Conditions: Dyslipidemias High Cholesterol Hypercholesterolemia
Keywords: obicetrapib statin LDL-C cholesterol atherosclerosis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 112
Healthy volunteers: no

Brief summary:
This study will be a placebo-controlled, double-blind, randomized, phase 2 study in participants with mild dyslipidemia to evaluate the efficacy, safety, and tolerability of obicetrapib and ezetimibe combination therapy.

Detailed description:
This study will be a placebo-controlled, double-blind, randomized, phase 2 study in participants with mild dyslipidemia to evaluate the efficacy, safety, and tolerability of obicetrapib and ezetimibe combination therapy. The screening period for this study will take up to 2 weeks. Following the screening period, eligible patients will be randomized to placebo, 5 mg obicetrapib + 10 mg ezetimibe; 5 mg obicetrapib + placebo ezetimibe; or placebo obicetrapib + 10 mg ezetimibe for an 8 week treatment period. After the treatment period, patients will continue for a 4 week safety follow-up and a 8 week PK follow-up.

Arms:
arm 1: placebo obicetrapib + placebo ezetimibe; once daily arm 2: 5 mg obicetrapib + 10 mg ezetimibe; once daily arm 3: 5 mg obicetrapib + placebo ezetimibe; once daily arm 4: placebo obicetrapib + 10 mg ezetimibe; once daily

Interventions: intervention 1: Obicetrapib 5mg intervention 2: Ezetimibe 10mg intervention 3: Placebo
Intervention descriptions: intervention 1: tablet intervention 2: tablet intervention 3: tablet

Protocol document:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
A Placebo-Controlled, Double-Blind, Randomized Phase 2 Study to 
Evaluate the Effect of Obicetrapib in Combination with Ezetimibe 
in Participants with Mild Dyslipidemia 
Investigational Product: Obicetrapib 
Protocol Number: TA-8995-303 
EudraCT Number: 2019-004935-22 
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: 4.0 
Date: 14 January 2021 
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 or Independent Ethics Committee and study personnel directly involved with 
conducting this protocol. Persons to whom the information is disclosed must be informed that the 
information is confidential and proprietary to NewAmsterdam Pharma BV and that it may not be 
further disclosed to third parties. 
NCT Number: NCT04770389
This NCT number has been applied to the document for the purposes of posting on clinicaltrials.gov




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INVESTIGATOR AGREEMENT 
By signing below I agree that: 
I have read this protocol. I approve this document and I agree that it contains all necessary details 
for carrying out the study as described. I will conduct this study in accordance with the design and 
specific provision of this protocol and will make a reasonable effort to complete the study within 
the time designated. I will provide copies of this protocol and access to all information furnished 
by NewAmsterdam Pharma BV to study personnel under my supervision. I will discuss this 
material with them to ensure they are fully informed about the study product and study procedures. 
I will let them know that this information is confidential and proprietary to NewAmsterdam 
Pharma 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 Food and Drug Administration Regulations, 
Institutional Review Board/Ethics Committee Regulations and International Council for 
Harmonisation Guidelines for Good Clinical Practices. 
 
 
 
 
 
 
______________________________________________  
____________________ 
Investigator’s Signature 
 
 
 
 
 
Date 
 
 
 
______________________________________________ 
Investigator’s Printed Name 
 


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SYNOPSIS 
TITLE:  A Placebo-Controlled, Double-Blind, Randomized Phase 2 Study to Evaluate the Effect 
of Obicetrapib in Combination with Ezetimibe in Participants with Mild Dyslipidemia 
PROTOCOL NUMBER:  TA-8995-303 
INVESTIGATIONAL PRODUCT:  Obicetrapib 
PHASE:  2 
INDICATION:  Mild dyslipidemia 
OBJECTIVES: 
The primary objective of this study is to evaluate the effect of obicetrapib in combination with 
ezetimibe compared to placebo on low-density lipoprotein cholesterol (LDL-C) at Day 57. 
The secondary objectives of this study include the following: 
 To evaluate the effect of obicetrapib monotherapy compared to placebo on LDL-C at Day 57;
 To evaluate the effect of obicetrapib in combination with ezetimibe compared to placebo on 
apolipoprotein B (ApoB) at Day 57; 
 To evaluate the effect of obicetrapib monotherapy compared to placebo on ApoB at Day 57; 
 To evaluate the effect of obicetrapib in combination with ezetimibe compared to ezetimibe
monotherapy on LDL-C at Day 57;  
 To evaluate the effect of obicetrapib monotherapy compared to ezetimibe monotherapy on 
LDL-C at Day 57; 
 To evaluate the effect of ezetimibe monotherapy compared to placebo on LDL-C at Day 57; 
and 
 To evaluate the effect of obicetrapib in combination with ezetimibe compared to ezetimibe 
monotherapy on ApoB at Day 57. 
The exploratory objectives of this study include the following: 
 To evaluate the effect of ezetimibe monotherapy compared to placebo on ApoB at Day 57; 
 To evaluate the effect of obicetrapib alone, ezetimibe alone, and obicetrapib in combination 
with ezetimibe on non-high-density lipoprotein cholesterol (non-HDL-C), very low-density 
lipoprotein cholesterol (VLDL-C), high-density lipoprotein cholesterol (HDL-C),
triglycerides (TG), apolipoprotein E (ApoE), and high-density lipoprotein (HDL)-ApoE (with 
and without apolipoprotein C3 [ApoC3]) at Day 57;  
 To evaluate the effect of obicetrapib alone, ezetimibe alone, and obicetrapib in combination 
with ezetimibe on the proportion of participants achieving predefined LDL-C targets at 
Day 57;  


