Clinical trial NCT05421078
Conditions: Dyslipidemia Hypercholesterolemia High Cholesterol
Keywords: obicetrapib statin LDL-C cholestero l atherosclerosis
Sponsor: NewAmsterdam Pharma
Start date: 2022-06-27; Completion date: 2023-04-21
Enrollment: 102 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will be a placebo-controlled, double-blind, randomized, phase 2 dose-finding study in Japanese patients to evaluate the efficacy, safety, and tolerability of obicetrapib as an adjunct to stable statin therapy.

Detailed description:
This study will be a placebo-controlled, double-blind, randomized, phase 2 dose-finding study to evaluate the efficacy, safety, and tolerability of obicetrapib as an adjunct to stable statin therapy in Japanese patients. The screening period for this study will take up to 2-weeks. Afterwards, patients will be randomized to placebo, 2.5 mg obicetrapib, 5 mg obicetrapib or 10 mg obicetrapib for an 8-week treatment period. After the treatment period, patients will continue for a 4-week safety follow-up visit.

Arms: arm 1: Once-daily placebo arm 2: once-daily Obicetrapib arm 3: once-daily Obicetrapib arm 4: once-daily Obicetrapib
Interventions: intervention 1: Obicetrapib intervention 2: Placebo
Intervention descriptions: intervention 1: tablet intervention 2: No active ingredient

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
A Placebo-Controlled, Double-Blind, Randomized, Phase 2 
Dose-Finding Study to Evaluate the Effect of Obicetrapib as an 
Adjunct to Stable Statin Therapy in Japanese Subjects 
Investigational Product: Obicetrapib 
Protocol Number: TA-8995-203 
Sponsor: 
NewAmsterdam Pharma BV  
Gooimeer 2-35 
1411 DC 
Naarden  
The Netherlands 
Telephone: +31 35 699 30 00 
Fax: +31 20 240 07 79 
Version Number: 1.1 
Date: 20 April 2022 
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the written 
consent of NewAmsterdam Pharma BV 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 BV. You are allowed to disclose the contents of this document only to your Institutional 
Review Board and study personnel directly involved with conducting this protocol. Persons to 
whom the information is disclosed must be informed that the information is confidential and 
proprietary to NewAmsterdam Pharma BV and that it may not be further disclosed to third 
parties. 
NCT number: NCT05421078
This NCT number has been applied to the document for the purposes of posting on clinicaltrials.gov


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SIGNATURE PAGE 
STUDY TITLE: A Placebo-Controlled, Double-Blind, Randomized, Phase 2 Dose-Finding 
Study to Evaluate the Effect of Obicetrapib as an Adjunct to Stable Statin Therapy in 
Japanese Subjects 
 
I, the undersigned, have read this protocol and agree that it contains all necessary information 
required to conduct the study. 
Signature 
 
 
 
 
 
 
 
Date 




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INVESTIGATOR AGREEMENT 
By signing below, I agree that: 
I have read this protocol. I approve this document and I agree that it contains all necessary details 
for carrying out the study as described. I will conduct this study in accordance with the design and 
specific provision of this protocol and will make a reasonable effort to complete the study within 
the time designated. I will provide copies of this protocol and access to all information furnished 
by NewAmsterdam Pharma BV to study personnel under my supervision. I will discuss this 
material with them to ensure they are fully informed about the study drug and study procedures. I 
will let them know that this information is confidential and proprietary to NewAmsterdam Pharma 
BV and that it may not be further disclosed to third parties. I understand that the study may be 
terminated or enrollment suspended at any time by NewAmsterdam Pharma BV, 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 the Pharmaceuticals and Medical Devices 
Agency Regulations, Institutional Review Board 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: A Placebo-Controlled, Double-Blind, Randomized, Phase 2 Dose-Finding Study to 
Evaluate the Effect of Obicetrapib as an Adjunct to Stable Statin Therapy in Japanese Subjects 
PROTOCOL NUMBER: TA-8995-203 
INVESTIGATIONAL PRODUCT: Obicetrapib 
PHASE: 2 
INDICATION: Dyslipidemia 
OBJECTIVES: 
The primary objective of this study is to evaluate the efficacy of obicetrapib, compared to placebo, 
in reducing serum low-density lipoprotein cholesterol (LDL-C) measured at Day 56 (Visit 5) when 
taken as an adjunct to a pre-existing stable statin therapy regime. 
The secondary objectives of this study include the following: 
• To evaluate the effect of obicetrapib, compared to placebo, on serum apolipoprotein B (ApoB), 
non-high-density lipoprotein cholesterol (non-HDL-C), and high-density lipoprotein 
cholesterol (HDL-C) concentrations at Day 56 (Visit 5), when taken as an adjunct to 
pre-existing stable statin therapy; 
• To assess the mean plasma levels of obicetrapib at steady state on Day 56 (Visit 5) and 
Day 84 (Visit 6); and 
• To evaluate the safety and tolerability profile of obicetrapib in Japanese subjects. 
POPULATION: 
The population for this study includes Japanese men and women, 18 to 75 years of age, inclusive, 
with a body mass index <35 kg/m2, fasting LDL-C levels >70 mg/dL, and triglyceride levels 
<400 mg/dL at the Screening Visit, who are currently receiving stable statin therapy. 
STUDY DESIGN AND DURATION: 
This study will be a placebo-controlled, double-blind, randomized, Phase 2 dose-finding study to 
evaluate the efficacy, safety, and tolerability of obicetrapib as an adjunct to stable statin therapy 
in Japanese participants. This study will take place at approximately 10 sites in Japan. 
Screening Period 
At the Screening Visit (Visit 1), and up to 2 weeks before the start of the treatment period, 
participants will be required to sign an informed consent form (ICF) before any study-related 
procedures are performed. After signing the ICF, participants will be assessed for study eligibility. 


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Treatment Period 
Up to 2 weeks after the Screening Visit, participants will return to the site on Day 1 (Visit 2) and 
confirm 
study 
eligibility 
before 
being 
randomized 
and 
beginning 
treatment. 
Approximately 100 eligible participants (25 participants per treatment group) will be randomized 
in a 1:1:1:1 ratio to 1 of the following treatment groups: 
• 2.5 mg obicetrapib (one 2.5 mg obicetrapib tablet); 
• 5 mg obicetrapib (one 5 mg obicetrapib tablet); 
• 10 mg obicetrapib (one 10 mg obicetrapib tablet); or 
• Placebo (1 placebo tablet). 
During the 8-week Treatment Period, the assigned study drugs will be administered by the 
participants orally once daily from Day 1 (Visit 2) to Day 56 (Visit 5). Participants will return to 
the site on Day 14 (Visit 3), Day 28 (Visit 4), and Day 56 (Visit 5) for efficacy, safety, and 
pharmacokinetic (PK) assessments. Participants, Investigators, the Clinical Research 
Organization, and the Sponsor will be blinded to all lipid results from Day 1 (Visit 2) for the first 
participant and continuing to database lock in order to protect blinding to treatment assignment. 
Safety Follow-Up and Additional Pharmacokinetic Period 
Participants will return to the site for a Safety Follow-up Visit on Day 84 (Visit 6), approximately 
4 weeks after the end of the Treatment Period, for final safety and PK assessments.   
DOSAGE FORMS AND ROUTE OF ADMINISTRATION: 
The study drugs to be used in this study include the following: 
• 2.5 mg obicetrapib tablet; 
• 5 mg obicetrapib tablet; 
• 10 mg obicetrapib tablet; and 
• Matching placebo tablet. 
The study drugs listed above will be packaged to provide doses of 2.5 mg, 
5 mg, 10 mg obicetrapib, or placebo only. Placebo tablets will be visually identical. Participants 
will be randomized to receive 1 of the 3 doses of obicetrapib or placebo only. One tablet of study 
drug will be administered by the participant orally once daily from Day 1 (Visit 2) to Day 56 
(Visit 5) at approximately the same time each morning. 
EFFICACY VARIABLES:  
The primary efficacy endpoint is the percent change from Day 1 to Day 56 in LDL-C for each 
obicetrapib group compared to the placebo group.  
The key secondary efficacy endpoints include the following: 
• Percent change from Day 1 to Day 56 in ApoB for each obicetrapib group compared to the 
placebo group; 


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• Percent change from Day 1 to Day 56 in non-HDL-C for each obicetrapib group compared to 
the placebo group; and 
• Percent change from Day 1 to Day 56 in HDL-C for each obicetrapib group compared to the 
placebo group. 
SAFETY VARIABLES: 
The safety and tolerability profile of obicetrapib will be assessed by clinical laboratory 
assessments (chemistry and hematology), vital signs, physical examinations, and the incidence of 
adverse events and events of special interest (ESIs). 
STATISTICAL ANALYSES: 
A Statistical Analysis Plan (SAP) will be finalized before database lock. Any changes to the 
methods described in the SAP will be described and justified as needed in the Clinical Study 
Report. All study-collected data will be summarized by treatment group using descriptive 
statistics, graphs, and/or raw data listings. Descriptive statistics for continuous variables will 
include number of participants (n), mean, standard deviation (SD), median, minimum, and 
maximum values. Analysis of categorical variables will include frequency and percentage. 
Analysis Populations 
The Intent-to-Treat (ITT) Population will include all participants randomized into the study. 
Treatment classification will be based on the randomized treatment.  
The Modified ITT (mITT) Population will include all participants in the ITT Population who 
receive at least 1 dose of any study drug and have a Baseline value for the LDL-C assessment. 
Any efficacy measurement obtained during the Safety Follow-up Visit after a participant 
permanently discontinues the study drug or after a participant receives an excluded medication 
and/or procedure will be removed from the mITT analysis. Treatment classification will be based 
on the randomized treatment. The mITT Population will be used for the primary analysis of all 
efficacy endpoints. 
The Per-Protocol (PP) Population will include all participants in the mITT Population who have 
a Baseline value for the LDL-C assessment, have a Day 56 value for the LDL-C assessment, and 
who do not experience a major protocol deviation that would potentially impact the primary 
efficacy endpoint. The PP Population, along with the reason for exclusion, will be finalized prior 
to study unblinding. 
The PK Population will include all participants in the mITT Population who have sufficient blood 
samples collected for valid estimation of PK parameters. 
The Safety Population will include all participants who receive at least 1 dose of any study drug. 
Treatment classification will be based on the actual treatment received. The Safety Population will 
be the primary population used for the safety analyses. 
Analysis of Efficacy  
The mITT Population will be the primary population for the efficacy analyses. Efficacy will also 
be analyzed using the ITT Population and the PP Population as supportive analyses. 


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The primary efficacy analysis of the percent change from Day 1 to Day 56 in LDL-C will be 
performed using a mixed model for repeated measures approach. The analysis will include fixed 
effects for treatment, visit, and treatment-by-visit interaction, along with a covariate of the 
Baseline value. The Restricted Maximum Likelihood estimation approach will be used with an 
unstructured covariance matrix. The least squares means, standard errors, and 2-sided 
95% confidence intervals for each treatment group and for the pairwise comparisons of each dose 
of obicetrapib to the placebo group will be provided. In order to maintain the overall alpha level 
on the primary endpoint, the hypothesis testing will be performed sequentially at the 2-sided 
alpha=0.05 significance level. The first comparison will be the 10 mg obicetrapib group versus 
placebo; if significant, comparison of the 5 mg obicetrapib group versus placebo will be 
performed, followed by the 2.5 mg obicetrapib group versus placebo. Hypothesis testing will 
proceed in this hierarchical step-down fashion until a comparison is not significant. At that point, 
all remaining sequential tests will be deemed not significant. Missing data will be imputed using 
multiple imputation methodology. Results will be combined using Rubin’s method. Full details of 
the model and imputation will be provided in the SAP.  
Similar models as described for the primary efficacy analyses will be used to analyze the 
secondary efficacy endpoints. No adjustment will be made for multiplicity in testing the secondary 
efficacy endpoints. Nominal p-values will be provided when applicable. Any additional sensitivity 
and/or supplemental analyses will be defined in the SAP. 
Analysis of Safety 
The Safety Population will be the primary population for the safety analyses. All safety endpoints 
will be summarized descriptively. No statistical inference will be applied to the safety endpoints. 
Analysis of Pharmacokinetics 
Plasma obicetrapib concentrations will be summarized with descriptive statistics based on the 
PK Population. Exploration of any relationships with obicetrapib exposure will be performed, as 
appropriate. 
SAMPLE SIZE DETERMINATION: 
A sample size of at least 100 evaluable participants (i.e., 25 participants per treatment group) will 
provide >90% power to detect a 30% difference in LDL-C reduction at Day 56 (SD of 25%) for 
each of the obicetrapib groups compared to the placebo group at a 2-sided significance level 
of 0.05. 
The sample size for this study was determined in order to provide sufficient power for the analyses 
of the primary efficacy endpoint described above. Therefore, assuming a dropout rate of 
approximately 7%, an estimated enrollment target of approximately 108 participants 
(i.e., 27 participants per treatment group) is planned for this study. This sample size will also 
contribute sufficient participant exposure and safety data. 
Participants will be stratified according to their Screening Visit (Visit 1) LDL-C levels (100 or 
<100 mg/dL). 
SITES: Approximately 10 sites in Japan. 


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SPONSOR: 
NewAmsterdam Pharma BV  
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 
Coordinating Investigator Signature Page ...................................................................................... 3 
Investigator Agreement ................................................................................................................... 4 
Synopsis .......................................................................................................................................... 5 
Table of Contents .......................................................................................................................... 10 
List of Abbreviations and Definition of Terms............................................................................. 14 
1 
Introduction and Background Information ............................................................................. 16 
1.1 
Cholesteryl Ester Transfer Protein Inhibitors ................................................................ 16 
1.2 
Obicetrapib .................................................................................................................... 17 
1.3 
Clinical Development of Obicetrapib ........................................................................... 17 
1.4 
Rationale ........................................................................................................................ 18 
1.5 
Risk/Benefit ................................................................................................................... 18 
1.6 
Coronavirus Disease 2019 Impacts ............................................................................... 18 
2 
Study Objectives ..................................................................................................................... 19 
2.1 
Primary Objective ......................................................................................................... 19 
2.2 
Secondary Objectives .................................................................................................... 19 
3 
Study Description.................................................................................................................... 20 
3.1 
Summary of Study Design ............................................................................................ 20 
3.1.1 
Screening Period ............................................................................................... 20 
3.1.2 
Treatment Period ............................................................................................... 20 
3.1.3 
Safety Follow-Up and Additional Pharmacokinetic Period .............................. 20 
3.1.4 
Coronavirus Disease 2019 Contingency Measures ........................................... 20 
3.2 
Study Indication ............................................................................................................ 20 
4 
Selection and Withdrawal of Participants ............................................................................... 21 
4.1 
Inclusion Criteria ........................................................................................................... 21 
4.2 
Exclusion Criteria .......................................................................................................... 22 
4.3 
Retesting ........................................................................................................................ 23 
4.4 
Rescreening ................................................................................................................... 23 
4.5 
Withdrawal Criteria ....................................................................................................... 24 
5 
Study Treatments .................................................................................................................... 25 


