECG (in the absence of confounders, 
such as left bundle branch block or left ventricular hypertrophy) (see Appendix F); 
o Definite evidence of inducible myocardial ischemia (see Appendix F);  
o Angiographic evidence of new or worse 70% lesion (50% for left main lesion) and/or 
thrombus in an epicardial coronary artery that is believed to be responsible for the 
myocardial ischemic symptoms/signs; or  
o Need for coronary revascularization procedure (PCI or CABG) for the presumed culprit 
lesion(s), as defined in the bullet above. This criterion would be fulfilled if 
revascularization was undertaken during the unscheduled hospitalization, or subsequent to 
transfer to another institution without interceding home discharge. 
 Negative cardiac biomarkers and no evidence of acute MI.  
More details regarding the diagnosis of unstable angina are provided in Appendix F. 
7.2.6 
Hospitalization for HF 
A HF hospitalization must meet all of the following criteria:20  
 The participant is admitted to the hospital with a primary diagnosis of HF; 
 The participant’s length of stay in hospital extends for at least 24 hours (or a change in calendar 
date if the hospital admission and discharge times are unavailable); 
 The participant exhibits documented new or worsening symptoms due to HF on presentation, 
including at least 1 of the following symptoms: dyspnea, decreased exercise tolerance, fatigue, 
or other symptoms of compromised or worsened end-organ perfusion (see Appendix F);  

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 The participant has objective evidence of new or worsening HF, including physical 
examination findings and/or laboratory abnormalities (see Appendix F); and 
 The participant receives at least 1 of the following treatments specifically for HF: significant 
augmentation in oral diuretic therapy, initiation of intravenous diuretic or vasoactive agent, or 
mechanical or surgical intervention. 
More details regarding the diagnosis of HF are provided in Appendix F. 
7.3 
HOMA-IR 
Samples will be collected for HOMA-IR at visits specified in the Schedule of Procedures 
(Appendix A). Samples should be collected while the participant is fasting (a minimum of 8 hours). 
7.4 
PK Sampling 
A Baseline PK sample will be collected prior to study drug administration for trough measurement 
of obicetrapib in plasma at visits specified in the Schedule of Procedures (Appendix A). 
7.5 
Lp(a) and ApoA1 
A plasma sample for Lp(a) and ApoA1 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). 
7.6 
Serum Archive Samples for Future Assessment 
Serum archive samples will be collected at Baseline (prior to the first dose at Visit 2) and at Visit 7 
(EOT) for potential future assessment of dyslipidemia and/or CV risk. Samples should be collected 
prior to study drug administration and while the participant is fasting (a minimum of 8 hours). 
Serum archive sample is not collected in China. 

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8 
SAFETY ASSESSMENTS 
The safety endpoints include the following: 
 Safety and tolerability profile of obicetrapib assessed by AEs, ESIs, vital signs (including 
blood pressure as assessed by office blood pressure measurements), ECGs, and clinical 
laboratory values; and 
 Assessment of ABPM measured at Screening (Visit 1) and at Day 270 (Visit 6). 
8.1 
Handling of CV Events 
All potential or suspected CV events will be reviewed and adjudicated by an independent CEC 
and reported in the appropriate clinical endpoint eCRF. In addition, these events are subject to 
normal AE/SAE reporting procedures. 
Timelines for CV event reporting will be identical to timelines for SAE reporting (Section 8.4). 
All CV events occurring from the time of informed consent until the end of study participation (up 
to 35 days post last dose) will be reported to 
 within 24 hours of 
knowledge of the occurrence.  
8.2 
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 an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of an 
investigational medicinal product, whether or not related to the investigational medicinal product. 
All AEs, including observed or volunteered problems, complaints, or symptoms, are to be recorded 
on the appropriate eCRF. 
AEs, which include clinical laboratory test variables, will be monitored and documented from the 
time of signing of informed consent at Screening (Visit 1) until the EOS Visit (35 days after the 
EOT Visit). Participants should be instructed to report any AE that they experience to the 
Investigator, whether or not they think the event is due to study treatment. Beginning at the time 
of signing of informed consent, 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 AE 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 Screening (Visit 1) 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 (eg, ECG) findings that are 
detected during the study or are present at Screening (Visit 1) and significantly worsen during the 

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study should be reported as AEs, as described below. The Investigator will exercise his/her medical 
and scientific judgment in deciding whether an abnormal laboratory finding or other abnormal 
assessment is clinically significant. Clinically significant abnormal laboratory values occurring 
during the clinical study will be followed until repeat tests return to normal, stabilize, or are no 
longer clinically significant. 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 the study drug is required as a result of the abnormality; or 
 Based on the clinical judgment of the Investigator. 
8.2.1 
Adverse (Drug) Reaction 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered adverse drug reactions. “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. 
8.2.2 
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.  
8.2.3 
Assessment of AEs 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 study drug 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 drug is to be assessed according to the 
following definitions: 
No (not related or unlikely to be related) – The time course between the administration of study 
drug 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 drug 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. 

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The definition implies a reasonable possibility of a causal relationship between the event and the 
study drug. This means that there are facts (evidence) or arguments to suggest a causal relationship. 
The following factors should also be considered: 
 The temporal sequence from study drug administration- 
The event should occur after the study drug is given. The length of time from study drug 
exposure to event should be evaluated in the clinical context of the event. 
 Underlying, concomitant, intercurrent diseases- 
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 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 drug- 
The known pharmacologic properties (absorption, distribution, metabolism, and excretion) of 
the study drug should be considered. 
8.2.4 
CV Events 
By the design of this study, CV events will be captured as exploratory endpoints (see Section 7); 
these events will be reviewed and adjudicated by an independent CEC and reported in the 
appropriate clinical endpoint eCRF. In addition, these events are subject to normal AE/SAE 
reporting procedures.  
8.2.5 
Events of Special Interest  
ESIs will be monitored over time by the independent DSMB on a bi-annual basis 
(ie, approximately every 6 months), regardless of whether these events were reported as AEs. Any 
events that qualify as an AE or SAE will be reported accordingly (see Sections 8.2, 8.3, and 8.4). 
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; 

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 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; 
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 <30 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  
 Macular degeneration.  
These ESIs will be monitored through review of the AE and laboratory databases. 
8.2.5.1 
Guidelines for management of elevated liver enzymes  
Participants with signs or symptoms consistent with liver injury (eg, nausea, vomiting, anorexia, 
fatigue, 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; 

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 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. 
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%). 
8.2.5.2 
Guidelines for monitoring and management of CK  
If at any time after Randomization (Visit 2) 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. 

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If no alternative explanation exists, consideration should be given to withdrawing the participant 
from 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 withdrawn and given no 
further doses of 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. 
Any event of rhabdomyolysis, regardless of CK level, should lead to study drug interruption or 
discontinuation until the contribution of obicetrapib has been excluded. 
8.2.5.3 
Guidelines for monitoring and management of NODM 
Diabetes mellitus may be newly diagnosed during the study as described in Section 8.2.5. 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. 
8.2.5.4 
Guidelines for monitoring and management of significant changes in renal function  
If at any time after Randomization (Visit 2) 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 <30 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. 
8.2.5.5 
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. 

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8.2.5.6 
Guidelines for management of macular degeneration 
In cases of suspected macular degeneration or acute vision loss, participants will be referred for 
an ophthalmological consultation. 
8.3 
Serious Adverse Events  
An AE or adverse reaction is considered serious if, in the view of either the Investigator or Sponsor, 
it results in any of the following outcomes: 
 Death; 
 A life-threatening AE; 
Note: An AE or adverse reaction is considered “life-threatening” if, in view of either the 
Investigator or Sponsor, its occurrence places the participant at immediate risk of death. It does 
not include an event that, had it occurred in a more severe form, might have caused death. 
 Requires hospitalization or prolongation of existing hospitalizations; 
Note: Any hospital admission with at least 1 overnight stay will be considered an inpatient 
hospitalization. An emergency room or urgent care visit without hospital admission will not 
be recorded as an SAE under this criterion, nor will hospitalization for a procedure scheduled 
or planned before signing of informed consent, or elective treatment of a pre-existing condition 
that did not worsen from Baseline. However, unexpected complications and/or prolongation 
of hospitalization that occur during elective surgery should be recorded as AEs and assessed 
for seriousness. Admission to the hospital for social or situational reasons (ie, no place to stay, 
live too far away to come for hospital visits, respite care) will not be considered inpatient 
hospitalizations.  
 A persistent or significant disability/incapacity or substantial disruption of the ability to 
conduct normal life functions;  
 A congenital anomaly/birth defect; or 
 An important medical event. 
Note: Important medical events that do not meet any of the above criteria may be considered 
an SAE when, based upon appropriate medical judgment, they may jeopardize the participant 
and may require medical or surgical intervention to prevent 1 of the outcomes listed above. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalizations, or the development of drug dependency. 
SAEs that meet the definition of CV outcome events should also be captured in the CV events 
eCRF.  
The plan for exemption from expedited SAE reporting for disease-related events will be described 
in the Statistical Analysis Plan (SAP), Data Management Plan, and CEC Charter documents.  

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8.4 
SAE Reporting − Procedures for Investigators 
Initial reports 
All SAEs occurring from the time of informed consent until the end of study participation (up to 
35 days post last dose) will be reported, regardless of the Investigator’s determination as to 
relatedness, to 
 within 24 hours of the knowledge of the occurrence. After 
the 30-day reporting window, any SAE that the Investigator considers related to study drug must 
be reported to 
 or the Sponsor/designee (
). 
To report the SAE, complete the SAE form electronically in the EDC system for the study. If the 
event meets serious criteria and it is not possible to access the EDC system, send an email to 
 at 
 or call the 
 SAE reporting 
line (telephone number listed in Section 8.7), and fax/email the completed back-up paper SAE 
form to 
 (contact information listed in Section 8.7) within 24 hours of awareness. When 
the EDC system becomes available, the SAE information must be entered within 24 hours of the 
system becoming available. 
Follow-up reports 
The Investigator must continue to follow the participant until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the 
participant dies. 
Within 24 hours of receipt of follow-up information, the Investigator must update the SAE form 
electronically in the EDC system for the study and submit any supporting documentation 
(eg, participant discharge summary or autopsy reports) to 
 via fax or 
email. If it is not possible to access the EDC system, refer to the procedures outlined above for 
initial reporting of SAEs.  
8.5 
Pregnancy Reporting 
If a participant becomes pregnant during the study, the Investigator is to stop dosing with the study 
drug immediately and permanently. However, the participant should be encouraged to remain in 
the study and to follow-up for study visits. See Section 4.3 for more details regarding withdrawal 
criteria and discontinuation of study drug.  
A pregnancy is not considered to be an AE or SAE; however, it must be reported to 
 
 within 24 hours of knowledge of the event. 
 will then 
provide the Investigator/site the Exposure In Utero (EIU) form (Part 1) for completion. The 
Investigator/site must complete the EIU form (Part 1) and fax/email it back to 
 
  
If the female partner of a male participant becomes pregnant while the participant is receiving 
study drug, the Investigator should notify 
 as described above.  
The pregnancy should be followed until the outcome of the pregnancy is known, whenever 
possible. Once the outcome of the pregnancy is known, the EIU form (Part 2) should be completed 
and faxed/emailed to 
. If the outcome of the pregnancy meets the criteria 
for immediate classification as an SAE (ie, postpartum complication, spontaneous abortion, 
stillbirth, neonatal death, or congenital anomaly), the Investigator should follow the procedures 
for reporting an SAE. 