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 To assess the mean trough plasma levels of obicetrapib alone, ezetimibe alone, and obicetrapib
in combination with ezetimibe at steady state on Day 57, Week 12, and Week 16; 
 To evaluate the effect of obicetrapib alone, ezetimibe alone, and obicetrapib in combination 
with ezetimibe on cholesteryl ester transfer protein (CETP) mass at Day 57, Week 12, and 
Week 16; and 
 To evaluate the safety and tolerability profiles of obicetrapib alone, ezetimibe alone, and 
obicetrapib in combination with ezetimibe assessed by clinical laboratory values and incidence 
of adverse events (AEs). 
POPULATION: 
The population for this study includes men and women 18 to 70 years of age, inclusive, with a 
body mass index <40 kg/m2 and mild dyslipidemia defined as fasting LDL-C levels >2.5 mmol/L 
(>100 mg/dL) and <4.5 mmol/L (<175 mg/dL) and TG levels <4.5 mmol/L (<400 mg/dL).  
STUDY DESIGN AND DURATION: 
This study will be a placebo-controlled, double-blind, randomized Phase 2 study in participants 
with mild dyslipidemia to evaluate the efficacy, safety, and tolerability of obicetrapib and 
ezetimibe combination therapy. The study will take place at approximately 10 to 15 sites in North 
America and Europe as appropriate. 
Screening Period 
At the Screening Visit (Visit 1), participants will be required to sign an informed consent form 
(ICF) before any study-related procedures are performed. After signing the ICF, participants will 
be assessed for study eligibility. Participants will also receive counselling regarding the 
Therapeutic Lifestyle Changes diet and will receive instructions on how to follow this diet. 
Participants will be required to begin the diet starting at the Screening Visit.  
Treatment Period 
Up to 2 weeks after the Screening Visit, participants will return to the site on Day 1 (Visit 2) to be 
randomized and begin 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: 
 Combination therapy: 5 mg obicetrapib + 10 mg ezetimibe; 
 Obicetrapib monotherapy: 5 mg obicetrapib + placebo ezetimibe;  
 Ezetimibe monotherapy: placebo obicetrapib + 10 mg ezetimibe; or 
 Placebo: placebo obicetrapib + placebo ezetimibe. 
During the 8-week Treatment Period, the assigned study drugs will be administered by the 
participant orally and once daily on Days 1 through 57. Participants will return to the site every 
4 weeks for efficacy, safety, PK, and CETP mass 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 through the PK Visit (Visit 6) for the last participant in order to 
protect blinding to treatment assignment. 


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Safety Follow-up Period 
Participants will return to the site for a Safety Follow-up Visit (Visit 5) approximately 4 weeks 
after the end of the Treatment Period for safety, PK, and CETP mass assessments. 
Pharmacokinetic Period 
Participants will return to the site for a PK Visit (Visit 6) approximately 8 weeks after the end of 
the Treatment Period for PK and CETP mass assessments. 
DOSAGE FORMS AND ROUTE OF ADMINISTRATION: 
The study drugs used in this study are as follows: 
 5 mg obicetrapib tablet; 
 10 mg ezetimibe tablet, over-encapsulated into a capsule;  
 Placebo tablet for obicetrapib; and 
 Placebo capsule for ezetimibe. 
Participants will be randomized to receive 2 of the study drugs listed above for the duration of the 
study. Both of the assigned study drugs will be administered by the participant orally and once 
daily on Days 1 through 57.  
EFFICACY VARIABLES:  
The primary efficacy endpoint is percent change from Day 1 to Day 57 in LDL-C for the 
combination therapy group compared to the placebo group. 
The secondary efficacy endpoints include the following, in hierarchical order: 
 Percent change from Day 1 to Day 57 in LDL-C for the obicetrapib monotherapy group 
compared to the placebo group; 
 Percent change from Day 1 to Day 57 in ApoB for the combination therapy group compared 
to the placebo group; 
 Percent change from Day 1 to Day 57 in ApoB for the obicetrapib monotherapy group 
compared to the placebo group; 
 Percent change from Day 1 to Day 57 in LDL-C for the combination therapy group compared 
to the ezetimibe monotherapy group;  
 Percent change from Day 1 to Day 57 in LDL-C for the obicetrapib monotherapy group 
compared to the ezetimibe monotherapy group;  
 Percent change from Day 1 to Day 57 in LDL-C for the ezetimibe monotherapy group 
compared to the placebo group; and  
 Percent change from Day 1 to Day 57 in ApoB for the combination therapy group compared 
to the ezetimibe monotherapy group.  


