Conditions: Dyslipidemias High Cholesterol Hypercholesterolemia Familial Hypercholesterolemia Lipid Metabolism Disorder Metabolic Disease Lipid Metabolism, Inborn Errors Genetic Disease, Inborn Hyperlipoproteinemias
Keywords: Obicetrapib BROOKLYN Cholesteryl ester transfer protein (CETP) inhibitor Heterozygous Familial Hypercholesterolemia (HeFH) LDL-C
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 354
Healthy volunteers: no

Brief summary:
This study will be a placebo-controlled, double-blind, randomized, phase 3 study to Evaluate the Efficacy, Safety, and Tolerability of Obicetrapib in Participants with a History of Heterozygous Familial Hypercholesterolemia (HeFH).

Detailed description:
This study will be a placebo-controlled, double-blind, randomized, phase 3 study in participants with HeFH to evaluate the efficacy, safety, and tolerability of obicetrapib as an adjunct to diet and maximally tolerated lipid-lowering therapy. The screening period for this study will take up to 14 days. Afterwards, patients will be randomized to placebo or 10 mg obicetrapib for an 365-day treatment period. After the treatment period, participants will have an end-of-study follow-up visit.

Arms:
arm 1: one placebo tablet once daily arm 2: one 10 mg Obicetrapib tablet once daily

Interventions: intervention 1: Obicetrapib intervention 2: Placebo
Intervention descriptions: intervention 1: 10 mg Obicetrapib tablet intervention 2: placebo tablet made to resemble active

Protocol document:
Prot_000.pdf: 
 
 
 
 
CLINICAL STUDY PROTOCOL 
 
Obicetrapib on Top of Maximum Tolerated Lipid-Modifying 
Therapies (BROOKLYN): A Placebo-Controlled, Double-Blind, 
Randomized, Phase 3 Study to Evaluate the Effect of 10 mg 
Obicetrapib in Participants With a History of HeFH and LDL-C 
70 mg/dL Who are Not Adequately Controlled by Their 
Lipid-Modifying Therapies 
 
Investigational Product: Obicetrapib 
Protocol Number: TA-8995-301 
EudraCT Number: 2021-005064-22 
 
Sponsor: 
NewAmsterdam B.V. 
Gooimeer 2-35 
1411 DC 
Naarden 
The Netherlands 
Telephone: +31 35 699 30 00 
Fax: +31 20 240 07 79 
 
Version Number: 3.0 
Original Protocol: 21 February 2022 
Amendment 1: 02 May 2022 
Amendment 2: 18 May 2022 
 
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the written 
consent of NewAmsterdam 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 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 B.V. and that it may not be further 
disclosed to third parties.


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SIGNATURE PAGE 
STUDY TITLE: Obicetrapib on Top of Maximum Tolerated Lipid-Modifying Therapies 
(BROOKLYN): A Placebo-Controlled, Double-Blind, Randomized, Phase 3 Study to 
Evaluate the Effect of 10 mg Obicetrapib in Participants With a History of HeFH and LDL-C 
70 mg/dL Who are Not Adequately Controlled by Their Lipid-Modifying Therapies 
 
I, the undersigned, have read this protocol and agree that it contains all necessary information 
required to conduct the study. 


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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 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 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 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 (BROOKLYN): 
A Placebo-Controlled, Double-Blind, Randomized, Phase 3 Study to Evaluate the Effect of 10 mg 
Obicetrapib in Participants With a History of HeFH and LDL-C 70 mg/dL Who are Not 
Adequately Controlled by Their Lipid-Modifying Therapies 
PROTOCOL NUMBER: TA-8995-301 
INVESTIGATIONAL PRODUCT: Obicetrapib 
PHASE: 3 
INDICATION: As an adjunct to diet and maximally tolerated lipid-lowering therapy for the 
treatment of adults with heterozygous familial hypercholesterolemia (HeFH) who require 
additional lowering of low-density lipoprotein (LDL) cholesterol (LDL-C) 
OBJECTIVES: 
The primary objective of this study is to evaluate the effect of obicetrapib on fasting LDL-C levels 
at Day 84. 
The secondary objectives of this study include the following: 
 To evaluate the effect of obicetrapib on fasting 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 fasting LDL-C levels at Days 180 and 365; 
 To evaluate the effect of obicetrapib on fasting lipoprotein (a) (Lp[a]) at Days 84 and 365; and 
 To evaluate the safety and tolerability profile of obicetrapib in a representative population of 
adult males and females with HeFH, 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 Number of participants reaching prespecified fasting LDL-C, non-HDL-C, and ApoB 
levels at Days 84 and 365; and 
o Fasting apolipoprotein A1 (ApoA1) at Days 84 and 365. 
 To evaluate trough levels of obicetrapib from Baseline to Day 365 in the obicetrapib group. 


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POPULATION: 
The population for this study will comprise participants with a history of HeFH 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 (HISs). HISs include 
atorvastatin 40 or 80 mg or rosuvastatin 20 or 40 mg. Participants with a history of HeFH, defined 
by existing confirmation via genetic testing, World Health Organization (WHO) Criteria/Dutch 
Lipid Clinical Network Criteria with a score of >8 points, and/or Simon Broome Register 
Diagnostic Criteria, will be enrolled. The study aims to enroll male and female participants 
18 years of age. 
STUDY DESIGN AND DURATION: 
This study will be a multisite, placebo-controlled, double-blind, randomized, Phase 3 study in 
approximately 300 participants with a history of HeFH 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 300 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. 
At least 70% of the participants enrolled into this study must be taking HISs. HeFH diagnosis is 
defined by existing confirmation via genetic testing, WHO Criteria/Dutch Lipid Clinical Network 
Criteria with a score of >8 points, and/or Simon Broome Register Diagnostic Criteria. 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. An End of Study (EOS) Visit will be conducted approximately 35 days after the 
participant’s last dose of study drug, during which vital signs; limited serum chemistry, 
hematology, and coagulation parameters; pharmacokinetics; concomitant medications; and AEs 
will be assessed. 
The study will be governed by a Steering Committee, and a Data and Safety Monitoring Board 
will provide independent oversight of participant safety. 
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; 


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2. Are male or female and 18 years of age at Screening; 
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; 
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 informed consent form; 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 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 method) or 
sterile sexual partner. 
3. Have a history of HeFH as defined by at least 1 of the following: 
o Genotyping by a central laboratory; 
Note: Confirmation by prior genetic testing is required (ie, genotyping is not a Screening 
assessment). 
o Clinical assessment using the WHO Criteria/Dutch Lipid Clinical Network Criteria with a 
score of >8 points; and/or 
o Meet the Simon Broome Register Diagnostic Criteria for definite or possible Familial 
Hypercholesterolemia (FH). 
4. Are on maximally tolerated lipid-modifying therapy, as an adjunct to diet, 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; and 
 For any participant not taking statin therapy due to statin intolerance, including those 
participants taking bempedoic acid or fibrate monotherapy, written confirmation will 


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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 
cardiovascular 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; 
o Bempedoic acid for at least 8 weeks in combination with maximally tolerated statin prior 
to Screening; and/or 
o A proprotein convertase subtilisin/kexin type 9 (PCSK9)-targeted therapy alone or in 
combination with other lipid-modifying therapy for at least 4 stable doses prior to 
Screening. 
Note: At least 70% of the participants enrolled into this study must be taking HISs. 
Documentation of the reason why a participant is unable to take HISs is required. HISs include 
the following: 
o Atorvastatin 40 or 80 mg; or 
o Rosuvastatin 20 or 40 mg. 
5. Have a fasting serum LDL-C 70 mg/dL (1.81 mmol/L) at Screening; 
Note: LDL-C at Screening will be calculated using the Friedewald equation unless 
TG 400 mg/dL (4.52 mmol/L) or LDL-C 50 mg/dL (1.30 mmol/L). If TG 400 mg/dL 
(4.52 mmol/L) or LDL-C 50 mg/dL (1.30 mmol/L), then LDL-C level will be measured 
directly by preparative ultracentrifugation, also referred to as beta quantification. 
6. Have fasting TG <400 mg/dL (<4.52 mmol/L) at Screening; 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. 
Exclusion criteria 
Participants who meet any of the following criteria will be excluded from participation in the 
study: 
1. Have current or any previous history of New York Heart Association class III or IV heart 
failure (HF) or left ventricular ejection fraction <30%; 
2. Have been hospitalized for HF within 5 years prior to Screening; 
3. Have had any of the following clinical events within 3 months prior to Screening: 
o Non-fatal myocardial infarction; 
o Non-fatal stroke; 


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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 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; 
Note: An abnormal ALT, AST, or total bilirubin must be confirmed by a repeat abnormal 
measurement at least 1 week apart. 
7. Have glycosylated hemoglobin 10.0% (0.100 hemoglobin fraction) or a fasting glucose 
270 mg/dL (15.0 mmol/L) at Screening; 
8. Have thyroid-stimulating hormone >1.5  ULN at Screening; 
9. Have creatine kinase >3  ULN at Screening; 
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; 
11. Have a known history of alcohol and/or drug abuse within 5 years prior to Randomization; 
12. Have received treatment with other investigational products or devices within 30 days of 
Screening 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 or 5 half-lives of the previous investigational product will be 
permitted. 
13. Are taking gemfibrozil; 
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); 


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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 on Days 1 to 365. Study drug should be administered with water. 
EFFICACY ENDPOINTS: 
The primary efficacy endpoint is the percent change from Baseline to Day 84 in fasting 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 fasting LDL-C in the obicetrapib group 
compared to the placebo group; 
 Percent change from Baseline to Days 84, 180, and 365 in fasting ApoB in the obicetrapib 
group compared to the placebo group; 
 Percent change from Baseline to Days 84, 180, and 365 in fasting non-HDL-C in the 
obicetrapib group compared to the placebo group; 
 Percent change from Baseline to Days 84, 180, and 365 in fasting HDL-C in the obicetrapib 
group compared to the placebo group; 
 Percent change from Baseline to Days 84 and 365 in fasting Lp(a) in the obicetrapib group 
compared to the placebo group; 
 Percent change from Baseline to Days 84, 180, and 365 in fasting TC in the obicetrapib group 
compared to the placebo group; and 
 Percent change from Baseline to Days 84, 180, and 365 in fasting TG in the obicetrapib group 
compared to the placebo group. 
The exploratory efficacy endpoints include the following: 
 Individual responsiveness defined as the number of participants reaching on treatment fasting 
LDL-C levels of <40 mg/dL (<1.04 mmol/L), <55 mg/dL (<1.42 mmol/L), <70 mg/dL 
(<1.81 mmol/L), and <100 mg/dL (<2.59 mmol/L) at Days 84 and 365; 


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 Individual responsiveness defined as the number of participants reaching on treatment fasting 
non-HDL-C levels of <85 mg/dL (<2.20 mmol/L), <100 mg/dL (<2.59 mmol/L), and 
<130 mg/dL (<3.37 mmol/L) at Days 84 and 365; 
 Individual responsiveness defined as the number of participants reaching on treatment fasting 
ApoB levels of <65 mg/dL (<0.65 g/L), <80 mg/dL (<0.80 g/L), and <130 mg/dL (<1.30 g/L) 
at Days 84 and 365; 
 Percent change from Baseline to Days 84 and 365 in fasting ApoA1 in the obicetrapib group 
compared to the placebo group; and 
 Trough levels of obicetrapib from Baseline to Day 365 in the obicetrapib group. 
SAFETY ENDPOINTS: 
The safety endpoints include the following: 
 Safety and tolerability profile of obicetrapib assessed by AEs, ESIs, vital signs (including 
blood pressure), ECGs, and clinical laboratory values. 
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. 
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. 


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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 supportive analyses. 
The primary efficacy endpoint is the percent change from Baseline to Day 84 in fasting 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 
covariate of Baseline LDL-C. The least squares (LS) mean, standard errors, and 2-sided 
95% confidence intervals for each treatment group and for the mean difference compared to 
placebo will be obtained. Model diagnostics for the ANCOVA model will be computed that 
include assessments for homogeneity of variance, normality of the residuals, and residual outliers. 
If substantial deviations from the model assumptions are observed, then supportive analyses, such 
as an ANCOVA model assuming unequal variances or non-parametric assessments, will be 
considered. 
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 access 
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 and exploratory efficacy endpoints will be analyzed using similar methods 
as in the primary efficacy analysis. For the binary exploratory efficacy endpoints, a logistic 
regression analysis will be performed with model covariates of treatment group and Baseline 
LDL-C. Odds ratio and 95% confidence interval for the odds ratio will be obtained. Nominal 
p-values will be provided when applicable. Descriptive and graphical summaries by treatment 
group will also be presented. 
Full details of the models and analyses to be performed will be provided in the SAP. 
Safety analysis 
The Safety Population will be the primary population for the safety analysis. All safety endpoints 
will be summarized descriptively. No statistical inference will be applied to the safety endpoints. 