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8.6 
Expedited Reporting 
The Sponsor/designee 
) will report all relevant information about Suspected Unexpected 
Serious Adverse Reactions (SUSARs) that are fatal or life-threatening to the FDA, applicable 
Competent Authorities in all Member States (including all Institutional Review Boards 
[IRBs]/Independent Ethics Committees [IECs]), and to the Central Ethics Committees no later 
than 7 calendar days (CDs) after knowledge by the Sponsor/designee of such a case. Relevant 
follow-up information will subsequently be communicated within an additional 8 CDs.  
All other SUSARs will be reported to the FDA, applicable Competent Authorities in all Member 
States (including all IRBs/IECs), and to the Central Ethics Committees within a maximum of 
15 CDs of first knowledge by the Sponsor/designee.  
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 drug. 
8.6.1 
Project Specific Exemption From SAE Immediate Reporting to Health Authorities 
and IRBs 
The guidance document of the Committee for Medicinal Products for Human Use (CHMP), 
“Detailed guidance on the collection, verification and presentation of adverse event/reaction 
reports arising from clinical trials on medicinal products for human use,” states that for trials in 
high morbidity and/or high mortality disease, where efficacy endpoints could also be adverse 
reactions reported as SUSARs, these serious events could be treated as disease-related events and 
not be subject to systematic unblinding and expedited reporting.22 
Moreover, the FDA guidance documents titled “Guidance for clinical investigators, sponsors, and 
IRBs. Adverse event reporting to IRBs  improving human subject protection” and “Guidances 
for industry and investigators on safety reporting requirements for investigational new drug 
applications and bioavailability/bioequivalence studies” state that only AEs which are unexpected, 
serious, and would have implications for the conduct of the study should be reported in an 
expedited manner.23,24 
Aggregate unblinded analysis by the independent DSMB will be conducted in order to identify 
safety concerns, such as potential imbalances in event rates between the drug treatment and control 
groups. Should the DSMB identify any potential safety concerns, they will be able to recommend 
reporting of these findings to the Health Authorities (HA), Investigators, Ethics Committees, and 
IRBs. Additionally, the DSMB will have the freedom to determine, based on their ongoing review 
of the safety data, if any of the exempted AEs should be changed to become subject to expedited 
reporting from that point on. A safety report will be submitted if an aggregate analysis indicates 
the anticipated SAEs are occurring more frequently in the treatment group compared to the placebo 
group. 

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8.8 
Clinical Laboratory Evaluations 
Clinical laboratory evaluations (including a full serum chemistry panel, hematology, coagulation, 
and urine dipstick analysis) will be collected at visits specified in the Schedule of Procedures 
(Appendix A). A limited serum chemistry panel will also be collected per the Schedule of 
Procedures (Appendix A). All safety laboratory samples should be collected while the participant 
is fasting (a minimum of 8 hours) and prior to the next dose of study drug (at applicable visits). 
Assessment of laboratory eligibility criteria will be based on central laboratory values obtained 
within timeframes defined in the inclusion and exclusion criteria. 
Urine dipstick analysis will be performed locally from a sample of mid-stream urine. In case of 
abnormal results, microscopy and other assessments will be performed at the local laboratory and 
the abnormality recorded as an AE. 
Please see Appendix B for a complete list of laboratory analytes.  
8.8.1 
Urine Albumin-Creatinine Ratio and Urine Protein-Creatinine Ratio 
A urine sample for urine albumin-creatinine ratio and urine protein-creatinine ratio will be 
collected at visits specified in the Schedule of Procedures (Appendix A). Samples should be 
collected while the participant is fasting (a minimum of 8 hours). 
8.8.2 
Aldosterone and hsCRP 
A plasma sample for aldosterone and hsCRP will be collected at visits specified in the Schedule 
of Procedures (Appendix A). Samples should be collected while the participant is fasting (a 
minimum of 8 hours). 
8.8.3 
Efficacy Endpoint Laboratory Assessments  
Although laboratory values that are part of the efficacy endpoints will not be provided to the sites, 
the Investigator will be notified of critical high LDL-C values as follows: 
 If before Day 84, when the LDL-C values of a participant are >200 mg/dL (>5.2 mmol/L) 
AND exhibit a >50% increase compared to Baseline; or 
 If after Day 84, when the LDL-C values of a participant are >200 mg/dL (>5.2 mmol/L) OR 
exhibit a >50% increase compared to Baseline.  
These critical high values will need to be confirmed by a repeat measurement (new fasting blood 
sample). The Investigator should be encouraged to consult with the Medical Monitor. Investigators 
and the blinded study team will be informed that random sham alerts will also be sent to sites, in 
order to maintain the study blind. 

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8.8.4 
Managing Abnormal and Critical Laboratory Values  
Any laboratory test result abnormality that fulfills the criteria for an SAE will be reported as such 
on the appropriate AE and SAE eCRF. Any treatment-emergent abnormal laboratory result that is 
clinically significant, ie, meets 1 or more of the following criteria, will be recorded as a single 
diagnosis on the AE eCRF: 
 Is accompanied by clinical symptoms; 
 Leads to a change in study drug (eg, study drug interruption or permanent discontinuation); 
and/or 
 Requires a change in concomitant therapy or a medical intervention (eg, the addition of, 
interruption of, or discontinuation of, or any other change in a concomitant medication, 
therapy, or treatment). 
These criteria apply to any protocol and non-protocol-specified safety and/or efficacy laboratory 
results from tests performed after the first dose of study drug that meet clinical significance criteria. 
These criteria do not apply to any abnormal laboratory test results which fall outside the laboratory 
reference range, but which do not meet clinical significance criteria (these will be analyzed and 
reported as laboratory abnormalities) or those which are a result of an AE or an endpoint which 
has already been reported. 
The Investigator is responsible for reviewing laboratory test results and determining whether an 
abnormal value in an individual participant represents a clinically significant change from the 
participant’s Baseline values. In general, laboratory abnormalities without clinical significance 
should not be recorded as AEs. Where applicable, the clinical sequelae, not the laboratory 
abnormality, should be recorded as the AE.  
Critical laboratory values are values that may warrant medical intervention to avoid possible harm 
to a participant. Critical laboratory values will be defined in the Laboratory Manual for the study, 
and the Medical Monitor and Investigator will be notified of the occurrence of a critical laboratory 
value (critical high or critical low) by a special annotation (flag) in the laboratory reports provided 
to the sites. 
If LDL-C values are confirmed critically high (see Section 8.8.3), OR if TG levels exceed 
500 mg/dL (5.7 mmol/L), the Investigator may need to take appropriate medical action, which 
could include the following: reinforce/intensify therapeutic lifestyle changes (including diet and 
physical activity), increase the dose of the present statin therapy, add ezetimibe, or prescribe a 
more potent lipid-modifying therapy to lower LDL-C. The Investigator should use the best clinical 
judgment for each participant. 
8.9 
Vital Signs 
Vital signs (consisting of heart rate and blood pressure) will be measured in triplicate prior to study 
drug administration at applicable visits (see Appendix A). On Day 1 (Visit 2), blood pressure will 
be measured prior to Randomization. When available, an automated blood pressure device is 
recommended for collection of blood pressure and the result should be recorded to the 
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Vital signs will be measured using the following standardized procedures:  
 Participants should not exercise, smoke, or consume caffeinated beverages or food 30 minutes 
prior to assessment of vital signs; and  
 Vital signs should be obtained prior to ECG recordings.  
8.9.1 
Blood Pressure Monitoring  
Blood pressure specifically will be measured using the following standardized procedures:  
 Participants should be seated for at least 5 minutes in the examination room with the back 
supported, feet flat on the floor, and the measurement arm supported so that the midpoint of 
the manometer cuff is at heart level; 
 An appropriately sized cuff should be used with the bladder centered over the brachial artery; 
 The cuff size and arm used for the measurement should be recorded; the same arm should be 
used for all readings; 
 Three seated blood pressure measurements (each measurement 1 to 2 minutes apart) should be 
obtained using the same arm at each site visit. Mean seated blood pressure is defined as the 
average of 3 seated blood pressure measurements at a single site visit; and 
 If the lowest and highest blood pressure measurements are >15 mmHg apart, additional 
readings should be performed. 
Blood pressure readings, both systolic and diastolic, will be evaluated over time by the independent 
DSMB, who will monitor unblinded safety data during the study on a bi-annual basis 
(ie, approximately every 6 months). Changes in blood pressure, as well as heart rate, will be 
compared between treatment groups with respect to mean and median values over time using both 
actual values and absolute changes from Baseline. In addition, treatment groups will be compared 
with respect to the incidence of hypertensive status and other vital sign abnormalities as defined 
in the SAP. 
8.9.1.1 
24-hour ABPM 
Participants from selected study sites who consent to participate in the ABPM substudy will have 
a 24-hour ABPM assessment conducted at applicable visits (see Appendix A). The 24-hour ABPM 
assessment at Screening (Visit 1) should be completed after the participant’s eligibility has been 
confirmed at that visit. It should be ensured that sufficient time is allotted during Screening 
(Visit 1) to allow for a repeat 24-hour ABPM assessment, if the first is not successful, prior to 
Randomization (Visit 2). For the 24-hour ABPM assessment at Visit 6 (Day 270), it should be 
ensured that a repeat assessment (if necessary) is completed within the respective visit window 
and that the assessment is not done concurrently with other study procedures. 
Please refer to the separate study manual for additional details surrounding the 24-hour ABPM 
assessment for the substudy. 
8.10 
Electrocardiograms 
A single 12-lead ECG will be performed in the supine position after 10 minutes of rest at visits 
specified in Appendix A. ECGs are to be assessed for clinical significance by a qualified medical 
designee at the study site.  

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8.11 
Physical Examinations 
Physical examinations will be completed at visits specified in Appendix A. The physical 
examination should comprise a focused examination, which includes general, respiratory, CV, 
abdominal, and extremities evaluations; ophthalmological examination; and recording of weight 
and height. Height will be measured at Screening (Visit 1) only and used to calculate body mass 
index. 

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9 
STATISTICS 
9.1 
Analysis Populations 
The Intent-to-Treat (ITT) Population will include all participants who are 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 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 
An 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 final 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, mean, 
standard deviation, median, minimum, and maximum values. Analyses 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 study drug. 
9.2.1 
Analysis of Efficacy 
9.2.1.1 
Primary efficacy analysis 
The ITT Population will be the primary population for the efficacy analysis. Efficacy will also be 
analyzed using the FAS, mITT Population, and PP Population as supplementary analyses. 
The primary efficacy endpoint is the percent change from Baseline to Day 84 in LDL-C in the 
obicetrapib group compared to the placebo group. The primary endpoint will be analyzed using an 
analysis of covariance (ANCOVA) model with a fixed effect for the treatment group and covariates 
of Baseline LDL-C, CV risk (HeFH or non-HeFH), and Baseline statin therapy (HIS or non-HIS). 
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. The model will 
be fit assuming unequal variances for each treatment group. 
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 

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and placebo 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 and exploratory efficacy analysis 
In order to control the Type I error rate, a fixed sequential testing procedure will be implemented. 
In a hierarchical step-down manner, the primary endpoint will be tested first, followed by the 
secondary efficacy endpoints in a pre-specified order. The pre-specified order of the hypothesis 
testing for the secondary endpoints will be described in the SAP. No adjustment for multiple 
comparisons will be made for the exploratory efficacy endpoints.  
Continuous secondary efficacy endpoints will be analyzed using similar methods as in the primary 
efficacy analysis. 
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% confidence interval 
for LS means will be provided for continuous variables. Odds ratio and 95% confidence interval 
for the odds ratio will be provided for exploratory efficacy endpoints corresponding to binary 
variables. For time-to-event endpoints, the log-rank test, stratified by CV risk (HeFH or 
non-HeFH) and Baseline statin therapy (HIS or non-HIS), will be used to compare differences in 
the time-to-event between obicetrapib and placebo. The hazard ratio and the associated 
95% confidence interval will be estimated using a stratified Cox proportional hazards model with 
treatment as an explanatory variable, stratified by CV risk (HeFH or non-HeFH) and Baseline 
statin therapy (HIS or non-HIS). Additionally, Kaplan-Meier estimates of the time-to-event will 
be determined and displayed graphically. The proportional hazard assumption will be evaluated, 
such as through the examination of complementary log-log (event times) versus log (time) plots, 
etc. If the proportional hazard assumption raises concerns, additional analyses will be considered 
and will be further detailed in the SAP. Nominal p-values will be provided when applicable. 
Descriptive and graphical summaries by treatment group will also be presented. A population PK 
analysis will be described in a separate document.  
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 analysis. All safety endpoints 
will be summarized descriptively. 
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. 