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The exploratory efficacy endpoints include the following: 
 Percent change from Day 1 to Day 57 in ApoB for the ezetimibe monotherapy group compared 
to the placebo group; 
 Pairwise comparisons among the various treatment groups for the percent change from Day 1 
to Day 57 in non-HDL-C, VLDL-C, HDL-C, TG, ApoE, and HDL-ApoE (with and without 
ApoC3); 
 Pairwise comparisons among the various treatment groups for the proportion of participants 
at Day 57 that achieve LDL-C <2.6 mmol/L (<100 mg/dL), LDL-C <1.8 mmol/L
(<70 mg/dL), and LDL-C <1.3 mmol/L (<50 mg/dL); 
 Pairwise comparisons among the various treatment groups for the change from Day 1 to 
Day 57, Day 1 to Week 12, and Day 1 to Week 16 in the mean trough plasma levels of 
obicetrapib; and 
 Pairwise comparisons among the various treatment groups for the change from Day 1 to 
Day 57, Day 1 to Week 12, and Day 1 to Week 16 in CETP mass. 
SAFETY VARIABLES: 
The safety and tolerability profiles of obicetrapib alone, ezetimibe alone, and obicetrapib in 
combination with ezetimibe will be assessed by clinical laboratory values and the incidence of 
AEs. 
STATISTICAL ANALYSES: 
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 after a participant receives a restricted lipid-altering therapy, 
outside of the current study design, 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 57 value for the LDL-C assessment, and 
who did not experience a major protocol deviation that potentially impacted the primary efficacy 
endpoint. The PP Population, along with the reason for exclusion, will be finalized prior to study 
unblinding. 
The PK Population will include all participants in the mITT Population who have sufficient blood 
samples collected for valid estimation of PK parameters. 


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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.  
The primary efficacy analysis of the percent change from Day 1 to Day 57 in LDL-C will be 
performed using a mixed model for repeated measures (MMRM) 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, for the pairwise comparisons of the 
combination therapy, obicetrapib monotherapy, and ezetimibe monotherapy to placebo, and for 
the pairwise comparisons of combination therapy and obicetrapib monotherapy versus ezetimibe 
monotherapy will be provided. The treatment comparison will be performed using a 2-sided test 
at the  = 0.05 level of significance. 
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 Statistical 
Analysis Plan (SAP). 
A similar MMRM model will be used for the analysis of the secondary and exploratory efficacy 
endpoints corresponding to the percent change from baseline. For the binary efficacy endpoints, a 
logistic regression analysis will be performed with model covariates of treatment group and 
baseline LDL-C.  
In order to maintain the overall Type I error rate, the secondary efficacy endpoints will be tested 
sequentially at the 0.05 significance level according to the pre-specified order of hierarchy. No 
adjustment will be made for multiplicity in testing the exploratory efficacy endpoints. Nominal 
p-values will be provided when applicable. Descriptive and graphical summaries by treatment 
group will also be presented. 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.
Pharmacokinetic Analysis 
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 (ie, 25 participants per treatment group) will 
provide >90% power to detect a 30% difference in LDL-C reduction at Day 57 (SD 15%) for the 
combination therapy group compared to the placebo group at a 2-sided significance level of 0.05. 


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The sample size for this study was determined in order to provide sufficient power (>80%) for the 
analyses of the primary efficacy endpoint and secondary efficacy endpoints described above. The 
sample size calculations used values reported from a previous clinical trial involving obicetrapib 
(TA-8995) as a starting point for the assumptions of the treatment difference and standard 
deviation.1 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 value 
(<3.5 mmol/L [<135 mg/dL] or 3.5 mmol/L [135 mg/dL]). 
SITES:  Approximately 10 to 15 sites in North America and Europe as appropriate 
SPONSOR: 
NewAmsterdam Pharma BV 
Gooimeer 2-35 
1411 DC 
Naarden 
The Netherlands 
Telephone: +31 35 699 30 00 
Fax: +31 20 240 07 79 
 
1 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. 


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TABLE OF CONTENTS 
Signature Page ................................................................................................................................ 2 
Investigator Agreement ................................................................................................................... 3 
Synopsis .......................................................................................................................................... 4 
Table of Contents .......................................................................................................................... 10 
List of Abbreviations and Definition of Terms............................................................................. 14 
1  Introduction and Background Information ............................................................................. 16 
1.1 
Cholesteryl Ester Transfer Protein Inhibition ............................................................... 16 
1.2 
Obicetrapib (TA-8995) .................................................................................................. 17 
1.3 
Clinical Development of Obicetrapib ........................................................................... 17 
1.4 
Rationale for Obicetrapib and Ezetimibe Combination Therapy .................................. 18 
1.5 
Risk/Benefit ................................................................................................................... 18 
2  Study Objectives ..................................................................................................................... 20 
2.1 
Primary Objective ......................................................................................................... 20 
2.2 
Secondary Objectives .................................................................................................... 20 
2.3 
Exploratory Objectives .................................................................................................. 20 
3  Study Description.................................................................................................................... 21 
3.1 
Summary of Study Design ............................................................................................ 21 
3.1.1  Screening Period ............................................................................................... 21 
3.1.2  Treatment Period ............................................................................................... 21 
3.1.3  Safety Follow-up Period .................................................................................... 21 
3.1.4  Pharmacokinetic Period ..................................................................................... 21 
3.2 
Study Indication ............................................................................................................ 22 
4  Selection and Withdrawal of Participants ............................................................................... 23 
4.1 
Inclusion Criteria ........................................................................................................... 23 
4.2 
Exclusion Criteria .......................................................................................................... 23 
4.3 
Retesting ........................................................................................................................ 24 
4.4 
Rescreening ................................................................................................................... 24 
4.5 
Withdrawal Criteria ....................................................................................................... 25 
5  Study Treatments .................................................................................................................... 26 
5.1 
Treatment Groups .......................................................................................................... 26 