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AEs will be categorized by primary system organ class and preferred term as coded using the 
Medical Dictionary for Regulatory Activities category designations. Summaries of AEs, including 
the number and percentage of participants who experience an AE, will be provided. 
Laboratory values will be summarized descriptively, including the change from Baseline, by 
treatment group, and overall. In addition, shift tables will be presented to describe the change in 
laboratory parameter values at post-Baseline visits using normal range categories (low, normal, 
and high). 
SAMPLE SIZE DETERMINATION: 
Enrollment of approximately 300 participants globally is planned for this study. 
Assuming an approximate 5% drop out rate, approximately 285 participants will be evaluable for 
efficacy. This sample size of at least 285 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. 
SITES: Approximately 60 study sites globally 
SPONSOR: 
NewAmsterdam B.V.  
Gooimeer 2-35 
1411 DC 
Naarden 
The Netherlands 
Telephone: +31 35 699 30 00 
Fax: +31 20 240 07 79 


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TABLE OF CONTENTS 
Signature Page ................................................................................................................................ 2 
Investigator Agreement ................................................................................................................... 3 
Synopsis .......................................................................................................................................... 4 
Table of Contents .......................................................................................................................... 13 
List of Abbreviations and Definition of Terms............................................................................. 17 
1  Introduction and Background Information ............................................................................. 19 
1.1 
Background Information on the Disease to be Treated ................................................. 19 
1.2 
Background Information on Cholesteryl Ester Transfer Protein Inhibition .................. 20 
1.3 
Obicetrapib (TA-8995) .................................................................................................. 20 
1.4 
Clinical Development of Obicetrapib ........................................................................... 20 
1.4.1  Dose Selection Rationale .................................................................................. 21 
1.5 
Rationale ........................................................................................................................ 21 
1.6 
Risk/Benefit ................................................................................................................... 22 
1.6.1  Coronavirus Disease 2019 Impacts ................................................................... 22 
2  Study Objectives ..................................................................................................................... 24 
2.1 
Primary Objective ......................................................................................................... 24 
2.2 
Secondary Objectives .................................................................................................... 24 
2.3 
Exploratory Objectives .................................................................................................. 24 
3  Study Description.................................................................................................................... 25 
3.1 
Summary of Study Design ............................................................................................ 25 
3.1.1  COVID-19 Contingency Measures ................................................................... 25 
3.2 
Study Indication ............................................................................................................ 26 
4  Selection and Withdrawal of Participants ............................................................................... 27 
4.1 
Inclusion Criteria ........................................................................................................... 27 
4.2 
Exclusion Criteria .......................................................................................................... 29 
4.3 
Withdrawal Criteria ....................................................................................................... 30 
4.4 
Retesting ........................................................................................................................ 31 
4.5 
Rescreening ................................................................................................................... 31 
5  Study Treatments .................................................................................................................... 32 
5.1 
Treatment Groups .......................................................................................................... 32 


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5.2 
Rationale for Dosing ..................................................................................................... 32 
5.3 
Randomization and Blinding ......................................................................................... 32 
5.4 
Breaking the Blind ........................................................................................................ 32 
5.5 
Drug Supplies ................................................................................................................ 33 
5.5.1  Formulation and Packaging ............................................................................... 33 
5.5.2  Study Drug Preparation and Dispensing ........................................................... 33 
5.5.3  Study Drug Administration ............................................................................... 33 
5.5.4  Treatment Compliance ...................................................................................... 33 
5.5.5  Storage and Accountability ............................................................................... 34 
5.6 
Prior and Concomitant Medications and/or Procedures ................................................ 34 
5.6.1  Excluded Medications and/or Procedures ......................................................... 34 
5.6.2  Restricted Medications and/or Procedures ........................................................ 34 
5.6.3  Documentation of Prior and Concomitant Medication Use .............................. 35 
5.6.4  Dietary Guidelines ............................................................................................. 35 
6  Study Procedures .................................................................................................................... 36 
7  Efficacy Assessments .............................................................................................................. 37 
7.1 
Lipid Profile/Biomarkers ............................................................................................... 37 
7.2 
PK Sampling ................................................................................................................. 38 
7.3 
Lp(a) and ApoA1 .......................................................................................................... 38 
7.4 
Serum Archive Samples for Future Assessment ........................................................... 38 
8  Safety Assessments ................................................................................................................. 39 
8.1 
Adverse Events .............................................................................................................. 39 
8.1.1  Adverse (Drug) Reaction .................................................................................. 40 
8.1.2  Unexpected Adverse Drug Reaction ................................................................. 40 
8.1.3  Assessment of AEs by the Investigator ............................................................. 40 
8.1.4  Events of Special Interest .................................................................................. 41 
8.1.4.1  Guidelines for management of elevated liver enzymes ...................... 42 
8.1.4.2  Guidelines for monitoring and management of CK ............................ 43 
8.1.4.3  Guidelines for monitoring and management of NODM ..................... 43 
8.1.4.4  Guidelines for monitoring and management of significant changes in 
renal function ...................................................................................... 44 
8.1.4.5  Guidelines for monitoring and management of changes to 
antihypertensive medication(s) ........................................................... 44 


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8.1.4.6  Guidelines for management of macular degeneration ........................ 44 
8.2 
Serious Adverse Events ................................................................................................. 44 
8.3 
SAE Reporting − Procedures for Investigators ............................................................. 45 
8.4 
Pregnancy Reporting ..................................................................................................... 46 
8.5 
Expedited Reporting ...................................................................................................... 46 
8.5.1  Project Specific Exemption From SAE Immediate Reporting to Health 
Authorities, Ethics Committees, and IRBs ........................................................ 46 
8.6 
Special Situation Reports .............................................................................................. 47 
8.7 
Clinical Laboratory Evaluations .................................................................................... 48 
8.7.1  Urine Albumin-Creatinine Ratio and Urine Protein-Creatinine Ratio .............. 48 
8.7.2  Aldosterone and High Sensitivity C-Reactive Protein ...................................... 48 
8.7.3  Efficacy Endpoint Laboratory Assessments ..................................................... 48 
8.7.4  Managing Abnormal and Critical Laboratory Values ....................................... 49 
8.8 
Vital Signs ..................................................................................................................... 49 
8.8.1  Blood Pressure Monitoring ............................................................................... 50 
8.9 
Electrocardiograms ........................................................................................................ 50 
8.10  Physical Examinations .................................................................................................. 50 
9  Statistics .................................................................................................................................. 51 
9.1 
Analysis Populations ..................................................................................................... 51 
9.2 
Statistical Methods ........................................................................................................ 51 
9.2.1  Analysis of Efficacy .......................................................................................... 51 
9.2.1.1  Primary efficacy analysis .................................................................... 51 
9.2.1.2  Secondary and exploratory efficacy analyses ..................................... 52 
9.2.2  Analysis of Safety ............................................................................................. 52 
9.2.2.1  Analysis of ESIs .................................................................................. 52 
9.2.3  Interim Analysis ................................................................................................ 53 
9.2.4  Data and Safety Monitoring Board ................................................................... 53 
9.2.5  Sample Size Determination ............................................................................... 53 
10  Data Management and Record Keeping ................................................................................. 54 
10.1  Data Management ......................................................................................................... 54 
10.1.1  Data Handling ................................................................................................... 54 
10.1.2  Computer Systems ............................................................................................. 54 
10.1.3  Data Entry ......................................................................................................... 54 


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10.1.4  Medical Information Coding ............................................................................. 54 
10.1.5  Data Validation ................................................................................................. 54 
10.2  Record Keeping ............................................................................................................. 54 
10.3  End of Study .................................................................................................................. 55 
11  Investigator Requirements and Quality Control ..................................................................... 56 
11.1  Ethical Conduct of the Study ........................................................................................ 56 
11.2  IRB/IEC ......................................................................................................................... 56 
11.3  Informed Consent .......................................................................................................... 56 
11.4  Subject Card .................................................................................................................. 57 
11.5  Study Monitoring Requirements ................................................................................... 57 
11.6  Disclosure of Data ......................................................................................................... 57 
11.7  Retention of Records ..................................................................................................... 57 
11.8  Publication Policy ......................................................................................................... 58 
11.9  Financial Disclosure ...................................................................................................... 58 
11.10 Insurance and Indemnity ............................................................................................... 58 
11.11 Legal Aspects ................................................................................................................ 58 
12  Study Administrative Information .......................................................................................... 59 
12.1  Protocol Amendments ................................................................................................... 59 
13  References ............................................................................................................................... 60 
Appendix A: Schedule of Procedures ........................................................................................... 62 
Appendix B: Clinical Laboratory Analytes .................................................................................. 64 
Appendix C: Diagnostic Scoring Table for Familial Hypercholesterolemia (Constructed by the 
Dutch Lipid Clinic Network) .................................................................................................. 66 
Appendix D: Simon Broome Register Diagnostic Criteria for Familial Hypercholesterolemia .. 67 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
Abbreviation 
Definition 
AE 
Adverse event 
ALT  
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
ApoA1 
Apolipoprotein A1 
ApoB 
Apolipoprotein B 
ASCVD 
Atherosclerotic cardiovascular disease 
AST 
Aspartate aminotransferase 
CD 
Calendar day 
CETP 
Cholesteryl ester transfer protein 
CFR 
Code of Federal Regulations 
CK 
Creatine kinase 
COVID-19 
Coronavirus Disease 2019 
CRA 
Clinical Research Associate 
CTA 
Clinical trial authorisation 
CV 
Cardiovascular 
CVD 
Cardiovascular disease 
DNA 
Deoxyribonucleic acid 
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 
HDL 
High-density lipoprotein 
HDL-C 
High-density lipoprotein cholesterol  
HeFH 
Heterozygous familial hypercholesterolemia 
HF 
Heart failure 


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Abbreviation 
Definition 
HIS 
High-intensity statin 
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 
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 
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-lowering 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-lowering 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 (4.92 mmol/L) and can be as high as 400 mg/dL 
(10.36 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 (1.81 mmol/L). Those unable to achieve these treatment goals with maximally 
tolerated statin therapy require additional lipid-lowering 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 (38.61 mg/dL) reduction in LDL-C is 
associated with a 22% reduction in the 5-year incidence of major coronary events, 
revascularizations, and ischemic strokes. Intensive statin therapy relative to low- or 
moderate-intensity statin treatment confers a greater benefit in patients at high CV risk.10 
Non-statin therapies may provide additional lowering of CV risk as demonstrated in the 


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IMPROVE-IT study adding ezetimibe to statin therapy.11,12 Unfortunately, despite being treated 
with maximally tolerated lipid-lowering 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 therapy despite treatment 
with maximally tolerated lipid-lowering 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. 
Two additional Phase 2 studies of obicetrapib (TA-8995-303 and TA-8995-201) have completed. 
The first study, TA-8995-303, evaluated the LDL-lowering effects of obicetrapib in combination 
with ezetimibe in participants with mild dyslipidemia. The second study, TA-8995-201, evaluated 
the LDL-lowering effects of obicetrapib as an adjunct to high-intensity statin (HIS) therapy in 
participants with dyslipidemia who are on HIS. In both studies, the primary efficacy endpoint was 
achieved. 
This study is a pivotal Phase 3 study to investigate the treatment of elevated LDL-C levels in 
participants with a history of HeFH. 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, and HDL-C levels were increased 
while 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 a history of HeFH 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 several 
limitations with this line of therapy, including very high costs and limited long-term success 
relative to statins. Because PCSK9-targeted therapies are injectable, this poses a less attractive 
option for patients who prefer oral medications. 


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Accordingly, there remains an unmet need for therapies to reduce elevated LDL-C levels and CV 
risk at an acceptable cost and with a favorable safety 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, and HDL-C levels were increased 
while 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 a history of HeFH 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 2020, Food and Drug 
Administration 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 
impacts of these implemented contingency measures on the outcomes of this study, including any 


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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 fasting 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 fasting 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 fasting LDL-C levels at Days 180 and 365; 
 To evaluate the effect of obicetrapib on fasting Lp(a) at Days 84 and 365; and 
 To evaluate the safety and tolerability profile of obicetrapib in a representative population of 
adult males and females with HeFH, 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 Number of participants reaching prespecified fasting LDL-C, non-HDL-C, and ApoB 
levels at Days 84 and 365; and 
o Fasting ApoA1 at Days 84 and 365. 
 To evaluate trough levels of obicetrapib from Baseline to Day 365 in the obicetrapib group. 


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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 300 participants with a history of HeFH 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 300 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. 
At least 70% of the participants enrolled into this study must be taking HISs. HeFH diagnosis is 
defined by existing confirmation via genetic testing, WHO Criteria/Dutch Lipid Clinical Network 
Criteria with a score of >8 points, and/or Simon Broome Register Diagnostic Criteria.17,18 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. An End of Study (EOS) Visit will be conducted approximately 35 days after the 
participant’s last dose of study drug, during which vital signs; limited serum chemistry, 
hematology, and coagulation parameters; pharmacokinetics (PK); concomitant medications; and 
AEs will be assessed. 
The study will be governed by a Steering Committee, and a Data and Safety Monitoring Board 
(DSMB) will provide independent oversight of participant safety. 
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 
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. 


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3.2 
Study Indication 
Obicetrapib is being developed as an adjunct to diet and maximally tolerated lipid-lowering 
therapy for the treatment of adults with HeFH 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; 
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; 
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 informed consent form (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 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 method) or 
sterile sexual partner. 
3. Have a history of HeFH as defined by at least 1 of the following: 
o Genotyping by a central laboratory; 
Note: Confirmation by prior genetic testing is required (ie, genotyping is not a Screening 
assessment). 
o Clinical assessment using the WHO Criteria/Dutch Lipid Clinical Network Criteria with a 
score of >8 points, as specified in Appendix C;17 and/or 
o Meet the Simon Broome Register Diagnostic Criteria for definite or possible FH, as 
specified in Appendix D.18  


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4. Are on maximally tolerated lipid-modifying therapy, as an adjunct to diet, 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; 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 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; 
o Bempedoic acid for at least 8 weeks in combination with maximally tolerated statin prior 
to Screening; 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. 
Note: At least 70% of the participants enrolled into this study must be taking HISs. 
Documentation of the reason why a participant is unable to take HISs is required. HISs include 
the following: 
o Atorvastatin 40 or 80 mg; or 
o Rosuvastatin 20 or 40 mg. 
5. Have a fasting serum LDL-C 70 mg/dL (1.81 mmol/L) at Screening; 
Note: LDL-C at Screening will be calculated using the Friedewald equation unless 
TG 400 mg/dL (4.52 mmol/L) or LDL-C 50 mg/dL (1.30 mmol/L). If TG 400 mg/dL 
(4.52 mmol/L) or LDL-C 50 mg/dL (1.30 mmol/L), then LDL-C level will be measured 
directly by preparative ultracentrifugation, also referred to as beta quantification. 
6. Have fasting TG <400 mg/dL (<4.52 mmol/L) at Screening; 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. 