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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). 
9.2.2.1 
Analysis of ESIs 
Liver-associated enzymes and total bilirubin will be summarized by the value and change from 
Baseline in the value, by treatment group and visit. In addition, the number and percent of 
participants with abnormal values for ALT, AST, and total bilirubin will be summarized. These 
summaries of participants with abnormal values will be performed overall; by normal Baseline; 
and by abnormal Baseline for ALT, AST, and total bilirubin individually. Hy’s Law criteria 
(>3  ULN for either ALT or AST, with accompanying total bilirubin >2  ULN) will also be 
applied to the data. Any potential Hy’s Law cases will be listed separately. 
Muscle-related abnormalities will be summarized by treatment group and by Baseline eGFR 
category. 
CK levels will be summarized by the value and change from Baseline in value, by treatment group 
and visit. In addition, the number and percent of participants with abnormal CK values will be 
summarized. These summaries of participants with abnormal CK values will be performed overall, 
by normal Baseline CK, and by abnormal Baseline CK. Values of CK from Baseline to EOT will 
be summarized by treatment group and by Baseline eGFR category. 
Cases of NODM will be recorded and summarized using the appropriate system organ class. These 
events will be summarized by severity and relationship to study drug for each treatment group. 
Fasting plasma glucose and HbA1c will be monitored as specified in Appendix A. 
Baseline eGFR will be summarized by treatment group for actual value and for Baseline eGFR 
categories. Shift tables of eGFR category from Baseline to EOT will be provided by treatment 
group. Shift tables of urine albumin-creatinine ratio and urine protein-creatinine ratio from 
Baseline to EOT will be provided by treatment group.  
The number and percentage of participants receiving antihypertensive medication(s) treatment at 
Baseline with changes to antihypertensive medication(s) due to changes in blood pressure will be 
summarized by treatment group. 
Cases of macular degeneration will be recorded and summarized using the appropriate system 
organ class. These events will be summarized by severity and relationship to study drug for each 
treatment group. 
9.2.3 
Interim Analysis 
No interim analysis is planned for the study. The study will be governed by a Steering Committee. 
9.2.4 
Clinical Events Committee 
An independent CEC will adjudicate all events of death and all potential or suspected CV events. 
A committee charter will be drafted to define the composition, roles, and responsibilities of the 
CEC.  

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9.2.5 
Data and Safety Monitoring Board 
An independent DSMB will monitor unblinded safety data, including blood pressure changes over 
time and the occurrence of ESIs, during the study on a bi-annual basis (ie, approximately every 
6 months). 
Additional information is provided in the DSMB Charter.  
9.2.6 
Sample Size Determination 
Enrollment of approximately 2400 participants globally is planned for this study. 
Assuming an approximate 5% drop out rate, approximately 2280 participants will be evaluable for 
efficacy. This sample size of at least 2280 evaluable participants will provide more than 
90% power to detect a 30% reduction of LDL-C (standard deviation 15%) levels in the obicetrapib 
group compared to the placebo group at a 1-sided significance level of 0.025. This sample size 
will also contribute to sufficient participant exposure and safety data. 
9.2.6.1 
ABPM substudy 
This substudy is designed for a non-inferiority assessment in systolic blood pressure from 
Screening (Visit 1) to Day 270 (Visit 6) between obicetrapib and placebo. The non-inferiority 
margin was selected in accordance with the United States FDA guidelines (Assessment of Pressor 
Effects of Drugs, Guidance for Industry).25 The non-inferiority margin was chosen to assess if 
obicetrapib is not substantially inferior to placebo for elevations in systolic blood pressure. The 
assumption for the common standard deviation is determined by a literature review and the 
obicetrapib Phase 2 program. From the reference paper by Vollmer et al, the estimate of the 
standard deviation for the change in systolic blood pressure (mmHg) for hypertensive participants 
based on 24-hour ABPM measurements was 8.0 (95% confidence interval: 6.9, 9.4).26 
A subset of approximately 200 participants from selected study sites who consent to participate 
will be enrolled in the ABPM substudy. For inclusion in the substudy analysis, participants must 
have an acceptable 24-hour ABPM data collection at Screening (Visit 1), as defined in a separate 
study manual. This sample size will allow for non-inferiority to be established between the 
obicetrapib group compared to the placebo group, with desired power of >80%, against a 
non-inferiority difference of 3 mmHg. This assumes a mean treatment difference of 0 mmHg for 
the obicetrapib group compared to the placebo group, with a standard deviation of 8 mmHg, at a 
1-sided significance level of 0.05. 

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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 study site on eCRFs and reviewed by the Clinical Research Associate 
(CRA) during monitoring visits. The CRAs will verify data recorded in the EDC system with 
source documents. All corrections or changes made to any study data must be appropriately tracked 
in an audit trail in the EDC system. An eCRF will be considered complete when all missing, 
incorrect, and/or inconsistent data have 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 study 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 
(CFR) 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 study 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 drug, 
regulatory documents, and other Sponsor correspondence pertaining to the study must be kept in 
the appropriate study files at the study 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 
IRB/IEC 
The IRB/IEC will review all appropriate study documentation in order to safeguard the rights, 
safety, and wellbeing of participants. The study will only be conducted at sites where IRB/IEC 
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/IEC by the Investigator in 
countries where submission is carried out by the site to the IRB/IEC. In countries where the 
Sponsor is responsible for submission to regulatory authorities/IRB/IEC, the documents will be 
submitted by the Sponsor or by designee based on Letter of Authorization. 
Federal regulations and International Council for Harmonisation (ICH) Guidelines require that 
approval be obtained from an IRB/IEC 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/IEC. 
No study drug will be released to the study site for dosing until written IRB/IEC authorization has 
been received by the Sponsor. 
It is the responsibility of the Sponsor or their designee (ie, 
) to obtain the approval of the 
responsible ethics committees according to the national regulations. 
The study will only start at the respective study sites once the respective committee’s written 
approval has been given. 
11.3 
Informed Consent 
The ICF and any changes to the ICF made during the course of the study must be agreed to by the 
Sponsor or designee and the IRB/IEC 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-specific activity is performed and should 
document in the source documentation that consent was obtained prior to enrollment in the study. 
The original signed copy of the ICF must be maintained by the Investigator and is subject to 
inspection by a representative of the Sponsor, their representatives, auditors, the IRB/IEC, and/or 
regulatory agencies. A copy of the signed ICF will be given to the participant. 

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In order to participate in the ABPM substudy, participants must provide written informed consent 
in a substudy-specific ICF. 
11.4 
Subject Card 
On enrollment in the study, the participant will receive a subject card to be carried at all times. The 
subject card will state that the participant is participating in a clinical research study, type of 
treatment, and contact details in case of an SAE. 
11.5 
Study Monitoring Requirements 
It is the responsibility of the Investigator to ensure that the study is conducted in accordance with 
the protocol; Declaration of Helsinki; ICH GCP E6; 21 CFR Parts 11, 50 A and B, 54, and 56; and 
applicable legal and regulatory requirements according to the country of conduct, 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 study site personnel the following documents: protocol, Investigator’s 
Brochure, eCRFs and procedures for their completion, informed consent process, and the 
procedure for reporting SAEs. 
The Investigator will permit the Sponsor or their designee to monitor the study as frequently as 
deemed necessary to determine that data recording and protocol adherence are satisfactory. During 
the monitoring visits, information recorded on the eCRFs will be verified against source 
documents and requests for clarification or correction may be made. After the eCRF data are 
entered by the study 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 CRA 
and provide any missing information, whenever possible. 
All monitoring activities will be reported and archived. In addition, monitoring visits will be 
documented at the study site by signature and date on the study-specific monitoring log. 
11.6 
Disclosure of Data 
Data generated by this study must be available for inspection by the FDA, the Sponsor or their 
designee, applicable HA, and the IRB/IEC 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. 
11.7 
Retention of Records 
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator 
will keep records, including the identity of all participating 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 

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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 or another institution. In countries where the local law permits, the 
acceptable designee may also be the Sponsor (eg, outside of European Union countries). 
11.8 
Publication Policy 
Following completion of the study, the data may be considered for publication in a scientific 
journal or for reporting at a scientific meeting. Each Investigator is obligated to keep data 
pertaining to the study confidential. The Investigator must consult with the Sponsor before any 
study data are submitted for publication. The Sponsor reserves the right to deny publication rights 
until mutual agreement on the content, format, interpretation of data in the manuscript, and journal 
selected for publication are achieved. 
11.9 
Financial Disclosure 
Investigators are required to provide financial disclosure information to the Sponsor to permit the 
Sponsor to fulfill its obligations under 21 CFR 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. 
11.10 
Insurance and Indemnity  
In accordance with the relevant national regulations, the Sponsor has taken out participant liability 
insurance for all participants who have given their consent to the clinical study. This cover is 
designed for the event that a fatality, physical injury, or damage to health occurs during the clinical 
study’s execution. 
11.11 
Legal Aspects 
The clinical study is submitted to the relevant national Competent Authorities in all participating 
countries to achieve a clinical trial authorisation (CTA). 
The study will commence (ie, initiation of study centers) when the CTA and favorable Ethics 
opinion have been received. 

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12 
STUDY ADMINISTRATIVE INFORMATION 
12.1 
Protocol Amendments 
Any amendments to the study protocol will be communicated to the Investigator by 
 or 
the Sponsor. All protocol amendments will undergo the same review nd approval process as the 
original protocol. A protocol amendment may be implemented after it has been approved by the 
IRB/IEC, unless immediate implementation of the change is necessary for participant safety. In 
this case, the situation must be documented and reported to the IRB/IEC 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. 
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. 
14. 
van Capelleveen JC, Kastelein JJ, 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. 
 

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15. 
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. 
16. 
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. 
17. 
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.  
18. 
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. 
19. 
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.  
20. 
Hicks KA, Mahaffey KW, Mehran R, et al. 2017 cardiovascular and stroke endpoint 
definitions for clinical trials. J Am Coll Cardiol. 2018;71(9):1021-1034. 
21. 
Thygesen K, Alpert JS, Jaffe AS, et al. Fourth universal definition of myocardial infarction 
(2018). J Am Coll Cardiol. 2018;72(18):2231-2264. 
22. 
European Commission. Communication from the Commission  Detailed guidance on the 
collection, verification and presentation of adverse event/reaction reports arising from 
clinical trials on medicinal products for human use (‘CT-3’). Official Journal of the 
European Union. 2011;C 172:1-13. 
23. 
United States Food and Drug Administration. Guidance for clinical investigators, sponsors, 
and IRBs. Adverse event reporting to IRBs  improving human subject protection. 
January 2009. https://www.fda.gov/media/72267/download. Accessed 09 December 2021. 
24. 
United States Food and Drug Administration. Guidances for industry and investigators on 
safety reporting requirements for investigational new drug applications and 
bioavailability/bioequivalence studies, and a small entity compliance guide; availability. 
Federal Register. 2012;77(245):75439-75440. 
25. 
United States Food and Drug Administration. Assessment of pressor effects of drugs. 
Guidance for industry. February 2022. https://www.fda.gov/media/113477/download. 
Accessed 14 June 2022. 
26. 
Vollmer WM, Appel LJ, Svetkey LP, et al. Comparing office-based and ambulatory blood 
pressure monitoring in clinical trials. J Hum Hypertens. 2005;19(1):77-82. 
 