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5.2 
Rationale for Dosing ..................................................................................................... 26 
5.3 
Randomization and Blinding ......................................................................................... 26 
5.4 
Breaking the Blind ........................................................................................................ 26 
5.5 
Drug Supplies ................................................................................................................ 27 
5.5.1  Formulation and Packaging ............................................................................... 27 
5.5.2  Study Drug Preparation and Dispensing ........................................................... 27 
5.5.3  Study Drug Administration ............................................................................... 28 
5.5.4  Treatment Compliance ...................................................................................... 28 
5.5.5  Storage and Accountability ............................................................................... 28 
5.6 
Prior and Concomitant Medications and/or Procedures ................................................ 28 
5.6.1  Excluded Medications and/or Procedures ......................................................... 28 
5.6.2  Documentation of Prior and Concomitant Medication Use .............................. 28 
6  Study Procedures .................................................................................................................... 29 
6.1 
Informed Consent .......................................................................................................... 29 
6.2 
Screening Visit (Visit 1, Day -14 to Day -1) ................................................................. 29 
6.3 
Treatment Period – Visits 2 Through 4 ......................................................................... 29 
6.3.1  Visit 2 (Day 1) ................................................................................................... 29 
6.3.2  Visit 3 (Day 29 ±3 Days) .................................................................................. 30 
6.3.3  Visit 4 (Day 57 ±3 Days) .................................................................................. 30 
6.4 
Safety Follow-up Visit (Visit 5, Day 85 ±3 Days) ........................................................ 31 
6.5 
Pharmacokinetic Visit (Visit 6, Day 113 ±7 Days) ....................................................... 31 
6.6 
Early Termination Visit and Withdrawal Procedures ................................................... 31 
7  Efficacy Assessments .............................................................................................................. 33 
8  Safety Assessments ................................................................................................................. 34 
8.1 
Adverse Events .............................................................................................................. 34 
8.1.1  Adverse (Drug) Reaction .................................................................................. 34 
8.1.2  Unexpected Adverse Drug Reaction ................................................................. 35 
8.1.3  Assessment of Adverse Events by the Investigator .......................................... 35 
8.2 
Serious Adverse Events ................................................................................................. 36 
8.3 
Serious Adverse Event Reporting − Procedures for Investigators ................................ 37 
8.4 
Pregnancy Reporting ..................................................................................................... 37 
8.5 
Expedited Reporting ...................................................................................................... 38 


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8.6 
Special Situation Reports .............................................................................................. 38 
8.7 
Clinical Laboratory Evaluations .................................................................................... 39 
8.8 
Vital Signs ..................................................................................................................... 39 
8.9 
Demographics ................................................................................................................ 39 
8.10  Electrocardiograms ........................................................................................................ 40 
8.11  Physical Examinations .................................................................................................. 40 
9  Statistics .................................................................................................................................. 41 
9.1 
Analysis Populations ..................................................................................................... 41 
9.2 
Statistical Methods ........................................................................................................ 41 
9.2.1  Analysis of Efficacy .......................................................................................... 41 
9.2.1.1  Primary efficacy analysis .................................................................... 41 
9.2.1.2  Secondary and exploratory efficacy analysis ...................................... 42 
9.2.2  Analysis of Safety ............................................................................................. 42 
9.2.3  Pharmacokinetic Analysis ................................................................................. 42 
9.2.4  Interim Analysis ................................................................................................ 42 
9.2.5  Sample Size Determination ............................................................................... 42 
10  Data Management and Record Keeping ................................................................................. 44 
10.1  Data Management ......................................................................................................... 44 
10.1.1  Data Handling ................................................................................................... 44 
10.1.2  Computer Systems ............................................................................................. 44 
10.1.3  Data Entry ......................................................................................................... 44 
10.1.4  Medical Information Coding ............................................................................. 44 
10.1.5  Data Validation ................................................................................................. 44 
10.2  Record Keeping ............................................................................................................. 44 
10.3  End of Study .................................................................................................................. 45 
11  Investigator Requirements and Quality Control ..................................................................... 46 
11.1  Ethical Conduct of the Study ........................................................................................ 46 
11.2  Institutional Review Board/Independent Ethics Committee ......................................... 46 
11.3  Informed Consent .......................................................................................................... 46 
11.4  Participant Card ............................................................................................................. 46 
11.5  Study Monitoring Requirements ................................................................................... 47 
11.6  Disclosure of Data ......................................................................................................... 47 