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4.2 
Exclusion Criteria 
Participants who meet any of the following criteria will be excluded from participation in the study: 
1. Have current or any previous history of New York Heart Association class III or IV heart 
failure (HF) or left ventricular ejection fraction <30%; 
2. Have been hospitalized for HF within 5 years prior to Screening; 
3. Have had any of the following clinical events within 3 months prior to Screening: 
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 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; 
Note: An abnormal ALT, AST, or total bilirubin must be confirmed by a repeat abnormal 
measurement at least 1 week apart. 
7. Have glycosylated hemoglobin (HbA1c) 10.0% (0.100 hemoglobin fraction) or a fasting 
glucose 270 mg/dL (15.0 mmol/L) at Screening; 
8. Have thyroid-stimulating hormone >1.5  ULN at Screening; 
9. Have creatine kinase (CK) >3  ULN at Screening; 
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; 
11. Have a known history of alcohol and/or drug abuse within 5 years prior to Randomization; 
12. Have received treatment with other investigational products or devices within 30 days of 
Screening 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 or 5 half-lives of the previous investigational product will be permitted. 
13. Are taking gemfibrozil; 
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; 


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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; 
 Requirement of prohibited concomitant medication; 
 Pregnancy (permanent discontinuation of study drug); 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. 
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 
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All participants who permanently discontinue study drug should continue scheduled study visits. 
In addition, all procedures and laboratory samples or tests requested for evaluation following 
administration of the study drug should be carried out when possible, whether or not a subject 
continues to receive treatment according to the protocol. 
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 EOS Visit approximately 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 withdraw consent to all follow-up will be asked about the reason(s) and will be assessed for 
the presence of any AEs. 
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 electronic case report form (eCRF). 
Withdrawn participants will not be replaced. 
4.4 
Retesting 
If laboratory abnormalities during Screening are considered by the Investigator to be transient, 
then the laboratory tests may be repeated once during Screening. 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 once, 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 300 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 on Days 1 to 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, and HDL-C levels were increased 
while 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 a history of HeFH 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. 
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 
in which knowledge of the participant’s study drug is necessary for clinical management, the 
Investigator should proceed with unblinding.  
Once a participant’s treatment assignment has been unblinded, the Medical Monitor or designee 
should be notified within 24 hours of unblinding of the treatment. Information relating to 
unblinding (eg, date and time of the call to the Medical Monitor by the Investigator, reason for 




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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 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 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 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. Participants taking 
PCSK9-targeted therapies should have received 4 stable doses prior to Screening. There should be 
no planned medication or dose changes for lipid-modifying therapy during study participation. If 
there are changes to lipid-modifying therapy during the study, these data will be recorded. 
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. 
Participants may continue taking very low dose statin therapy throughout the study, provided that 
the dose is stable and well tolerated. Participants are also not required to be taking statins. Reasons 
for not using statin therapy must be documented (eg, the participant is statin intolerant). 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 attributed to the 


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statin in question in the source documentation and eCRF as part of 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-lowering 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, 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), 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 of the reason why a participant is unable to take HISs is required. 
5.6.4 
Dietary Guidelines 
Participants will be instructed to follow a lipid-lowering diet 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 fasting 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 fasting LDL-C in the obicetrapib group 
compared to the placebo group; 
 Percent change from Baseline to Days 84, 180, and 365 in fasting ApoB in the obicetrapib 
group compared to the placebo group; 
 Percent change from Baseline to Days 84, 180, and 365 in fasting non-HDL-C in the 
obicetrapib group compared to the placebo group; 
 Percent change from Baseline to Days 84, 180, and 365 in fasting HDL-C in the obicetrapib 
group compared to the placebo group; 
 Percent change from Baseline to Days 84 and 365 in fasting Lp(a) in the obicetrapib group 
compared to the placebo group; 
 Percent change from Baseline to Days 84, 180, and 365 in fasting TC in the obicetrapib group 
compared to the placebo group; and 
 Percent change from Baseline to Days 84, 180, and 365 in fasting TG in the obicetrapib group 
compared to the placebo group. 
The exploratory efficacy endpoints include the following: 
 Individual responsiveness defined as the number of participants reaching on treatment fasting 
LDL-C levels of <40 mg/dL (<1.04 mmol/L), <55 mg/dL (<1.42 mmol/L), <70 mg/dL 
(<1.81 mmol/L), and <100 mg/dL (<2.59 mmol/L) at Days 84 and 365; 
 Individual responsiveness defined as the number of participants reaching on treatment fasting 
non-HDL-C levels of <85 mg/dL (<2.20 mmol/L), <100 mg/dL (<2.59 mmol/L), and 
<130 mg/dL (<3.37 mmol/L) at Days 84 and 365; 
 Individual responsiveness defined as the number of participants reaching on treatment fasting 
ApoB levels of <65 mg/dL (<0.65 g/L), <80 mg/dL (<0.80 g/L), and <130 mg/dL (<1.30 g/L) 
at Days 84 and 365; 
 Percent change from Baseline to Days 84 and 365 in fasting ApoA1 in the obicetrapib group 
compared to the placebo group; and 
 Trough levels of obicetrapib from Baseline to Day 365 in the obicetrapib group. 
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). 


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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 (4.52 mmol/L) or LDL-C 50 mg/dL (1.30 mmol/L). If TG 400 mg/dL 
(4.52 mmol/L) or LDL-C 50 mg/dL (1.30 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 
PK Sampling 
A PK sample will be collected prior to study drug administration for trough measurement of 
obicetrapib in plasma at Baseline and visits specified in the Schedule of Procedures (Appendix A). 
7.3 
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). 
7.4 
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 biomarkers related to 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). 


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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), ECGs, and clinical laboratory values. 
8.1 
Adverse Events 
An AE is defined as any untoward medical occurrence in a clinical investigation participant 
administered a pharmaceutical product, which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and/or unintended sign (including 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 until the EOS Visit (approximately 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 should be recorded as medical history and not 
be reported as an AE unless the medical condition or signs or symptoms present at Baseline change 
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 and significantly worsen during the 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. 


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8.1.1 
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. 
8.1.2 
Unexpected Adverse Drug Reaction 
An unexpected adverse drug reaction is defined as an adverse reaction, the nature or severity of 
which is not consistent with the applicable product information.  
8.1.3 
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 rules out 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. 
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. 


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 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. 
8.1.4 
Events of Special Interest  
ESIs will be monitored over time by the independent DSMB, as described in the DSMB charter, 
regardless of whether these events were reported as AEs. Any events that qualify as an AE or SAE 
will be reported accordingly (see Sections 8.1, 8.2, and 8.3). 
ESIs will include the following hepatic abnormalities, muscle-related abnormalities, new-onset 
diabetes mellitus (NODM) and/or hyperglycemia, renal abnormalities, changes to antihypertensive 
medication(s) due to changes in blood pressure, and ophthalmic events (ie, macular degeneration), 
described as follows: 
 AST or ALT >3  ULN; 
 Bilirubin >2  ULN; 
 CK >5  ULN; 
 NODM or worsening of glycemic control;  
Note: NODM is defined by 1 or more of the following criteria, based upon information from 
AE, medication, and laboratory data:  
o AE indicating new type 1 or type 2 diabetes; 
o Initiation of anti-diabetes medication with confirmation of the diagnosis of diabetes by 
blinded external review by experts in diabetology; 
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). 


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 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 database. 
8.1.4.1 
Guidelines for management of elevated liver enzymes  
Participants with signs or symptoms consistent with liver injury (eg, nausea, vomiting, anorexia, 
fatigue, right upper abdominal pain or discomfort) should undergo immediate testing of ALT, 
AST, gamma-glutamyl transferase, bilirubin, alkaline phosphatase, prothrombin time, and 
international normalized ratio.  
In the absence of clinical symptoms, participants with ALT or AST >3  ULN (if normal at 
Baseline) or >2-fold change (if abnormal at Baseline) should be retested within 48 to 72 hours for 
the usual serum measurements (ALT, AST, alkaline phosphatase, and bilirubin) to confirm the 
abnormalities and to determine if the associated values are increasing or decreasing. There should 
also be an inquiry about symptoms at the time of follow-up. 
If the above abnormalities are confirmed: 
 Repeat liver enzyme and serum bilirubin tests 2 or 3 times weekly. The frequency of retesting 
can decrease to once a week or less if abnormalities stabilize or the study drug has been 
discontinued and the participant is asymptomatic; 
 Obtain a more detailed history of symptoms and prior or concurrent diseases; 
 Obtain a history of concomitant drug use (including nonprescription medications and herbal 
and dietary supplement preparations), alcohol use, recreational drug use, and special diet; 
 Rule out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic hepatitis; 
nonalcoholic steatohepatitis; hypoxic/ischemic hepatopathy; and biliary tract disease; 
 Obtain a history of exposure to environmental chemical agents; 
 Obtain additional tests to evaluate liver function, as appropriate (eg, international normalized 
ratio, direct bilirubin); and 
 Consider gastroenterology or hepatology consultations. 
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%). 


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8.1.4.2 
Guidelines for monitoring and management of CK  
If at any time after Randomization 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 dipstick urinalysis with microscopy, if indicated; 
 Measurement of clinical chemistries to assess the possibility of lactic acidosis; and 
 Follow-up of symptoms and CK until the abnormality has resolved. 
If, based on the above evaluation, an alternative explanation is suspected, consideration can be 
given to resuming study drug once CK returns to Baseline levels. 
If no alternative explanation exists, consideration should be given to 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, 
should 
lead 
to 
study 
drug 
interruption/discontinuation until the contribution of obicetrapib has been excluded. 
8.1.4.3 
Guidelines for monitoring and management of NODM 
Diabetes mellitus may be newly diagnosed during the study as described in Section 8.1.4. If a 
participant is newly diagnosed with diabetes mellitus during the course of the study, the 
Investigator will recommend referral for initial diabetes education and management by an 
appropriate healthcare provider (eg, diabetologist, endocrinologist, or primary care provider). 
Interventions for management may include diet and lifestyle counseling, self-monitoring of blood 


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glucose, oral glucose-lowering medications, injectable medications, or insulin as deemed 
necessary by the treating physician based on the level of hyperglycemia and relevant symptoms. 
8.1.4.4 
Guidelines for monitoring and management of significant changes in renal function  
If at any time after Randomization 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. 
8.1.4.5 
Guidelines for monitoring and management of changes to antihypertensive 
medication(s) 
Any changes to antihypertensive medication(s) due to changes in blood pressure in those 
participants receiving antihypertensive medication(s) treatment at Baseline will be assessed by the 
Investigator, primary care physician, or other appropriate health care provider to assess for 
etiologies of blood pressure change, to confirm clinical safety of the participant, to assess the need 
for any AE or SAE reporting, and to arrange for appropriate medical follow-up. 
8.1.4.6 
Guidelines for management of macular degeneration 
In cases of suspected macular degeneration or acute vision loss, participants will be referred for 
an ophthalmological consultation. 
8.2 
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. 


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 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. 
8.3 
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 [±7] 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 35-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 8.6), and fax/email the completed back-up paper SAE 
form to 
 (contact information listed in Section 8.6) 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 


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email. If it is not possible to access the EDC system, refer to the procedures outlined above for 
initial reporting of SAEs.  
8.4 
Pregnancy Reporting 
If a participant becomes pregnant during the study, the Investigator is to stop dosing with 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/study site the Exposure In Utero (EIU) form (Part 1) for completion. The 
Investigator/study 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. 
8.5 
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 Food and Drug 
Administration (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. 
8.5.1 
Project Specific Exemption From SAE Immediate Reporting to Health Authorities, 
Ethics Committees, and IRBs 
The FDA guidance documents titled “Guidance for clinical investigators, sponsors, and IRBs. 
Adverse event reporting to IRBs  improving human subject protection” and “Guidances for 


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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.20,21 
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. 
8.6 
Special Situation Reports 
Special situation reports include reports of overdose, misuse, abuse, medication error, and reports 
of adverse reactions associated with product complaints. 
 Overdose: Refers to the administration of a quantity of a medicinal product given per 
administration or cumulatively (accidentally or intentionally), which is above the maximum 
recommended dose according to the protocol. Clinical judgment should always be applied. In 
cases of a discrepancy in the drug accountability, overdose will be established only when it is 
clear that the participant has taken additional dose(s), or the Investigator has reason to suspect 
that the participant has taken additional dose(s).  
 Misuse: Refers to situations where the medicinal product is intentionally and inappropriately 
used in a way that is not in accordance with the protocol instructions or local prescribing 
information and may be accompanied by harmful physical and/or psychological effects.  
 Abuse: Is defined as persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects. 
 Medication error: Is any unintentional error in the prescribing, dispensing, or administration 
of a medicinal product by a healthcare professional, participant, or consumer, respectively. The 
administration or consumption of the unassigned treatment and administration of an expired 
product are always reportable as medication errors; cases of participants missing doses of 
investigational product are not considered reportable as medication errors. 
 Product complaint: Is defined as any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug or device after it is released for distribution. A special situations form 
will only be completed if a complaint is associated with an adverse drug reaction.  
All special situation events as described above must be reported on the special situation report 
form and faxed/emailed to 
 (contact information listed below) within 
24 hours of knowledge of the event. All AEs associated with these special situation reports should 
be reported as AEs or SAEs as well as recorded on the AE eCRF and/or the SAE report form. 
Details of the symptoms and signs, clinical management, and outcome should be provided, when 
available. 