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5.1 
Treatment Groups .......................................................................................................... 25 
5.2 
Rationale for Dosing ..................................................................................................... 25 
5.3 
Randomization and Blinding ......................................................................................... 25 
5.4 
Breaking the Blind ........................................................................................................ 25 
5.5 
Drug Supplies ................................................................................................................ 26 
5.5.1 
Formulation and Packaging ............................................................................... 26 
5.5.2 
Study Drug Preparation and Dispensing ........................................................... 26 
5.5.3 
Study Drug Administration ............................................................................... 27 
5.5.4 
Treatment Compliance ...................................................................................... 27 
5.5.5 
Storage and Accountability ............................................................................... 27 
5.6 
Prior and Concomitant Medications and/or Procedures ................................................ 27 
5.6.1 
Excluded Medications and/or Procedures ......................................................... 27 
5.6.2 
Allowed Medications and/or Procedures .......................................................... 28 
5.6.3 
Documentation of Prior and Concomitant Medication Use .............................. 28 
5.6.4 
Drugs to be Used with Caution ......................................................................... 28 
6 
Study Procedures .................................................................................................................... 29 
7 
Efficacy Assessments.............................................................................................................. 30 
8 
Safety Assessments ................................................................................................................. 31 
8.1 
Adverse Events .............................................................................................................. 31 
8.1.1 
Adverse (Drug) Reaction .................................................................................. 31 
8.1.2 
Unexpected Adverse Drug Reaction ................................................................. 32 
8.1.3 
Assessment of Adverse Events by the Investigator .......................................... 32 
8.1.4 
Events of Special Interest .................................................................................. 33 
8.1.4.1 Guidelines for management of elevated liver enzymes ...................... 34 
8.1.4.2 Guidelines for monitoring and management of creatine kinase ......... 34 
8.1.4.3 Guidelines for monitoring and management of new-onset diabetes 
mellitus ................................................................................................ 35 
8.1.4.4 Guidelines for monitoring and management of significant changes in 
renal function ...................................................................................... 35 
8.1.4.5 Guidelines for management of macular degeneration ........................ 35 
8.2 
Serious Adverse Events ................................................................................................. 35 
8.3 
Serious Adverse Event Reporting − Procedures for Investigators ................................ 36 
8.4 
Pregnancy Reporting ..................................................................................................... 36 


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8.5 
Expedited Reporting ...................................................................................................... 37 
8.6 
Special Situation Reports .............................................................................................. 37 
8.7 
Clinical Laboratory Evaluations .................................................................................... 38 
8.8 
Vital Signs ..................................................................................................................... 39 
8.9 
Weight and Height ........................................................................................................ 39 
8.10 Demographics ................................................................................................................ 39 
8.11 Electrocardiograms ........................................................................................................ 39 
8.12 Physical Examinations .................................................................................................. 39 
9 
Statistics .................................................................................................................................. 40 
9.1 
Analysis Populations ..................................................................................................... 40 
9.2 
Statistical Methods ........................................................................................................ 40 
9.2.1 
Analysis of Efficacy .......................................................................................... 40 
9.2.1.1 Primary efficacy analysis .................................................................... 40 
9.2.1.2 Secondary efficacy analysis ................................................................ 41 
9.2.2 
Analysis of Safety ............................................................................................. 41 
9.2.2.1 Analysis of events of special interest .................................................. 41 
9.2.3 
Analysis of Pharmacokinetics ........................................................................... 42 
9.2.4 
Interim Analysis ................................................................................................ 42 
9.2.5 
Sample Size Determination ............................................................................... 42 
10 Data Management and Record Keeping ................................................................................. 43 
10.1 Data Management ......................................................................................................... 43 
10.1.1 Data Handling ................................................................................................... 43 
10.1.2 Computer Systems ............................................................................................. 43 
10.1.3 Data Entry ......................................................................................................... 43 
10.1.4 Medical Information Coding ............................................................................. 43 
10.1.5 Data Validation ................................................................................................. 43 
10.2 Record Keeping ............................................................................................................. 44 
10.3 End of Study .................................................................................................................. 44 
11 Investigator Requirements and Quality Control ..................................................................... 45 
11.1 Ethical Conduct of the Study ........................................................................................ 45 
11.2 Institutional Review Board/Independent Ethics Committee ......................................... 45 
11.3 Informed Consent .......................................................................................................... 45 


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11.4 Participant Card ............................................................................................................. 45 
11.5 Study Monitoring Requirements ................................................................................... 46 
11.6 Disclosure of Data ......................................................................................................... 46 
11.7 Retention of Records ..................................................................................................... 46 
11.8 Publication Policy ......................................................................................................... 47 
11.9 Financial Disclosure ...................................................................................................... 47 
11.10 Insurance and Indemnity ............................................................................................... 47 
11.11 Legal Aspects ................................................................................................................ 47 
12 Study Administrative Information .......................................................................................... 48 
12.1 Protocol Amendments ................................................................................................... 48 
13 References ............................................................................................................................... 49 
Appendix A: Schedule of Procedures ........................................................................................... 50 
Appendix B: Clinical Laboratory Analytes .................................................................................. 52 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
Abbreviation 
Definition 
AE 
Adverse event 
ApoA1 
Apolipoprotein A1 
ApoB 
Apolipoprotein B 
ApoE 
Apolipoprotein E 
ALT 
Alanine aminotransferase 
ASCVD 
Atherosclerotic cardiovascular disease 
AST 
Aspartate aminotransferase 
CETP 
Cholesteryl ester transfer protein 
CK 
Creatine kinase 
COVID-19 
Coronavirus Disease 2019 
CRA 
Clinical Research Associate 
CRO 
Clinical Research Organization 
CT 
Computed tomography 
CTN 
Clinical trial notification 
CV 
Cardiovascular 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
eGFR 
Estimated glomerular filtration rate 
EIU 
Exposure In Utero 
EOT 
End of Treatment 
ESI 
Events of special interest 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HbA1c 
Glycosylated hemoglobin 
HDL 
High-density lipoprotein 
HDL-C 
High-density lipoprotein cholesterol 
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) 
mITT 
Modified Intent-to-Treat 


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Abbreviation 
Definition 
NODM 
New-onset diabetes mellitus 
non-HDL-C 
Non-high-density lipoprotein cholesterol 
PCSK9 
Proprotein convertase subtilisin kexin type 9 
PK 
Pharmacokinetic(s) 
PMDA 
Pharmaceuticals and Medical Devices Agency 
PP 
Per-Protocol 
QTc 
Heart rate-corrected QT interval 
QTcF 
Heart rate-corrected QT interval using Fridericia’s formula 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment-emergent adverse event 
TG 
Triglyceride(s) 
ULN 
Upper limit of normal 


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1 
INTRODUCTION AND BACKGROUND INFORMATION  
Dyslipidemia is a collective term used to describe a spectrum of disorders in lipid metabolism 
arising from a combination of genetic, environmental, and pathological factors. It is characterized 
by elevations in serum total cholesterol, low-density lipoprotein (LDL) cholesterol (LDL-C) and 
triglyceride (TG) concentrations, and/or an attenuation of the high-density lipoprotein (HDL) 
cholesterol (HDL-C) fraction. Diagnosis is made by measurement of serum lipids and is classified 
by the pattern of elevation/reduction in the lipid/lipoprotein fractions, mode of inheritance (or lack 
thereof), and presence of clinical manifestations. Dyslipidemia can lead to symptomatic 
obstructive or occlusive atherosclerotic disease of various vascular arterial beds. Normalization of 
the lipid profile to guideline-mandated targets, therefore, is widely accepted as the cornerstone of 
cardiovascular (CV) protection strategies.1 
If lifestyle modification strategies alone prove inadequate, statins are generally the drug of first 
choice to treat dyslipidemia. Patients unable to achieve treatment goals with a maximally tolerated 
statin therapy require an additional lipid-lowering therapy such as ezetimibe. Those intolerant to 
statins or unable to achieve treatment goals with statin (± ezetimibe) may be offered bempedoic 
acid, an inhibitor of cholesterol synthesis by the liver, or modulators of proprotein convertase 
subtilisin kexin type 9 (PCSK9) function such as inclisiran, an interfering RNA that blocks 
translation of PCSK9 protein, or monoclonal antibodies that directly inhibit PCSK9, such as 
alirocumab and evolocumab.  
However, there are several limitations with these lines of therapy, such as very high costs, 
availability restricted predominantly to specialist clinics, a paucity of long-term efficacy data 
relative to statins, and muscle-related events with PCSK9 inhibitors. Furthermore, because PCSK9 
inhibitors are injectable, they pose a less attractive option for patients who prefer oral medications, 
and they have not received the expected utilization by clinicians or patients. The 2 non-statin oral 
LDL-C-lowering therapies, ezetimibe and bempedoic acid, have a modest effect on LDL-C 
reduction and, therefore, often do not provide the efficacy required for high-risk atherosclerotic 
cardiovascular disease (ASCVD) patients.  
Above all, there remains an unmet medical need for therapies to reduce LDL-C levels and CV risk 
at an acceptable cost, in a convenient dosage form, and with a favorable tolerability and safety 
profile to maintain long-term lipid-lowering efficacy and patient adherence to therapy.  
1.1 
Cholesteryl Ester Transfer Protein Inhibitors 
Cholesteryl ester transfer protein (CETP) is a plasma glycoprotein produced in the liver and 
adipose tissue. It circulates in the blood, bound primarily to HDL-C, and is involved in the transfer 
of cholesteryl esters and TG between lipoproteins. In particular, CETP mediates the transfer of 
cholesteryl esters from HDL to apolipoprotein B (ApoB)-containing particles, i.e., very 
low-density lipoprotein and LDL-C, in exchange for TG.  
Inhibition of CETP activity reduces LDL-C levels and increases HDL-C. 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 particles.2,3 The LDL-C lowering effect mediated by 
CETP inhibition is anticipated to benefit patients with elevated LDL-C and increased CV risk. 


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1.2 
Obicetrapib  
Obicetrapib is a highly selective and potent CETP inhibitor, which has been developed for the 
treatment of dyslipidemia and CV risk. It is a small molecule that blocks the transfer of cholesteryl 
ester from non-atherogenic HDL particles to particles in lipoprotein fractions (including LDL) that 
cause atherosclerosis and reduces the concentration of cholesterol not only in LDL, but also in 
other atherogenic lipoproteins. Moreover, obicetrapib treatment will not only reduce the number 
of ApoB-containing particles that constitute LDL-C, it can also upregulate the concentration of 
apolipoprotein E (ApoE), which results in the removal of cholesterol via the liver and also reduced 
lipoprotein (a) (Lp[a]). 4  Finally, obicetrapib not only potently increases HDL-C and the 
concentration of apolipoprotein A1 (ApoA1)-containing lipoproteins but has also been shown to 
be a potent inducer of cholesterol efflux, which is the main driver of reverse cholesterol transport.5 
This effect is considered important because it can lead to regression of established atheroma burden. 
1.3 
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 and thorough QT/QTc study (TA-8995-04) of 
obicetrapib has been completed and demonstrated no adverse effect on QTcF prolongation. A 
drug-drug interaction study (TA-8995-05) has also shown no significant effect of obicetrapib on 
P-glycoprotein activity but did indicate that obicetrapib is a mild inducer of cytochrome P450 3A4. 
A mass balance study (TA-8995-07) in healthy males concluded that obicetrapib is steadily 
absorbed, and the principal route of excretion was in the feces. Furthermore, bioequivalence 
between obicetrapib capsule and tablet formulations (TA-8995-08) has previously been 
demonstrated. 
A Phase 2 patient study (TA-8995-03) was conducted in Denmark and the Netherlands to evaluate 
the optimal dose of obicetrapib alone and in combination with medium-intensity statins in patients 
with mild dyslipidemia. A daily dose of 10 mg obicetrapib in combination with medium-intensity 
statins resulted in an incremental LDL-C reduction of up to 45.3% and a total LDL-C reduction of 
68.2%, while statin monotherapy or obicetrapib monotherapy achieved a comparatively weaker 
LDL-C reduction of 45.4%.4 When compared with statin treatment alone at the end of the 
12-week Treatment Period, all treatment groups with obicetrapib in combination with 
medium-intensity statins had significantly higher mean HDL-C levels; significantly greater 
increases in ApoA1 and ApoE levels; and a higher reduction in ApoB, Lp(a), and non-high-density 
lipoprotein cholesterol (non-HDL-C) levels.4  
Currently, Phase 3 studies are ongoing in which obicetrapib is added to a pre-existing maximally 
tolerated lipid-lowering therapy regime taken by participants with established sequelae of ASCVD. 
Indeed, the Phase 2 study (TA-8995-03) of obicetrapib described above was conducted in Northern 
European, predominantly Caucasian participants. Thus, there is a lack of clinical experience with 
obicetrapib when used in combination with moderate intensity stable statin therapy among 
individuals from the Asia-Pacific region. Study TA-8995-203 is designed to fill the gap in clinical 
experience and characterize the safety, efficacy, and pharmacokinetics (PK) profile of obicetrapib 
within this population.  


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1.4 
Rationale 
This dose-finding, Phase 2, double-blind, randomized study of obicetrapib versus placebo aims to 
confirm the safety and efficacy of the active compound in Japanese participants.  
1.5 
Risk/Benefit 
Obicetrapib has undergone extensive nonclinical testing according to the International Council for 
Harmonisation (ICH) guidelines, including repeat-dose toxicity studies of up to 39 weeks duration. 
In addition, obicetrapib has been investigated in 8 completed clinical studies, of which 6 studies 
were in Phase 1 of clinical development and 2 studies were in Phase 2. A total of approximately 
500 participants have been exposed to obicetrapib in these studies. In Phase 1, a total of 
159 participants received single oral doses between 5 and 150 mg of obicetrapib, and 
76 participants received consecutive doses between 1 and 25 mg of obicetrapib for periods up to 
28 days. In Phase 2, a total of 268 patients received 1 to 10 mg of obicetrapib for up to 12 weeks. 
In healthy volunteer studies, single doses of obicetrapib up to 150 mg and multiple doses up to 
25 mg/day over 28 days were generally well tolerated. Obicetrapib was also well tolerated after 
daily dosing of 10 mg for 12 weeks, both alone and in combination with 2 different statins. There 
were no dose-related adverse events (AEs) identified and no clinically significant changes in vital 
signs, 12-lead electrocardiograms (ECGs), hematology, or biochemistry in any clinical trials. Most 
treatment-emergent AEs (TEAEs) were mild or moderate in severity. None of the severe TEAEs 
were considered related to the study drug. The number of patients experiencing TEAEs and their 
severity were similar across all treatment groups. Incidence rates of drug-related TEAEs were also 
comparable for all treatment groups; the number of TEAEs in the obicetrapib treatment groups did 
not indicate a dose-dependent effect. There were 7 patients, who were randomized to receive 
obicetrapib alone or in combination with statin, with a treatment-emergent serious AE (SAE), none 
of which were suspected to be related to study drug. One patient had a treatment-emergent SAE 
that resulted in study discontinuation. 
1.6 
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. 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 protocol includes the guidance for COVID-19 situations, see Section 3.1.4 for details. 
The impacts of implementing COVID contingency measures on the outcomes of this study, 
including any protocol deviations that result from COVID-19 illness, 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 efficacy of obicetrapib, compared to placebo, 
in reducing serum LDL-C measured at Day 56 (Visit 5) when taken as an adjunct to a pre-existing 
stable statin therapy regime. 
2.2 
Secondary Objectives 
The secondary objectives of this study include the following: 
• To evaluate the effect of obicetrapib, compared to placebo, on serum ApoB, non-HDL-C, and 
HDL-C concentrations at Day 56 (Visit 5), when taken as an adjunct to pre-existing stable 
statin therapy; 
• To assess the mean plasma levels of obicetrapib at steady state on Day 56 (Visit 5) and 
Day 84 (Visit 6); and 
• To evaluate the safety and tolerability profile of obicetrapib in Japanese subjects. 