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11.7  Retention of Records ..................................................................................................... 47 
11.8  Publication Policy ......................................................................................................... 48 
11.9  Insurance and Indemnity ............................................................................................... 48 
11.10 Legal Aspects ................................................................................................................ 48 
12  Study Administrative Information .......................................................................................... 49 
12.1  Protocol Amendments ................................................................................................... 49 
13  References ............................................................................................................................... 50 
Appendix A: Schedule of Procedures ........................................................................................... 51 
Appendix B: Clinical Laboratory Analytes .................................................................................. 53 
Appendix C: Diet Guidelines ........................................................................................................ 55 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
Abbreviation 
Definition 
AE 
Adverse event 
ApoA1 
Apolipoprotein A1 
ApoB 
Apolipoprotein B 
ApoC3 
Apolipoprotein C3 
ApoE 
Apolipoprotein E 
CETP 
Cholesteryl ester transfer protein 
CRA 
Clinical Research Associate 
CTA 
Clinical trial authorisation 
CVD 
Cardiovascular disease 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EIU 
Exposure In Utero 
EU 
European Union 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HbA1c 
Glycosylated hemoglobin 
HDL 
High-density lipoprotein 
HDL-C 
High-density lipoprotein cholesterol 
HMGCR 
3-hydroxy-3-methylglutaryl-Coenzyme A reductase 
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) 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-Treat 
MMRM 
Mixed model for repeated measures 
NODM 
New-onset diabetes mellitus 
Non-HDL-C 
Non-high-density lipoprotein cholesterol 
PK 
Pharmacokinetic(s) 
PP 
Per-Protocol 


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Abbreviation 
Definition 
SAE 
Serious adverse event 
SAMS 
Statin-associated muscle symptoms 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment-emergent adverse event 
TG 
Triglycerides 
TLC 
Therapeutic Lifestyle Changes 
ULN 
Upper limit of normal 
VLDL 
Very low-density lipoprotein 
VLDL-C 
Very low-density lipoprotein cholesterol 
 
 
 
 
 
 
 
 
 


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1 
INTRODUCTION AND BACKGROUND INFORMATION  
Despite advances in treatment, cardiovascular disease (CVD) is the leading cause of death 
globally, resulting in over 17 million deaths per year.1 Elevated low-density lipoprotein (LDL) 
cholesterol (LDL-C) is a major modifiable risk factor for the development of CVD.2,3 Lowering 
LDL-C has been shown to reduce the risk of death or myocardial infarction, and the clinical risk 
reduction is linearly proportional to the absolute LDL-C reduction.4 Approximately 100 million 
people worldwide are treated with lipid lowering therapies, predominantly statins, to reduce 
LDL-C and the associated risk of cardiovascular events. 
Statins are generally well tolerated, but their use is limited in a substantial number of patients due 
to various adverse effects, including statin-associated muscle symptoms (SAMS) and new-onset 
diabetes mellitus (NODM). SAMS comprise myopathy, myalgia, and the most severe 
manifestation, rhabdomyolysis, which can result in serious complications including renal failure. 
However, in most cases, patients experience mild to moderate muscle pain and weakness. The risk 
of NODM increases with intensive statin therapy, particularly in patients with prediabetes.5 These 
manifestations, and other adverse events (AEs), may lead to discontinuation of statin therapy. This 
is commonly referred to as statin intolerance5 and may occur in 10% to 15% of patients,6 depriving 
patients of the cardioprotective benefits of statins. In addition, discontinuation of statin therapy 
can increase the risk of acute cardiovascular events.7 Indeed, it is estimated that 9% of all 
cardiovascular events across the European Union (EU) are the consequence of statin intolerance. 
An alternative to statins is the use of proprotein convertase subtilisin/kexin 9 inhibitors. However, 
there are several limitations with this line of therapy, including very high costs. Based on currently 
completed, long-term studies, outcomes are not as successful compared to statins, and 
muscle-related events are still reported.5 
Accordingly, there remains an unmet need for therapies to reduce elevated LDL-C levels and 
cardiovascular risk, at an acceptable cost, and with a more favorable safety profile to encourage 
long-term use and patient compliance. 
1.1 
Cholesteryl Ester Transfer Protein Inhibition 
Cholesteryl ester transfer protein (CETP) is a plasma glycoprotein produced in the liver and 
adipose tissue. It circulates in the blood bound primarily to high-density lipoprotein (HDL) 
cholesterol (HDL-C) and is involved in the transfer of cholesteryl esters and triglycerides (TG) 
between lipoproteins. In particular, it mediates the transfer of cholesteryl esters from HDL to the 
apolipoprotein B (ApoB)-containing particles, very low-density lipoprotein (VLDL) and LDL-C, 
in exchange for TG. As a result, cholesteryl ester from HDL can be taken up by the liver through 
scavenger receptor class B type 1; this action also leads to decreased HDL-C levels and ultimately 
to increased LDL-C levels. 
Inhibition of CETP activity reduces LDL-C levels and increases HDL-C levels. These effects are 
not only caused by inhibition of CETP-mediated cholesterol transfer from HDL to LDL, but also 
by a decrease in the number of ApoB-containing lipoproteins and an increase in apolipoprotein A1 
(ApoA1)-containing lipoproteins. The LDL-C lowering effect, which arises from CETP inhibition 
and occurs through upregulation of the LDL-receptor, will benefit patients with elevated LDL-C 
and increased cardiovascular risk. 
Ference and colleagues have recently investigated the association between changes in LDL-C 
levels (and other lipoproteins) and the risk of cardiovascular events related to variants in the CETP 