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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. 
8.7.4 
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 8.7.3), OR if TG levels exceed 
500 mg/dL (5.65 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. 
8.8 
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 
nearest mmHg. 


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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.  
8.8.1 
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. 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 Statistical Analysis Plan (SAP). 
8.9 
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.  
8.10 
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, 
cardiovascular, abdominal, and extremities evaluations; ophthalmological examination; and 
recording of weight and height. Height will be measured at Screening 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 supportive analyses. 
The primary efficacy endpoint is the percent change from Baseline to Day 84 in fasting 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 
covariate of Baseline LDL-C. The least squares (LS) mean, standard errors, and 2-sided 
95% confidence intervals for each treatment group and for the mean difference compared to 
placebo will be obtained. Model diagnostics for the ANCOVA model will be computed that 
include assessments for homogeneity of variance, normality of the residuals, and residual outliers. 
If substantial deviations from the model assumptions are observed, then supportive analyses, such 
as an ANCOVA model assuming unequal variances or non-parametric assessments, will be 
considered. 


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The primary estimand will correspond to a treatment policy estimand. The target population will 
comprise participants who are randomized into the study. The primary summary measure to access 
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. 
9.2.1.2 
Secondary and exploratory efficacy analyses 
In order to control the Type I error rate, a fixed sequential testing procedure will be implemented. 
In a hierarchical step-down manner, the 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 and exploratory efficacy endpoints will be analyzed using similar methods 
as in the primary efficacy analysis. For the binary exploratory efficacy endpoints, a logistic 
regression analysis will be performed with model covariates of treatment group and Baseline 
LDL-C. Odds ratio and 95% confidence interval for the odds ratio will be obtained. Nominal 
p-values will be provided when applicable. Descriptive and graphical summaries by treatment 
group will also be presented. 
Full details of the models and analyses to be performed will be provided in the SAP. 
9.2.2 
Analysis of Safety 
The Safety Population will be the primary population for the safety analysis. All safety endpoints 
will be summarized descriptively. No statistical inference will be applied to the safety endpoints. 
AEs will be categorized by primary system organ class and preferred term as coded using the 
Medical Dictionary for Regulatory Activities category designations. Summaries of AEs, including 
the number and percentage of participants who experience an AE, will be provided. 
Laboratory values will be summarized descriptively, including the change from Baseline, by 
treatment group, and overall. In addition, shift tables will be presented to describe the change in 
laboratory parameter values at post-Baseline visits using normal range categories (low, normal, 
and high). 
9.2.2.1 
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 


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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. 
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. Muscle-related abnormalities will be 
summarized by treatment group and by Baseline eGFR category. 
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. A DSMB will provide independent oversight 
of participant safety.  
9.2.4 
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. 
Additional information is provided in the DSMB Charter.  
9.2.5 
Sample Size Determination 
Enrollment of approximately 300 participants globally is planned for this study. 
Assuming an approximate 5% drop out rate, approximately 285 participants will be evaluable for 
efficacy. This sample size of at least 285 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. 


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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 study 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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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 
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 


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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 can 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 Investigators by 
 or 
the Sponsor. All protocol amendments will undergo the same review and approval process as the 
original protocol. A protocol amendment may be implemented after it has been approved by the 
IRB/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, European Commission, Heads of Medicines Agencies. 
Guidance on the management of clinical trials during the COVID-19 (coronavirus) 
pandemic. Version 4. April 2021. Accessed 11 July 2021. 
https://ec.europa.eu/health/sites/default/files/files/eudralex/vol-10/guidanceclinicaltrials_
covid19_en.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. 
Austin MA, Hutter CM, Zimmern RL, et al. Genetic causes of monogenic heterozygous 
familial hypercholesterolemia: a HuGE prevalence review. Am J Epidemiol. 
2004;160(5):407-420. 
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. 
Office of the Commissioner (OC), Center for Drug Evaluation and Research (CDER), 
Center for Biologics Evaluation and Research (CBER), et al. Guidance for clinical 
investigators, sponsors, and IRBs. Adverse event reporting to IRBs  improving human 
subject protection. US Dept of Health and Human Services, Food and Drug Administration. 
January 2009. Accessed 09 December 2021. https://www.fda.gov/media/72267/download.  
21. 
US Dept of Health and Human Services, 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. Fed Regist. 2012;77(245):75439-75440. 
 


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APPENDIX A: SCHEDULE OF PROCEDURES 
  
Screening 
Treatment Period 
EOS 
Visit
V1 
V2 
V3 
V4 
V5 
V6 
V7/EOT/ET1 
V8 
Study Day
-14 to -1 
1 
30 
84 
180 
270 
365 
35 days after 
last dose 
Window (±Days)
±3 
 
±3 
±7 
±7 
±7 
±7 
±7 
Informed consent 
X 
 
 
 
 
 
 
 
Assessment of eligibility 
X2 
X2 
 
 
 
 
 
 
Demographics and medical history 
X 
 
 
 
 
 
 
 
Pregnancy test, FSH3 
X 
X 
X 
X 
X 
X 
X 
 
TSH 
X 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
Study drug administration 
 
X 
X 
X 
X 
X 
X 
 
Physical examination4 
X 
 
 
 
 
 
X 
 
Weight, height, and BMI 
X5 
 
 
 
 
 
X 
 
Vital signs6 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG7 
 
X 
 
 
 
 
X 
 
Lipid profile/biomarkers (fasting)8 
X 
X 
X 
X 
X 
X 
X 
 
Serum archive sample for future 
assessment of biomarkers related to 
dyslipidemia and/or CV risk (fasting)8,9 
 
X 
 
 
 
 
X 
 
UACR, UPCR (fasting)8  
 
X 
X 
X 
X 
X 
X 
 
Aldosterone, hsCRP (fasting)8  
 
X 
X 
X 
X 
X 
X 
 
Lp(a), ApoA1 (fasting)8,9  
X 
X 
 
X 
 
 
X 
 
Full serum chemistry (fasting)8,9  
 
X 
 
 
X 
 
X 
 
Limited serum chemistry (fasting)8,9  
X 
 
X 
X 
 
X 
 
X 
Urinalysis (local)10 
X 
X 
 
 
 
 
X 
 
Hematology and coagulation (fasting)8,9 
X 
X 
 
 
X 
 
X 
X 
PK sample (central)9,11 
 
X 
 
 
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 
EOS 
Visit
V1 
V2 
V3 
V4 
V5 
V6 
V7/EOT/ET1 
V8 
Study Day
-14 to -1 
1 
30 
84 
180 
270 
365 
35 days after 
last dose 
Window (±Days)
±3 
 
±3 
±7 
±7 
±7 
±7 
±7 
Study drug return/compliance 
calculations 
 
 
X 
X 
X 
X 
X 
 
AEs assessment 
X 
X 
X 
X 
X 
X 
X 
X 
 
1. 
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 EOS Visit approximately 35 days later. The ET Visit procedures are identical to the 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 withdraw consent to all follow-up will be asked about the reason(s) and will be 
assessed for the presence of any AEs. 
2. 
Assessment of laboratory eligibility criteria will be based on central laboratory values obtained within timeframes defined in the inclusion and exclusion criteria. 
3. 
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 in females <55 years of age and postmenopausal, defined as 1 year since their last menstrual period. 
4. 
The physical examination should comprise a focused examination, which includes general, respiratory, cardiovascular, abdominal, and extremities evaluations; ophthalmological 
examination; and recording of weight and height. 
5. 
Height will be measured at Screening only and used to calculate BMI. 
 
6. 
Vital signs (consisting of heart rate and blood pressure) will be measured as described in Section 8.8. 
 
7. 
A single l2-lead ECG will be performed in the supine position after 10 minutes of rest. 
8. 
Participants must fast for a minimum of 8 hours prior to samples being collected.  
9. 
Samples should be collected prior to study drug administration. 
10. Urinalysis will be performed locally by dipstick analyses 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. 
11. 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. 
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; hsCRP = high sensitivity C-reactive protein; 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 (4.52 mmol/L) or 
LDL-C 50 mg/dL (1.30 mmol/L). If TG 400 mg/dL (4.52 mmol/L) or LDL-C 50 mg/dL (1.30 mmol/L), then 
LDL-C level will be measured directly by preparative ultracentrifugation.  
 
Endocrinology 
Follicle-stimulating hormone [1] 
Thyroid-stimulating hormone 
Human chorionic gonadotropin [2] 
 
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 gonadotropin 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 time 
International normalized ratio 
Prothrombin time 
 
 
Urinalysis 
Bilirubin 
Blood 
Glucose 
Ketones 
Leukocyte esterase 
Microscopy [1] 
Nitrite 
pH 
Protein 
Urobilinogen 
1. 
Urinalysis will be performed locally by dipstick analyses 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 ApoB-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: Austin MA, Hutter CM, Zimmern RL, et al. Genetic causes of monogenic heterozygous familial 
hypercholesterolemia: a HuGE prevalence review. Am J Epidemiol. 2004;160(5):407-420 

SAP_001.pdf: 
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CONFIDENTIAL 
Statistical Analysis Plan 
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Page 1 of 32 
 
STATISTICAL ANALYSIS PLAN 
 
Protocol Title: 
Obicetrapib on Top of Maximum Tolerated Lipid-Modifying 
Therapy (BROOKLYN): a Placebo-Controlled, Double-
Blind Randomized Phase 3 Study to Evaluate the Effect of 
10 mg Obicetrapib in Participants With a History of HeFH 
and LDL-C ≥70 mg/dL Who are Not Adequately Controlled 
by Their Lipid-Modifying Therapies 
 
Protocol Number: 
TA-8995-301 
Protocol Version/Date: 
3.0/18 May 2022 
Investigational Product: Obicetrapib 
 
 
Sponsor: 
NewAmsterdam Pharma B.V. 
Gooimeer 2-35 
1411 DC 
Naarden 
The Netherlands 
 
 
SAP Version/Date: 
3.0/26-JUNE-2024 
 
CONFIDENTIAL 
 
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.  
 


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SIGNATURE PAGE 
 
Protocol Title: 
Obicetrapib on Top of Maximum Tolerated Lipid-Modifying 
Therapy (BROOKLYN): a Placebo-Controlled, Double-Blind 
Randomized Phase 3 Study to Evaluate the Effect of 10 mg 
Obicetrapib in Participants With a History of HeFH and LDL-
C ≥70 mg/dL Who are Not Adequately Controlled by Their 
Lipid-Modifying Therapies 
 
Protocol Number: 
TA-8995-301 
SAP Version/Date: 
3.0/26-JUNE-2024 
We, the undersigned, have reviewed and approved this Statistical Analysis Plan: 
 
  
Signature 
 Date 
 
 


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VERSION HISTORY 
 
 
Version 
Version Date 
Description 
1.0 
10 January 2024 
First SAP version 
2.0 
13 May 2024 
SAP was updated following comments 
from FDA 
3.0 
26 June 2024 
Minor clarifications, updates, and 
corrections of typing errors 
 
Version 2.0 (13-MAY-2024): Summary of changes from SAP Version 1.0 (10-JAN-2024) 
 
Section 
Change* 
Rationale 
3.1.7 
More detailed description of how 
dropouts and missing data were 
handled are included  
Following FDA recommendation 
3.4.1 
More details added for the primary 
analysis 
If the number of retrieved 
dropouts will be such that the 
model convergence is 
questionable and the given 
parameter estimates cannot be 
obtained, provided additional 
details for analysis 
3.4.1 
Tipping points analysis included as 
sensitivity analysis 
Following FDA recommendation 
3.4.2 
For the percentage change from 
Baseline to Day 180 in LDL-C, the LDL-
C will be calculated using the 
Friedewald equation and the Martin-
Hopkins equation unless the 
Triglyceride value is ≥400 mg/dL or the 
LDL-C value is ≤50 mg/dL; in which 
case, the LDL-C level measured 
directly by PUC will be used in the 
analysis. 
Because PUC assessments are 
not performed at Day 180 as per 
the 
protocol 
unless 
the 
conditions for Triglycerides or 
LDL-C described are met at the 
Day 180 assessment. 
 
* Please note that minor clarifications, updates, and corrections of typing errors are not listed. 
 