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APPENDIX A: SCHEDULE OF PROCEDURES 
  
Screening 
Treatment Period 
EOS1 
Visit
V1 
V2 
V3 
V4 
V5 
V6 
V7/EOT/ET2 
V8 
Study Day
-28 to -1 
1 
30 
84 
180 
270 
365 
35 days after 
last dose 
Window (±days)
 
 
±3 
±7 
±7 
±7 
±7 
±7 
Informed consent3 
X 
 
 
 
 
 
 
 
Assessment of eligibility 
X4 
X4 
 
 
 
 
 
 
Demographics and medical history 
X 
 
 
 
 
 
 
 
Pregnancy test, FSH5 
X 
X 
 
 
X 
 
X 
 
TSH 
X 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
Study drug administration 
 
X 
X 
X 
X 
X 
X 
 
Physical examination6 
X 
 
 
 
 
 
X 
 
Weight, height, and BMI 
X7 
 
 
 
 
 
X 
 
Vital signs8 
X 
X 
X 
X 
X 
X 
X 
X 
24-hr ABPM9 
X10 
 
 
 
 
X11 
 
 
12-lead ECG12 
 
X 
 
 
 
 
X 
 
Lipid profile/biomarkers (fasting)13 
X 
X 
X 
X 
X 
X 
X 
 
Serum archive sample for future 
assessment of biomarkers related to 
dyslipidemia and/or CV risk (fasting)13,14,15 
 
X 
 
 
 
 
X 
 
UACR, UPCR (fasting)13 
 
X 
 
 
 
 
X 
 
Aldosterone, hsCRP (fasting)13 
X16 
X 
 
 
 
 
X 
 
Lp(a), ApoA1 (fasting)13,14 
X 
X 
 
X 
 
 
 
 
Insulin for HOMA-IR (fasting)13  
X 
X 
 
X 
X 
X 
X 
 
Full serum chemistry (fasting)13,14 
 
X 
 
 
X 
 
X 
 
Limited serum chemistry (fasting)13,14 
X 
 
X 
X 
 
X 
 
 
Urine dipstick analysis17 
X 
X 
 
 
 
 
X 
 
Hematology and coagulation (fasting)13,14 
X 
X 
 
 
X 
 
X 
 
PK sample (central)14,18 
 
X 
 
 
X 
 
X 
 
Prior/concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug dispensation 
 
X 
X 
X 
X 
X 
 
 
Footnotes are at the end of the table. 
 

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Screening 
Treatment Period 
EOS1 
Visit
V1 
V2 
V3 
V4 
V5 
V6 
V7/EOT/ET2 
V8 
Study Day
-28 to -1 
1 
30 
84 
180 
270 
365 
35 days after 
last dose 
Window (±days)
 
 
±3 
±7 
±7 
±7 
±7 
±7 
Study drug return/compliance calculations 
 
 
X 
X 
X 
X 
X 
 
CV events assessment19 
X 
X 
X 
X 
X 
X 
X 
X 
AEs assessment 
X 
X 
X 
X 
X 
X 
X 
X 
 
1. 
The onsite EOS Visit will include an assessment of vital signs, concomitant medications, CV events, and AEs will be completed and documented in the participant’s record. 
2. 
For participants who permanently discontinue from study treatment and who decline continued study participation, an ET Visit will be scheduled as soon as possible followed 
by an onsite EOS Visit 35 days later. If the discontinuation occurs at a specific onsite visit, this visit will become the ET Visit and EOT Visit procedures should be followed. 
Participants who withdraw consent to all follow-up will be asked about the reason(s) and will be assessed for the presence of any AEs. For participants who completely withdraw 
consent, life status will be obtained at study end through public record information according to local guidelines and as allowed by local regulations. 
3. 
Informed consent will be obtained from participants before the initiation of any study-specific procedures. In order to participate in the ABPM substudy, participants must 
provide written informed consent in a substudy-specific ICF. 
4. 
Assessment of laboratory eligibility criteria will be based on central laboratory values obtained within timeframes defined in the inclusion and exclusion criteria. 
5. 
Urine pregnancy tests will be performed for females of childbearing potential only (performed locally using central laboratory kit supplies). FSH will only be performed at 
Screening (Visit 1) in females <55 years of age and postmenopausal, defined as 1 year since their last menstrual period. 
6. 
The physical examination should comprise a focused examination, which includes general, respiratory, CV, abdominal, and extremities evaluations; ophthalmological 
examination; and recording of weight and height. 
7. 
Height will be measured at Screening (Visit 1) only and used to calculate BMI. 
 
8. 
Vital signs (consisting of heart rate and blood pressure) will be measured as described in Section 8.9. 
 
9. 
Only participants who consent to participate in the ABPM substudy will have this assessment performed.  
10. The 24-hour ABPM assessment at Screening (Visit 1) should be completed after the participant’s eligibility has been confirmed at that visit. It should be ensured that sufficient 
time is allotted during Screening (Visit 1) to allow for a repeat 24-hour ABPM assessment, if the first is not successful, prior to Randomization (Visit 2). Additional details 
surrounding this substudy are included in a separate study manual. 
11. It should be ensured that a repeat assessment (if necessary) is completed within the respective visit window and that the assessment is not done concurrently with other study 
procedures.  
12. A single l2-lead ECG will be performed in the supine position after 10 minutes of rest. 
13. Participants must fast for a minimum of 8 hours prior to samples being collected.  
14. Samples should be collected prior to study drug administration. 
15. Serum archive sample is not collected in China. 
16. Only hsCRP will be assessed at Screening (Visit 1). 
17. Urine dipstick analysis will be performed locally from a sample of mid-stream urine. In case of abnormal results, microscopy and other assessments will be performed at the 
local laboratory and the abnormality recorded as an AE. 
18. A PK sample will be collected prior to study drug administration for trough measurement of obicetrapib in plasma. At Visits 2, 5, and 7, participants should take study drug 
after a trough PK sample has been drawn. 
19. CV events include CV death, non-fatal myocardial infarction, non-fatal stroke, non-elective coronary revascularization, hospitalization for unstable angina and/or chest pain, 
hospitalization for heart failure, and transient ischemic attack. 
ABPM = ambulatory blood pressure monitoring; AE = adverse event; ApoA1 = apolipoprotein A1; BMI = body mass index; CV = cardiovascular; ECG = electrocardiogram; 
EOS = End of Study; EOT = End of Treatment; ET = Early Termination; FSH = follicle-stimulating hormone; HOMA-IR = homeostatic model assessment of insulin resistance; 
 

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hsCRP = high sensitivity C-reactive protein; ICF = informed consent form; Lp(a) = lipoprotein (a); PK = pharmacokinetic(s); TSH = thyroid-stimulating hormone; UACR = urine 
albumin-creatinine ratio; UPCR = urine protein-creatinine ratio; V = Visit. 
 

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APPENDIX B: CLINICAL LABORATORY ANALYTES 
Full Serum Chemistry Panel 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Bicarbonate 
Bilirubin (direct, indirect, and total) 
Blood urea nitrogen 
Calcium 
Chloride 
Creatine kinase 
Creatinine 
Estimated glomerular filtration rate [1] 
Gamma-glutamyl transferase 
Glucose (fasting) 
Glycosylated hemoglobin (HbA1c) 
Inorganic phosphorus 
Potassium 
Sodium 
Total protein  
Uric acid 
1. 
Calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. 
 
Limited Serum Chemistry Panel 
Alanine aminotransferase 
Alkaline phosphatase 
Aspartate aminotransferase 
Bilirubin (total) 
Creatine kinase 
Creatinine 
Estimated glomerular filtration rate [1] 
Gamma-glutamyl transferase 
Glucose (fasting) 
HbA1c 
1. 
Calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. 
 
Lipid Profile/Biomarkers 
Apolipoprotein B 
High-density lipoprotein cholesterol 
Low-density lipoprotein cholesterol 
(LDL-C) [1] 
Non-high-density lipoprotein cholesterol 
Total cholesterol 
Triglycerides (TG) 
1. 
At Baseline (Visit 2), Day 84 (Visit 4), and Day 365 (Visit 7)/End of Treatment/Early Termination, LDL-C will be 
measured for all participants by preparative ultracentrifugation, also referred to as beta quantification. At all other 
scheduled visits, LDL-C will be calculated using the Friedewald equation unless TG 400 mg/dL (4.5 mmol/L) or 
LDL-C 50 mg/dL (1.3 mmol/L). If TG 400 mg/dL (4.5 mmol/L) or LDL-C 50 mg/dL (1.3 mmol/L), then LDL-C 
level will be measured directly by preparative ultracentrifugation.  
 
Endocrinology 
Homeostatic model assessment of insulin 
resistance 
Insulin 
 
Follicle-stimulating hormone [1] 
Human chorionic gonadotrophin [2] 
Thyroid-stimulating hormone 
 
1. 
Follicle-stimulating hormone will only be performed in females <55 years of age and postmenopausal, defined as 1 year 
since their last menstrual period. 
2. 
Human chorionic gonadotrophin will be performed for females of childbearing potential.  
 

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Hematology 
Hematocrit 
Hemoglobin 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin concentration 
Mean corpuscular volume 
Platelets 
Red blood cell count 
Reticulocyte 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.  
 
Coagulation 
Activated partial thromboplastin 
International normalized ratio 
Prothrombin time 
 
 
Urine Dipstick Analysis 
Bilirubin 
Blood 
Glucose 
Ketones 
Leukocyte esterase 
Microscopy [1] 
Nitrite 
pH 
Protein 
Urobilinogen 
1. 
Urine dipstick analysis will be performed locally from a sample of mid-stream urine. In case of abnormal results, 
microscopy and other assessments will be performed at the local laboratory and the abnormality recorded as an adverse 
event. 
 
Other Laboratory Analytes 
Aldosterone 
Apolipoprotein A1  
High sensitivity C-reactive protein  
Lipoprotein (a)  
Urine albumin-creatinine ratio 
Urine protein-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 
a) First-degree relative with tendon xanthomata and/or arcus cornealis; OR 
b) 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 250-329 mg/dL (6.5-8.5 mmol/L) 
5 
c) LDL-C 190-249 mg/dL (4.9-6.4 mmol/L) 
3 
d) LDL-C 155-189 mg/dL (4.0-4.9 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 
6-8 points 
Possible when 
3-5 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 21 April 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 

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APPENDIX E: CORRECTION FACTORS FOR LIPID-MODIFYING 
DRUGS 
Lipid-Modifying Drug 
Dose 
Reduction in Percentage 
Correction Factor1 
Atorvastatin 
10 mg 
37 
1.59 
20 mg 
43 
1.75 
40 mg 
49 
1.96 
80 mg 
55 
2.22 
Fluvastatin 
20 mg 
21 
1.27 
40 mg 
27 
1.37 
80 mg 
33 
1.49 
Pravastatin 
10 mg 
20 
1.25 
20 mg 
24 
1.32 
40 mg 
39 
1.64 
Rosuvastatin 
5 mg 
38 
1.61 
10 mg 
43 
1.75 
20 mg 
48 
1.92 
40 mg 
53 
2.13 
Simvastatin 
5 mg 
23 
1.30 
10 mg 
27 
1.37 
20 mg 
32 
1.47 
40 mg 
37 
1.59 
Statin/Ezetimibe 
Low-dose/10 mg 
44 
1.79 
Mid-dose/10 mg 
45 
1.81 
High-dose/10 mg 
53 
2.13 
Ezetimibe 
10 mg 
19 
1.23 
Correction factor = 100/(100  reduction in percentage). 
1. 
The correction factor should be multiplied by a historical or Screening LDL-C value. For example, a patient taking 
atorvastatin 80 mg, with an LDL-C of 93 mg/dL, has the equivalent of an “off-treatment” LDL-C value of 206.46 mg/dL 
(93 mg/dL  2.22 = 206.46 mg/dL).  
LDL-C = low-density lipoprotein cholesterol. 
Sources: 
Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, 
and stroke: systematic review and meta-analysis. BMJ. 2003;326(7404):1423. doi:10.1136/bmj.326.7404.1423 
Davidson MH, Ballantyne CM, Kerzner B, et al. Efficacy and safety of ezetimibe coadministered with statins: randomised, 
placebo-controlled, blinded experience in 2382 patients with primary hypercholesterolemia. Int J Clin Pract. 
2004;58(8):746-755 
Source: Besseling J, Kindt I, Hof M, et al. Severe heterozygous familial hypercholesterolemia and risk for 
cardiovascular disease: a study of a cohort of 14,000 mutation carriers. Atherosclerosis. 2014;233(1):219-223 