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gene alone and in combination with variants in the 3-hydroxy-3-methylglutaryl-Coenzyme A 
reductase (HMGCR) gene.8 The results of these Mendelian randomization analyses demonstrate 
that treatment with a CETP inhibitor as monotherapy has the potential to effectively reduce the 
risk of cardiovascular events. Both genetic and therapeutic inhibition of CETP leads to 
quantitatively concordant changes in LDL-C and ApoB levels when considered in the absence of 
HMGCR inhibition. A further Mendelian randomization analysis concluded that the clinical 
benefit of lower TG levels was similar to the clinical benefit of lower LDL-C levels per unit 
difference in ApoB and may be related to the absolute reduction in ApoB-containing lipoprotein 
particles.9 Therefore, treatment with a potent CETP inhibitor without a statin could lead to large 
absolute reductions in both LDL-C and ApoB, which could in turn lead to large relative reductions 
in cardiovascular events. Future cardiovascular outcome studies evaluating CETP inhibitor 
therapy in statin intolerant patients could test this hypothesis directly.8 This has indeed been 
confirmed in a recent review where it was concluded that CETP inhibitors could represent a useful 
addition to drugs currently being used to treat high-risk patients intolerant to or not adequately 
treated with statins.10 Recently, the Clinical Trial Service Unit, University of Oxford, also 
presented that the absolute reduction in major adverse cardiovascular events 2 years after the 
REVEAL study was completed was nearly double (approximately 18%) compared to that seen at 
the end of the 4-year treatment period with the CETP inhibitor anacetrapib (approximately 9%). 
In addition, between-group differences in the risk of coronary death emerged in the later years of 
follow-up; and, importantly, no safety concerns were described for non-vascular mortality or 
morbidity.11 In conclusion, CETP inhibition as monotherapy robustly lowers LDL-C and reduces 
CVD risk in those patients who are intolerant to statins, and the REVEAL study has shown no 
long-term on-target safety issues. 
1.2 
Obicetrapib (TA-8995) 
Obicetrapib (TA-8995) has been shown to be a selective CETP inhibitor. In addition to shuttling 
cholesterol esters from LDL-C to HDL-C particles, obicetrapib has several additional 
compound-specific activities that are hypothesized to be beneficial in patients. Obicetrapib 
treatment has recently been shown to reduce the number of ApoB-containing particles that 
constitute LDL-C. Obicetrapib increases apolipoprotein E, which leads to removal of cholesterol 
via the liver and also reduces lipoprotein (a) (Lp(a)). Finally, obicetrapib not only potently 
increases HDL-C and the number of ApoA1-containing lipoproteins, but has been demonstrated 
to be a potent inducer of cholesterol efflux, which is the main driver of reverse cholesterol 
transport.12 This effect is considered important because it is expected to reduce 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 thorough QT/QTc study (TA-8995-04) has been 
completed and obicetrapib was shown to have no effect on corrected QT interval by Fridericia. A 
drug-drug interaction study (TA-8995-05) has also been conducted; this study showed no 
significant effect of obicetrapib on P-glycoprotein activity, but this study showed that obicetrapib 
is a mild inducer of cytochrome P450 3A4. A mass balance study in healthy males concluded that 
obicetrapib is steadily absorbed, and the principal route of excretion was in the feces 
(TA-8995-07). Finally, bioequivalence between obicetrapib capsule and tablet formulations was 
investigated (TA-8995-08) and established. 