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TABLE OF CONTENTS 
1 
Introduction ......................................................................................................................... 8 
2 
Study Overview ................................................................................................................... 8 
2.1 
Study Objectives .......................................................................................................... 8 
2.1.1 
Primary Objective ................................................................................................. 8 
2.1.2 
Secondary Objectives ........................................................................................... 8 
2.1.3 
Exploratory Objectives .......................................................................................... 8 
2.2 
Study Design ............................................................................................................... 8 
2.2.1 
Overview ............................................................................................................... 8 
2.2.2 
Sample Size Determination ..................................................................................12 
2.3 
Study Endpoints ..........................................................................................................12 
2.3.1 
Primary Efficacy Endpoints ..................................................................................12 
2.3.2 
Secondary Efficacy Endpoints .............................................................................12 
2.3.3 
Exploratory Efficacy Endpoints ............................................................................12 
2.3.4 
Safety Endpoints ..................................................................................................13 
3 
Statistical Methodology ......................................................................................................13 
3.1 
General Considerations ..............................................................................................13 
3.1.1 
Analysis Day ........................................................................................................13 
3.1.2 
Analysis Visits ......................................................................................................13 
3.1.3 
Handling of missed/delayed visits due to COVID-19 ............................................14 
3.1.4 
Definition of Baseline ...........................................................................................14 
3.1.5 
Summary Statistics ..............................................................................................14 
3.1.6 
Hypothesis Testing ..............................................................................................14 
3.1.7 
Evaluation of Site Effect .......................................................................................14 
3.1.8 
Handling of Dropouts and Missing Data ...............................................................15 
3.1.9 
Laboratory Values Above or Below Limits of Quantification .................................15 
3.2 
Analysis Populations ...................................................................................................15 
3.2.1 
Intent-to-Treat (ITT) Population ............................................................................15 
3.2.2 
The Full Analysis Set (FAS) .................................................................................15 
3.2.3 
Modified Intent-to-Treat (mITT) Population ..........................................................15 
3.2.4 
Modified Intent-to-Treat (mITT) On-Treatment Population....................................16 
3.2.5 
Per-Protocol (PP) Population ...............................................................................16 
3.2.6 
Safety Population .................................................................................................16 
3.3 
Participant Data and Study Conduct ...........................................................................16 
3.3.1 
Participant Disposition .........................................................................................16 
3.3.2 
Protocol Deviations ..............................................................................................16 
3.3.3 
Analysis Populations ............................................................................................16 
3.3.4 
Demographic and Baseline Characteristics ..........................................................17 
3.3.5 
Medical History ....................................................................................................17 
3.3.6 
Concomitant Medications .....................................................................................18 
3.3.7 
Study Drug Exposure and Compliance ................................................................18 


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3.4 
Efficacy Assessment ...................................................................................................19 
3.4.1 
Primary Efficacy Endpoints ..................................................................................19 
3.4.2 
Secondary Efficacy Endpoints .............................................................................24 
3.4.3 
Exploratory Efficacy Endpoints ............................................................................24 
3.4.4 
Subgroup Analysis ...............................................................................................25 
3.5 
Safety Assessment .....................................................................................................26 
3.5.1 
Adverse Events (AEs) ..........................................................................................26 
3.5.2 
Event of Special Interest ......................................................................................26 
3.5.3 
Clinical Laboratory Tests .....................................................................................28 
3.5.4 
Vital Signs ............................................................................................................28 
3.5.5 
Electrocardiograms ..............................................................................................29 
3.5.6 
Physical Examinations .........................................................................................29 
4 
Data Safety Monitoring Board ............................................................................................29 
5 
analysis Timing ..................................................................................................................29 
5.1 
Interim Analysis ..........................................................................................................29 
5.2 
Pre-Final Analysis .......................................................................................................29 
5.3 
Final Analysis ..............................................................................................................29 
6 
Changes from Protocol-Specified Statistical Analyses .......................................................30 
7 
Programming Specifications ..............................................................................................30 
Appendix A:  References ..........................................................................................................31 
Appendix B:  preffered terms for hypertension ..........................................................................32 
 
 
 


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LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
ADaM 
Analysis Data Model 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
ApoA1  
Apolipoprotein A1 
ApoB  
Apolipoprotein B 
AST  
Aspartate aminotransferase 
ATC 
Anatomical therapeutic chemical 
BMI 
Body mass index 
CDISC 
Clinical Data Interchange Standards Consortium 
CRF 
Case report form 
CSR 
Clinical Study Report 
CV 
Cardiovascular 
CK 
Creatine kinase 
DLCN 
Dutch Lipid Clinical Network 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eGFR  
Estimated glomerular filtration rate 
EMEA 
Europe, Middle East and Africa 
EOS  
End of Study 
EOT  
End of Treatment 
ESI  
Event of special interest 
ET  
Early Termination 
FAS 
Full Analysis Set 
HbA1c  
Glycosylated hemoglobin 
HDL-C  
High-density lipoprotein cholesterol 
HeFH  
Heterozygous familial hypercholesterolemia 
HIS  
High-intensity statin(s) 
ICF 
Informed consent form 
ITT  
Intent-to-Treat 
LDL  
Low-density lipoprotein 
LDL-C  
Low-density lipoprotein cholesterol 
Lp(a)  
Lipoprotein (a) 
LS  
Least squares 
MAR 
Missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT  
Modified Intent-to-Treat 
MMRM 
Mixed model for repeated measures 
MNAR 
Missing not at random 
NODM  
New-onset diabetes mellitus 
Non-HDL-C  
Non-high-density lipoprotein cholesterol 
PK 
Pharmacokinetics 
PP 
Per-Protocol 
PT 
Preferred term 


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Abbreviation 
Definition 
PUC 
Preparative ultracentrifugation 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SDTM 
Study Data Tabulation Model 
SI 
Statin intolerant 
SOC 
System organ class 
TC 
Total cholesterol 
TFL 
Tables, figures, and listings 
TG 
Triglycerides 
TEAE 
Treatment-emergent adverse event 
TESAE 
Treatment-emergent serious adverse event 
WHO 
World Health Organization 
 
 
 


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1 INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to provide a description of the statistical 
methods to be implemented for the analysis of data from the study with protocol number TA-8995-
301. The SAP will be finalized prior to database lock. Any deviations from the SAP after database 
lock will be documented in the final Clinical Study Report (CSR). 
2 STUDY OVERVIEW 
2.1 Study Objectives 
2.1.1 Primary Objective 
The primary objective of this study is to evaluate the effect of obicetrapib on low-density 
lipoprotein cholesterol (LDL-C) levels at Day 84. 
2.1.2 Secondary Objectives 
The secondary objectives of this study include the following: 
• 
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 LDL-C levels at Days 180 and 365; 
• 
To evaluate the effect of obicetrapib on lipoprotein (a) (Lp[a]) at Days 84 and 365; and 
• 
To evaluate the safety and tolerability profile of obicetrapib in a representative population 
of adult males and females with heterozygous familial hypercholesterolemia (HeFH), 
assessed by adverse events (AEs), events of special interest (ESIs), vital signs (including 
blood pressure), electrocardiogram (ECG) measurements, and clinical laboratory values.  
2.1.3 Exploratory Objectives 
The exploratory objectives of this study include the following: 
• 
To evaluate the effect of obicetrapib on the following: 
o Number of participants achieving prespecified LDL-C, non-HDL-C, and ApoB 
levels at Days 84 and 365; and 
o Fasting Apolipoprotein A1 (ApoA1) at Days 84 and 365. 
• 
To evaluate trough levels of obicetrapib from Baseline to Day 84, 180 and 365 in the 
obicetrapib group. 
2.2 Study Design 
2.2.1 Overview 
This study is a multisite, placebo-controlled, double-blind, randomized Phase 3 study in 
approximately 300 participants with a history of HeFH who are not adequately controlled by their 
lipid-modifying therapy to evaluate the efficacy, safety, and tolerability of obicetrapib. 
Approximately 300 eligible participants will be randomized in a 2:1 ratio, respectively, to the  


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following treatment groups: 
• 
Obicetrapib group: one 10 mg obicetrapib tablet once daily; or 
• 
Placebo group: 1 placebo tablet once daily. 
At least 70% of the participants enrolled into this study must be taking high intensity statins (HISs). 
HeFH diagnosis is defined by existing confirmation via genetic testing, WHO Criteria/Dutch Lipid 
Clinical Network (DLCN) Criteria with a score of >8 points, and/or Simon Broome Register 
Diagnostic Criteria [1,2]. 
 
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. The End Of Study (EOS) Visit will be conducted 
approximately 35 days after the participant’s last dose of study drug, during which vital signs; 
limited serum chemistry, hematology, and coagulation parameters; pharmacokinetics; 
concomitant medications; and AEs will be assessed.  
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 products will be identical. Medication bottles with a unique code will be 
assigned to participants at various points in the study by the Medpace Interactive Response 
Technology system. 
Refer to Table 1 Schedule of Procedures for a complete list of procedures to be completed at 
each study visit. 
 
 
 
 
 
 


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Table 1 Schedule of Procedures 
 
Screening 
Treatment Period 
EOS 
Visit 
V1 
V2 
V3 
V4 
V5 
V6 
V7/EOT/ET1 
V8 
Study Day 
-14 to -1 
1 
30 
84 
180 
270 
365 
35 days after 
last dose 
Window (±days) 
±3 
 
±3 
±7 
±7 
±7 
±7 
±7 
Informed consent 
X 
 
 
 
 
 
 
 
Assessment of eligibility 
X2 
X2 
 
 
 
 
 
 
Demographics and medical history 
X 
 
 
 
 
 
 
 
Pregnancy test, FSH3 
X 
X 
X 
X 
X 
X 
X 
 
TSH 
X 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
Study drug administration 
 
X 
X 
X 
X 
X 
X 
 
Physical examination4 
X 
 
 
 
 
 
X 
 
Weight, height, and BMI 
X5 
 
 
 
 
 
X 
 
Vital signs6 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG7 
 
X 
 
 
 
 
X 
 
Lipid profile/biomarkers (fasting)8 
X 
X 
X 
X 
X 
X 
X 
 
Serum archive sample for future 
assessment of biomarkers related to 
dyslipidemia and/or CV risk (fasting)8,9 
 
 
 
X 
 
 
 
 
 
 
X 
 
UACR, UPCR (fasting)8 
 
X 
X 
X 
X 
X 
X 
 
Aldosterone, hsCRP (fasting)8 
 
X 
X 
X 
X 
X 
X 
 
Lp(a), ApoA1(fasting)8,9 
X 
X 
 
lX 
 
 
 
 
Full serum chemistry (fasting)8,9 
 
X 
 
 
X 
 
X 
 
Limited serum chemistry (fasting)8,9 
X 
 
X 
X 
 
X 
 
X 
Urinalysis (local)10 
X 
X 
 
 
 
 
X 
 
Hematology and coagulation (fasting)8,9 
X 
X 
 
 
X 
 
X 
X 
PK sample (central)9,11 
 
X 
 
X12 
X 
 
X 
X 
Prior/concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug dispensation 
 
X 
X 
X 
X 
X 
 
 
Study drug return/compliance calculations 
 
 
X 
X 
X 
X 
X 
 
AEs assessment 
X 
X 
X 
X 
X 
X 
X 
X 
  
1. 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. The ET Visit procedures are identical to the 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 withdraw consent to all follow-up will be asked about the reason(s) and will be assessed for the presence of any AEs..  
2. Assessment of laboratory eligibility criteria will be based on central laboratory values obtained within timeframes defined in the inclusion and exclusion criteria.  
3. 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 in females <55 years of age 
and postmenopausal, defined as ≥1 year since their last menstrual period.  


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4. 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.  
5. Height will be measured at Screening only and used to calculate BMI.  
6. Vital signs (consisting of heart rate and blood pressure) will be measured as described in Section 8.8.  
7. A single l2-lead ECG will be performed in the supine position after 10 minutes of rest.  
8. Participants must fast for a minimum of 8 hours prior to samples being collected.  
9. Samples should be collected prior to study drug administration.  
10. Urinalysis will be performed locally by dipstick analyses 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.  
11. 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. 
12. The PK sample at Visit 4 is not designated in the protocol, however the PK will be assessed using residual serum from the Day 84 limited chemistry panel to confirm patients are taking IP.  
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; hsCRP = high sensitivity C-reactive protein; 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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2.2.2 Sample Size Determination 
Enrollment of approximately 300 participants globally is planned for this study. 
Assuming an approximate 5% drop out rate, approximately 285 participants will be evaluable for 
efficacy. This sample size of at least 285 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. 
 
2.3 Study Endpoints  
2.3.1 Primary Efficacy Endpoints 
The primary efficacy endpoint is the percentage change from Baseline to Day 84 in LDL-C in the 
obicetrapib group compared to the placebo group.  
2.3.2 Secondary Efficacy Endpoints 
The secondary efficacy endpoints include the following: 
• 
Percentage change from Baseline to Days 180 and 365 in LDL-C in the obicetrapib group 
compared to the placebo group; 
• 
Percentage change from Baseline to Days 84, 180, and 365 in ApoB in the obicetrapib 
group compared to placebo group; 
• 
Percentage change from Baseline to Days 84, 180, and 365 in non-HDL-C in the 
obicetrapib group compared to placebo group; 
• 
Percentage change from Baseline to Days 84, 180, and 365 in HDL-C in the obicetrapib 
group compared to placebo group; 
• 
Percentage change from Baseline to Days 84 and 365 in Lp(a) in the obicetrapib group 
compared to placebo group; 
• 
Percentage change from Baseline to Days 84, 180, and 365 in TC in the obicetrapib group 
compared to placebo group; 
• 
Percentage change from Baseline to Days 84, 180, and 365 in TG in the obicetrapib group 
compared to placebo group. 
2.3.3 Exploratory Efficacy Endpoints 
The exploratory efficacy endpoints include the following: 
• 
Individual responsiveness defined as the number of participants reaching on treatment 
LDL-C levels of <40 mg/dL (<1.04 mmol/L), <55 mg/dL (<1.42 mmol/L), <70 mg/dL (1.81 
mmol/L), and <100 mg/dL (<2.59 mmol/L) at Days 84 and 365; 
• 
Individual responsiveness defined as the number of participants reaching on treatment 
non-HDL-C levels of <85 mg/dL (<2.20 mmol/L), <100 mg/dL (<2.59 mmol/L), and <130 
mg/dL (<3.37 mmol/L) at Days 84 and 365; 