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APPENDIX F: ENDPOINT DEFINITIONS PER THE 2017 
CARDIOVASCULAR AND STROKE ENDPOINT DEFINITIONS FOR 
CLINICAL TRIALS20 
CARDIOVASCULAR DEATH 
Cardiovascular (CV) death includes death resulting from an acute myocardial infarction (MI), 
sudden cardiac death, death due to heart failure (HF), death due to stroke, death due to CV 
procedures, death due to CV hemorrhage, and death due to other CV causes. 
Classifying CV mortality more specifically (MI, sudden death, etc) is usually not needed for 
outcome trials. Moreover, such classification is difficult because the classifications refer both to 
underlying cause (eg, acute MI, which can cause fatal arrhythmias or HF) and to mode of death 
(sudden/arrhythmic; HF, which can result from an MI or worsening HF), and they overlap 
substantially. The following definitions can, however, be used if desired: 
1. Death due to acute MI refers to death by any CV mechanism (eg, arrhythmia, sudden death, 
HF, stroke, pulmonary embolus, peripheral arterial disease) 30 days2 after an MI, related to 
the immediate consequences of the MI, such as progressive HF or recalcitrant arrhythmia. We 
note that there may be assessable mechanisms of CV death during this time period, but for 
simplicity, if the CV death occurs 30 days after the MI, it will be considered a death due to 
MI. 
Acute MI should be verified to the extent possible by the diagnostic criteria outlined for acute 
MI or by autopsy findings showing recent MI or recent coronary thrombosis. 
Death resulting from a procedure to treat an MI (percutaneous coronary intervention [PCI], 
coronary artery bypass graft [CABG] surgery), or to treat a complication resulting from MI, 
should also be considered a death due to acute MI.  
Death resulting from an elective coronary procedure to treat myocardial ischemia (ie, chronic 
stable angina) or death due to an MI that occurs as a direct consequence of a CV 
investigation/procedure/operation should be considered a death due to a CV procedure. 
2. Sudden cardiac death refers to death that occurs unexpectedly and not within 30 days of an 
acute MI. Sudden cardiac death includes the following scenarios: 
a. Death witnessed and occurring without new or worsening symptoms; 
b. Death witnessed within 60 minutes of the onset of new or worsening cardiac symptoms, 
unless the symptoms suggest acute MI; 
c. Death witnessed and attributed to an identified arrhythmia (eg, captured on an 
electrocardiogram [ECG], witnessed on a monitor, or unwitnessed but found on 
implantable cardioverter-defibrillator [ICD] review); 
 
2 The 30 day cut-off is arbitrary.  

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d. Death after unsuccessful resuscitation from cardiac arrest (eg, ICD unresponsive sudden 
cardiac death, pulseless electrical activity arrest); 
e. Death after successful resuscitation from cardiac arrest and without identification of a 
specific cardiac or non-cardiac etiology; and  
f. Unwitnessed death in a participant seen alive and clinically stable 24 hours prior to being 
found dead without any evidence supporting a specific non-CV cause of death (information 
regarding the participant’s clinical status preceding death should be provided, if available). 
General considerations: 
Unless additional information suggests an alternate specific cause of death (eg, death 
due to other CV causes), if a participant is seen alive within 24 hours of being found 
dead, sudden cardiac death (Criterion 2f) should be recorded. For participants who 
were not observed alive within 24 hours of death, undetermined cause of death should 
be recorded (eg, a participant found dead in bed, but who had not been seen by family 
for >24 hours). 
3. Death due to HF refers to death in association with clinically worsening symptoms and/or signs 
of HF regardless of HF etiology. Deaths due to HF can have various etiologies, including single 
or recurrent MIs, ischemic or non-ischemic cardiomyopathy, hypertension, or valvular disease. 
4. Death due to stroke refers to death after a stroke that is either a direct consequence of the stroke 
or a complication of the stroke. Acute stroke should be verified to the extent possible by the 
diagnostic criteria outlined for stroke. 
5. Death due to CV procedures refers to death caused by the immediate complications of a cardiac 
procedure. 
6. Death due to CV hemorrhage refers to death related to hemorrhage such as a non-stroke 
intracranial hemorrhage (eg, subdural hematoma), non-procedural or non-traumatic vascular 
rupture (eg, aortic aneurysm), or hemorrhage causing cardiac tamponade. 
7. Death due to other CV causes refers to CV death not included in the above categories but with 
a specific, known cause (eg, pulmonary embolism or peripheral arterial disease). 
 

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NON-CARDIOVASCULAR DEATH 
Non-CV death is defined as any death with a specific cause that is not thought to be CV in nature. 
Detailed recommendations on the classification of non-CV causes of death are beyond the scope 
of this appendix. The level of detail required and the optimum classification will depend on the 
nature of the study population and the anticipated number and type of non-CV deaths. Any specific 
anticipated safety concern should be included as a separate cause of death. The following is a 
suggested list of non-CV causes of death: 
 Pulmonary; 
 Renal; 
 Gastrointestinal; 
 Hepatobiliary; 
 Pancreatic; 
 Infection (includes sepsis); 
 Inflammatory (eg, Systemic Inflammatory Response Syndrome, other immune conditions 
[including autoimmune]; may include anaphylaxis from environmental factors [eg, food 
allergies]); 
 Hemorrhage that is neither CV bleeding nor a stroke; 
 Non-CV procedure or surgery; 
 Trauma (includes homicide); 
 Suicide; 
 Non-prescription drug reaction or overdose; 
 Prescription drug reaction or overdose (may include anaphylaxis); 
 Neurological (non-CV) (excludes CV death from ischemic stroke, hemorrhagic stroke, or 
undetermined cause of stroke or CV hemorrhage of central nervous system); 
 Malignancy (eg, leukemia, lymphoma, or other malignancy); and 
 Other non-CV. 

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UNDETERMINED CAUSE OF DEATH  
Undetermined cause of death refers to death not attributable to 1 of the above categories of CV 
death or to a non-CV cause. Inability to classify the cause of death may be due to lack of 
information (eg, the only available information is “participant died”) or when there is insufficient 
supporting information or detail to assign the cause of death. In general, most deaths should be 
classifiable as CV or non-CV, and the use of this category of death, therefore, should be 
discouraged and should apply to few participants in well-run clinical studies. 
A common analytic approach for cause of death analyses is to assume that all undetermined cases 
are included in the CV category (eg, presumed CV death, specifically “death due to other CV 
causes”). Nevertheless, the appropriate classification and analysis of undetermined causes of death 
depends on the population, the intervention under investigation, the duration of follow-up, and the 
disease process (presuming CV death does not seem appropriate, for example, for people with late 
stage cancer, advanced pulmonary disease, long-standing infections, etc). The approach should be 
prespecified and described in the protocol and other study documentation such as the endpoint 
adjudication procedures and/or the Statistical Analysis Plan. 

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UNSTABLE ANGINA 
Unstable angina requiring hospitalization is defined as all of the following:  
1. Ischemic discomfort (angina or symptoms thought to be equivalent) 10 minutes in duration 
occurring: 
o At rest; or 
o In an accelerating pattern with frequent episodes associated with progressively decreased 
exercise capacity. 
2. Prompting an unscheduled hospitalization within 24 hours of the most recent symptoms. 
Hospitalization is defined as an admission to an inpatient unit or a visit to an emergency 
department that results in at least a 24-hour stay (or a change in calendar date if the hospital 
admission or discharge times are not available). 
3. At least 1 of the following: 
a. New or worsening ST or T wave changes on resting ECG (in the absence of confounders, 
such as left bundle branch block or left ventricular hypertrophy) as follows: 
 Transient ST elevation (duration <20 minutes), defined as a new ST elevation at the 
J point in 2 contiguous leads with the following cut-points: 0.1 mV in all leads other 
than leads V2 to V3 where the following cut-points apply: 0.2 mV in men 40 years 
(0.25 mV in men <40 years) or 0.15 mV in women; or 
 ST depression and T-wave changes, defined as new horizontal or down-sloping 
ST depression 0.05 mV in 2 contiguous leads and/or new T-wave inversion 0.3 mV 
in 2 contiguous leads with prominent R wave or R/S ratio >1. 
b. Definite evidence of inducible myocardial ischemia as demonstrated by:  
 An early positive exercise stress test, defined as an ST elevation or 2 mm 
ST depression prior to 5 metabolic equivalents; 
OR 
 Stress echocardiography (reversible wall motion abnormality); or 
 Myocardial scintigraphy (reversible perfusion defect); or 
 Magnetic resonance imaging (myocardial perfusion deficit under pharmacologic 
stress); and  
 Believed to be responsible for the myocardial ischemic symptoms/signs. 
c. Angiographic evidence of new or worse 70% lesion (50% for left main lesion) and/or 
thrombus in an epicardial coronary artery that is believed to be responsible for the 
myocardial ischemic symptoms/signs; or 
d. Need for coronary revascularization procedure (PCI or CABG) for the presumed culprit 
lesion(s), as defined in 3c. This criterion would be fulfilled if revascularization was 
undertaken during the unscheduled hospitalization, or subsequent to transfer to another 
institution without interceding home discharge. 

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4. Negative cardiac biomarkers and no evidence of acute MI.  
General considerations 
1. Escalation of pharmacotherapy for ischemia, such as intravenous nitrates or increasing dosages 
of β-blockers, should be considered supportive but not diagnostic of unstable angina. However, 
a typical presentation and admission to the hospital with escalation of pharmacotherapy, 
without any of the additional findings listed under category 3, would be insufficient to support 
classification as hospitalization for unstable angina. 
2. If participants are admitted with suspected unstable angina, and subsequent testing reveals a 
non-cardiac or non-ischemic etiology, this event should not be recorded as hospitalization for 
unstable angina. Potential ischemic events meeting the criteria for MI should not be 
adjudicated as unstable angina. 
3. Planned hospitalization or rehospitalization for performance of an elective revascularization in 
participants who do not fulfill the criteria for unstable angina should not be considered a 
hospitalization for unstable angina. For example: 
o Hospitalization of a participant with stable exertional angina for coronary angiography and 
PCI that is prompted by a positive outpatient stress test should not be considered 
hospitalization for unstable angina; and 
o Rehospitalization of a participant meeting the criteria for unstable angina who was 
stabilized, discharged, and subsequently readmitted for revascularization, does not 
constitute a second hospitalization for unstable angina. 
4. A participant who undergoes an elective catheterization where incidental coronary artery 
disease is found and who subsequently undergoes coronary revascularization will not be 
considered as meeting the hospitalization for unstable angina endpoint. 

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STROKE AND TRANSIENT ISCHEMIC ATTACK 
These definitions of stroke and transient ischemic attack (TIA) apply to a wide range of clinical 
trials. They are general, overarching, and widely applicable definitions combined with a specific 
clinical measurement of disability. They are flexible in their application and consistent with 
contemporary understanding of the pathophysiology of stroke. This approach enables clinical trials 
to assess the clinically relevant consequences of vascular brain injury for determining the safety 
or effectiveness of an intervention. 
The distinction between an ischemic stroke and a TIA is the presence of cerebral infarction. 
Persistence of symptoms is an acceptable indicator of acute infarction. Thus, duration of symptom 
persistence that will be used to distinguish between transient ischemia and acute infarction should 
be defined for any clinical trial in which it is used. 
In trials involving participants with stroke, evidence of vascular central nervous system injury 
without recognized 
neurological 
dysfunction 
may 
be 
observed. 
Examples 
include 
microhemorrhage, asymptomatic infarction, and asymptomatic hemorrhage. When encountered, 
the clinical relevance of these findings may be unclear. If appropriate for a given clinical trial, 
however, they should be precisely defined and categorized. 
Subdural hematomas are intracranial hemorrhagic events and not strokes. 
TIA 
TIA is defined as a transient episode of focal neurological dysfunction caused by brain, spinal 
cord, or retinal ischemia, without acute infarction. 
Stroke 
Stroke is defined as an acute episode of focal or global neurological dysfunction caused by brain, 
spinal cord, or retinal vascular injury as a result of hemorrhage or infarction. Classification of 
stroke is as follows: 
a. Ischemic stroke: 
Ischemic stroke is defined as an acute episode of focal cerebral, spinal, or retinal dysfunction 
caused by infarction of central nervous system tissue. 
Hemorrhage may be a consequence of ischemic stroke. In this situation, the stroke is an 
ischemic stroke with hemorrhagic transformation and not a hemorrhagic stroke. 
b. Hemorrhagic stroke: 
Hemorrhagic stroke is defined as an acute episode of focal or global cerebral or spinal 
dysfunction caused by intraparenchymal, intraventricular, or subarachnoid hemorrhage. 
c. Undetermined stroke: 
Undetermined stroke is defined as an acute episode of focal or global neurological dysfunction 
caused by presumed brain, spinal cord, or retinal vascular injury as a result of hemorrhage or 
infarction but with insufficient information to allow categorization as either ischemic or 
hemorrhagic. 