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3 
STUDY DESCRIPTION 
3.1 
Summary of Study Design 
This study will be a placebo-controlled, double-blind, randomized, Phase 2 dose-finding study to 
evaluate the efficacy, safety, and tolerability of obicetrapib as an adjunct to stable statin therapy in 
Japanese participants. This study will take place at approximately 10 sites in Japan. 
3.1.1 
Screening Period 
At the Screening Visit (Visit 1), and up to 2 weeks before the start of the treatment period, 
participants will be required to sign an informed consent form (ICF) before any study-related 
procedures are performed. After signing the ICF, participants will be assessed for study eligibility. 
3.1.2 
Treatment Period 
Up to 2 weeks after the Screening Visit, participants will return to the site on Day 1 (Visit 2) and 
confirm study eligibility before being randomized and beginning treatment. Approximately 
100 eligible participants (25 participants per treatment group) will be randomized in a 1:1:1:1 ratio 
to 1 of the following treatment groups: 
• 2.5 mg obicetrapib (one 2.5 mg obicetrapib tablet); 
• 5 mg obicetrapib (one 5 mg obicetrapib tablet); 
• 10 mg obicetrapib (one 10 mg obicetrapib tablet); or 
• Placebo (1 placebo tablet). 
During the 8-week Treatment Period, the assigned study drugs will be administered by the 
participants orally once daily from Day 1 (Visit 2) to Day 56 (Visit 5). Participants will return to 
the site on Day 14 (Visit 3), Day 28 (Visit 4), and Day 56 (Visit 5) for efficacy, safety, and PK 
assessments. Participants, Investigators, the Clinical Research Organization (CRO), and the 
Sponsor will be blinded to all lipid results from Day 1 (Visit 2) for the first participant and 
continuing to database lock in order to protect blinding to treatment assignment. 
3.1.3 
Safety Follow-Up and Additional Pharmacokinetic Period 
Participants will return to the site for a Safety Follow-up Visit on Day 84 (Visit 6), approximately 
4 weeks after the end of the Treatment Period, for final safety and PK assessments.  
3.1.4 
Coronavirus Disease 2019 Contingency Measures 
In cases of COVID-19 limitations, it is the Investigator’s responsibility to assure the safety of 
participants. If investigators need to implement contingency measures, the investigators will 
communicate with the Sponsor and discuss the best practice with the sponsor. In the absence of a 
COVID-19 impact, it is expected that Investigators and participants follow the protocol 
requirements as set forth. 
3.2 
Study Indication 
The indication for this study is the pharmacotherapeutic treatment of dyslipidemia. 


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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. Understanding of the study procedures, willingness to adhere to the study schedules, and 
agreement to participate in the study by giving written informed consent prior to screening 
procedures; 
2. Japanese men or women, 18 to 75 years of age, inclusive, at the Screening Visit;  
o Women 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 Women of childbearing potential must have a negative urine pregnancy test at the 
Screening Visit. Note: Women are not considered to be of childbearing potential if they 
meet 1 of the following criteria as documented by the Investigator: 
▪ They have had a hysterectomy or tubal ligation at a minimum of 1 cycle prior to signing 
the ICF; or 
▪ They are postmenopausal, defined as 1 year since their last menstrual period for 
women 55 years of age or 1 year since their last menstrual period and have a 
follicle-stimulating hormone (FSH) level in the postmenopausal range for women 
<55 years of age. 
o Women of childbearing potential must agree to complete abstinence or to use an effective 
method of avoiding pregnancy from screening to 90 days after the last visit. Men whose 
partners are of childbearing potential must agree to complete abstinence or to have the 
partner use an effective method of avoiding pregnancy from screening to 90 days after the 
last visit. Effective methods of avoiding pregnancy are contraceptive methods with a Pearl 
index of <1 (oral contraceptives or intrauterine devices) used consistently and correctly or 
a sterile sexual partner; 
3. Fasting LDL-C levels >70 mg/dL and TG levels <400 mg/dL at the Screening Visit;  
4. Currently receiving stable statin therapy with either atorvastatin 10 or 20 mg/day or 
rosuvastatin 5 or 10 mg/day ONLY for at least 8 weeks prior to screening with the intention of 
remaining on the same stable dose throughout the study duration. 
o Patients on stable statin therapy with either atorvastatin or rosuvastatin AND taking 
concomitant daily oral ezetimibe as a second line agent are also eligible to participate. 


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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. Body mass index 35 kg/m2 at the Screening Visit; 
2. Current clinically active/acute episode of CV disease, including but not limited to: 
o Major adverse CV event within 3 months prior to randomization, including: 
▪ Non-fatal myocardial infarction; 
▪ Non-fatal stroke; 
▪ Hospitalization for heart failure; or 
▪ Hospitalization for unstable angina. 
o New York Heart Association Functional Classification Class III or IV heart failure. 
3. Patients who meet the lipid management targets as specified in the 2017 Japan Atherosclerosis 
Society Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases; 
4. Have an existing diagnosis of homozygous familial hypercholesterolemia; 
5. Have an existing diagnosis of CETP deficiency; 
6. Glycosylated hemoglobin (HbA1c) 10% at the Screening Visit; 
7. Uncontrolled hypertension, i.e., supine systolic blood pressure 160 mmHg and/or supine 
diastolic blood pressure 100 mmHg, taken as the average of triplicate measurements. 
One retest will be allowed, at which point if the retest result is no longer exclusionary, the 
participant may be randomized; 
8. Active muscle disease or persistent creatine kinase (CK) concentration >3 × the upper limit of 
normal (ULN). One retest will be allowed after 1 week to verify the result, at which point if 
the retest result is no longer exclusionary, the participant may be randomized; 
9. Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2, calculated using the Chronic 
Kidney Disease Epidemiology Collaboration equation6; 
10. Hepatic dysfunction as evidenced by any laboratory abnormality as follows: gamma-glutamyl 
transferase, alanine aminotransferase (ALT), or aspartate aminotransferase (AST) >2 × ULN, 
or total bilirubin >1.5 × ULN; 
11. Anemia, defined as hemoglobin concentration <11 g/dL for men and hemoglobin 
concentration <9 g/dL for women; 
12. History of malignancy within 5 years prior to screening, with the exception of non-melanoma 
skin cancers; 
13. History of alcohol and/or drug abuse within 5 years prior to screening; 
14. Treatment with a statin that is not either atorvastatin or rosuvastatin; 
15. Treatment with other investigational products or devices within 30 days or 5 half-lives, 
whichever is longer, prior to screening; 


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16. Treatment with any PCSK9 inhibitor within 10 weeks prior to randomization or bempedoic 
acid within 2 weeks prior to randomization; 
17. Evidence of any other clinically significant, non-cardiac disease or condition that, in the opinion 
of the Investigator, would preclude participant in the study; or 
18. Known CETP inhibitor allergy or intolerance. 
4.3 
Retesting 
If laboratory abnormalities during screening are considered by the Investigator to be transient, then 
the laboratory tests may be repeated once during screening. The Investigator’s rationale for 
retesting should be documented. If the retest result is no longer exclusionary, the participant may 
be randomized. 
4.4 
Rescreening 
A participant who is screened and does not meet the study eligibility criteria may be considered 
for rescreening upon Sponsor and/or Medical Monitor consultation and approval. Rescreened 
participants will be assigned a new participant number. Rescreening should occur no less than 
5 days after the last Screening Visit. 
 
 


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4.5 
Withdrawal Criteria 
Participation in this study may be discontinued for any of the following reasons: 
• The participant withdraws consent or requests discontinuation from the study for any reason; 
• 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 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; 
• Pregnancy; 
• Requirement of prohibited concomitant medication; 
• Participant failure to comply with protocol requirements or study-related procedures; or 
• Termination of the study by the Sponsor or the regulatory authority. 
Unless the participant withdraws consent, participants who discontinue study drug early should be 
encouraged to complete the full panel of assessments scheduled for the Early Termination Visit 
promptly and complete a Safety Follow-up Visit 4 weeks after the last dose. If a participant 
withdraws prematurely from the study due to the above criteria or any other reason, study staff 
should make every effort to complete the full panel of assessments scheduled for the Early 
Termination Visit and complete a Safety Follow-up Visit 4 weeks after the last dose. PK samples 
will not be collected during the Safety Follow-up Visit for participants who discontinue study drug 
early without withdrawing consent or for participants who withdraw prematurely from the study. 
The reason for participant withdrawal must be documented in the electronic case report form 
(eCRF). 
In the case of participant lost to follow-up, attempts to contact the participant must be made and 
documented in the participant’s medical records. Withdrawn participants will not be replaced. 


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5 
STUDY TREATMENTS 
5.1 
Treatment Groups 
Participants will be randomized in a 1:1:1:1 ratio to 1 of the following treatment groups: 
• 2.5 mg obicetrapib (one 2.5 mg obicetrapib tablet); 
• 5 mg obicetrapib (one 5 mg obicetrapib tablet); 
• 10 mg obicetrapib (one 10 mg obicetrapib tablet); or 
• Placebo (1 placebo tablet). 
5.2 
Rationale for Dosing 
In clinical studies of 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 of 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 and concentrations were reduced, and 
HDL-C levels were increased while LDL-C levels were decreased. There were no dose-related 
AEs identified and no clinically significant changes in vital signs, ECGs, or hematology or 
biochemistry parameters in any clinical studies. A statistically significant reduction in Lp(a) levels 
from Baseline was also observed at the 10 mg obicetrapib dose level. A 2.5 mg dose is being 
investigated in this study to determine a definitive optimal dose specific to a Japanese population. 
Therefore, the present study will investigate doses of 2.5 mg, 5 mg, and 10 mg obicetrapib in 
participants currently receiving a stable statin therapy. 
5.3 
Randomization and Blinding 
Participants who meet all eligibility criteria will be randomized into the study. Participants will be 
randomized in a 1:1:1:1 ratio to the 2.5 mg obicetrapib, 5 mg obicetrapib, 10 mg obicetrapib, or 
placebo treatment groups. At randomization, participants will be stratified according to their 
Screening Visit (Visit 1) LDL-C level (100 or <100 mg/dL). An automated interactive response 
technology (IRT) system will be used to assign the participant to 1 of the 4 treatment groups, and 
visits will be registered in the IRT for Screening and Visits 1 through 5 as well as Early 
Termination, if applicable. 
Participants, Investigators, the CRO, and the Sponsor will be blinded to all lipid results from 
Day 1 (Visit 2) for the first participant and continuing to database lock in order to protect blinding 
to treatment assignment. 
5.4 
Breaking the Blind 
Unblinding by request of an Investigator should occur only in the event of an emergency or AE, 
for which it is necessary to know the study drugs to determine an appropriate course of therapy for 
the participant. If the Investigator or qualified designee must identify the treatment assignment of 
an individual participant, the Investigator or qualified designee should request the treatment 
assignment from the IRT system. The Investigator is advised not to reveal the treatment assignment 
to other sites or Sponsor personnel. 


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Prior to unblinding, and if the situation allows, the Investigator should consult with the Sponsor’s 
Medical Monitor. If this is impractical, the Investigator must notify the Sponsor’s Medical Monitor 
as soon as possible, without revealing the treatment assignment of the unblinded participant. The 
Investigator must document the participant identification and the date and time for breaking the 
blind and must clearly explain the reasons for breaking the blind. 
Medically necessary care should not be delayed for unblinding information (i.e., the Investigator 
should treat the participant based on the participant’s signs/symptoms without waiting for the 
unblinding process to be completed). 
For participants who are unblinded and withdrawn from the study, study staff should make every 
effort to complete the full panel of assessments scheduled for the Early Termination Visit and 
complete a Safety Follow-up Visit (Visit 6) 4 weeks after the last dose. 
5.5 
Drug Supplies 
5.5.1 
Formulation and Packaging 
The study drugs will consist of 2.5 mg, 5 mg, and 10 mg obicetrapib tablets and matching placebo 
tablet. All study drugs are manufactured in accordance with current Good Manufacturing Practice. 
Obicetrapib tablets are
 
. Matching placebo 
tablets will also be provided. 
 
 
 
  
The tablets are packaged in high-density polyethylene bottles, using tamper-evident/child-resistant 
screw caps made of polypropylene, and each bottle will contain 40 tablets. The tablets should be 
stored at ambient conditions below 25°C. 
The physical, chemical, and pharmaceutical formulation properties and characteristics of the 
obicetrapib tablets are described in the Investigator’s Brochure. 
All study drugs will be labelled in accordance with all applicable local regulatory requirements. 
5.5.2 
Study Drug Preparation and Dispensing 
The study drugs to be used in this study include the following: 
• 2.5 mg obicetrapib tablet; 
• 5 mg obicetrapib tablet;  
• 10 mg obicetrapib tablet; and 
• Matching placebo tablet. 
The study drugs listed above will be packaged to provide doses of 2.5 mg, 5 mg, 10 mg obicetrapib, 
or placebo only. Participants will be randomized to receive 1 of the 3 doses of obicetrapib or 
placebo only from Day 1 (Visit 2) to Day 56 (Visit 5). Placebo tablets will be visually identical. 
At Visits 2 and 4, participants will receive one 40-count bottle with the study drug appropriate for 
the participant’s treatment group. Each bottle will provide a sufficient supply for at least 4 weeks 


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of dosing. Participants will be instructed to take 1 tablet from the bottle each day. The bottles will 
be clearly labelled. Participants will be instructed to bring the bottle and all unused study drugs to 
the site at the next visit. 
This study protocol includes the guidance for COVID-19 situations. See Section 3.1.4 for details. 
In the absence of a COVID-19 impact, it is expected that Investigators and participants follow the 
protocol requirements as set forth. 
5.5.3 
Study Drug Administration 
One tablet of study drug will be administered by the participant orally once daily from 
Day 1 (Visit 2) to Day 56 (Visit 5). Study drugs should be administered at approximately the same 
time each morning. On days with visits scheduled, study drugs should be administered following 
all fasted blood sample collections. If a participant forgets to take study drug on a given day, they 
should take the next dose as normal and should not take a double dose to make up for the forgotten 
dose. 
5.5.4 
Treatment Compliance 
Participants will return used and unused bottles of study drug at Visits 3, 4, 5, 6, and ET. The 
number of tablets returned should be counted and documented in the source documentation and in 
the eCRF for compliance. Any discrepancies between the number of days and the number of tablets 
administered should be clarified and documented in the source. 
Compliance with study drug dosing will be assessed using the following formula: 
 
𝐶𝑜𝑚𝑝𝑙𝑖𝑎𝑛𝑐𝑒 (%) = (# 𝑡𝑎𝑏𝑙𝑒𝑡𝑠 𝑑𝑖𝑠𝑝𝑒𝑛𝑠𝑒𝑑−# 𝑡𝑎𝑏𝑙𝑒𝑡𝑠 𝑟𝑒𝑡𝑢𝑟𝑛𝑒𝑑)
# 𝑒𝑥𝑝𝑒𝑐𝑡𝑒𝑑 𝑑𝑜𝑠𝑖𝑛𝑔 𝑑𝑎𝑦𝑠
× 100 
5.5.5 
Storage and Accountability 
All study drugs must be stored at ambient conditions below 25°C in a secure area with access 
limited to the Investigator and authorized site personnel. 
In accordance with regulatory requirements, the Investigator or designated site personnel must 
document the amount of study 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 must not receive treatment with other investigational products or devices within 
30 days or 5 half-lives, whichever is longer, prior to screening. 
Participants must not receive treatment with any PCSK9 inhibitor within 10 weeks prior to 
randomization or bempedoic acid within 2 weeks prior to randomization. 