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• 
Individual responsiveness defined as the number of participants reaching on treatment 
ApoB levels of <65mg/dL (<0.65 mmol/L), <80 mg/dL (<0.80 mmol/L), and <130 mg/dL 
(<1.30 mmol/L) at Days 84 and 365; 
• 
Percentage change from Baseline to Day 84 and 365 in ApoA1 in the obicetrapib group 
compared to the placebo group; and 
• 
Trough levels of obicetrapib from Baseline to Days 84, 180 and 365 in the obicetrapib 
group; 
2.3.4 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), ECG, and clinical 
laboratory values. 
3 STATISTICAL METHODOLOGY 
3.1 General Considerations 
3.1.1 Analysis Day 
Analysis day will be calculated from the date of first dose of study drug. The day of the first dose 
of study drug will be Day 1, and the day immediately before Day 1 will be Day -1. There will be no 
Day 0. 
3.1.2 Analysis Visits 
Scheduled visits will be assigned to analysis visits as recorded on the CRF.  
For each analysis visit, if a scheduled visit occurs within the analysis day window, then the 
measurement from this scheduled visit will be used. If no scheduled visit occurs or laboratory 
results of the scheduled visit were unreportable, the unscheduled measurement closest to the 
target day will be used. If measurements are equidistant to the target day, the latter will be used.  
Otherwise, unscheduled visits will not be re-assigned and will remain labelled as unscheduled. If 
laboratory measurements for the scheduled visit were taken while a participant was not in a fasting 
state and laboratory measurements are available from an unscheduled visit during which the 
participant was in a fasting state (and the visit occurred within seven days of the scheduled visit), 
those fasted labs will be utilized in place of the unfasted labs. 
Early termination (ET) visits will be assigned to analysis visits according to the following visit 
windows in Table 2: 
Table 2 Analysis Visit Windows 
Analysis Visit 
Target 
Analysis 
Day 
Low Analysis Day 
High Analysis Day 
Day 1 (Visit 2) 
1 
NA 
NA 
Day 30 (Visit 3) 
30 
2 
57 
Day 84 (Visit 4) 
84 
58 
132 
Day 180 (Visit 5) 
180 
133 
225 


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3.1.3 Handling of missed/delayed visits due to COVID-19 
Due to the pandemic of Coronavirus Disease 2019 (COVID-19), study visits for some participants 
may be partially completed, delayed, or cancelled, with the corresponding information collected 
on the CRF. The sites were given the following instructions: 
• 
If the visit window is exceeded by more than 7 days for the Visit 3 (Day 30) assessment, 
the visit should be recorded as an unscheduled visit. 
• 
If the visit window is exceeded by more than 14 days for Visit 4 (Day 84), Visit 5 (Day 180), 
Visit 6 (Day 270), or Visit 7 (Day 365); then the visit should be recorded as an unscheduled 
visit. 
3.1.4 Definition of Baseline  
Baseline is defined as the last measurement prior to the first dose of study drug, unless otherwise 
stated. 
3.1.5 Summary Statistics 
Categorical data will generally be summarized with counts and percentages of participants. The 
denominator used for the percentage calculation will be clearly defined. Continuous data will 
generally be summarized with descriptive statistics including n (number of non-missing values), 
mean, median, standard deviation, 1st and 3rd quartiles, minimum, and maximum. 
3.1.6 Hypothesis Testing 
The hypothesis testing of the percentage change in LDL-C from Baseline to Day 84 is statistically 
defined as: 
H0: µ1-µ0 = 0, H1: µ1-µ0 ≠ 0, 
where µ0 - the percentage change in LDL-C in the placebo group, 
           µ1 - the percentage change in LDL-C in the obicetrapib group. 
A fixed sequential testing procedure will be implemented in order to control the Type I error rate. 
In a hierarchical step-down manner, the primary endpoint will be tested first, followed by the 
secondary efficacy endpoints in a pre-specified order (see Section 3.4.2). No adjustment for 
multiple comparison will be made for the exploratory efficacy endpoints. 
3.1.7 Evaluation of Site Effect 
This is a multi-center study. Sites will not be pooled for any planned inferential analysis but may 
be pooled for subgroup analysis to assess the heterogeneity of treatment effects among pooled 
sites. The final pooling algorithm, if needed, will be specified before treatment unblinding and will 
be provided as an addendum to the SAP. Additionally, a review of by-site effects will be performed 
in the context of data listing review. 
Day 270 (Visit 6) 
270 
226 
317 
Day 365 (EOT)/(Visit 7) 
365 
318 
N/A 


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3.1.8 Handling of Dropouts and Missing Data 
 
The objective is for missing data to be kept to a minimum. Continued efforts will be made to 
measure endpoints on all participants, including those who may have discontinued study drug. 
Accordingly, site investigators have been robustly trained about the importance of participant 
retention and multiple approaches will be implemented to retain participants who fail to actively 
maintain contact with the investigator. 
 
Date Values 
In cases of incomplete dates (e.g., AE, concomitant medication, and medical history start and/or 
stop dates), the missing component(s) will be assumed as the most conservative value possible. 
For example, if the start date is incomplete, the first day of the month will be imputed for the 
missing day and January will be imputed for the missing month. If a stop date is incomplete, the 
last day of the month will be imputed for the missing day and December will be imputed for the 
missing month. Incomplete start and stop dates will be listed as collected without imputation. 
Date imputation will only be used for computational purposes such as treatment-emergent status. 
Actual date values, as they appear in the original CRFs, will be presented within the data listings. 
Non-Date Values 
For sensitivity analyses of the primary efficacy endpoint, missing values will be imputed using 
multiple imputation methods (see Section 3.4.1). For the analyses of secondary and exploratory 
efficacy endpoints, no imputation will be made for missing values. Safety data will be used 
according to availability, with no imputation for missing data. 
3.1.9 Laboratory Values Above or Below Limits of Quantification 
For laboratory values less than the lower limit of quantification (LLQ), half of the lower limit value 
(i.e., LLQ/2) will be used in the analysis. For values greater than the upper limit of quantification 
(ULQ), the upper limit value (i.e., ULQ) will be used in the analyses. 
3.2 Analysis Populations 
3.2.1 Intent-to-Treat (ITT) Population 
The ITT Population will include all participants who are randomized into the study. Treatment 
classification will be based on the randomized treatment. 
3.2.2 The Full Analysis Set (FAS) 
The 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. 
3.2.3 Modified Intent-to-Treat (mITT) Population 
The 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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3.2.4 Modified Intent-to-Treat (mITT) On-Treatment Population 
The mITT On-Treatment Population will include all randomized participants who have data for 
both the Day 1 and Day 84 LDL-C assessments. Participants in the obicetrapib group with PK 
values less than 3 standard deviations from the mean obicetrapib concentration should be 
excluded. Treatment classification will be based on the randomized treatment. 
Rationale:  in previous studies, such as ROSE (protocol number TA-8995-201), TULIP (protocol 
number TA-8995-03), and ROSE2 (protocol number TA-8995-202), it was demonstrated that the 
minimally observed obicetrapib concentration for Cmax was less than three standard deviations 
from the mean at respectively Week 4 and Week 12 [3-5].  
3.2.5 Per-Protocol (PP) Population 
The 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. 
3.2.6 Safety Population 
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. 
3.3 Participant Data and Study Conduct 
3.3.1 Participant Disposition 
Counts and percentages of participants who were randomized, completed the treatment period, 
discontinued treatment (including primary reason for discontinuation), completed the study, and 
prematurely discontinued from the study (including primary reason for discontinuation) will be 
summarized by treatment group and overall.  
For each scheduled visit, counts and percentages of participants who did not complete the visit, 
partially completed the visit in-person, or completed the visit via virtual method will be summarized 
by treatment group and overall. The denominator for calculating percentages will be based on the 
number of randomized participants. 
3.3.2 Protocol Deviations 
Protocol deviations will be identified based on clinical data as defined in the Protocol Deviation 
Plan, where all protocol deviations will be defined as either CSR reportable or non-CSR 
reportable.  The CSR reportable protocol deviations will be categorized and separated by 
treatment group. The CSR reportable deviations will include all randomized participants using 
counts and percentages.  
3.3.3 Analysis Populations 
Counts and percentages of participants in each analysis population will be summarized by 
treatment group and in total based on all randomized participants. Reasons for exclusion from PP 
Population will also be summarized. 


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3.3.4 Demographic and Baseline Characteristics 
The following demographic and Baseline characteristics will be summarized with descriptive 
statistics or counts and percentages of participants as appropriate by treatment group and overall, 
for the ITT Population: 
• 
Age and age categories (<65 years, 65 to 74 years, and 75+ years) 
• 
Sex 
• 
Race 
• 
Ethnicity 
• 
Height 
• 
Weight 
• 
Body Mass Index (BMI) 
• 
Region (North America and EMEA (Europe, Middle East, and Africa)) 
• 
Diabetes (yes, no) 
• 
HDL-C (<40mg/dL, 40 - <60 mg/dL, ≥60mg/dL) 
• 
ApoB (<60mg/dL, 60 - <90 mg/dL, ≥90mg/dL) 
• 
ApoA1 (<110 mg/dL, ≥110 and <125 mg/dL, ≥125mg/dL) 
• 
Lipoprotein(a) (<75nmol/L, ≥75 and <125 nmol/L, ≥125nmol/L) 
• 
Non-HDL-C (<100 mg/dL, ≥100 and <130 mg/dL, ≥130mg/dL) 
• 
LDL-C (<70mg/dL, ≥70 and <100 mg/dL, ≥100mg/dL) 
• 
TG (<150 mg/dL, ≥150mg/dL) 
• 
HbA1c (<5.7%, ≥5.75 to ≤6.4%, >6.4%) 
• 
Urinary albumin:creatinine ratio (normal, micro-albuminuria, macro-albuminuria) 
• 
eGFR (<60ml/min/1.73 m2, ≥60 to <90ml/min/1.73 m2, ≥90ml/min/1.73 m2) 
• 
Statin treatment (high dose (HIS), low or moderate dose (non-HIS), none (SI)). High dose 
statin includes atorvastatin 40 or 80 mg, rosuvastatin 20 or 40 mg. Participants will be 
defined as having high dose statin treatment based on the data collected in the eCRF and 
if any following were used at Baseline: average daily dose of atorvastatin ≥40 mg or 
average daily dose of rosuvastatin of ≥20 mg. Additionally, these medications can be a 
part of combination medications (e.g. Rosuzet 10/20mg; combination of ezetimibe 10mg 
and Rosuvastatin 20mg). Participants having other doses of statin or other statin treatment 
will be defined as low or moderate (non-HIS). Participants that are not taking statin are 
defined as statin intolerant (SI). 
• 
Ezetimibe use (yes, no) 
• 
A high-sensitivity C-reactive protein [hs-CRP] (<2mg/dL, ≥2mg/dL) 
• 
HeFH (Genotyping confirmed or DLCN>8 points of Simon Broome definite; Simon Broome 
possible Familial Hypercholesterolemia (FH) diagnosis) 
If they differ from the ITT Population, summaries will also be provided for the FAS, the mITT 
Population, the mITT On-Treatment, the PP Population, and the Safety Population. Demographic 
characteristics data will be provided in participant listings.  
3.3.5 Medical History 
Medical history will be coded to system organ class and preferred term using the current Medical 
Dictionary for Regulatory Activities (MedDRA) version. Counts and percentages of participants 


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with medical history by system organ class (SOC) and preferred term (PT) will be summarized by 
treatment group and in total based on all randomized participants. 
A listing of all medical history data will be provided. 
3.3.6 Concomitant Medications 
The Prior & Concomitant Medications case report form where medication start and stop dates are 
recorded, will be used to determine whether the medications are prior or concomitant to the study 
treatment. Concomitant medications are defined as those used on or after the first dose of the 
study drug. Prior medications are defined as those used prior to and stopped before the first dose 
of study drug. All prior and concomitant medications will be coded using the current World Health 
Organization (WHO) Drug Dictionary. Counts and percentages of participants taking prior and 
concomitant medications will be summarized by anatomical therapeutic chemical (ATC) class and 
preferred term by treatment group and overall, for the Safety Population. 
Concomitant medications will be listed. 
3.3.7 Study Drug Exposure and Compliance 
Participants’ exposure to randomized study drug will be summarized with descriptive statistics for 
the Safety Population and mITT On-Treatment Population. Days of exposure to study drug will be 
calculated as 
date of last dose of study drug – date of first dose of study drug + 1. 
For participants’ whose date of first dose from the initial bottle dispensed was not available, the 
date of randomization will be used to assign the date of first dose. For participants who failed to 
provide the date of last dose of study drug, the earliest date between the end of treatment date 
and the date of the end of study/early termination will be used. 
Days of exposure to study drug will be summarized by treatment group based on the Safety 
Population with counts and percentages of participants with exposure in the following categories: 
• 
<3 weeks 
• 
3 – <5 weeks 
• 
5 – <7 weeks 
• 
7 – <9 weeks 
• 
9 – <11 weeks 
• 
11 – <13 weeks 
• 
13 – <19 weeks 
• 
19 – <25 weeks 
• 
25 – <28 weeks 
• 
28 – <34 weeks 
• 
34 – <40 weeks 
• 
40 – <50 weeks 
• 
50 – <54 weeks 
• 
>=54 weeks 
The percentage overall compliance to study drug will be calculated using the following formula: 
# 𝑡𝑎𝑏𝑙𝑒𝑡𝑠 𝑑𝑖𝑠𝑝𝑒𝑛𝑠𝑒𝑑−#𝑡𝑎𝑏𝑙𝑒𝑡𝑠 𝑟𝑒𝑡𝑢𝑟𝑛𝑒𝑑
# 𝑒𝑥𝑝𝑒𝑐𝑡𝑒𝑑 𝑑𝑜𝑠𝑖𝑛𝑔 𝑑𝑎𝑦𝑠
× 100 


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If study drug is not returned, the number of tablets returned and lost will be considered 0 for the 
compliance calculation. The expected dosing days will be calculated as the earliest date between 
the end of treatment date and the date of early termination – the date of randomization- missed 
doses+1 (missed doses defined as number of doses missed during IP interruptions due to AE or 
IP interruptions that are longer than 14 days).  
Percent compliance to the study drug regimen will be summarized by treatment group and in total 
based on the Safety Population and mITT On-Treatment with descriptive statistics and with counts 
and percentages of participants with compliance in the following categories: 
• 
<80% 
• 
80% to 120% 
• 
>120% 
Study drug interruptions due to AE or IP interruptions longer than 14 days will be listed. 
3.4 Efficacy Assessment 
The ITT Population will be the primary population for the efficacy analysis. Efficacy will also be 
analyzed in the FAS, mITT Population, mITT On-Treatment Population, and PP Population as 
supportive analyses. 
3.4.1 Primary Efficacy Endpoints 
Primary Analysis 
The primary efficacy endpoint is the percentage change from Baseline to Day 84 in LDL-C in the 
obicetrapib group compared to placebo group.  
The LDL-C values measured by preparative ultracentrifugation (PUC) will be used. If the latter is 
not available, the LDL-C values will be assumed missing. 
All the analysis for primary efficacy endpoint will be repeated with LDL-C values calculated as 
follows: 
1. LDL-C will be calculated using the Friedewald equation unless triglycerides ≥400 mg/dL 
or LDL-C ≤50 mg/dL; where, LDL-C level will be measured directly by PUC. 
2. LDL-C will be calculated using the Martin-Hopkins equation unless triglycerides ≥400 
mg/dL or LDL-C ≤50 mg/dL; where, LDL-C level will be measured directly by PUC. 
 