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Stroke disability  
Disability should be measured by a reliable and valid scale in all cases, typically at each visit and 
90 days after the event. For example, the modified Rankin Scale may be used to address this 
requirement (see Table A1). 
Table A1. Modified Rankin Scale for Stroke Disability 
Scale 
Disability 
0 
No symptoms at all. 
1 
No significant disability despite symptoms; able to carry out all usual duties and activities. 
2 
Slight disability; unable to carry out all previous activities, but able to look after own affairs without 
assistance. 
3 
Moderate disability; requiring some help, but able to walk without assistance. 
4 
Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs 
without assistance. 
5 
Severe disability; bedridden, incontinent, and requiring constant nursing care and attention. 
6 
Dead. 
 

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HEART FAILURE EVENT 
A HF event includes hospitalization for HF and may include urgent outpatient visits. 
HF hospitalizations should remain delineated from urgent visits. If urgent visits are included in the 
HF event endpoint, the number of urgent visits needs to be explicitly presented separately from 
the hospitalizations.  
A HF hospitalization is defined as an event that meets ALL of the following criteria: 
1. The participant is admitted to the hospital with a primary diagnosis of HF;  
2. The participant’s length of stay in hospital extends for at least 24 hours (or a change in 
calendar date if the hospital admission and discharge times are unavailable); 
3. The participant exhibits documented new or worsening symptoms due to HF on presentation, 
including at least 1 of the following:  
a. Dyspnea (dyspnea with exertion, dyspnea at rest, orthopnea, or paroxysmal nocturnal 
dyspnea); 
b. Decreased exercise tolerance; 
c. Fatigue; or 
d. Other symptoms of compromised or worsened end-organ perfusion or volume overload 
(must be specified and described by the protocol). 
4. The participant has objective evidence of new or worsening HF, consisting of at least 
2 physical examination findings OR 1 physical examination finding and at least 1 laboratory 
criterion, including:  
a. Physical examination findings considered to be due to HF, including new or worsened:  
 Peripheral edema;  
 Increasing abdominal distention or ascites (in the absence of primary hepatic disease); 
 Pulmonary rales/crackles/crepitations;  
 Increased jugular venous pressure and/or hepatojugular reflux; 
 S3 gallop; or 
 Clinically significant or rapid weight gain thought to be related to fluid retention. 
b. Laboratory evidence of new or worsening HF, if obtained within 24 hours of presentation, 
including: 
 Increased B-type natriuretic peptide (BNP)/N-terminal pro-BNP (NT-proBNP) 
concentrations consistent with decompensation of HF (such as BNP >500 pg/mL or 
NT-proBNP >2000 pg/mL). In participants with chronically elevated natriuretic 
peptides, a significant increase should be noted above Baseline; 
 Radiological evidence of pulmonary congestion; 
 Non-invasive diagnostic evidence of clinically significant elevated left- or right-sided 
ventricular filling pressure or low cardiac output. For example, echocardiographic 

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criteria could include septal or lateral E/e’ >15 or >12, respectively; a D dominant 
pulmonary venous inflow pattern; a plethoric inferior vena cava with minimal collapse 
on inspiration; or a decreased left ventricular outflow tract minute stroke distance (time 
velocity integral); OR 
 Invasive diagnostic evidence with right heart catheterization showing a pulmonary 
capillary wedge pressure (pulmonary artery occlusion pressure) 18 mmHg, a central 
venous pressure 12 mmHg, or a cardiac index <2.2 L/min/m2. 
Note: All results from diagnostic tests should be reported, if available, even if they do not meet 
the above criteria, because they provide important information for the adjudication of these 
events. 
5. The participant receives at least 1 of the following treatments specifically for HF: 
a. Significant augmentation in oral diuretic therapy (eg, doubling of loop diuretic dose, 
initiation of maintenance loop diuretic therapy, initiation of combination diuretic therapy);  
b. Initiation of intravenous diuretic (even a single dose) or vasoactive agent (eg, inotrope, 
vasopressor, or vasodilator); or 
c. Mechanical or surgical intervention, including the following: 
 Mechanical circulatory support (eg, intra-aortic balloon pump, ventricular assist 
device, extracorporeal membrane oxygenation, total artificial heart); or 
 Mechanical fluid removal (eg, ultrafiltration, hemofiltration, dialysis). 
General considerations (HF hospitalization) 
Combination diuretic therapy could include 1) a thiazide-type diuretic (eg, hydrochlorothiazide, 
metolazone, chlorothiazide) plus a loop diuretic; or 2) a mineralocorticoid receptor antagonist 
(eg, spironolactone or eplerenone) plus a loop diuretic. 
An urgent HF visit is defined as an event that meets all of the following:  
1. The participant has an urgent, unscheduled office/practice or emergency department visit for a 
primary diagnosis of HF, but not meeting the criteria for a HF hospitalization; 
2. The participant meets all signs and symptoms for HF hospitalization as indicated above; and 
3. The participant receives at least 1 of the following treatments specifically for HF:  
a. Initiation of intravenous diuretic or vasoactive agent (eg, inotrope, vasopressor, or 
vasodilator);3 
b. Mechanical or surgical intervention, including: 
 Mechanical circulatory support (eg, intra-aortic balloon pump, ventricular assist 
device, extracorporeal membrane oxygenation, total artificial heart); or 
 Mechanical fluid removal (eg, ultrafiltration, hemofiltration, dialysis). 
 
3 Note that significant augmentation of oral diuretic therapy will NOT be sufficient to fulfill the urgent HF visit 
criteria.  

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General considerations (urgent HF visit) 
Clinic visits for scheduled administration of HF therapies or procedures (eg, intravenous diuretics, 
intravenous vasoactive agents, or mechanical fluid removal) do NOT qualify as non-hospitalized 
HF events. 

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INTERVENTIONAL CARDIOLOGY 
Clinical definitions 
1. Clinically driven target lesion revascularization: Revascularization is clinically driven if the 
target lesion diameter stenosis is >50% by quantitative coronary angiography (QCA) and the 
participant has clinical or functional ischemia which cannot be explained by another native 
coronary or bypass graft lesion. Clinical or functional ischemia includes any of the following: 
a. A history of angina pectoris, presumably related to the target vessel; 
b. Objective signs of ischemia at rest (ECG changes) or during exercise test (or equivalent), 
presumably related to the target vessel; or 
c. Abnormal results of any invasive functional diagnostic test (eg, coronary flow reserve or 
fractional flow reserve). 
Note: Target lesion revascularization of a >70% diameter stenosis by QCA in the absence of 
the above signs or symptoms may be considered clinically driven. 
Note: In the absence of QCA data or if a <50% stenosis is present, target lesion 
revascularization may be considered clinically driven by the Clinical Events Committee (CEC) 
if severe ischemic signs and symptoms attributed to the target lesion are present. 
2. Non-target lesion and non-target lesion revascularization: A lesion for which revascularization 
is not attempted or one in which revascularization is performed using a non-study device, 
respectively. 
3. Non-target vessel and non-target vessel revascularization: A vessel for which revascularization 
is not attempted or one in which revascularization is performed using a non-study device, 
respectively. 
4. PCI status: 
a. Elective: The procedure can be performed on an outpatient basis or during a subsequent 
hospitalization without significant risk of MI or death. For stable inpatients, the procedure 
is being performed during this hospitalization for convenience and ease of scheduling and 
NOT because the participant’s clinical situation demands the procedure prior to discharge.  
b. Urgent: The procedure should be performed on an inpatient basis and prior to discharge 
because of significant concerns that there is risk of myocardial ischemia, MI, and/or death. 
Participants who are outpatients or in the emergency department at the time that the cardiac 
catheterization is requested would warrant hospital admission based on their clinical 
presentation.  
c. Emergency: The procedure should be performed as soon as possible because of substantial 
concerns that ongoing myocardial ischemia and/or MI could lead to death. “As soon as 
possible” refers to a participant who is of sufficient acuity that one would cancel a 
scheduled case to perform this procedure immediately in the next available room during 
business hours, or one would activate the on-call team were this to occur during off-hours. 
d. Salvage: The procedure is a last resort. The participant is in cardiogenic shock when the 
PCI begins (ie, the time at which the first guide wire or intracoronary device is introduced 

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into a coronary artery or bypass graft for the purpose of mechanical revascularization) OR 
within the last 10 minutes prior to the start of the case or during the diagnostic portion of 
the case, the participant has also received chest compressions or has been on unanticipated 
circulatory support (eg, intra-aortic balloon pump, extracorporeal membrane oxygenation, 
or cardiopulmonary support). 
5. PCI: Placement of an angioplasty guide wire, balloon, or other device (eg, stent, atherectomy 
catheter, brachytherapy delivery device, or thrombectomy catheter) into a native coronary 
artery or CABG for the purpose of mechanical coronary revascularization. In the assessment 
of the severity of coronary lesions with the use of intravascular ultrasound, coronary flow 
reserve, or fractional flow reserve, insertion of a guide wire will NOT be considered PCI. 
6. Procedural success: Achievement of <30% residual diameter stenosis of the target lesion 
assessed by visual inspection or QCA and no in-hospital major adverse cardiac events, a 
composite of death, MI, or repeat coronary revascularization of the target lesion. Ideally, the 
assessment of the residual stenosis at the end of the procedure should be performed by an 
angiographic core laboratory. 
Note: For some device interventions (eg, balloon angioplasty), achievement of <50% diameter 
stenosis by visual inspection or QCA is an acceptable definition for procedural success. 
7. Target lesion: Any lesion treated or attempted to be treated during the PCI with the study 
device. The target lesion includes the arterial segment treated with the study device (stent, in 
most cases) plus 5 mm proximal and 5 mm distal to the treatment site. 
8. Target lesion failure: The composite of ischemia-driven revascularization of the target lesion, 
MI related to the target vessel, or cardiac death related to the target vessel. If it cannot be 
determined with certainty whether the MI or death was related to the target vessel, it is 
considered a target lesion failure. 
9. Target lesion revascularization: Any repeat percutaneous intervention of the target lesion 
(including 5 mm proximal and 5 mm distal to the target lesion) or surgical bypass of the target 
vessel performed for restenosis or other complication involving the target lesion. In the 
assessment of target lesion revascularization, angiograms should be assessed by an 
angiographic core laboratory (if designated) and made available to the CEC for review upon 
request. 
10. Target vessel: A major native coronary artery (eg, left main coronary artery, left anterior 
descending coronary artery, left circumflex coronary artery, or right coronary artery) or bypass 
graft containing the target lesion. A native coronary artery target vessel includes the arterial 
segments upstream and downstream to the target lesion plus major side branches. 
11. Target vessel failure: The composite of ischemia-driven revascularization of the target vessel, 
MI related to the target vessel, or cardiac death related to the target vessel. If it cannot be 
determined with certainty whether the MI or death was related to the target vessel, it is 
considered a target vessel failure. 
12. Target vessel, non-target lesion, and target vessel, non-target lesion revascularization: Any 
lesion or revascularization of a lesion in the target vessel other than the target lesion, 
respectively. 