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5.6.2 
Allowed Medications and/or Procedures 
Participants must be currently receiving stable statin therapy with either atorvastatin 10 or 
20 mg/day or rosuvastatin 5 or 10 mg/day ONLY for at least 8 weeks prior to screening with the 
intention of remaining on the same stable dose throughout the study duration. Concomitant 
treatment with ezetimibe in addition to stable statin therapy is permitted. 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.  
5.6.3 
Documentation of Prior and Concomitant Medication Use 
Medications used within 28 days prior to the Screening Visit will be recorded. Any medications 
administered in addition to the study drugs, whether allowed per the protocol or not, must be 
documented on the concomitant medication eCRF. 
5.6.4 
Drugs to be Used with Caution 
Participants must use the following drugs with caution during the study period: 
• 
Potent CYP3A3 Inhibitors (e.g., itraconazole, fluconazole, voriconazole) 
• 
Potent CYP2C9 Inhibitors (e.g., amiodarone, miconazole, bucolome, fluconazole) 
 


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STUDY PROCEDURES 
Study procedures will follow the Schedule of Procedures (Appendix A).  
This study protocol includes the guidance for COVID-19 situations. See Section 3.1.4 for details. 
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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7 
EFFICACY ASSESSMENTS 
The primary efficacy endpoint is the percent change from Day 1 to Day 56 in LDL-C for each 
obicetrapib group compared to the placebo group.  
The key secondary efficacy endpoints include the following: 
• Percent change from Day 1 to Day 56 in ApoB for each obicetrapib group compared to the 
placebo group; 
• Percent change from Day 1 to Day 56 in non-HDL-C for each obicetrapib group compared to 
the placebo group; and 
• Percent change from Day 1 to Day 56 in HDL-C for each obicetrapib group compared to the 
placebo group. 
Blood samples for the lipid profile must be obtained under fasting conditions (i.e., after the 
participant has fasted for approximately 8 hours). For the purposes of this study, fasting will be 
defined as nothing by mouth except water and any essential medications. If a participant is not 
fasting, the Investigator should reschedule the visit as soon as possible. LDL-C level will be 
calculated using the Friedewald equation unless TG 400 mg/dL or LDL-C 50 mg/dL. 
If TG 400 mg/dL or LDL-C 50 mg/dL, then LDL-C level will be measured directly by 
preparative ultracentrifugation, also referred to as beta quantification. 7  In addition, for all 
participants, LDL-C will be measured by preparative ultracentrifugation, also referred to as beta 
quantification, at Baseline (Visit 2) and at the end of the 8-week Treatment Period (Visit 5). 


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8 
SAFETY ASSESSMENTS 
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. 
Participants in this study who experience an AE or SAE with or without a causal relationship with 
the study drug will be followed until the AE or SAE resolves or stabilizes per the Investigator’s 
judgment. All AEs, including observed or volunteered problems, complaints, or symptoms, are to 
be recorded on the appropriate eCRF. 
AEs, which include clinical laboratory assessment variables, will be monitored and documented 
from the Screening Visit (Visit 1) until completion of Visit 6. 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 drug. Beginning at the date of the Screening Visit (Visit 1), Investigators should make an 
assessment for AEs at each visit and record the event on the appropriate AE eCRF. 
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified by the Investigator and recorded on the eCRF. However, if an 
observed or reported sign or symptom is not considered a component of a specific disease or 
syndrome by the Investigator, it should be recorded as a separate AE on the eCRF. Additionally, 
the condition that led to a medical or surgical procedure (e.g., surgery, endoscopy, tooth extraction, 
or transfusion) should be recorded as an AE, not the procedure itself.  
Any medical condition already present at the Screening Visit (Visit 1) should be recorded as part 
of the medical history and not 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 findings (e.g., ECG) that are 
detected during the study or are present at the Screening Visit (Visit 1) and significantly worsen 
during the study should be reported as AEs, as described below. The Investigator will exercise his 
or her medical and scientific judgment in deciding whether an abnormal laboratory finding, or 
other abnormal assessment is clinically significant. Clinically significant abnormal laboratory 
values occurring during the study will be followed until repeat tests return to normal, stabilize, or 
are no longer clinically significant. Abnormal test results that are determined to be an error should 
not be reported as an AE. Laboratory abnormalities or other abnormal clinical findings (e.g., ECG 
abnormalities) should be reported as an AE if any of the following are applicable: 
• If an intervention is required as a result of the abnormality; 
• If action taken with the study drug is required as a result of the abnormality; or  
• Based on the clinical judgment of the Investigator. 
8.1.1 
Adverse (Drug) Reaction 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered an adverse drug reaction. “Responses” to a medicinal product means that a causal 


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relationship between a medicinal product and an AE is at least a reasonable possibility, i.e., 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 Adverse Events by the Investigator 
The Investigator will assess the severity (intensity) of each AE as mild, moderate, or severe, and 
will also categorize each AE as to its potential relationship to 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 (unrelated, not related, 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. 
• 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. 


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• 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 
Events of special interest (ESIs) will be monitored over time, 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 hepatic abnormalities, muscle-related abnormalities, new-onset diabetes mellitus 
(NODM) and/or hyperglycemia, renal abnormalities, and ophthalmic events (i.e., 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; 
o HbA1c 6.5% (48 mmol/mol); 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% and/or a new concomitant medication or increase in current antidiabetic therapy in a 
participant with a Baseline HbA1c 6.5%. 
• Both eGFR <30 mL/min/1.73 m2 AND a >25% decrease in eGFR from Baseline, calculated 
using the Chronic Kidney Disease Epidemiology Collaboration equation; and  
• Macular degeneration.  
These ESIs will be monitored through review of the AE and laboratory databases. 


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8.1.4.1 
Guidelines for management of elevated liver enzymes  
Discontinuation of study drug should be considered if any of the following occurs and other causes 
of liver enzyme elevations, such as concomitant medication, have been considered and ruled out: 
• 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%). 
Participant management is at the discretion of the Investigator. It is recommended to examine for 
the presence of associated signs and symptoms, e.g., jaundice and hepatomegaly, and to perform 
additional diagnostic investigations, including abdominal ultrasound and a viral serology screen. 
8.1.4.2 
Guidelines for monitoring and management of creatine kinase  
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 it is reasonably possible, 
preferably within 3 to 7 days of the laboratory result becoming available. 
A repeat CK assessment will include a query for related symptoms. 
If the repeat CK assessment confirms an unexplained (i.e., 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 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. 


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If the repeat CK assessment confirms an unexplained (i.e., 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.  
8.1.4.3 
Guidelines for monitoring and management of new-onset diabetes mellitus 
Diabetes mellitus may be newly diagnosed during the study as described in Section 8.1.4. If a 
participant is newly diagnosed with diabetes mellitus during the course of the study, the 
Investigator will recommend referral for initial diabetes education and management by an 
appropriate healthcare provider (e.g., diabetologist, endocrinologist, or primary care provider). 
Interventions for management may include diet and lifestyle counseling, self-monitoring of blood 
glucose, oral glucose-lowering medications, injectable medications, or insulin as deemed 
necessary by the treating physician based on the level of hyperglycemia and relevant symptoms. 
8.1.4.4 
Guidelines for monitoring and management of significant changes in renal function  
If at any time after randomization a participant experiences both an eGFR <30 mL/min/1.73 m2 
AND a >25% decrease in eGFR from Baseline, calculated using the Chronic Kidney Disease 
Epidemiology Collaboration equation, 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. The Investigator will ensure optimal hydration of the participant and consider 
and/or review any potential nephrotoxic or reversible causes of the notable eGFR decrease (e.g., 
non-steroidal anti-inflammatory drug use). Additionally, the Investigator may discuss the 
management of the case with the Medical Monitor. 
8.1.4.5 
Guidelines for management of macular degeneration 
In cases of suspected macular degeneration, 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. 
• 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 a 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 


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for seriousness. Admission to the hospital for social or situational reasons (i.e., 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 
Serious Adverse Event Reporting − Procedures for Investigators 
Initial reports 
All SAEs occurring from the Screening Visit (Visit 1) until completion of Visit 6 must be reported 
to 
 within 24 hours of the knowledge of the occurrence. After completion 
of Visit 6, any SAE that the Investigator considers related to study drug must be reported to the 
 or the Sponsor/designee. 
To report the SAE, complete the SAE form electronically in the electronic data capture (EDC) 
system for the study. When the form is completed, 
 personnel will be notified 
electronically by the EDC system and will retrieve the form. If the event meets serious criteria and 
it is not possible to access the EDC system, send an email to 
 
 at 
medpace-safetynotification@medpace.com or call the 
 reporting line (phone 
number listed below), and fax/email the completed 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 
(e.g., participant discharge summary or autopsy reports) to 
 via fax or 
email. If it is not possible to access the EDC system, refer to the procedures outlined above for 
initial reporting of SAEs.  
8.4 
Pregnancy Reporting 
If a participant becomes pregnant during the study or within the Safety Follow-up Period defined 
in the protocol, the Investigator is to stop dosing with study drug(s) immediately and the participant 


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should be withdrawn from the study. Early study termination procedures should be implemented 
at that time.  
A pregnancy is not considered to be an AE or SAE; however, it must be reported to 
 
 within 24 hours of knowledge of the event. 
 will then 
provide the Investigator/site the Exposure In Utero (EIU) form for completion. 
The Investigator/site must complete the EIU form and fax/email it back to 
.  
If the female partner of a male participant becomes pregnant while the participant is receiving 
study drug or within the Safety Follow-up Period defined in the protocol, the Investigator should 
notify 
 as described above.  
The pregnancy should be followed until the outcome of the pregnancy, whenever possible. 
Once the outcome of the pregnancy is known, the EIU form should be completed and 
faxed/emailed to 
. If the outcome of the pregnancy meets the criteria for 
immediate classification as an SAE (i.e., 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 as soon as possible to the PMDA, 
Japan, and in any case no later than 7 days after knowledge by the Sponsor/designee of such a case. 
Relevant follow-up information will subsequently be communicated within an additional 7 days.  
All other SUSARs will be reported to the PMDA as soon as possible but within a maximum of 
15 days 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 investigational medicinal product. 
8.6 
Special Situation Reports 
Special situation reports include reports of overdose, misuse, abuse, medication error, and reports 
of adverse reactions associated with product complaints. 
• Overdose: Refers to the administration of a quantity of a medicinal product given per 
administration or cumulatively (accidentally or intentionally), which is above the maximum 
recommended dose according to the protocol. Clinical judgement should always be applied. In 
cases of a discrepancy in the drug accountability, overdose will be established only when it is 
clear that the participant has taken additional dose(s), or the Investigator has reason to suspect 
that the participant has taken additional dose(s).  
• Misuse: Refers to situations where the medicinal product is intentionally and inappropriately 
used 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.  




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An FSH test will be performed at the Screening Visit prior to participation in the study in women 
<55 years of age for whom it has been 1 year since their last menstrual period to confirm a 
postmenopausal state. 
Blood samples for PK assessment will be collected as indicated in Appendix A. On Day 1 (Visit 2), 
a PK sample will be collected pre-dose. The subsequent post-dose PK samples should be collected 
once at approximately the same time at each visit. 
8.8 
Vital Signs 
Vital signs will be taken as indicated in Appendix A. Vital signs will include body temperature, 
heart rate, and triplicate blood pressure (systolic and diastolic) measurements. Participants should 
be in the supine position after at least 10 minutes rest prior to the vital sign measurements. 
8.9 
Weight and Height 
Weight and height will be measured at the Screening Visit and will be used to calculate body mass 
index. Measurement of weight should be performed with the participant dressed in indoor clothing, 
with shoes removed, and bladder empty. 
8.10 
Demographics 
Participant demographic data (e.g., gender, race, ethnicity, and birth date/year) will be collected at 
the Screening Visit. 
8.11 
Electrocardiograms 
A single, standard 12-lead ECG will be performed by the Investigator or trained site personnel at 
the Screening Visit and read locally. 
8.12 
Physical Examinations 
A physical examination will be performed as indicated in Appendix A.  


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9 
STATISTICS 
9.1 
Analysis Populations 
The Intent-to-Treat (ITT) Population will include all participants randomized into the study. 
Treatment classification will be based on the randomized treatment.  
The Modified ITT (mITT) Population will include all participants in the ITT Population who 
receive at least 1 dose of any study drug and have a Baseline value for the LDL-C assessment. Any 
efficacy measurement obtained during the Safety Follow-up Visit after a participant permanently 
discontinues the study drug or after a participant receives an excluded medication and/or procedure 
will be removed from the mITT analysis. Treatment classification will be based on the randomized 
treatment. The mITT Population will be used for the primary analysis of all efficacy endpoints. 
The Per-Protocol (PP) Population will include all participants in the mITT Population who have a 
Baseline value for the LDL-C assessment, have a Day 56 value for the LDL-C assessment, and 
who do not experience a major protocol deviation that would potentially impact the primary 
efficacy endpoint. The PP Population, along with the reason for exclusion, will be finalized prior 
to study unblinding. 
The PK Population will include all participants in the mITT Population who have sufficient blood 
samples collected for valid estimation of PK parameters. 
The Safety Population will include all participants who receive at least 1 dose of any study drug. 
Treatment classification will be based on the actual treatment received. The Safety Population will 
be the primary population used for the safety analyses. 
9.2 
Statistical Methods 
A Statistical Analysis Plan (SAP) will be finalized before database lock. Any changes to the 
methods described in the SAP will be described and justified as needed in the Clinical Study Report. 
All study-collected data will be summarized by treatment group using descriptive statistics, graphs, 
and/or raw data listings. Descriptive statistics for continuous variables will include number of 
participants (n), mean, standard deviation (SD), median, minimum, and maximum values. Analysis 
of categorical variables will include frequency and percentage. 
9.2.1 
Analysis of Efficacy 
The mITT Population will be the primary population for the efficacy analyses. Efficacy will also 
be analyzed using the ITT Population and the PP Population as supportive analyses. 
9.2.1.1 
Primary efficacy analysis 
The primary efficacy analysis of the percent change from Day 1 to Day 56 in LDL-C will be 
performed using a mixed model for repeated measures approach. The analysis will include fixed 
effects for treatment, visit, and treatment-by-visit interaction, along with a covariate of the 
Baseline value. The Restricted Maximum Likelihood estimation approach will be used with an 
unstructured covariance matrix. The least squares means, standard errors, and 2-sided 
95% confidence intervals for each treatment group and for the pairwise comparisons of each dose 
of obicetrapib to the placebo group will be provided. In order to maintain the overall alpha level 
on the primary endpoint, the hypothesis testing will be performed sequentially at the 2-sided 
alpha=0.05 significance level. The first comparison will be the 10 mg obicetrapib group versus 


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placebo; if significant, comparison of the 5 mg obicetrapib group versus placebo will be performed, 
followed by the 2.5 mg obicetrapib group versus placebo. Hypothesis testing will proceed in this 
hierarchical step-down fashion until a comparison is not significant. At that point, all remaining 
sequential tests will be deemed not significant. Missing data will be imputed using multiple 
imputation methodology. Results will be combined using Rubin’s method. Full details of the 
model and imputation will be provided in the SAP. 
9.2.1.2 
Secondary efficacy analysis 
Similar models as described for the primary efficacy analyses will be used to analyze the secondary 
efficacy endpoints. No adjustment will be made for multiplicity in testing the secondary efficacy 
endpoints. Nominal p-values will be provided when applicable. Any additional sensitivity and/or 
supplemental analyses will be defined in the SAP. 
9.2.2 
Analysis of Safety 
The Safety Population will be the primary population for the safety analyses. All safety endpoints 
will be summarized descriptively. No statistical inference will be applied to the safety endpoints. 
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 events of special interest 
Liver-associated enzymes and total bilirubin will be summarized by the value and change from 
Baseline in the value, by treatment group and visit. In addition, the number and percent of 
participants with abnormal values for ALT, AST, and total bilirubin will be summarized. These 
summaries of participants with abnormal values will be performed overall; by normal Baseline; 
and by abnormal Baseline for ALT, AST, and total bilirubin individually. Hy’s Law criteria 
(>3  ULN for either ALT or AST, with accompanying total bilirubin >2  ULN) will also be 
applied to the data. Any potential Hy’s Law cases will be listed separately. 
Muscle-related abnormalities will be summarized by treatment group. 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.  
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 End of Treatment (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. Values of CK 


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from Baseline to EOT will be summarized by treatment group and by Baseline eGFR category. 
Muscle-related abnormalities will be summarized by treatment group and by Baseline eGFR 
category. 
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 
Analysis of Pharmacokinetics  
Plasma obicetrapib concentrations will be summarized with descriptive statistics based on the 
PK Population. Exploration of any relationships with obicetrapib exposure will be performed, as 
appropriate. 
9.2.4 
Interim Analysis 
No interim analysis is planned for this study. 
9.2.5 
Sample Size Determination 
A sample size of at least 100 evaluable participants (i.e., 25 participants per treatment group) will 
provide >90% power to detect a 30% difference in LDL-C reduction at Day 56 (SD of 25%) for 
each of the obicetrapib groups compared to the placebo group at a 2-sided significance level 
of 0.05. 
The sample size for this study was determined in order to provide sufficient power for the analyses 
of the primary efficacy endpoint described in Section 7. Therefore, assuming a dropout rate of 
approximately 7%, an estimated enrollment target of approximately 108 participants 
(i.e., 27 participants per treatment group) is planned for this study. This sample size will also 
contribute sufficient participant exposure and safety data. 
Participants will be stratified according to their Screening Visit (Visit 1) LDL-C levels (100 or 
<100 mg/dL). 