Primary Estimand 
To assess the primary efficacy endpoint, the primary estimand is defined by the following key 
attributes: 
- 
Treatment: obicetrapib versus placebo 
- 
Target Population: participants who are randomized into the study 
- 
Analysis Population: The ITT Population 
- 
Intercurrent events: treatment discontinuation, prohibited medication use 


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- 
Analysis set and handling of intercurrent events: Treatment policy strategy will be 
used. All available values of LDL-C at Baseline and Day 84 will be included in the 
calculation of the percentage change from Baseline to Day 84. 
- 
Population level summary: The difference in LS mean percentage change in LDL-C from 
Baseline to Day 84 between treatment groups 
 
The analysis of covariance (ANCOVA) model with a fixed effect for the treatment group and 
covariates of Baseline LDL-C will be used to analyze the primary efficacy endpoint. 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 estimated.  The model will be fit 
assuming unequal variances for each treatment group. If substantial deviations from the model 
assumptions are observed, then supportive analyses, such non-parametric assessments, will be 
considered.  
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. 
If the number of retrieved dropouts is such that the model convergence is questionable and the 
given parameter estimates cannot be obtained, then missing data at the Day 84 assessment will 
be estimated based on the placebo treatment group as described in subsequent sections of the 
SAP corresponding to the first sensitivity analysis. 
Missing data at Day 84 will be imputed using a retrieved dropout imputation model assuming the 
data are missing not at random (MNAR). At Day 84, the data will be split into two groups as 
follows: (1) all participants that did not discontinue treatment and had a non-missing value at Day 
84; and (2) either participants that had a missing value at Day 84, or participants that had 
discontinued treatment and had a non-missing value at Day 84. For the second group, 100 data 
sets will be imputed. The variables for the imputation model will consist of the LDL-C values from 
Baseline and Day 84, along with treatment group. Each data set will be combined with the first 
group to obtain 100 imputed data sets with no missing values at Day 84. For each imputation data 
set, the percent change from Baseline to Day 84 will be analyzed using the ANCOVA model 
described above. The results of these 100 analyses will be combined to construct the treatment 
estimates using the parameter estimates and associated standard errors. Similarly, the difference 
of the adjusted treatment means (obicetrapib vs. placebo) will be presented with the associated 
standard error and two-sided 95% confidence interval. Randomly chosen seed numbers will be 
selected for the analysis and will be retained. 
Sample SAS code is shown below: 
1.1 
Note: Missing value imputation only using participant group (2): participants that had a 
missing value at Day 84, or participants that had discontinued treatment and had a non-
missing value at Day 84  
  TREATMENT = 0 (Placebo),  1 (Obicetrapib) 
  LDLC_BASE = Baseline LDL_C value  


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  LDLC_Day84 = LDL_C value at Day 84 
***************************************************************************************************  
proc mi data=LDL_C seed=154264 nimpute=100 out= LDL_C_IMP;  
  class TREATMENT; 
  monotone method=reg;  
  var TREATMENT LDLC_BASE LDLC_DAY84; 
run; 
***************************************************************************************************  
1.2           
******************************************************************************************************** 
Note:  LDL_C_IMP dataset must be merged with dataset containing participants from 
group (1): participants that did not discontinue treatment and had a non-missing value at 
Day 84. 
Note:  For each imputation dataset, the percentage change from Baseline to Day 84 will 
be analyzed using an ANCOVA approach with a fixed effect for the treatment group and 
covariates of Baseline LDL-C. 
  TREATMENT = 0 (Placebo),  1 (Obicetrapib) 
  BASE = Baseline LDL_C value  
  PCHG = Percent change from Baseline to Day 84 
  
***************************************************************************************************  
proc mixed data= TEMP;   
  by _imputation_; 
  class TREATMENT ;   
  model PCHG = TREATMENT  BASE / ddfm=satterth  solution cl; 
  repeated / group=TREATMENT; 
  lsmeans  TREATMENT / cl diffs;   
run; 
***************************************************************************************************  
1.3          
******************************************************************************************************** 
Note:  MI Analyze to combine imputations. 
***************************************************************************************************  
proc mianalyze parms(classvar=full)=mixLSM; 
  class TREATMENT; 
  modeleffects TREATMENT; 
  ods output parameterestimates=mi_LSM; 
run; 
proc mianalyze parms(classvar=full)=mixDIFF; 
  class TREATMENT; 
  modeleffects TREATMENT; 
  ods output parameterestimates=minus_mi_DIFF; 
run; 
***************************************************************************************************  
Sensitivity Analyses 
The first sensitivity analysis will be performed imputing missing LDL-C values at Day 84 based on 
the assumption the data are MNAR using a control-based pattern mixture method. At Day 84, the 
data will be split into two groups as follows: (1) all participants randomized to the obicetrapib 
treatment group that had a non-missing value at Day 84; and (2) either participants randomized 
to the placebo treatment group, or participants that had a missing value at Day 84. For the second 
group, 100 data sets will be imputed. The variables for the imputation model will consist of the 


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LDL-C values from Baseline and Day 84. In this manner, missing data at the Day 84 assessment 
will be estimated from the placebo treatment group. Each data set will be combined with the first 
group to obtain 100 imputed data sets with no missing values at Day 84. For each imputation data 
set, the percent change from Baseline to Day 84 will be analyzed using the ANCOVA model 
described above. The results of these 100 analyses will be combined to construct the treatment 
estimates using the parameter estimates and associated standard errors. Similarly, the difference 
of the adjusted treatment means (obicetrapib vs. placebo) will be presented with the associated 
standard error and two-sided 95% confidence interval. Randomly chosen seed numbers will be 
selected for the analysis and will be retained. 
The second sensitivity analysis will be performed using a tipping point approach in the following 
steps [6-7]: 
1. The missing data will be imputed using multiple imputation assuming MAR with a shift 
parameter in each treatment group.  
2. The multiply imputed data will be analyzed using a standard multiple imputation method 
combining rule (Rubin’s Rule). 
3. Step 1 and 2 will be repeated such that the shift parameter for each treatment group will 
be increased in the negative and /or positive direction by a certain amount in each step 
until the “tipping point” is reached (i.e., where statistical significance is lost). The more the 
tipping point diverges from the observed data, the more robust the conclusions from the 
primary analysis. 
The same analysis method as specified for primary analysis will be applied when analyzing 
adjusted data generated under each plausible shift parameter.  
The third sensitivity analysis will be performed using the ANCOVA model from the primary 
analysis for the ITT Population using only observed cases with no imputation for missing data. 
Supplemental Analyses 
Supplemental analyses will be performed for the primary efficacy endpoint in order to assess any 
differences with the results from the primary analysis and investigate what effect, if any, protocol 
violations have on the trial results. In the first supplemental analysis, a mixed model for repeated 
measures (MMRM) approach will be utilized. The LDL-C values measured by preparative 
ultracentrifugation will be used. The analysis will include fixed effects for treatment group, visit, 
and treatment-by-visit interaction, along with covariates of the Baseline LDL-C value as a 
continuous covariate. The restricted maximum likelihood estimation approach will be used with 
an unstructured covariance matrix. The LS mean, standard errors, and 2-sided 95% confidence 
intervals for the treatment group and for the comparison of the treatment group to the placebo 
group will be provided. The MMRM approach will include all available assessments of percent 
change in LDL-C from Day 1, Day 30, Day 84, Day 180, Day 270, and Day 365. The model 
assumes that the data are missing at random (MAR). For missing data, the model will use all 
information from the other time points to estimate the mean treatment difference at the given time 
point. No imputation of missing data will be performed. The analysis will be conducted for ITT 
Population. 
The analysis will be implemented using SAS® Proc Mixed. The sample SAS code can be found 
below: 
Note:   


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  USUBJID = unique participant identifier  
  TREATMENT = 0 (Placebo),  1 (Obicetrapib) 
  VISIT = visit  
  LDLC_BASE = Baseline LDL_C value 
  PCHG = Percent change from Baseline 
***************************************************************************************************  
 
proc mixed;   
  class USUBJID TREATMENT VISIT CVRISK  STATIN;   
  model PCHG = TREATMENT  LDLC_BASE  VISIT  TREATMENT*VISIT / solution cl;   
  Repeated VISIT / TYPE=UN sub=USUBJID;   
  lsmeans VISIT*TREATMENT / cl diffs;   
run; 
***************************************************************************************************  
Additional supplementary analysis will be performed using the ANCOVA model from the primary 
analysis based on the FAS, mITT, mITT On-Treatment, and PP populations. No imputation for 
missing data will be performed for the analysis. 
Secondary Estimand 
A secondary estimand will be assessed for the primary efficacy endpoint. The secondary 
estimand is defined by the following key attributes: 
- 
Treatment: obicetrapib versus placebo 
- 
Target Population: participants who are randomized into the study 
- 
Analysis Population: The ITT Population 
- 
Intercurrent events: treatment discontinuation, prohibited medication use 
- 
Analysis set and handling of intercurrent events: A hypothetical strategy will be used. 
All available values of LDL-C at Baseline and Day 84 will be included in the calculation of 
the percentage change from Baseline to Day 84. 
- 
Population level summary: The difference in LS mean percentage change in LDL-C from 
Baseline to Day 84 between treatment groups. 
This hypothetical estimand represents the treatment effect of obicetrapib relative to placebo at 
Day 84 in the randomized participants had they remained on their randomized treatment for the 
entire planned treatment period. This estimand uses a hypothetical strategy to handle intercurrent 
events and is intended to provide an estimation of the achievable study treatment effect if 
participants take the treatment as planned. The resulting missing values (corresponding to 
unobserved values or excluded values following study drug discontinuation or the use of 
prohibited medication) will be implicitly handled by using a MMRM approach under the 
assumption of missing at random. The model will be similar to the MMRM approach described 
previously for the supplemental analysis of the primary efficacy endpoint. The supplementary 
analysis for the primary efficacy endpoint assessed by secondary estimand will be performed 
using the mITT On-Treatment populations. 


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3.4.2 Secondary Efficacy Endpoints 
Similar ANCOVA models as described for the primary analyses will be used to analyze the 
secondary efficacy endpoints and will be tested sequentially at the 0.05 significant level according 
to the order specified below:   
• 
Percentage change from Baseline to Days 180 and 365 in LDL-C in the obicetrapib group 
compared to the placebo group; 
• 
Percentage change from Baseline to Days 84, 180, and 365 in ApoB in the obicetrapib 
group compared to placebo group; 
• 
Percentage change from Baseline to Days 84, 180, and 365 in non-HDL-C in the 
obicetrapib group compared to placebo group; 
• 
Percentage change from Baseline to Days 84, 180, and 365 in HDL-C in the obicetrapib 
group compared to placebo group; 
• 
Percentage change from Baseline to Days 84 and 365 in Lp(a) in the obicetrapib group 
compared to placebo group; 
• 
Percentage change from Baseline to Days 84, 180, and 365 in TC in the obicetrapib group 
compared to placebo group; 
• 
Percentage change from Baseline to Days 84, 180, and 365 in TG in the obicetrapib group 
compared to placebo group. 
For the percentage change from Baseline to Day 180 in LDL-C, the LDL-C will be calculated using 
the Friedewald equation unless the Triglyceride value is ≥400 mg/dL or the LDL-C value is ≤50 
mg/dL; in which case, the LDL-C level measured directly by PUC will be used in the analysis. The 
latter approach will be used because PUC assessments are not performed at Day 180 as per the 
protocol, unless the conditions for Triglycerides or LDL-C described above are met at the Day 
180 assessment. The analysis will be repeated using the Martin-Hopkins equation as described 
in the Section 3.4.1 above. 
3.4.3 Exploratory Efficacy Endpoints  
Similar ANCOVA models as described for the primary analyses will be used to assess the 
percentage change from Baseline to Day 84 and 365 in fasting ApoA1 in the obicetrapib group 
compared to the placebo group. 
The proportion of participants at Days 84 and 365 who achieved 
• 
LDL-C levels of <40 mg/dL (<1.04 mmol/L), <55 mg/dL (<1.42 mmol/L), <70 mg/dL (1.81 
mmol/L), and <100 mg/dL (<2.59 mmol/L) at Days 84 and 365; 
• 
non-HDL-C levels of <85 mg/dL (<2.20 mmol/L), <100 mg/dL (<2.59 mmol/L), and <130 
mg/dL (<3.37 mmol/L) at Days 84 and 365; 
• 
ApoB levels of <65mg/dL (<0.65 mmol/L), <80 mg/dL (<0.80 mmol/L), and <130 mg/dL 
(<1.30 mmol/L) at Days 84 and 365 
in the obicetrapib group compared to the placebo group, will be examined using logistic regression 
models with covariates of treatment group and respective Baseline values as covariates. Odds 
ratio with 95% confidence intervals will be estimated. 