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13. Target vessel revascularization: Any repeat percutaneous intervention or surgical bypass of 
any segment of the target vessel. In the assessment of target vessel revascularization, 
angiograms should be assessed by an angiographic core laboratory (if designated) and made 
available to the CEC for review upon request. 
14. Vascular complications include the following:  
o Access site hematoma: Development of a new, localized collection of blood at a vascular 
access site sufficient to produce a palpable mass within 72 hours of a procedure; 
o Arteriovenous fistula: Development of a new, unintended communication between an 
artery and a vein occurring at a vascular access site within 72 hours of a procedure; 
o Peripheral ischemia: Development of new arterial insufficiency sufficient to produce 
clinical signs or symptoms of ischemia (pallor, pain, paresthesia) distal to a vascular access 
site within 72 hours of a procedure; 
o Peripheral nerve injury: Development of new sensory or motor loss of peripheral nerve 
function from external nerve compression (eg, as a result of positioning during a 
procedure), or internal compression or direct nerve damage from the procedure, occurring 
within 72 hours of a procedure; 
o Pseudoaneurysm: Development of a new localized collection of blood with a persistent 
communication (neck) originating at a vascular access site and occurring within 72 hours 
of a procedure; or 
o Retroperitoneal hemorrhage: Development of new bleeding into the retroperitoneal space 
originating at a vascular access site and occurring within 72 hours of a procedure. 
Angiographic definitions  
1. Abrupt closure is defined as a new intra-procedural severely reduced flow (Thrombolysis in 
Myocardial Infarction [TIMI] Grade 0 to 1) within the target vessel that persists and requires 
intervention by stenting or other treatment, or results in MI or death. Abrupt closure requires 
an association with a vascular dissection, thrombus, or severe spasm at the treatment site or 
within the instrumented vessel. 
2. Coronary lesions treated are defined as shown in Table A2: 
Table A2. Coronary Lesions Treated and Definitions 
Coronary Artery Segments 
Definition 
Right coronary artery ostium 
Origin of the right coronary artery, including the first 3 mm of 
the artery. 
Proximal right coronary artery 
Proximal portion of the right coronary artery, from the ostium 
of the right coronary artery to the origin of the first right 
ventricular branch (pRCA). 
Mid right coronary artery 
Middle portion of the right coronary artery, from the origin of 
the first right ventricular branch to the acute margin (mRCA). 
Distal right coronary artery 
Distal portion of the right coronary artery, from the acute 
margin to the origin of the posterior descending artery (dRCA). 
Right posterior descending artery 
In right dominant and mixed circulations, the vessel that runs 
in the posterior interventricular groove and supplies septal 
perforator branches (PDA). 

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Coronary Artery Segments 
Definition 
Posterolateral segmental artery 
In right dominant circulations, the distal continuation of the 
right coronary artery in the posterior atrioventricular groove 
after the origin of the right posterior descending artery (PLSA). 
First right posterolateral branch 
In right dominant circulations, the first posterolateral branch 
originating from the right posterior atrioventricular artery 
(RPL1). 
Second right posterolateral branch 
In right dominant circulations, the second posterolateral branch 
originating from the right posterior atrioventricular artery 
(RPL2). 
Third right posterolateral branch 
In right dominant circulations, the third posterolateral branch 
originating from the right posterior atrioventricular artery 
(RPL3). 
Posterior descending septal perforator 
Septal perforator vessel originating from the posterior 
descending artery. 
Right ventricular branch 
Branch arising from the right coronary artery to supply the 
right ventricular wall (RV). 
Left main coronary artery ostium 
Origin of the left coronary artery, including the first 3 mm of 
the artery. 
Left main coronary artery body 
Body of the left main coronary artery, from the ostium to the 
bifurcation (LM). 
Left main coronary artery bifurcation 
Distal end of the left main, including the terminal 3 mm 
through the bifurcation of the left main into the left anterior 
descending and left circumflex arteries. 
Left anterior descending artery ostium 
Origin of the left anterior descending coronary artery, 
including the first 3 mm of the artery. 
Proximal left anterior descending artery 
Proximal portion of the left anterior descending coronary 
artery, from the ostium to the origin of the first septal (pLAD). 
Mid left anterior descending artery 
Middle portion of the left anterior descending coronary artery, 
from the origin of the first septal artery to the origin of the 
third septal artery (mLAD). 
Distal left anterior descending artery 
Distal portion of the left anterior descending coronary artery, 
from the origin of the third septal artery to the terminus 
(dLAD). 
First diagonal branch 
First of the 3 longest branches originating from the left anterior 
descending artery to supply the anterolateral wall of the left 
ventricle (D1). 
First diagonal lateral branch 
Branch of the first diagonal branch. 
Second diagonal branch 
Second of the 3 longest branches originating from the left 
anterior descending artery to supply the anterolateral wall of 
the left ventricle (D2). 
Second diagonal lateral branch 
Branch of the second diagonal branch. 
Third diagonal branch 
Third of the 3 longest branches originating from the left 
anterior descending artery to supply the anterolateral wall of 
the left ventricle (D3). 
Third diagonal lateral branch 
Branch of the third diagonal branch. 
Anterior descending septal perforator 
Septal perforator vessel originating from the left anterior 
descending artery to supply the interventricular septum. 
Left circumflex artery ostium 
Origin of the left circumflex coronary artery, including the first 
3 mm of the artery. 
Proximal left circumflex artery 
Proximal portion of the left circumflex coronary artery, from 
the ostium to the origin (or the nominal location of) the first 
marginal branch (pLCX). 

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Coronary Artery Segments 
Definition 
Mid left circumflex artery 
Middle portion of the left circumflex coronary artery, from the 
origins of (or nominal locations of) the first marginal to the 
second marginal (mLCX). 
Distal left circumflex artery 
Distal portion of the left circumflex coronary artery, from the 
origin of (or the nominal location of) the second marginal to 
the terminus (in right dominant systems), or to the origin of the 
first left posterolateral in all other dominance systems (dLCX). 
First obtuse marginal branch 
First of the 3 longest branches originating from the left 
circumflex artery to supply the lateral wall of the left ventricle 
(OM1). 
First obtuse marginal lateral branch 
Branch of the first marginal branch. 
Second obtuse marginal branch 
Second of the 3 longest branches originating from the left 
circumflex artery to supply the lateral wall of the left ventricle 
(OM2). 
Second obtuse marginal lateral branch 
Branch of the second marginal branch. 
Third obtuse marginal branch 
Third of the 3 longest branches originating from the left 
circumflex artery to supply the lateral wall of the left ventricle 
(OM3). 
Third obtuse marginal lateral branch 
Branch of the third marginal branch. 
Left atrioventricular artery 
In left dominant and mixed circulations, the distal continuation 
of the left circumflex coronary artery in the posterior 
atrioventricular groove. 
Left posterior descending artery 
In left dominant circulations, the vessel that arises from the 
distal continuation of the left atrioventricular artery, travels in 
the posterior interventricular groove, and supplies septal 
perforator branches (LPDA). 
First left posterolateral branch 
In left dominant and mixed circulations, the first posterolateral 
branch originating from the posterior atrioventricular left 
circumflex artery (LPL1). 
Second left posterolateral branch 
In left dominant and mixed circulations, the second 
posterolateral branch originating from the posterior 
atrioventricular left circumflex artery (LPL2). 
Third left posterolateral branch 
In left dominant and mixed circulations, the third posterolateral 
branch originating from the posterior atrioventricular left 
circumflex artery (LPL3). 
Ramus intermedius branch 
Branch vessel whose origin bisects the origins of the left 
anterior descending and circumflex arteries (RI). 
Ramus intermedius lateral branch 
Branch of the ramus intermedius branch. 
3. Dissection is defined based on the National Heart, Lung, and Blood Institute Dissection 
Classification System as follows: 
o Grade A: Minor radiolucencies within the lumen during contrast injection with no 
persistence after dye clearance; 
o Grade B: Parallel tracts or double lumen separated by a radiolucent area during contrast 
injection with no persistence after dye clearance; 
o Grade C: Extraluminal cap with persistence of contrast after dye clearance from the lumen; 
o Grade D: Spiral luminal filling defect with delayed but complete distal flow; 

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o Grade E: New persistent filling defect with delayed antegrade flow; and 
o Grade F: Non-A through E types with total coronary occlusion and no distal antegrade 
flow. 
Note: Grade E and F dissections may represent thrombus. 
4. Late loss is defined as the minimum lumen diameter (MLD) assessed at follow-up angiography 
minus the MLD assessed immediately after the index procedure. MLDs are measured by QCA. 
5. MLD is the mean minimum lumen diameter (typically measured in-lesion, in-stent, and in 
segment) derived from 2 orthogonal views by QCA. 
6. No reflow is defined as an acute reduction in coronary flow (TIMI Grade 0 to 1) in the absence 
of dissection, thrombus, spasm, or high-grade residual stenosis at the original target lesion. 
7. Percent diameter stenosis is the value calculated as 100  (1 – MLD/reference vessel diameter 
[RVD]) using the mean values determined by QCA from 2 orthogonal views (when possible). 
8. RVD is defined as the average of normal segments within 10 mm proximal and 10 mm distal 
to the target lesion from 2 orthogonal views using QCA. 
9. Restenosis is defined as re-narrowing of the vessel following the treatment of a prior stenosis 
and is classified further as follows: 
o Binary restenosis is defined as a diameter stenosis of >50% at the previously treated lesion 
site, including the originally treated site plus the adjacent vascular segments 5 mm 
proximal and 5 mm distal to the site; and 
o In-stent restenosis is defined as a previously stented lesion with a >50% diameter stenosis. 
10. Thrombus (angiographic) is defined as a discrete, mobile, intraluminal filling defect with 
defined borders with or without associated contrast staining. 
11. TIMI flow grades are defined as follows:  
o Grade 0 (no perfusion): There is no antegrade flow beyond the point of occlusion;  
o Grade 1 (penetration without perfusion): The contrast material passes beyond the area of 
obstruction but “hangs up” and fails to opacify the entire coronary bed distal to the 
obstruction for the duration of the cineangiographic filming sequence; 
o Grade 2 (partial perfusion): The contrast material passes across the obstruction and 
opacifies the coronary bed distal to the obstruction. However, the rate of entry of contrast 
material into the vessel distal to the obstruction or its rate of clearance from the distal bed 
(or both) is perceptibly slower than its entry into or clearance from comparable areas not 
perfused by the previously occluded vessel (eg, the opposite coronary artery or the 
coronary bed proximal to the obstruction); and 
o Grade 3 (complete perfusion): Antegrade flow into the bed distal to the obstruction occurs 
as promptly as antegrade flow into the bed proximal to the obstruction and clearance of 
contrast material from the involved bed is as rapid as from an uninvolved bed in the same 
vessel or the opposite artery. 
12. Vessels are defined as follows: 
o Left main coronary artery; 

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o Left anterior descending artery with septal and diagonal branches; 
o Left circumflex artery with obtuse marginal branches; 
o Ramus intermedius artery; 
o Right coronary artery and any of its branches; 
o Posterior descending artery; 
o Saphenous vein bypass graft(s); and 
o Arterial bypass graft(s): Right internal mammary graft, left internal mammary graft, radial 
artery graft, and gastroepiploic artery graft. 

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PERIPHERAL VASCULAR INTERVENTION 
1. Peripheral vascular intervention (PVI): PVI4 is a catheter-based or open surgical procedure 
designed to improve arterial or venous blood flow or otherwise modify or revise vascular 
conduits. Procedures may include, but are not limited to, percutaneous transluminal balloon 
angioplasty, stent placement, thrombectomy, embolectomy, atherectomy, dissection repair, 
aneurysm exclusion, treatment of dialysis conduits, placement of various devices, intravascular 
thrombolysis or other pharmacotherapies, and open surgical bypass or revision.  
In general, the intention to perform percutaneous PVI is denoted by the insertion of a guide 
wire into a peripheral artery or vein. 
The target vessel(s) and the type of revascularization procedure (eg, surgical bypass, 
thrombectomy, endarterectomy, percutaneous transluminal angioplasty, stent placement, 
thromboembolectomy, and thrombolysis) should be specified and recorded. For the sake of 
simplicity, this definition applies to the extracranial carotid artery and other non-cardiac 
arteries and veins and excludes the intracranial vessels and lymphatics.  
2. Procedural success: In the case of percutaneous intervention for obstructive lesions, procedural 
success is defined as the achievement of a satisfactory final residual diameter stenosis by 
angiography at the end of the procedure (and without flow limiting dissection or 
hemodynamically significant translesional pressure gradient). The specific parameter for final 
percent residual stenosis is typically between <30% and <50%; selection of the appropriate 
percentage may vary depending upon the specific intervention applied, the vascular territory, 
and anticipated or desired therapeutic response. Procedural success also implies absence of 
in-hospital major adverse events (AEs) (eg, death, stroke, MI, acute onset of limb ischemia, 
need for urgent/emergent vascular surgery, and other procedure-specific major AEs). The 
balloon inflation, stent placement, or other therapeutic intervention may be preceded by use of 
adjunctive devices (eg, percutaneous mechanical thrombectomy, directional or rotational 
atherectomy, laser, and chronic total occlusion crossing device), as predefined in the protocol. 
3. Procedural status: non-elective and elective:  
a. Non-elective: Non-elective procedures include emergent and urgent procedures. A 
non-elective procedure is a procedure that is performed without delay, because there is 
clinical consensus that the procedure should occur imminently. Non-elective procedures 
imply a degree of instability of the participant, urgency of the medical condition, or 
instability of the threatening lesion. Emergent and urgent are defined as follows: 
 Emergent: A procedure that is performed immediately because of the acute nature of 
the medical condition (eg, acute limb ischemia, acute aortic dissection) and the 
increased morbidity or mortality associated with a temporal delay in treatment; or 
 Urgent: An urgent procedure is one that is not an emergency but is required to be 
performed on a timely basis (24 hours) (eg, a participant who has been stabilized 
 
4 We note that peripheral vascular disease includes veins, arteries, and lymphatics. However, for simplicity, this 
definition will focus on peripheral artery and venous interventions. 