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The first patient study conducted was a Phase 2 clinical study (TA-8995-03) in Denmark and the 
Netherlands where the aim was to evaluate the optimal dose of obicetrapib alone and in 
combination with statins in participants with mild dyslipidemia. This study concluded that a daily 
dose of 5 mg obicetrapib resulted in an LDL-C reduction of 45.3%, an ApoB reduction of 33.6%, 
an HDL-C increase of 157.1%, an ApoA1 increase of 57.5%, and a significant increase in HDL-C 
efflux capacity.13 A second patient study (TA-8995-06) was conducted where the effect of 
obicetrapib on Lp(a) was investigated following 12 weeks of treatment. There was a statistically 
significant reduction in Lp(a) levels following 12 weeks of treatment; however, the magnitude of 
the changes (approximately a 10% reduction) was not likely to be clinically relevant. 
1.4 
Rationale for Obicetrapib and Ezetimibe Combination Therapy 
An important therapeutic goal is to maximize LDL-C reduction for patients who cannot tolerate 
statin therapy. Ezetimibe selectively inhibits intestinal cholesterol absorption. Ezetimibe used as 
monotherapy for patients with hypercholesterolemia significantly reduces serum LDL-C levels, 
as evidenced by a meta-analysis of 8 randomized, double-blind, placebo-controlled studies, with 
a statistically significant mean reduction in LDL-C of 18.58% compared with placebo.14 
Ezetimibe in combination with statin therapy further reduces LDL-C levels. A meta-analysis of 
27 studies, including more than 21,000 patients, demonstrated a 15.1% greater reduction in LDL-C 
in patients treated with statin and ezetimibe in combination compared with statin alone.15 Although 
there is a lack of evidence that ezetimibe monotherapy reduces cardiovascular events, the 
IMPROVE-IT study,16 in which simvastatin 40 mg daily was compared with a combination of 
simvastatin 40 mg plus ezetimibe 10 mg in 18,144 patients with acute coronary syndrome, 
demonstrated a modest but statistically significant further reduction in future cardiovascular events 
(a 2% absolute risk reduction over 7 years) in the combination group compared with statins alone. 
These large long-term studies have also demonstrated an excellent safety profile for ezetimibe. 
Importantly, additional Mendelian randomization studies have revealed that the CETP inhibitor 
HMGCR inhibitor interaction does not occur when a CETP inhibitor is combined with ezetimibe. 
Accordingly, to evaluate the potential for ezetimibe to further augment LDL-C as well as ApoB 
reduction achieved by a CETP inhibitor, this study will test the effect of obicetrapib and ezetimibe 
combination therapy compared to obicetrapib monotherapy and ezetimibe monotherapy in 
participants with mild dyslipidemia. 
1.5 
Risk/Benefit 
Obicetrapib has undergone extensive nonclinical testing in the standard battery of tests according 
to 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 subjects have been exposed to obicetrapib in these studies. 
In Phase 1, a total of 159 subjects received single oral doses between 5 and 150 mg of obicetrapib, 
and 76 subjects 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. 
Obicetrapib has been shown to be a selective CETP inhibitor. In addition to shuttling cholesterol 
esters from LDL-C to HDL-C particles, obicetrapib has several additional compound-specific 
activities that are hypothesized to be beneficial in patients. A dose of 5 mg obicetrapib resulted in 
an LDL-C reduction of 45.3%, an ApoB reduction of 33.6%, an HDL-C increase of 157.1%, an 


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ApoA1 increase of 57.5%, and a significant increase in HDL-C efflux capacity.13 This effect is 
considered important because it is expected to reduce established atheroma burden. 
Single doses of obicetrapib up to 150 mg and multiple doses up to 25 mg administered over 28 days 
were generally well tolerated and safe in these studies. No clinically significant effects on vital 
sign measurements (systolic and diastolic blood pressure, heart rate, and body temperature), 
12-lead electrocardiogram (ECG) findings, or results of safety laboratory tests or physical 
examinations were observed with obicetrapib treatment. In particular, no clinically significant 
changes in aldosterone, sodium, potassium, or bicarbonate concentrations were observed.  
In addition, no dose-related effects have been observed on the type, frequency, or intensity of 
treatment-emergent AEs (TEAEs) in clinical studies of obicetrapib to date. In patient studies, most 
TEAEs were mild or moderate in severity. Of the patients with severe TEAEs, 2 were suspected 
to be related to both obicetrapib and statin treatment. 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 display a dose-dependent effect. There were 7 randomized patients with a 
treatment-emergent serious AE (SAE), none of which were suspected to be study drug related. 
One patient had treatment-emergent SAEs that resulted in study discontinuation. No deaths 
occurred during these studies. 
 


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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to evaluate the effect of obicetrapib in combination with 
ezetimibe compared to placebo on LDL-C at Day 57. 
2.2 
Secondary Objectives 
The secondary objectives of this study include the following: 
 To evaluate the effect of obicetrapib monotherapy compared to placebo on LDL-C at Day 57; 
 To evaluate the effect of obicetrapib in combination with ezetimibe compared to placebo on 
ApoB at Day 57; 
 To evaluate the effect of obicetrapib monotherapy compared to placebo on ApoB at Day 57; 
 To evaluate the effect of obicetrapib in combination with ezetimibe compared to ezetimibe 
monotherapy on LDL-C at Day 57;  
 To evaluate the effect of obicetrapib monotherapy compared to ezetimibe monotherapy on 
LDL-C at Day 57;  
 To evaluate the effect of ezetimibe monotherapy compared to placebo on LDL-C at Day 57; 
and 
 To evaluate the effect of obicetrapib in combination with ezetimibe compared to ezetimibe 
monotherapy on ApoB at Day 57. 
2.3 
Exploratory Objectives 
The exploratory objectives of this study include the following: 
 To evaluate the effect of ezetimibe monotherapy compared to placebo on ApoB at Day 57; 
 To evaluate the effect of obicetrapib alone, ezetimibe alone, and obicetrapib in combination 
with ezetimibe on non-HDL-C, VLDL cholesterol (VLDL-C), HDL-C, TG, apolipoprotein E 
(ApoE), and HDL-ApoE (with and without apolipoprotein C3 [ApoC3]) at Day 57;  
 To evaluate the effect of obicetrapib alone, ezetimibe alone, and obicetrapib in combination 
with ezetimibe on the proportion of participants achieving predefined LDL-C targets at 
Day 57; 
 To assess the mean trough plasma levels of obicetrapib alone, ezetimibe alone, and obicetrapib 
in combination with ezetimibe at steady state on Day 57, Week 12, and Week 16; 
 To evaluate the effect of obicetrapib alone, ezetimibe alone, and obicetrapib in combination 
with ezetimibe on CETP mass at Day 57, Week 12, and Week 16; and 
 To evaluate the safety and tolerability profiles of obicetrapib alone, ezetimibe alone, and 
obicetrapib in combination with ezetimibe assessed by clinical laboratory values and incidence 
of AEs. 