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10 
DATA MANAGEMENT AND RECORD KEEPING 
10.1 
Data Management 
10.1.1 
Data Handling 
Data will be recorded at the site on eCRFs and reviewed by the Clinical Research Associate (CRA) 
during monitoring visits. The CRAs will verify data recorded in the EDC system with source 
documents. All corrections or changes made to any study data must be appropriately tracked in an 
audit trail in the EDC system. An eCRF will be considered complete when all missing, incorrect, 
and/or inconsistent data has been accounted for. 
10.1.2 
Computer Systems 
Data will be processed using a validated computer system conforming to regulatory requirements. 
10.1.3 
Data Entry 
Data must be recorded using the EDC system as the study is in progress. All site personnel must 
log into the system using their secure username and password in order to enter, review, or correct 
study data. These procedures must comply with Title 21 of the Code of Federal Regulations Part 11 
and other appropriate international regulations. All passwords will be strictly confidential. 
10.1.4 
Medical Information Coding 
For medical information, the following thesauri will be used: 
• Medical Dictionary for Regulatory Activities (latest) for medical history and AEs; and  
• World Health Organization 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 investigative site for resolution through data queries. 
The eCRFs must be reviewed and electronically signed by the Investigator. 


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10.2 
Record Keeping 
Records of participants, source documents, monitoring visit logs, eCRFs, inventory of study 
product, regulatory documents, and other Sponsor correspondence pertaining to the study must be 
kept in the appropriate study files at the site. Source data 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.  
10.3 
End of Study 
The end of the study (“study completion”) is defined as the date of the last protocol-specified 
visit/assessment (including telephone contact) for the last participant in the study.  
 


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11 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL  
11.1 
Ethical Conduct of the Study 
Good Clinical Practice (GCP) is an international ethical and scientific quality standard for 
designing, conducting, recording, and reporting studies that involve human participants. 
Compliance with this standard provides public assurance that the rights, safety, and wellbeing of 
study participants are protected, consistent with the principles that have their origin in the 
Declaration of Helsinki, and that the clinical study data are credible. 
11.2 
Institutional Review Board/Independent Ethics Committee  
The Institutional Review Board (IRB)/Independent Ethics Committee (IEC) will review all 
appropriate study documentation in order to safeguard the rights, safety, and well-being of 
participants. The study will only be conducted at sites where IRB/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. 
Federal regulations and 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 site for dosing until written IRB/IEC authorization has been 
received by the Sponsor and the execution of contract with the study site. 
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-related activity is performed and should 
document in the source documentation that consent was obtained prior to enrollment in the study. 
The original signed copy of the ICF must be maintained by the Investigator and is subject to 
inspection by a representative of the Sponsor, their representatives, auditors, the IRB/IEC, and/or 
regulatory agencies. A copy of the signed ICF will be given to the participant. 
11.4 
Participant Card 
On enrollment in the study, the participant will receive a participant card to be carried at all times. 
The participant card will state that the participant is participating in a clinical research study, type 
of treatment, number of doses received, and contact details in case of an SAE.  


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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, the Japanese Ministerial Ordinance on GCP for 
Drugs, Directive 2001/20/EC, and applicable regulatory requirements, and that valid data are 
entered into the eCRFs. 
To achieve this objective, the monitor’s duties are to aid the Investigator and, at the same time, the 
Sponsor in the maintenance of complete, legible, well organized, and easily retrievable data. 
Before the enrollment of any participant in this study, the Sponsor or their designee will review 
with the Investigator and site personnel the following documents: protocol, Investigator’s 
Brochure, eCRFs and procedures for their completion, informed consent process, and the 
procedure for reporting SAEs. 
The Investigator will permit the Sponsor or their designee to monitor the study as frequently as 
deemed necessary to determine that data recording and protocol adherence are satisfactory. During 
the monitoring visits, information recorded on the eCRFs will be verified against source 
documents and requests for clarification or correction may be made. After the eCRF data is entered 
by the site, the CRA will review the data for safety information, completeness, accuracy, and 
logical consistency. Computer programs that identify data inconsistencies may be used to help 
monitor the clinical study. If necessary, requests for clarification or correction will be sent to 
Investigators. The Investigator and his/her staff will be expected to cooperate with the monitor and 
provide any missing information, whenever possible. 
All monitoring activities will be reported and archived. In addition, monitoring visits will be 
documented at the investigational site by signature and date on the study-related monitoring log. 
11.6 
Disclosure of Data 
Data generated by this study must be available for inspection by the Japanese health authorities, 
namely the PMDA, the Sponsor or their designee, applicable foreign health authorities, 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 participants (sufficient information to link records, 
e.g., eCRFs and hospital records), all original signed ICFs, copies of all eCRFs, SAE forms, source 
documents, and detailed records of treatment disposition. The records should be retained by the 
Investigator according to specifications in the ICH guidelines, local regulations, or as specified in 
the Clinical Study Agreement, whichever is longer. The Investigator must obtain written 
permission from the Sponsor before disposing of any records, even if retention requirements have 
been met. 


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If the Investigator relocates, retires, or for any reason withdraws from the study, the Sponsor should 
be prospectively notified. The study records must be transferred to an acceptable designee, such 
as another Investigator, another institution, or to the Sponsor. 
11.8 
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 Code of Federal Regulations Part 54. In addition, 
Investigators must commit to promptly updating this information if any relevant changes occur 
during the study and for a period of 1 year after the completion of the study. 
11.10 
Insurance and Indemnity 
In accordance with the relevant national regulations, the Sponsor has taken out patient 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 to achieve a clinical 
trial notification (CTN). 
The study will commence (i.e., initiation of study centers) when the CTN has been cleared and 
favorable Ethics opinion has 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. 
de Grooth GJ, Klerkx AH, Stroes ES, et al. A review of CETP and its relation to 
atherosclerosis. J Lipid Res. 2004;45(11):1967-1974. 
2. 
Ference BA, Kastelein JJ, Ginsberg HN, et al. Association of genetic variants related to 
CETP inhibitors and statins with lipoprotein levels and cardiovascular risk. JAMA. 
2017;318(10):947-956. 
3. 
Tall AR, Rader DJ. Trials and tribulations of CETP inhibitors. Circ Res. 
2018;122(1):106-112. 
4. 
Hovingh GK, Kastelein JJ, van Deventer SJ, et al. Cholesterol ester transfer protein 
inhibition by TA-8995 in patients with mild dyslipidaemia (TULIP): a randomised, 
double-blind, placebo-controlled phase 2 trial. Lancet. 2015;386(9992):452-460. 
5. 
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. 
6. 
CKD Epidemiology Collaboration, Levey AS, Inker LA. CKD-EPI equations for 
glomerular filtration rate (GFR). MDCalc. https://www.mdcalc.com/ckd-epi-equations-
glomerular-filtration-rate-gfr. Accessed 19 November 2021. 
7. 
Friedewald W. LDL calculated. MDCalc. https://www.mdcalc.com/ldl-calculated. 
Accessed 19 November 2021. 


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APPENDIX A: SCHEDULE OF PROCEDURES 
 
Screeninga,b 
 
Treatment Period 
Safety Follow-Up 
Early 
Termination 
Visit 
Visit 
1 
2 
3 
4 
5 
6 
Week 
Up to -2 
0 
2 
4 
8 
12 
Day ( Visit Window) 
-14 to -1 
1 
14 (2) 
28 (2) 
56 (2) 
84 (2) 
Unscheduled 
Informed consentc 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
Xd 
 
 
 
 
 
Demographic information 
X 
 
 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
 
 
Prior/concomitant medications 
X 
X 
X 
X 
X 
X 
X 
Weight and heighte 
X 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
X 
 
 
Vital signsf 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGg 
X 
 
 
 
 
 
 
Urine pregnancy testh 
X 
 
 
 
 
X 
X 
FSH testi 
X 
 
 
 
 
 
 
Fasting (approximately 8 hours) 
chemistry and hematologyj 
X 
X 
X 
X 
X 
X 
X 
Fasting (approximately 8 hours) lipid 
profilek 
X 
X 
X 
X 
X 
 
X 
PK samplel 
 
X 
X 
X 
X 
Xm 
X 
Randomization 
 
X 
 
 
 
 
 
Dispense study drugn 
 
X 
 
X 
 
 
 
Study drug administrationo 
 
X 
X 
X 
X 
 
 
Study drug compliance  
 
 
X 
X 
X 
X 
X 
Register visit in IRT 
X 
X 
X 
X 
X 
 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
Note: When several assessments are required at the same visit, samples for clinical laboratory assessments should be collected after completing other assessments, such as physical 
examinations, vital signs, and 12-lead ECGs. 
Note: In cases of COVID-19 limitations, it is the Investigator’s responsibility to assure the safety of participants. If investigators need to implement contingency measures, the 
investigators will communicate with the Sponsor and discuss the best practice with the sponsor. In the absence of a COVID-19 impact, it is expected that Investigators and participants 
follow the protocol requirements as set forth.  
a. 
If laboratory abnormalities during screening are considered by the Investigator to be transient, then the laboratory tests may be repeated once during screening. The Investigator’s 
rationale for retesting should be documented. If the retest result is no longer exclusionary, the participant may be randomized. 
b. 
A participant who is screened and does not meet the study eligibility criteria may be considered for rescreening upon Sponsor and/or Medical Monitor consultation and approval. 
Rescreened participants will be assigned a new participant number. Rescreening should occur no less than 5 days after the last Screening Visit. 
c. 
Signed informed consent must be obtained before any study-related procedures are performed. 


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d. 
Confirm the participant continues to meet the inclusion and exclusion criteria and assess any updates since the Screening Visit. 
e. 
Weight and height will be measured at the Screening Visit and will be used to calculate body mass index. Measurement of weight should be performed with the participant 
dressed in indoor clothing, with shoes removed, and bladder empty. 
f. 
Vital signs will include body temperature, heart rate, and triplicate blood pressure (systolic and diastolic) measurements. Participants should be in the supine position after at 
least 10 minutes rest prior to the vital sign measurements. 
g. 
A single, standard 12-lead ECG will be performed by the Investigator or trained site personnel at the Screening Visit and read locally. 
h. 
For women of childbearing potential only. 
i. 
An FSH test will be performed in women <55 years of age for whom it has been 1 year since their last menstrual period to confirm a postmenopausal state. 
j. 
At the Screening Visit only, the chemistry panel will include HbA1c. 
k. 
LDL-C level will be calculated using the Friedewald equation unless TG 400 mg/dL or LDL-C 50 mg/dL. If TG 400 mg/dL or LDL-C 50 mg/dL, then LDL-C level will 
be measured directly by preparative ultracentrifugation, also referred to as beta quantification. (Source: LDL calculated. MDCalc. https://www.mdcalc.com/ldl-calculated. 
Accessed 19 November 2021.) In addition, for all participants, LDL-C will be measured by preparative ultracentrifugation, also referred to as beta quantification, at Baseline 
(Visit 2) and at the end of the 8-week Treatment Period (Visit 5). See Appendix B for full list of lipid profile parameters. 
l. 
On Day 1, a PK sample will be collected pre-dose. The subsequent post-dose PK samples should be collected once at approximately the same time at each visit. 
m. PK samples will not be collected during the Safety Follow-up Visit for participants who discontinue study drug early without withdrawing consent or for participants who 
withdraw prematurely from the study. 
n. 
At Visits 2 and 4 participants will receive one 40-count bottle with the study drug appropriate for the participant’s treatment group. 
o. 
One tablet of study drug will be administered by the participant orally once daily from Day 1 to Day 56. Study drugs should be administered at approximately the same time 
each morning. On days with visits scheduled, study drugs should be administered following all fasted blood sample collections. 
COVID-19 = Coronavirus Disease 2019; ECG = electrocardiogram; FSH = follicle-stimulating hormone; HbA1c = glycosylated hemoglobin; IRT = interactive response technology; 
LDL = low-density lipoprotein; LDL-C = low-density lipoprotein cholesterol; PK = pharmacokinetic; TG = triglycerides. 
 


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APPENDIX B: CLINICAL LABORATORY ANALYTES 
Standard Safety Chemistry Panel 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Amylase 
Aspartate aminotransferase 
Bicarbonate 
Blood urea nitrogen 
Calcium 
Chloride 
Creatine kinase 
Creatinine 
Estimated glomerular filtration rate [1] 
Gamma-glutamyl transferase 
Glucose (fasting) 
Glycosylated hemoglobin [2] 
High-sensitivity C-reactive protein 
Inorganic phosphorus 
Lactate dehydrogenase 
Lipase 
Potassium 
Sodium 
Total bilirubin 
Total protein 
Uric acid 
1. 
Calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. (Source: CKD-EPI equations for 
glomerular filtration rate [GFR]. MDCalc. https://www.mdcalc.com/ckd-epi-equations-glomerular-filtration-rate-gfr. 
Accessed 19 November 2021.) 
2. 
Screening Visit only. 
 
Endocrinology 
Follicle-stimulating hormone [1] 
 
1. 
A follicle-stimulating hormone test will be performed in women <55 years of age for whom it has been 1 year since 
their last menstrual period. 
 
Hematology 
Hematocrit 
Hemoglobin 
Platelets 
Red blood cell count 
White blood cell count and differential [1] 
 
1. 
Manual microscopic review is performed only if white blood cell count and/or differential values are out of reference 
range. 
 