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following initial treatment of acute limb ischemia, and there is clinical consensus that 
a definitive procedure should occur within the next 24 hours). 
b. Elective: An elective procedure is one that is scheduled and is performed on a participant 
with stable disease, or in whom there is no urgency and/or increased morbidity or mortality 
associated with a planned procedure. 
4. Target lesion: A target lesion is any vascular segment treated or attempted to be treated during 
the study procedure with the index device. The target lesion is the treated segment starting 
10 mm proximal and ending 10 mm distal to the index device or therapy (stent, balloon, 
atherectomy catheter, or aortic stent-graft). 
5. Target vessel: A target vessel is any vessel (eg, non-cardiac or non-intracranial) that contains 
the target lesion treated with the study device. The target vessel includes the target lesion as 
well as the entire length of native vessel upstream and downstream from the target lesion, 
including side branches. For the arteries of the leg, the vasculature is divided into 3 vessel 
“levels:” aorto-iliac, femoral-popliteal, and tibial-crural. 
6. Non-target lesion and non-target lesion revascularization: A lesion for which revascularization 
is not attempted or one in which revascularization is performed using a non-study device, 
respectively. 
7. Non-target vessel and non-target vessel revascularization: A vessel for which revascularization 
is not attempted or one in which revascularization is performed using a non-study device, 
respectively. 
8. Target vessel, non-target lesion and target vessel, non-target lesion revascularization: Any 
lesion or revascularization of a lesion in the target vessel other than the target lesion, 
respectively. 
9. Target lesion revascularization: Target lesion revascularization is any repeat intervention of 
the target lesion (including 10 mm proximal and 10 mm distal to the index device, as target 
lesion is defined above) or surgical intervention/bypass of the target vessel performed for 
restenosis or other complication involving the target lesion. In the assessment of target lesion 
revascularization, angiograms should be assessed by an angiographic core laboratory (if 
designated). Angiograms (and core laboratory assessment thereof) and other source 
documentation should be made available to the CEC for review upon request. 
10. Target vessel revascularization: Target vessel revascularization is any repeat intervention or 
surgical bypass of any segment of the target vessel. In the assessment of target vessel 
revascularization, angiograms should be assessed by an angiographic core laboratory (if 
designated). Angiograms (and core laboratory assessment thereof) and other source 
documentation should be made available to the CEC for review upon request. 
11. Clinically driven target lesion revascularization: Clinically driven target lesion 
revascularization is defined as target lesion revascularization performed due to target lesion 
diameter stenosis >50% AND either evidence of clinical or functional ischemia (eg, 
recurrent/progressive intermittent claudication, critical limb ischemia) OR recurrence of the 
clinical syndrome for which the initial procedure was performed. Clinically driven target lesion 
revascularization occurs in the absence of protocol-directed surveillance ultrasound or 
angiography. 

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12. Vessel patency: Vessel patency at a given time point will be determined by the absence of 
clinically driven target lesion revascularization and/or absence of recurrent target lesion 
diameter stenosis >50% by imaging (eg, invasive angiography or most commonly, duplex 
ultrasonography). If patency data are incorporated within the primary endpoint of a clinical 
study, the angiographic images or duplex ultrasonographic images should be assessed by 
appropriate core laboratories and made available to the CEC for review upon request. 
13. Restenosis: Re-narrowing of the artery following the treatment of a prior stenosis, defined 
further as follows: 
o Binary restenosis: A diameter stenosis of >50% at the previously treated lesion site, 
including the originally treated site plus the adjacent vascular segments 10 mm proximal 
and 10 mm distal to the site (or as otherwise defined by the Protocol, as noted above); or 
o In-stent restenosis: A previously stented lesion that has >50% diameter stenosis. 

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STENT THROMBOSIS  
Stent thrombosis: timing 
Stent thrombosis should be reported as a cumulative value over time and at the various individual 
time points as specified below. Time 0 is defined as the time point after the guiding catheter has 
been removed and the participant has left the cardiac catheterization laboratory. Stent thrombosis 
timing is described in Table A3. 
Table A3. Stent Thrombosis: Timing  
Type of Stent Thrombosis  
Timing  
Acute stent thrombosis1 
0 to 24 hours post stent implantation 
Subacute stent thrombosis1 
>24 hours to 30 days post stent implantation 
Late stent thrombosis2 
>30 days to 1 year post stent implantation 
Very late stent thrombosis2 
>1 year post stent implantation 
1. 
Acute or subacute stent thrombosis can also be replaced by the term early stent thrombosis. Early stent thrombosis (0 to 
30 days) will be used herein. 
2. 
Includes “primary” as well as “secondary” late stent thrombosis; “secondary” late stent thrombosis is a stent thrombosis 
after a target lesion revascularization. 
Stent thrombosis: categories 
We propose 3 categories of evidence to define stent thrombosis, as follows:  
1. Definite stent thrombosis is defined as follows: 
Definite stent thrombosis is considered to have occurred by either angiographic or pathological 
confirmation: 
a. Angiographic confirmation of stent thrombosis5 is defined as: 
 The presence of a thrombus6 that originates in the stent or in the segment 5 mm 
proximal or distal to the stent and presence of at least 1 of the following criteria within 
a 48-hour time window: 
 Acute onset of ischemic symptoms at rest; 
 New ischemic ECG changes that suggest acute ischemia; 
 Typical rise and fall in cardiac biomarkers (refer to definition of spontaneous MI); 
 Nonocclusive thrombus; or 
Note: Intracoronary thrombus is defined as a (spherical, ovoid, or irregular) 
noncalcified filling defect or lucency surrounded by contrast material (on 3 sides or 
within a coronary stenosis) seen in multiple projections, or persistence of contrast 
material within the lumen, or a visible embolization of intraluminal material 
downstream. 
 
5 The incidental angiographic documentation of stent occlusion in the absence of clinical signs or symptoms is not 
considered a confirmed stent thrombosis (silent occlusion). 
6 Intracoronary thrombus. 

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 Occlusive thrombus. 
Note: TIMI 0 or TIMI 1 intrastent or proximal to a stent up to the most adjacent 
proximal side branch or main branch (if originates from the side branch). 
b. Pathological confirmation of stent thrombosis is defined as evidence of recent thrombus 
within the stent determined at autopsy or via examination of tissue retrieved following 
thrombectomy. 
2. Probable stent thrombosis is defined as follows: 
Clinical definition of probable stent thrombosis is considered to have occurred after 
intracoronary stenting in the following cases: 
a. Any unexplained death within the first 30 days;7 or 
b. Irrespective of the time after the index procedure, any MI that is related to documented 
acute ischemia in the territory of the implanted stent without angiographic confirmation of 
stent thrombosis and in the absence of any other obvious cause. 
3. Possible stent thrombosis is defined as follows:  
Clinical definition of possible stent thrombosis is considered to have occurred with any 
unexplained death from 30 days after intracoronary stenting until end of study follow-up. 
 
7 For studies with an ST-elevation MI population, one may consider the exclusion of unexplained death within 
30 days as evidence of probable stent thrombosis. 

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APPENDIX G: UNIVERSAL DEFINITIONS OF MYOCARDIAL INJURY 
AND MYOCARDIAL INFARCTION: SUMMARY FROM THE FOURTH 
UNIVERSAL DEFINITION OF MYOCARDIAL INFARCTION (2018)21  
CRITERIA FOR MYOCARDIAL INJURY 
The term myocardial injury should be used when there is evidence of elevated cardiac troponin 
(cTn) values with at least 1 value above the 99th percentile upper reference limit (URL). The 
myocardial injury is considered acute if there is a rise and/or fall of cTn values. 

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CRITERIA FOR ACUTE MYOCARDIAL INFARCTION 
 (TYPES 1, 2, AND 3 MI)  
The term acute myocardial infarction (MI) should be used when there is acute myocardial injury 
with clinical evidence of acute myocardial ischemia and with detection of a rise and/or fall of cTn 
values with at least 1 value above the 99th percentile URL and at least 1 of the following: 
 Symptoms of myocardial ischemia; 
 New ischemic electrocardiogram (ECG) changes; 
 Development of pathological Q waves; 
 Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality 
in a pattern consistent with an ischemic etiology; or 
 Identification of a coronary thrombus by angiography or autopsy (not for types 2 or 3 MI). 
Post-mortem demonstration of acute athero-thrombosis in the artery supplying the infarcted 
myocardium meets criteria for type 1 MI. 
Evidence of an imbalance between myocardial oxygen supply and demand unrelated to acute 
athero-thrombosis meets criteria for type 2 MI. 
Cardiac death in participants with symptoms suggestive of myocardial ischemia and presumed 
new ischemic ECG changes before cTn values become available or abnormal meets criteria for 
type 3 MI. 

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CRITERIA FOR CORONARY PROCEDURE-RELATED MYOCARDIAL 
INFARCTION (TYPES 4 AND 5 MI) 
Percutaneous coronary intervention (PCI)-related MI is termed type 4a MI. 
Coronary artery bypass grafting (CABG)-related MI is termed type 5 MI. 
Coronary procedure-related MI 48 hours after the index procedure is arbitrarily defined by an 
elevation of cTn values >5  for type 4a MI and >10  for type 5 MI of the 99th percentile URL in 
participants with normal Baseline values. Participants with elevated pre-procedural cTn values, in 
whom the pre-procedural cTn levels are stable (20% variation) or falling, must meet the criteria 
for a >5- or >10-fold increase and manifest a change from the Baseline value of >20%, in addition 
to at least 1 of the following: 
 New ischemic ECG changes (this criterion is related to type 4a MI only); 
 Development of new pathological Q waves; 
 Imaging evidence of loss of viable myocardium that is presumed to be new and in a pattern 
consistent with an ischemic etiology; or 
 Angiographic findings consistent with a procedural flow-limiting complication such as 
coronary dissection, occlusion of a major epicardial artery or graft, side-branch 
occlusion-thrombus, disruption of collateral flow, or distal embolization. 
Isolated development of new pathological Q waves meets the type 4a MI or type 5 MI criteria with 
either revascularization procedure if cTn values are elevated and rising but less than the 
pre-specified thresholds for PCI and CABG. 
Other types of 4 MI include type 4b MI stent thrombosis and type 4c MI restenosis that both meet 
type 1 MI criteria. 
Post-mortem demonstration of a procedure-related thrombus meets the type 4a MI criteria or 
type 4b MI criteria if associated with a stent. 

NewAmsterdam Pharma B.V. 
Clinical Study Protocol TA-8995-302 
Confidential & Proprietary 
Page 108 of 108 
Version 6.0, 22 December 2022 
CRITERIA FOR PRIOR OR SILENT/UNRECOGNIZED MYOCARDIAL 
INFARCTION  
Any 1 of the following criteria meets the diagnosis for prior or silent/unrecognized MI: 
 Abnormal Q waves with or without symptoms in the absence of non-ischemic causes; 
 Imaging evidence of loss of viable myocardium in a pattern consistent with ischemic etiology; 
or 
 Patho-anatomical findings of a prior MI.