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The logistic regression model will be implemented using SAS® Proc LOGISTIC. The sample SAS 
code can be found below: 
Note:   
  TREATMENT =  0 (Placebo),  1 (Obicetrapib) 
  BASE            = Baseline LDL_C value  
  LDLC40       = LDL_C value less than 40mg/dL at DAY84 (YES/NO) for example 
**********************************************************************************************************  
proc logistic data= LDL_C; 
      Class TREATMENT(ref=0) / Param= Ref; 
      Model LDLC70= TREATMENT BASE / alpha=0.05 expb plcl plrl orpvalue lackfit; 
     Ods output 
 
ParameterEstimates= Log_LDLC40_ParameterEstimates  
 
CLoddsPL= Log_ LDLC40_OddsRatios 
; 
Run; 
**********************************************************************************************************  
3.4.4 Subgroup Analysis 
The primary efficacy endpoint also will be analyzed by the following subgroups: 
• 
Age categories (<65 years, 65 to 74 years, and 75+ years) 
• 
Sex (male, female) 
• 
Race (white, Asian, Black or African American, Other) 
• 
Ethnicity (Hispanic/Latino, Not Hispanit/Latino) 
• 
BMI (<25 kg/m2, 25 -30 kg/m2, ≥30 kg/m2) 
• 
Region (North America and EMEA (Europe, Middle East, and Africa)) 
• 
Diabetes (yes, no) 
• 
HDL-C (<40mg/dL, 40 - <60 mg/dL, ≥60mg/dL) 
• 
ApoB (<60mg/dL, 60 - <90 mg/dL, ≥90mg/dL) 
• 
ApoA1 (<110 mg/dL, ≥110 and <125 mg/dL, ≥125mg/dL) 
• 
Lipoprotein(a) (<75nmol/L, ≥75 and <125 nmol/L, ≥125nmol/L) 
• 
Non-HDL-C (<100 mg/dL, ≥100 and <130 mg/dL, ≥130mg/dL) 
• 
LDL-C (<70mg/dL, ≥70 and <100 mg/dL, ≥100mg/dL) 
• 
TG (<150 mg/dL, ≥150mg/dL) 
• 
HbA1c (<5.7%, ≥5.75 to ≤6.4%, >6.4%) 
• 
Urinary albumin:creatinine ratio (normal, micro-albuminuria, macro-albuminuria) 
• 
eGFR (<60ml/min/1.73 m2, ≥60 to <90ml/min/1.73 m2, ≥90ml/min/1.73 m2) 
• 
Statin treatment (high dose, low or moderate dose, none) 
• 
Ezetimibe use (yes, no) 
• 
Hs-CRP (<2mg/dL, ≥2mg/dL) 
• 
HeFH (Genotyping confirmed or DLCN>8 points of Simon Broome definite; Simon Broome 
possible FH diagnosis) 
The ANCOVA model with fixed effects for the treatment group, subgroup variable, treatment-by-
subgroup variable and covariates of Baseline LDL-C will be used. 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, within each level of the subgroup, will be estimated. No 
imputation of missing data will be performed; therefore, the subgroup analysis will be performed 


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using only observed data. For the primary efficacy endpoint, the LDL-C values measured by PUC 
will be used. However, if the analysis for the primary efficacy endpoint specified above will show 
a difference between the 3 LDL-C approaches, then Friedewald and Martin-Hopkins equations 
may be considered for subgroup analysis.      
3.5 Safety Assessment 
Safety Population will be the primary population for the safety analyses. All safety endpoints will 
be summarized descriptively by treatment group and overall. No statistical inference will be 
applied to the safety endpoints. 
3.5.1 Adverse Events (AEs) 
AEs will be categorized by primary system organ class and preferred term as coded using the 
current MedDRA version category designation. 
An overview of treatment-emergent AEs (TEAEs) will be provided including counts and 
percentages of participants with the following: 
• 
Any TEAEs (overall and by maximum severity) 
• 
Any TEAEs (non-serious) 
• 
Any study drug related TEAEs (overall and by maximum severity) 
• 
Any TEAEs leading to discontinuation of study drug 
• 
Any treatment-emergent serious AEs (TESAEs) 
• 
Any study drug related TESAEs  
• 
Any TEAEs leading to death. 
The TEAEs described above will be summarized separately by system organ class and preferred 
term. The non-serious TEAEs occurring in more than 2% of participants in any treatment group 
and preferred term will be summarized. 
Listings will be presented specifically for TEAEs, TESAEs and TEAEs leading to discontinuation 
of study drug and TEAEs leading to death. 
3.5.2 Event of Special Interest 
 
Events of special interest (ESIs) 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 macular 
degeneration described as follows: 
• 
AST or ALT > 3×ULN; 
• 
Total bilirubin > 2×ULN; 
• 
Creatine kinase (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; 


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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 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<30mL/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 µmol/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 those 
participants not receiving antihypertensive medication(s) treatment at Baseline; and 
• 
Macular degeneration. 
 
An overview of ESIs described above will be provided including counts, percentages of 
participants by treatment group, and a listing of each ESI.  
 
Values and changes from baseline will be summarized for ALT, AST, and total bilirubin by visit 
and treatment group.  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.  
 
Values and changes from Baseline will be summarized for CK levels by visit and 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 Table 1 Schedule of 
Procedures.  
 
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.  
 
Participants will be identified as those who had a diagnosis of hypertension in their medical history 
and received antihypertensive medication(s) at Baseline. If participants had an adverse event 
related to hypertension after Baseline (see Appendix B for preferred terms) and had any change 
in antihypertension medication within 30 days of the start date of the adverse event, that change 


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in antihypertension medication will be considered as due to a change in blood pressure. The 
number and percentage of participants will be summarized by treatment group. 
 
Participants will be identified who did not have a prior diagnosis of hypertension in their medical 
history and did not receive antihypertensive medication(s) at Baseline. If participants had an 
adverse event of hypertension and initiated antihypertension medication within 30 days of the 
start date of the adverse event, the adverse event will be classified as a change in blood pressure. 
The number and percentage of participants 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.  
3.5.3 Clinical Laboratory Tests 
Blood and urine samples for clinical laboratory evaluations (including a full serum chemistry panel, 
hematology, coagulation, and urine dipstick analysis) will be collected at visits specified in Table 
1. A limited serum chemistry panel will also be collected as specified in Table 1. 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). Urinalysis will be performed locally by 
dipstick analysis from a sample of mid-stream urine. See clinical protocol (Appendix B) for a 
complete list of analytes.  
Laboratory values will be summarized descriptively, including the change from Baseline. In 
addition, shift tables for all parameters will be presented to describe the change in laboratory 
parameter values at end of treatment visit using normal range categories (low, normal, and high). 
Chemistry and hematology laboratory parameters will be listed. 
3.5.4 Vital Signs 
Vital signs (heart rate and blood pressure) measured in triplicate prior to study administration at 
applicable visits as indicated in Table 1. Values will be summarized with descriptive statistics, 
including the change from Baseline at each visit by treatment group and overall.  
Additional summaries of blood pressure measurements will be performed, within treatment group 
and time point, using counts of triplicate means that meet the following criteria:  
• 
Systolic blood pressure: 
o ≥160 mmHg 
o ≥180 mmHg 
o change from Baseline by ≥20 mmHg 
• 
Diastolic blood pressure: 
o ≥100 mmHg 
o ≥110 mmHg 
o change from Baseline by ≥15 mmHg. 
As described above, the number and percentage of participants receiving antihypertensive 
medications at Baseline with changes to antihypertensive medications due to change in blood 
pressure will be summarized by treatment group. The number of participants who were not 
hypertensive or on any antihypertensive medications at Baseline, but started one or more 
antihypertensive drugs during the treatment period, will be summarized by treatment group. 


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Vital signs will be listed. 
3.5.5 Electrocardiograms 
A single 12-lead ECG will be performed at Visit 2 and Visit 7/EOT/ET and will be read locally.  
ECG parameters will be recorded as normal, abnormal or not done. Abnormal values will be 
assessed as clinically significant or not clinically significant. Counts and percentages for ECG 
parameters will be summarized by treatment group and in total. 
3.5.6 Physical Examinations 
Physical examinations (with focused examination on general, respiratory, CV, abdominal, and 
extremities evaluations) and recording of weight and height will be performed at Screening Visit 
and Visit 7/EOT/ET. Height will be measured at Screening Visit only and used to calculate body 
mass index. BMI will be calculated as weight/(height/100)2 (kg/m2); rounded and displayed to 1 
decimal place. 
Physical examination, parameters, will be recorded as normal, abnormal or not done. Abnormal 
values will be assessed as clinically significant or not clinically significant. Count and percentages 
for physical parameters will be summarized by treatment group and in total. 
4 DATA SAFETY MONITORING BOARD 
An independent Data Safety Monitoring Board (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). Participants, investigators, site staff and in 
general all personnel directly involved in the conduct of the study will remain blinded to the 
participants’ treatment assignment until the completion of the study. 
Details related to the DSMB responsibilities, authorities, and procedures will be documented in a 
DSMB Charter.  
5 ANALYSIS TIMING 
5.1 Interim Analysis 
No interim analysis is planned.  
5.2 Pre-Final Analysis 
After the database is locked and exclusions from analysis populations have been finalized, the 
randomized treatment assignments will be unblinded and the pre-final analysis will be generated. 
Pre-final tables, figures, and listings (TFLs) will be provided approximately 3 weeks after database 
lock.  
5.3 Final Analysis 
After all comments on the pre-final analysis have been resolved and the study database is 
declared final, the final analysis will be generated. If there were no changes to the pre-final 
analysis or the study database, the pre-final TFLs may be considered final. In addition to TFLs, 
SDTM data and ADaM data along with associated files will be provided. Associated files may 
include annotated case report forms (CRFs), SDTM specifications, SDTM programs, ADaM 


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specifications, ADaM programs, TFL programs, and CDISC Define packages for both SDTM and 
ADaM data.  
6 CHANGES FROM PROTOCOL-SPECIFIED STATISTICAL ANALYSES 
There have been four changes from the protocol v3.0. 
The first change is in the description of the study objectives and endpoints, the term ‘fasting’ from 
version 3.0 of the protocol, which precedes the specified lipid parameter, has been removed. The 
Schedule of Procedures, along with Section 8.7 of the protocol, specifies that all laboratory 
samples should be collected while the participant is fasting; therefore, the corresponding 
language was removed from the objective and endpoint descriptions in the SAP. Additionally, the 
primary efficacy endpoint for the LDL-C assessment will utilize values collected via preparative 
ultracentrifugation (PUC), also referred to as beta quantification, which is not sensitive to fasting 
status.    
The second change is the inclusion of subgroup analysis. 
The third change is the inclusion of the evaluation of trough levels of obicetrapib from Baseline to 
Day 84 and 180 in the obicetrapib group. 
The fourth change is the change in the variance for the primary analysis. The model will assume 
unequal variances for each treatment group. Therefore, supportive analysis of the primary efficacy 
assessment will not require consideration of an ANCOVA model assuming unequal variances, as 
described in v3.0 of the protocol. 
 
7 PROGRAMMING SPECIFICATIONS 
Analyses will be performed using SAS® version 9.4 or higher. All available data will be presented 
in participant  data listings which will be sorted by  participant  and visit date as applicable. Detailed 
Programming Specifications will be provided in a separate document. 
 
 


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APPENDIX A:  REFERENCES 
1. World Health Organization. Familial hypercholesterolaemia (FH): report of a second WHO 
consultation 04 September 1998 https://apps.who.int/iris/handle/10665/66346. Accessed 21 
April 2022. 
 
2. Austin MA, Hutter Cm, Zimmern RL, 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. 
 
3.Hovingh GK, Kastelein JJ, van Deventer SJ et al. Cholesterol ester transfer protein inhibition 
by TA-8995 in patients with mild dyslipidaemia (TULIP): a randomized, double-blind, placebo-
controlled phase 2 trial. The Lancet 2015; 386 (9992):452-460. 
 
4.Nicholls SJ, Ditmarsch M, Kastelein JJ et el. Lipid lowering effects of the CETP inhibitor 
obicetrapib in combination with high-intensity statins: a randomized phase 2 trial. Nature 
Medicine 2022; 28 (8): 1672-1678. 
 
5. Ballantyne CM, Ditmarsch M, Kastelein JJ et al. Obicetrapib plus ezetimibe as an adjunct to 
high-intensity statin therapy: a randomized phase 2 trial. Journal of Clinical Lipidology; 2023 
June 3. 
 
6. Ratitch B, O’Kelly M, Tosiello R. Missing data in clinical trials: from clinical assumptions to 
statistical analysis using pattern mixture models. Pharmaceutical statistics 2013; 12 (6):337-347. 
 
7. Yuan Y. Sensitivity analysis in multiple imputation for missing data. In Proceedings of the 
SAS Global Forum 2014 conference 
(https://support.sas.com/resources/papers/proceedings14/SAS270-2014.pdf).  
 
 


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APPENDIX B:  PREFFERED TERMS FOR HYPERTENSION 
Preferred Term 
Accelerated hypertension 
Blood pressure ambulatory increased 
Blood pressure diastolic increased 
Blood pressure inadequately controlled 
Blood pressure increased 
Blood pressure orthostatic increased 
Blood pressure systolic increased 
Diastolic hypertension 
Essential hypertension 
Hypertension 
Malignant hypertension 
Mean arterial pressure increased 
Systolic hypertension 
Blood pressure abnormal 
Blood pressure ambulatory abnormal 
Blood pressure diastolic abnormal 
Blood pressure orthostatic abnormal 
Blood pressure systolic abnormal 
Labile blood pressure 
Hypertensive crisis 
Hypertensive emergency 
Hypertensive urgency 
Orthostatic hypertension