Pregnancy Test 
Urine [1] 
 
1. 
For women of childbearing potential only. 
 


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Lipid Profile 
Apolipoprotein B 
Apolipoprotein E (ApoE) 
High-density lipoprotein-ApoE [1]  
High-density lipoprotein cholesterol 
Low-density lipoprotein cholesterol [2] 
Non-high-density lipoprotein cholesterol 
Triglycerides 
Very low-density lipoprotein cholesterol 
1. 
With and without apolipoprotein C3. 
2. 
Calculated using the Friedewald equation unless triglycerides (TGs) 400 mg/dL or low-density lipoprotein cholesterol 
(LDL-C) 50 mg/dL. If TG 400 mg/dL or LDL-C 50 mg/dL, then LDL-C level will be measured directly by 
preparative ultracentrifugation, also referred to as beta quantification. (Source: LDL calculated. MDCalc. 
https://www.mdcalc.com/ldl-calculated. Accessed 19 November 2021.) In addition, for all participants, LDL-C will be 
measured by preparative ultracentrifugation, also referred to as beta quantification, at Baseline (Day 1; Visit 2) and at 
the end of the 8-week Treatment Period (Day 56; Visit 5). 
 

SAP_001.pdf: 
NewAmsterdam Pharma BV 
CONFIDENTIAL 
         Statistical Analysis Plan 
Protocol TA-8995-203 
Version V2.0, 9 May 2023 
STATISTICAL ANALYSIS PLAN 
Protocol Title: 
A Placebo-Controlled, Double-Blind, Randomized, Phase 
2 Dose Finding Study to Evaluate the Effect of 
Obicetrapib as an Adjunct to Stable Statin Therapy in 
Japanese Subjects 
Protocol Number: 
TA-8995-203 
Protocol Version/Date: 
V1.1 / 20 April 2022 
Investigational Product: Obicetrapib 
Sponsor: 
NewAmsterdam Pharma BV 
Gooimeer 2-35 
1411 DC 
Naarden  
The Netherlands 
Telephone: +31 35 699 30 00 
Fax: +31 20 240 07 79 
SAP Version/Date: 
V2.0 / 9 May 2023 
CONFIDENTIAL 
The information in this document is confidential and is not to be disclosed without the written 
consent of NewAmsterdam Pharma BV 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 BV. You are allowed to disclose the contents of this document only to your Institutional 
Review Board and study personnel directly involved with conducting this protocol. Persons to 
whom the information is disclosed must be informed that the information is confidential and 
proprietary to NewAmsterdam Pharma BV and that it may not be further disclosed to third 
parties. 
NCT number: NCT05421078
This NCT number has been applied to the document for the purposes of posting on clinicaltrials.gov


NewAmsterdam Pharma BV  
CONFIDENTIAL 
         Statistical Analysis Plan 
Protocol TA-8995-203 
 
Version 2.0, 9 May 2023 
Page 2 of 25 
 
SIGNATURE PAGE 
Protocol Title: 
A Placebo-Controlled, Double-Blind, Randomized, Phase 2 
Dose Finding Study to Evaluate the Effect of Obicetrapib as 
an Adjunct to Stable Statin Therapy in Japanese Subjects 
Protocol Number: 
TA-8995-203 
SAP Version/Date: 
V2.0 / 9 May 2023 
We, the undersigned, have reviewed and approved this Statistical Analysis Plan: 
 
  
Signature 
 Date 


NewAmsterdam Pharma BV  
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         Statistical Analysis Plan 
Protocol TA-8995-203 
 
Version 2.0, 9 May 2023 
Page 3 of 25 
 
VERSION HISTORY 
Version 
Version Date 
Description 
1.0 
04 July 2022 
Original signed version 
2.0 
9 May 2023 
3.2.3 Added Modified Intent-to-Treat On-
Treatment Population 
3.3.7 Removed imputation rule for missing 
date of first dose of study drug 
3.4 Added figures to be created 
3.4.2 Removed high-density lipoprotein-
ApoE from lipid profile parameter 
3.7.1 Added listing for TEAEs of special 
interest 
 
 


NewAmsterdam Pharma BV  
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         Statistical Analysis Plan 
Protocol TA-8995-203 
 
Version 2.0, 9 May 2023 
Page 4 of 25 
 
TABLE OF CONTENTS 
1 
Introduction ......................................................................................................................... 7 
2 
Study Overview ................................................................................................................... 7 
2.1 
Study Objectives .......................................................................................................... 7 
2.1.1 
Primary Objective ................................................................................................. 7 
2.1.2 
Secondary Objectives ........................................................................................... 7 
2.2 
Study Design ............................................................................................................... 7 
2.2.1 
Overview ............................................................................................................... 7 
2.2.2 
Randomization and Blinding ................................................................................. 9 
2.2.3 
Study Drug ............................................................................................................ 9 
2.2.4 
Sample Size Determination ................................................................................... 9 
2.3 
Study Endpoints ..........................................................................................................10 
2.3.1 
Primary Efficacy Endpoint ....................................................................................10 
2.3.2 
Secondary Efficacy Endpoints .............................................................................10 
2.3.3 
Safety Endpoints ..................................................................................................10 
3 
Statistical Methodology ......................................................................................................10 
3.1 
General Considerations ..............................................................................................10 
3.1.1 
Analysis Day ........................................................................................................10 
3.1.2 
Analysis Visits ......................................................................................................10 
3.1.3 
Definition of Baseline ...........................................................................................11 
3.1.4 
Summary Statistics ..............................................................................................11 
3.1.5 
Evaluation of Site Effect .......................................................................................11 
3.1.6 
Handling of Dropouts and Missing Data ...............................................................11 
3.2 
Analysis Populations ...................................................................................................11 
3.2.1 
Intent-to-Treat (ITT) Population ............................................................................11 
3.2.2 
Modified Intent-to-Treat (mITT) Population ..........................................................11 
3.2.3 
Modified Intent-to-Treat (mITT) On-Treatment Population....................................12 
3.2.4 
Per-Protocol (PP) Population ...............................................................................12 
3.2.5 
PK Population ......................................................................................................12 
3.2.6 
Safety Population .................................................................................................12 
3.3 
Subject Data and Study Conduct ................................................................................12 
3.3.1 
Subject Disposition ..............................................................................................12 
3.3.2 
Protocol Deviations ..............................................................................................13 
3.3.3 
Analysis Populations ............................................................................................13 
3.3.4 
Demographic and Baseline Characteristics ..........................................................13 
3.3.5 
Medical History ....................................................................................................13 
3.3.6 
Prior and Concomitant Medications .....................................................................13 
3.3.7 
Study Drug Exposure and Compliance ................................................................14 
3.4 
Efficacy Assessment ...................................................................................................14 
3.4.1 
Primary Efficacy Endpoint ....................................................................................14 


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         Statistical Analysis Plan 
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Page 5 of 25 
 
3.4.2 
Secondary Efficacy Endpoints .............................................................................19 
3.4.3 
Other Efficacy Endpoints .....................................................................................19 
3.4.4 
Subgroups ...........................................................................................................19 
3.5 
Pharmacokinetic Assessment .....................................................................................19 
3.6 
Pharmacodynamic Assessment ..................................................................................19 
3.7 
Safety Assessment .....................................................................................................20 
3.7.1 
Adverse Events (AEs) ..........................................................................................20 
3.7.2 
Clinical Laboratory Tests .....................................................................................20 
3.7.3 
Vital Signs ............................................................................................................21 
3.7.4 
Electrocardiograms ..............................................................................................21 
3.7.5 
Physical Examinations .........................................................................................21 
3.7.6 
Events of Special Interest ....................................................................................21 
4 
Analysis Timing ..................................................................................................................22 
4.1 
Interim Analysis ..........................................................................................................22 
4.2 
Final Analysis ..............................................................................................................22 
5 
Changes from Protocol-Specified Statistical Analyses .......................................................22 
6 
Programming Specifications ..............................................................................................22 
Appendix A:  References ..........................................................................................................24 
Appendix B:  Laboratory Tests ..................................................................................................24 
 
 
 


NewAmsterdam Pharma BV  
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         Statistical Analysis Plan 
Protocol TA-8995-203 
 
Version 2.0, 9 May 2023 
Page 6 of 25 
 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADaM 
Analysis Data Model 
AE 
Adverse event 
ApoB 
Apolipoprotein B 
ATC 
Anatomical therapeutic chemical 
CDISC 
Clinical Data Interchange Standards Consortium 
CRF 
Case Report Form 
CRO 
Clinical Research Organization 
CSR 
Clinical Study Report 
ESI 
Events of Special Interest 
HDL-C 
High Density Lipoprotein Cholesterol 
ICF 
Informed Consent Form 
IRT 
Interactive Response Technology 
ITT 
Intent-to-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intention-to-Treat 
MMRM 
Mixed Model for Repeated Measure 
LDL-C 
Low Density Lipoprotein Cholesterol 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PP 
Per-Protocol 
PUC 
Preparative Ultracentrifugation 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SDTM 
Study Data Tabulation Model 
TEAE 
Treatment-emergent adverse event 
TESAE 
Treatment-emergent serious adverse event 
WHO 
World Health Organization 
 
 
 


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         Statistical Analysis Plan 
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Version 2.0, 9 May 2023 
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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 NewAmsterdam Pharma BV Protocol 
TA-8995-203. 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 efficacy of obicetrapib, compared to 
placebo, in reducing serum low density lipoprotein cholesterol (LDL-C) measured at Day 56 
(Visit 5) when taken as an adjunct to a pre-existing stable statin therapy regime. 
2.1.2 Secondary Objectives 
The secondary objectives of this study include the following: 
 
To evaluate the effect of obicetrapib, compared to placebo, on serum apolipoprotein B 
(ApoB), non-high-density lipoprotein cholesterol (non-HDL-C), and high density 
lipoprotein cholesterol (HDL-C) concentrations at Day 56 (Visit 5), when taken as an 
adjunct to pre-existing stable statin therapy; 
 
To assess the mean plasma levels of obicetrapib at steady state on Day 56 (Visit 5) and 
Day 84 (Visit 6); and 
 
To evaluate the safety and tolerability profile of obicetrapib in Japanese subjects. 
2.2 Study Design 
2.2.1 Overview 
The population for this study includes Japanese men and women, 18 to 75 years of age, 
inclusive, with a body mass index <35 kg/m2, fasting LDL-C levels >70 mg/dL, and triglyceride 
levels <400 mg/dL at the Screening Visit, who are currently receiving stable statin therapy. 
This study will be a placebo-controlled, double-blind, randomized, Phase 2 dose-finding study to 
evaluate the efficacy, safety, and tolerability of obicetrapib as an adjunct to stable statin therapy 
in Japanese participants. This study will take place at approximately 10 sites in Japan. 
The total duration for the double-blind period for each subject will be up to 14 weeks, including 
up to 2 weeks for Screening, 8 weeks for blinded study treatment, and 4 weeks for safety follow-
up. Please refer to Appendix A (Schedule of Procedures) of the study protocol for details. 
At the Screening Visit (Visit 1), and up to 2 weeks before the start of the treatment period, 
participants will be required to sign an informed consent form (ICF) before any study-related 
procedures are performed. After signing the ICF, participants will be assessed for study 
eligibility. 
Up to 2 weeks after the Screening Visit, participants will return to the site on Day 1 (Visit 2) and 
confirm study eligibility before being randomized and beginning treatment. Approximately 100 


NewAmsterdam Pharma BV  
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         Statistical Analysis Plan 
Protocol TA-8995-203 
 
Version 2.0, 9 May 2023 
Page 8 of 25 
 
eligible participants (25 participants per treatment group) will be randomized in a 1:1:1:1 ratio to 
1 of the following treatment groups: 
 
2.5 mg obicetrapib (one 2.5 mg obicetrapib tablet); 
 
5 mg obicetrapib (one 5 mg obicetrapib tablet); 
 
10 mg obicetrapib (one 10 mg obicetrapib tablet); or 
 
Placebo (1 placebo tablet). 
During the 8-week Treatment Period, the assigned study drugs will be administered by the 
participants orally once daily from Day 1 (Visit 2) to Day 56 (Visit 5). Participants will return to 
the site on Day 14 (Visit 3), Day 28 (Visit 4), and Day 56 (Visit 5) for efficacy, safety, and 
Pharmacokinetics (PK) assessments. Participants, Investigators, the Clinical Research 
Organization (CRO), and the Sponsor will be blinded to all lipid results from Day 1 (Visit 2) for 
the first participant and continuing to database lock in order to protect blinding to treatment 
assignment. 
Participants will return to the site for a Safety Follow-up Visit on Day 84 (Visit 6), approximately 
4 weeks after the end of the Treatment Period, for final safety and PK assessments. 
Coronavirus Disease 2019 Contingency Measures 
In cases of COVID-19 limitations, it is the Investigator’s responsibility to assure the safety of 
participants. If investigators need to implement contingency measures, the investigators will 
communicate with the Sponsor and discuss the best practice with the sponsor. In the absence 
of a COVID-19 impact, it is expected that Investigators and participants follow the protocol 
requirements as set forth.


NewAmsterdam Pharma BV  
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         Statistical Analysis Plan 
Protocol TA-8995-203 
 
Version V2.0, 9 May 2023 
 
 
 
 
 
 
2.2.2 Randomization and Blinding 
Participants who meet all eligibility criteria will be randomized into the study. Participants will be 
randomized in a 1:1:1:1 ratio to the 2.5 mg obicetrapib, 5 mg obicetrapib, 10 mg obicetrapib, or 
placebo treatment groups. At randomization, participants will be stratified according to their 
Screening Visit (Visit 1) LDL-C level (≥100 or <100 mg/dL). An automated interactive response 
technology (IRT) system will be used to assign the participant to 1 of the 4 treatment groups, 
and visits will be registered in the IRT for Screening and Visits 1 through 5 as well as Early 
Termination, if applicable. 
Participants, Investigators, the CRO, and the Sponsor will be blinded to all lipid results from Day 
1 (Visit 2) for the first participant and continuing to database lock in order to protect blinding to 
treatment assignment. 
2.2.3 Study Drug 
The study drugs to be used in this study include the following: 
 
2.5 mg obicetrapib tablet; 
 
5 mg obicetrapib tablet; 
 
10 mg obicetrapib tablet; and 
 
Matching placebo tablet. 
The study drugs listed above will be packaged to provide doses of 2.5 mg, 5 mg, 10 mg 
obicetrapib, or placebo only. Placebo tablets will be visually identical. Participants will be 
randomized to receive 1 of the 3 doses of obicetrapib or placebo only. One tablet of study drug 
will be administered by the participant orally once daily from Day 1 (Visit 2) to Day 56 (Visit 5) at 
approximately the same time each morning. 
2.2.4 Sample Size Determination 
A sample size of at least 100 evaluable participants (i.e., 25 participants per treatment group) 
will provide >90% power to detect a 30% difference in LDL-C reduction at Day 56 (standard 
deviation (SD) of 25%) for each of the obicetrapib groups compared to the placebo group at a 2-
sided significance level of 0.05. 
The sample size for this study was determined in order to provide sufficient power for the 
analyses of the primary efficacy endpoint described in Section 3.4. Therefore, assuming a 
dropout rate of approximately 7%, an estimated enrollment target of approximately 108 
participants (i.e., 27 participants per treatment group) is planned for this study. This sample size 
will also contribute sufficient participant exposure and safety data. 
Participants will be stratified according to their Screening Visit (Visit 1) LDL-C levels (≥100 or 
<100 mg/dL). 


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2.3 Study Endpoints 
2.3.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is the percent change from Day 1 to Day 56 in LDL-C for each 
obicetrapib group compared to the placebo group.  
2.3.2 Secondary Efficacy Endpoints 
The key secondary efficacy endpoints include the following: 
 
Percent change from Day 1 to Day 56 in ApoB for each obicetrapib group compared to 
the placebo group; 
 
Percent change from Day 1 to Day 56 in non-HDL-C for each obicetrapib group 
compared to the placebo group; and 
 
Percent change from Day 1 to Day 56 in HDL-C for each obicetrapib group compared to 
the placebo group. 
2.3.3 Safety Endpoints 
The safety and tolerability profile of obicetrapib will be assessed by clinical laboratory 
assessments (chemistry and hematology), vital signs, physical examinations, and the incidence 
of adverse events and events of special interest (ESIs). 
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 case report form (CRF). 
Early termination visits will be assigned to analysis visits according to the following visit 
windows: 
Analysis Visit 
Target Analysis Day Low Analysis Day 
High Analysis Day 
Day 1 
1 
NA 
NA 
Week 2 
14 
2 
21 
Week 4 
28 
22 
42 
Week 8 
56 
43 
70 
Safety Follow-up 
84 
71 
 
Unscheduled visits recorded on the CRF will not be re-assigned and remain labeled as 
unscheduled. 


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3.1.3 Definition of Baseline  
Unless otherwise stated, Baseline will be defined as the last measurement prior to the first dose 
of study drug. 
3.1.4 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, minimum, and maximum. 
3.1.5 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. 
3.1.6 Handling of Dropouts and Missing Data 
Date Values 
In cases of incomplete dates (e.g. adverse event (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 data 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 (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. 
3.2 Analysis Populations 
3.2.1 Intent-to-Treat (ITT) Population 
The Intent-to-Treat (ITT) Population will include all participants randomized into the study. 
Treatment classification will be based on the randomized treatment. 
3.2.2 Modified Intent-to-Treat (mITT) Population 
The Modified ITT (mITT) Population will include all participants in the ITT Population who 
receive at least 1 dose of any study drug and have a Baseline value for the LDL-C assessment. 
Any efficacy measurement obtained during the Safety Follow-up Visit after a participant 


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permanently discontinues the study drug or after a participant receives an excluded medication 
and/or procedure will be removed from the mITT analysis. Treatment classification will be based 
on the randomized treatment. The mITT Population will be used for the primary analysis of all 
efficacy endpoints. 
3.2.3 Modified Intent-to-Treat (mITT) On-Treatment Population 
The mITT On-Treatment Population will include all randomized participants who have a Baseline 
value for LDL-C assessment, have a Day 56 value for the LDL-C assessment, and plasma 
obicetrapib concentration at Day 56 is >100 ng/mL. Treatment classification will be based on the 
randomized treatment. 
Rationale: <100 ng/mL is more than three standard deviations from the mean plasma obicetrapib 
concentration observed in both the ROSE (TA-8995-201) and TULIP (TA-8995-03) [with a very 
similar patient population compared to ROSE2 (TA-8995-202)] at respectively week 4 and week 
12. In addition, in none of the previous conducted studies (3 clinical studies and 2 Phase 1 PK / 
PD studies the minimal observed obicetrapib concentration for Cmax was below 100 ng/mL. 
3.2.4 Per-Protocol (PP) Population 
The Per-Protocol (PP) Population will include all participants in the mITT Population who have a 
Baseline value for the LDL-C assessment, have a Day 56 value for the LDL-C assessment, and 
who do not experience a major protocol deviation that would potentially impact the primary 
efficacy endpoint. Major protocol deviations will be defined in the Protocol Deviation Plan within 
the trial master file to align with International Conference on Harmonization guidelines. The PP 
Population, along with the reason for exclusion, will be finalized prior to study unblinding. The 
PP Population will be a secondary population for analysis of the primary efficacy endpoint. 
3.2.5 PK Population 
The PK Population will include all participants in the mITT Population who have sufficient blood 
samples collected for valid estimation of PK parameters. 
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 Subject Data and Study Conduct 
3.3.1 Subject Disposition 
Subject disposition will be presented for ITT Population. Counts and percentages of participants 
who are randomized, complete the study, complete the treatment, prematurely discontinue from 
the study, reasons for study discontinuation, and primary reason for early termination was due 
to COVID-19 will be summarized by treatment and overall. For each scheduled visit, counts and 
percentages of participants who do not complete the visit, partially complete the visit in-person, 
or complete the visit virtually will be summarized by treatment. The denominator for calculating 
percentages will be based on the number of randomized participants. 
Data listings for subject disposition and exclusion and inclusion criteria violations will be 
provided. 


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3.3.2 Protocol Deviations 
Protocol deviations will be identified based on the clinical data as defined in the Protocol 
Deviation Plan. The Protocol Deviation Plan will define all protocol deviations as either CSR 
reportable or non-CSR reportable deviations. Counts and percentages of participants with CSR 
reportable protocol deviations by deviation category will be summarized by treatment and in 
total based on ITT Population. A listing of CSR-reportable protocol deviations will be generated. 
3.3.3 Analysis Populations 
Counts and percentages of participants in each analysis population will be summarized by 
treatment and in total based on ITT Population. Reasons for exclusion from PP Population will 
also be summarized. 
3.3.4 Demographic and Baseline Characteristics 
The following demographic and baseline characteristics will be summarized: 
 
Age (years) and age categories (<65 years, 65-75 years) 
 
Sex 
 
Childbearing potential 
 
Race 
 
Ethnicity 
 
Height (cm) 
 
Weight (kg) 
 
Body mass index (BMI) (kg/m2) and BMI categories (<30 kg/m2, ≥30 kg/m2)  
 
Stratification group (LDL-C value ≥100 or <100 mg/dL) 
 
Current statin therapy (Atorvastatin 10 mg, 20mg/day, Rosuvastatin 5, 10 mg/day) 
Demographic and baseline characteristics will be summarized with descriptive statistics or 
counts and percentages of participants as appropriate by treatment and in total for the mITT 
Population and each of the ITT Population, the PP Population, the mITT On-Treatment 
Population and the Safety Population if they differ from the mITT. 
3.3.5 Medical History 
Medical history will be coded to system organ class and preferred term using the Medical 
Dictionary for Regulatory Activities (MedDRA) with the version specified in Data Management 
Plan. Counts and percentages of participants with medical history by system organ class and 
preferred term will be summarized by treatment and in total based on ITT Population. 
3.3.6 Prior and Concomitant Medications 
Medication start and stop dates that are recorded on the Prior & Concomitant Medications case 
report form 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 
study treatment. Prior medications are defined as those used prior to and stopped before the 
first dose of study treatment. All prior and concomitant medication verbatim terms will be coded 
using the World Health Organization (WHO) Drug Dictionary with the version specified in Data 
Management Plan. The numbers and percentages of participants taking prior and concomitant 
medications in each treatment and in total will be summarized by anatomical therapeutic 
chemical (ATC) class and preferred term for the Safety Population. 


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3.3.7 Study Drug Exposure and Compliance 
Participants’ exposure to randomized study medication will be summarized with descriptive 
statistics by treatment for the Safety Population. Days of exposure is defined as: 
𝐸𝑥𝑝𝑜𝑠𝑢𝑟𝑒 (𝑑𝑎𝑦𝑠) =  𝑑𝑎𝑡𝑒 𝑜𝑓 𝑙𝑎𝑠𝑡 𝑑𝑜𝑠𝑒 𝑜𝑓 𝑠𝑡𝑢𝑑𝑦 𝑑𝑟𝑢𝑔−𝑑𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑟𝑠𝑡 𝑑𝑜𝑠𝑒+ 1 
For those 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 end of study/early termination will be used. 
A summary will be provided to display counts and percentages of participants in each treatment 
with exposure in the following categories: <4 weeks, 4 – <8 weeks, and 8+ weeks. 
Summary statistics will be presented for percent overall compliance to study medication by 
treatment. Counts and percentages of participants will also be tabulated by groups with overall 
compliance < 80%, 80% to 120%, and > 120%. 
The percent overall compliance to study medication will be calculated as: 
𝐶𝑜𝑚𝑝𝑙𝑖𝑎𝑛𝑐𝑒 (%) = (# 𝑡𝑎𝑏𝑙𝑒𝑡𝑠 𝑑𝑖𝑠𝑝𝑒𝑛𝑠𝑒𝑑−# 𝑡𝑎𝑏𝑙𝑒𝑡𝑠 𝑟𝑒𝑡𝑢𝑟𝑛𝑒𝑑)
# 𝑒𝑥𝑝𝑒𝑐𝑡𝑒𝑑 𝑑𝑜𝑠𝑖𝑛𝑔 𝑑𝑎𝑦𝑠
 × 100 
The number of expected dosing days = (the earliest date between the end of treatment date and 
the date of early termination – the date of randomization + 1). 
A separate listing of derived exposure and compliance will be provided for ITT Population. 
3.4 Efficacy Assessment 
The mITT Population will be the primary population for the efficacy analyses. Efficacy will also 
be analyzed using the ITT Population, the mITT On-Treatment Population, and the PP 
Population as supportive analyses for selected endpoints. 
LDL-C will be collected using the following two approaches: 
1. LDL-C level will be calculated using the Friedewald equation unless TG ≥400 mg/dL or 
LDL-C ≤50 mg/dL. If TG ≥400 mg/dL or LDL-C ≤50 mg/dL, then LDL-C level will be 
measured directly by preparative ultracentrifugation (PUC), also referred to as beta 
quantification. 
2. In addition, for all participants, LDL-C will be measured by PUC at Baseline (Visit 2) and 
at the end of the 8-week Treatment Period (Visit 5). 
3.4.1 Primary Efficacy Endpoint 
Primary Analysis 
The primary efficacy endpoint is the percent change from Day 1 to Day 56 in LDL-C (as 
determined by approach 1) for each obicetrapib group compared to the placebo group. The 
percent change will be calculated from Day 1 (Baseline) to each measurement taken at Day 14, 
Day 28, and Day 56. 
The mean percent change from Day 1 to Day 56 in LDL-C for each treatment is defined 
mathematically as 𝜇𝑗, where j stands for jth treatment (j=0,1,2,3) and the subscripts 0, 1, 2, and 3 
refer to the placebo, Obicetrapib 10 mg, 5 mg, and 2.5 mg group, respectively. The hypotheses 


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testing to the difference in the mean percent change in LDL-C from Day 1 to Day 56 between 
the jth obicetrapib group and the placebo group is then defined statistically as following: 
𝐻0:𝜇𝑗−𝜇0 = 0, 𝐻1:𝜇𝑗−𝜇0 ≠0, where j = 1,2,3 
The primary efficacy analysis of the percent change from Day 1 to Day 56 in LDL-C will be 
performed using a mixed model for repeated measure (MMRM) approach. The analysis will 
include fixed effects for treatment, visit, and treatment-by-visit interaction, along with a covariate 
of the Baseline value as a continuous covariate. It is to note that randomization was stratified by 
categories of LDL-C value (≥100 or <100 mg/dL) only to ensure similar distribution of LDL-C 
values across all treatment. However, the MMRM model will include the original scale of the 
LDL-C value as a continuous covariate, not categorical. 
The Restricted Maximum Likelihood estimation approach will be used with an unstructured 
covariance matrix. The least squares means, standard errors, and 2-sided 95% confidence 
intervals for each treatment group and for the pairwise comparisons of each dose of obicetrapib 
to the placebo group will be provided. The least squares means for the pairwise comparison and 
its standard error will be used for the hypothesis testing. The ratio of estimate to standard error 
will be approximately t distributed. The null hypothesis of no treatment effect will be rejected if 
the p-value, the probability of obtaining the observed or more extreme value of t statistic under 
the null hypothesis, is less than or equal to 0.05. 
In order to maintain the overall alpha level on the primary endpoint, the hypothesis testing will 
be performed sequentially at the 2-sided alpha=0.05 significance level. The first comparison will 
be the 10 mg obicetrapib group versus placebo; if significant, comparison of the 5 mg 
obicetrapib group versus placebo will be performed, followed by the 2.5 mg obicetrapib group 
versus placebo. Hypothesis testing will proceed in this hierarchical step-down fashion until a 
comparison is not significant. At that point, all remaining sequential tests will be deemed not 
significant. 
The MMRM approach will include all available assessments of percent change in LDL-C from 
Baseline to Day 14, Day 28, and Day 56. The model assumes the data are missing at random 
(MAR). If any data are missing, the model will use all information from the other time points as 
well as Baseline covariate values to estimate the mean treatment difference at the given time 
point. No imputation of missing data will be performed for the primary efficacy endpoint analysis. 
In order to address the effect of intercurrent events, “While-on-Treatment Strategies” will be 
employed1. For participants who are withdrawn from the study because of the use of an 
excluded medication and/or procedure, data occurring after the intercurrent event of excluded 
medications use will be excluded from the primary analysis. For participants who are withdrawn 
from the trial, data occurring after the intercurrent event of failure to adhere to treatment dosing 
will be excluded from the primary analysis. Failure to adhere to treatment dosing will be defined 
as study drug compliance <75% at the time of study withdrawal. 
The MMRM analysis will be implemented using SAS® Proc Mixed. Example SAS code can be 
found below: 
******************************************************************************************************** 
Note:  
  USUBJID = unique subject identifier  
  TREATMENT = 0 (Placebo), 1 (2.5 mg obicetrapib), 2 (5 mg obicetrapib), 3 (10 mg  
  obicetrapib)  


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  VISIT = Visit  
  BASE = Baseline value  
  PCHG = Percent change from Baseline 
******************************************************************************************************** 
proc mixed;  
  class USUBJID TREATMENT VISIT;  
  model PCHG = TREATMENT BASE VISIT TREATMENT*VISIT / solution cl;  
  repeated VISIT / TYPE=UN sub=USUBJID;  
  lsmeans VISIT*TREATMENT / cl diffs;  
run;  
********************************************************************************************************  
Values, changes from Baseline, and percent change from Baseline of LDL-C will be 
summarized using descriptive statistics at scheduled visits and Baseline by treatment group. 
Counts and percentages of participants will be summarized by treatment for each type of data 
pattern. There will be 16 data patterns for four time points (Baseline, Day 14, Day 28 and Day 
56) each having two possible outcomes (LDL-C data reported or missing). 
Waterfall plot of percent change in LDL-C from Baseline to each scheduled visit will be created. 
Line plot of the mean (+/- 2 * SE) and the median (and IQR) percent change in LDL-C from 
Baseline to each scheduled visit will be created. Figures will be created for LDL-C values 
collected using two approaches described above.  
The main analyses for the primary efficacy endpoint will be repeated for the ITT Population, the 
mITT On-Treatment Population, and PP Population. 
Sensitivity Analyses 
Three sensitivity analyses will be performed for the primary efficacy endpoint: 
1. MMRM with imputation 
2. Analysis covariance (ANCOVA) 
3. ANCOVA using LDL-C by PUC 
All sensitivity analyses will be conducted on the mITT Population. 
Sensitivity Analysis 1 
The first sensitivity analysis will be performed in two steps. In the first step, missing data will be 
assumed missing not at random (MNAR). Missing data at Days 14, 28 and 56 will be imputed 
using multiple imputation methodology in two steps. Initially, 25 data sets will be imputed for 
non-monotone missing values in the original dataset. In the second step the remaining 
monotone missing values in the 25 data sets will be imputed based on the observations in the 
Placebo group. Upon completion of the trial, if the percentage of cases with incomplete data is 
larger than initially anticipated then the number of imputations will be increased for the final 
analysis. 
The variables for the imputation model will consist of LDL-C values from Baseline and Days 14, 
28 and 56. For each imputation dataset, the percent change from Baseline to Day 56 will be 
analyzed using the MMRM model described for the primary analysis. The results from these 25 
analyses will be combined using Rubin’s method to construct the treatment estimates using the 
parameter estimates and associated standard errors. Similarly, the difference of the adjusted 


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treatment means (the three doses of obicetrapib therapy – Placebo) will be presented with the 
associated standard error and 95% confidence interval. Randomly chosen seed numbers will be 
selected for the analysis and will be retained. 
Example SAS code to create a dataset for non-monotone missing values is shown below: 
******************************************************************************************************** 
Note:  
  non-MONOTONE missing values  
  TREATMENT = 0 (Placebo), 1 (2.5 mg obicetrapib), 2 (5 mg obicetrapib), 3 (10 mg  
  obicetrapib)  
  LDLC_BASE = LDL_C Baseline value  
  LDLC_Day14 = LDL_C value at Day 14  
  LDLC_Day28 = LDL_C value at Day 28  
  LDLC_Day56 = LDL_C value at Day 56 
******************************************************************************************************** 
proc mi data=LDLC_Wide seed=20220101 out=LDLC_25MCMC nimpute=25;  
  var TREATMENT LDLC_base LDLC_Day14 LDLC_Day28 LDLC_Day56;  
  mcmc impute=monotone chain=multiple;  
run;  
******************************************************************************************************** 
In the second step, the remaining monotone missing values will be imputed. Example SAS code 
to complete this step is shown below: 
******************************************************************************************************** 
Note:  
MONOTONE missing values  
TREATMENT = 0 (Placebo), 1 (2 mg obicetrapib), 2 (5 mg obicetrapib), 3 (10 mg obicetrapib) 
LDLC_BASE = LDL_C Baseline value  
LDLC_Day14 = LDL_C value at Day 14  
LDLC_Day28 = LDL_C value at Day 28  
LDLC_Day56 = LDL_C value at Day 56 
******************************************************************************************************** 
proc mi data= LDLC_25MCMC seed=810456 out= LDLC_Mono nimpute=1 simple;  
  by _Imputation;  
  class TREATMENT; 
  monotone method=reg;  
  mnar model (LDLC_Day14 LDLC_Day28 LDLC_Day56 / modelobs=(TREATMENT=”0”)); 
  var LDLC_base LDLC_Day14 LDLC_Day28 LDLC_Day56;  
run;  
******************************************************************************************************** 
For each imputation dataset, the percent change from Baseline to Day 14, Day 28 and Day 56 
will be analyzed using similar MMRM approach. Then the parameter estimates will be combined 
using Rubin’s method. Example SAS code to combine the parameter estimates is shown below: 
******************************************************************************************************** 
Note:  
  MIANALYZE to combine imputations 
******************************************************************************************************** 
proc mianalyze parms(classvar=full)=mixLSM;  
  class TREATMENT;  


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  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 Analysis 2 
In the second sensitivity analysis, the percent change from Day 1 to Day 56 in LDL-C, via 
approach 1, for the obicetrapib groups compared to the placebo group will be analyzed using an 
Analysis of Covariance (ANCOVA) model with fixed effects of treatment group and the Baseline 
LDL-C value as a continuous covariate. The least squares means, standard errors, and 2-sided 
95% confidence intervals for each treatment group, for the pairwise comparisons of three 
obicetrapib will be provided. The treatment comparison will be performed using a 2-sided test at 
the α = 0.05 level of significance. No imputation of missing data will be performed for this 
sensitivity analysis. 
Example SAS code can be found below: 
*********************************************************************************************************** 
Note:  
  USUBJID = unique subject identifier  
  TREATMENT = 0 (Placebo), 1 (2.5 mg obicetrapib), 2 (5 mg obicetrapib), 3 (10 mg  
  obicetrapib)  
  BASE = Baseline value  
  PCHG = Percent change from Baseline 
********************************************************************************************************** 
proc glm data=LDL_C;  
  class TREATMENT;  
  model PCHG = TREATMENT BASE / ss1 ss3; 
  means TREATMENT;  
  lsmeans TREATMENT / cov stderr pdiff cl;  
  estimate " 2.5 mg obicetrapib - Placebo" TREATMENT -1 1 0 0;  
  estimate " 5 mg obicetrapib - Placebo"    TREATMENT -1 0 1 0;  
  estimate " 10 mg obicetrapib - Placebo"  TREATMENT -1 0 0 1;  
run; 
********************************************************************************************************** 
Sensitivity Analysis 3 
In the final sensitivity analysis, the percent change from Day 1 to Day 56 in LDL-C will be 
assessed where the LDL-C values were determined by approach 2. The percent change from 
Day 1 to Day 56 in LDL-C by PUC for the obicetrapib groups compared to the placebo group will 
be analyzed using an ANCOVA similar to the model described in the second sensitivity analysis. 
No imputation of missing data will be performed for this sensitivity analysis. 
Values, changes from Baseline, and percent change from Baseline of LDL-C by PUC will be 
summarized using descriptive statistics at scheduled visits and Baseline by treatment group. 


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Counts and percentages of participants will be summarized by treatment for each type of data 
pattern. There will be four data patterns for two time points (Baseline and Day 56) each having 
two possible outcomes (LDL-C data reported or missing). 
3.4.2 Secondary Efficacy Endpoints 
Similar MMRM models as described for the primary efficacy analyses will be used to analyze 
the secondary efficacy endpoints based on the mITT Population. No adjustment will be made for 
multiplicity in testing the secondary efficacy endpoints. Nominal p-values will be provided when 
applicable.  
Values, changes from Baseline, and percent change from Baseline of each lipid profile will be 
summarized using descriptive statistics at scheduled visits and Baseline by treatment group. 
The following endpoints will be examined: 
 
Percent change from Day 1 to Day 56 in ApoB for each obicetrapib group compared to 
the placebo group; 
 
Percent change from Day 1 to Day 56 in non-HDL-C for each obicetrapib group 
compared to the placebo group; and 
 
Percent change from Day 1 to Day 56 in HDL-C for each obicetrapib group compared to 
the placebo group. 
Waterfall plot of percent change in ApoB from Baseline to each scheduled visit will be created. 
3.4.3 Other Efficacy Endpoints 
The percent change from Day 1 to Day 56 in Apolipoprotein E (ApoE), Triglycerides, and Very 
low-density lipoprotein cholesterol will be examined through similar MMRM models as described 
for the primary efficacy analyses based on the mITT Population. Values, changes from 
Baseline, and percent change from Baseline of each lipid profile will be summarized using 
descriptive statistics at scheduled visits and Baseline by treatment group. 
3.4.4 Subgroups 
Not applicable. 
3.5 Pharmacokinetic Assessment 
Plasma obicetrapib concentrations will be summarized with descriptive statistics based on the 
PK Population. Exploration of any relationships with obicetrapib exposure will be performed, as 
appropriate. 
On Day 1, a PK sample will be collected pre-dose. The subsequent post-dose PK samples 
should be collected once at approximately the same time at each visit. 
3.6 Pharmacodynamic Assessment 
Not applicable. 


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3.7 Safety Assessment 
The Safety Population will be the primary population for the safety analyses. All safety 
endpoints will be summarized descriptively. No statistical inference will be applied to the safety 
endpoints. 
3.7.1 Adverse Events (AEs) 
AEs will be categorized by primary system organ class and preferred term as coded using the 
MedDRA (with the version specified in Data Management Plan) category designations.  
Treatment-emergent adverse events (TEAEs) are defined as AEs that start after the first dose of 
study drug.  
Adverse events of special interest will be flagged in CRF. 
An overview of AEs will be provided including counts and percentages of participants (and event 
counts) by treatment and in total with the following: 
 
Any TEAEs overall and by maximum severity 
 
Any study drug related TEAEs overall and by maximum severity 
 
Any TEAEs of special interest 
 
Any treatment-emergent serious AEs (TESAEs) 
 
Any study drug related TESAEs 
 
Any TEAEs leading to discontinuation of study drug 
 
Any AEs leading to death 
Counts and percentages of participants (and event counts) will also be presented by system 
organ class and preferred term for each of the categories in the overview. 
Listings will be presented specifically for TEAEs, TESAEs, TEAEs leading to discontinuation of 
study drug, and TEAEs of special interest. 
3.7.2 Clinical Laboratory Tests 
Blood and urine samples for clinical laboratory tests will be collected at timepoints indicated in  
Appendix A (Schedule of Procedures) of the study protocol and processed by a central 
laboratory. See Appendix B for a complete list of analytes. 
Blood samples for chemistry and hematology must be obtained under fasting conditions (i.e., 
after the participant has fasted for approximately 8 hours). For the purposes of this study, 
fasting will be defined as nothing by mouth except water and any essential medications. If a 
participant is not fasting, the Investigator should reschedule the visit as soon as possible. 
Estimated glomerular filtration rate will be calculated using the Chronic Kidney Disease 
Epidemiology Collaboration equation. At the Screening Visit only, the chemistry panel will 
include HbA1c. 
A urine pregnancy test will be performed for women of childbearing potential at the Screening 
Visit (Visit 1) prior to their participation in the study and at the Safety Follow-Up Visit (Visit 6), 
and the Early Termination Visit, if appropriate. 


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An FSH test will be performed at the Screening Visit prior to participation in the study in women 
<55 years of age for whom it has been ≥1 year since their last menstrual period to confirm a 
postmenopausal state. 
For each laboratory test, values, changes from Baseline, percent change from Baseline will be 
presented at each scheduled visit and Baseline by treatment and in total. According to the 
availability of laboratory data, additional 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). 
3.7.3 Vital Signs 
Vital signs will include body temperature, heart rate, and triplicate blood pressure (systolic and 
diastolic) measurements and measured at all scheduled timepoints. Participants should be in 
the supine position after at least 10 minutes rest prior to the vital sign measurements. 
Weight and height will be measured at the Screening Visit and will be used to calculate body 
mass index as following: 
𝐵𝑀𝐼(𝑘𝑔𝑚2
⁄
) = 𝑤𝑒𝑖𝑔ℎ𝑡(𝑘𝑔) (ℎ𝑒𝑖𝑔ℎ𝑡(𝑚))2
⁄
 
Measurement of weight should be performed with the participant dressed in indoor clothing, with 
shoes removed, and bladder empty. 
Values and changes from Baseline will be summarized with descriptive statistics at each visit by 
treatment. 
3.7.4 Electrocardiograms 
A single, standard 12-lead ECG will be performed by the Investigator or trained site personnel at 
the Screening Visit and read locally. Summary statistics will be provided for the overall 
interpretation by treatment and in total. A separate data listing by participant will be provided for 
ECG data. 
3.7.5 Physical Examinations 
Physical examinations will be performed at Screening Visit and Visit 5. Data collected related to 
physical examinations will be listed. 
3.7.6 Events of Special Interest 
Liver-associated enzymes and total bilirubin will be summarized by the value and change from 
Baseline in the value, by treatment group and visit. In addition, the number and percent of 
participants with abnormal values for ALT, AST, and total bilirubin will be summarized. These 
summaries of participants with abnormal values will be performed overall; by normal Baseline; 
and by abnormal Baseline for ALT, AST, and total bilirubin individually. Hy’s Law criteria (>3 × 
ULN for either ALT or AST, with accompanying total bilirubin >2 × ULN) will also be applied to 
the data. Any potential Hy’s Law cases will be listed separately. 
Muscle-related abnormalities will be summarized by treatment group. 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.  


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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 
(Schedule of Procedures) of the study protocol. 
Baseline eGFR will be summarized by treatment group for actual value and for Baseline eGFR 
categories. Shift tables of eGFR category from Baseline to End of Treatment (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. Values of CK from 
Baseline to EOT will be summarized by treatment group and by Baseline eGFR category. 
Muscle related abnormalities will be summarized by treatment group and by Baseline eGFR 
category. 
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. 
4 ANALYSIS TIMING 
4.1 Interim Analysis 
No interim analysis is planned for this study.  
4.2 Final Analysis 
Upon completion of the study (all enrolled participants have completed the double-blind 
treatment and Safety Follow-up periods or are withdrawn from the study), the database will be 
locked and the final analysis will be generated. The final analysis will be performed on all 
available efficacy and safety data as described in the above sections of the SAP. The 
corresponding TFLs will be provided after database lock. In addition to TFLs, SDTM data and 
ADaM data along with associated files will be provided. Associated files may include the 
following: annotated case report forms (CRFs), SDTM specifications, SDTM programs, ADaM 
specifications, ADaM programs, TFL programs, and CDISC Define packages for both SDTM 
and ADaM data. 
The result of this analysis will be used for the clinical study report.  
5 CHANGES FROM PROTOCOL-SPECIFIED STATISTICAL ANALYSES 
Following changes are made to the statistical analysis described in v1.1 of the protocol. 
 
mITT On-Treatment Population has been added to supportive analyses for the primary 
efficacy endpoint 
 
High-density lipoprotein-ApoE has been removed from lipid profile parameters.  
Any deviations from the protocol or SAP will be described in the CSR. 
6 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 
ICH guidance for industry E9(R1) Statistical Principles for Clinical Trials: Addendum: Estimands 
and Sensitivity Analysis in Clinical Trials, 2017 
APPENDIX B:  LABORATORY TESTS 
Standard Safety Chemistry Panel 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Amylase 
Aspartate aminotransferase 
Bicarbonate 
Blood urea nitrogen 
Calcium 
Chloride 
Creatine kinase 
Creatinine 
Estimated glomerular filtration rate [1] 
Gamma-glutamyl transferase 
Glucose (fasting) 
Glycosylated hemoglobin [2] 
High-sensitivity C-reactive protein 
Inorganic phosphorus 
Lactate dehydrogenase 
Lipase 
Potassium 
Sodium 
Total bilirubin 
Total protein 
Uric acid 
1. 
Calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. (Source: CKD-EPI 
equations for glomerular filtration rate [GFR]. MDCalc. https://www.mdcalc.com/ckd-epi-equations-
glomerular-filtration-rate-gfr. Accessed 19 November 2021.) 
2. 
Screening Visit only. 
 
Endocrinology 
Follicle-stimulating hormone [1] 
 
1. 
A follicle-stimulating hormone test will be performed in women <55 years of age for whom it has been 1 year 
since their last menstrual period. 
 
Hematology 
Hematocrit 
Hemoglobin 
Platelets 
Red blood cell count 
White blood cell count and differential [1] 
 
1. 
Manual microscopic review is performed only if white blood cell count and/or differential values are out of 
reference range. 
 
Pregnancy Test 
Urine [1] 
 
1. 
For women of childbearing potential only. 
 


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Lipid Profile 
Apolipoprotein B 
High-density lipoprotein cholesterol 
Low-density lipoprotein cholesterol [1] 
Non-high-density lipoprotein cholesterol 
Triglycerides 
Very low-density lipoprotein cholesterol 
Apolipoprotein E (ApoE) 
 
1. 
Calculated using the Friedewald equation unless triglycerides (TGs) 400 mg/dL or low-density lipoprotein 
cholesterol (LDL-C) 50 mg/dL. If TG 400 mg/dL or LDL-C 50 mg/dL, then LDL-C level will be measured 
directly by preparative ultracentrifugation, also referred to as beta quantification. (Source: LDL calculated. 
MDCalc. https://www.mdcalc.com/ldl-calculated. Accessed 19 November 2021.) In addition, for all 
participants, LDL-C will be measured by preparative ultracentrifugation, also referred to as beta quantification, 
at Baseline (Day 1; Visit 2) and at the end of the 8-week Treatment Period (Day 56; Visit 5).