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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 study in participants 
with mild dyslipidemia to evaluate the efficacy, safety, and tolerability of obicetrapib and 
ezetimibe combination therapy. The study will take place at approximately 10 to 15 sites in North 
America and Europe as appropriate. 
The population for this study includes men and women 18 to 70 years of age, inclusive, with a 
body mass index <40 kg/m2 and mild dyslipidemia defined as fasting LDL-C levels >2.5 mmol/L 
(>100 mg/dL) and <4.5 mmol/L (<175 mg/dL) and TG levels <4.5 mmol/L (<400 mg/dL). 
3.1.1 
Screening Period 
At the Screening Visit (Visit 1), participants will be required to sign an informed consent form 
(ICF) before any study-related procedures are performed. After signing the ICF, participants will 
be assessed for study eligibility. Participants will also receive counselling regarding the 
Therapeutic Lifestyle Changes (TLC) diet and will receive instructions on how to follow this diet 
(see Appendix C). Participants will be required to begin the diet starting at the Screening Visit. 
3.1.2 
Treatment Period 
Up to 2 weeks after the Screening Visit, participants will return to the site on Day 1 (Visit 2) to be 
randomized and begin 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: 
 Combination therapy: 5 mg obicetrapib + 10 mg ezetimibe; 
 Obicetrapib monotherapy: 5 mg obicetrapib + placebo ezetimibe;  
 Ezetimibe monotherapy: placebo obicetrapib + 10 mg ezetimibe; or 
 Placebo: placebo obicetrapib + placebo ezetimibe. 
During the 8-week Treatment Period, the assigned study drugs will be administered by the 
participant orally and once daily on Days 1 through 57. Participants will return to the site every 
4 weeks for efficacy, safety, PK, and CETP mass 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 through the PK Visit (Visit 6) for the last participant in order to 
protect blinding to treatment assignment. 
3.1.3 
Safety Follow-up Period 
Participants will return to the site for a Safety Follow-up Visit (Visit 5) approximately 4 weeks 
after the end of the Treatment Period for safety, PK, and CETP mass assessments. 
3.1.4 
Pharmacokinetic Period 
Participants will return to the site for a PK Visit (Visit 6) approximately 8 weeks after the end of 
the Treatment Period for PK and CETP mass assessments. 


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3.2 
Study Indication 
The indication for this study is mild 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 diet, 
and agreement to participate in the study by giving written informed consent prior to Screening 
procedures; 
2. Men or women 18 to 70 years of age, inclusive; 
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 post-menopausal, 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 menopausal range for women 
<55 years of age; 
o Women of childbearing potential must agree to use an effective method of avoiding 
pregnancy from the Screening Visit to 90 days after the last visit. Men whose partners are 
of childbearing potential must agree to use an effective method of avoiding pregnancy from 
the Screening Visit to 90 days after the last visit. Effective methods of avoiding pregnancy 
are contraceptive methods with a Pearl index of <1 used consistently and correctly 
(including implantable contraceptives, injectable contraceptives, oral contraceptives, 
transdermal contraceptives, intrauterine devices, diaphragm with spermicide, male or 
female condoms with spermicide, or cervical cap) or a sterile sexual partner; 
3. Fasting LDL-C levels >2.5 mmol/L (>100 mg/dL) and <4.5 mmol/L (<175 mg/dL) and TG 
levels <4.5 mmol/L (<400 mg/dL) (Visit 1); and 
4. Willingness to maintain a stable diet and physical activity level throughout the study. 
4.2 
Exclusion Criteria 
Participants who meet any of the following criteria will be excluded from participation in the study: 
1. Body mass index 40 kg/m2; 
2. Participation in another clinical study involving an investigational or marketed drug within 
30 days prior to the Screening Visit; 
3. Currently taking any lipid-altering therapy; 


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4. Any clinical manifestation of atherosclerotic CVD or any evidence of ischemic coronary 
disease present on the 12-lead ECG at the Screening Visit; 
5. Diagnosis of type 1 or type 2 diabetes mellitus; or glycosylated hemoglobin (HbA1c) 6.5% 
at the Screening Visit if no prior diagnosis of diabetes mellitus; 
6. Uncontrolled hypertension, ie, sitting systolic blood pressure >160 mmHg and/or sitting 
diastolic blood pressure >90 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; 
7. Active muscle disease or persistent creatine kinase 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; 
8. History of torsades de pointes; 
9. Estimated glomerular filtration rate <60 mL/min calculated using the Chronic Kidney Disease 
Epidemiology Collaboration equation; 
10. Hepatic dysfunction as evidenced by any laboratory abnormality as follows: gamma-glutamyl 
transferase, alanine aminotransferase, or aspartate aminotransferase >2  ULN, or total 
bilirubin >1.5  ULN; 
11. Anemia, defined as hemoglobin concentration <11 g/dL for males and hemoglobin 
concentration <9 g/dL for females; 
12. History of malignancy within the past 5 years, with the exception of non-melanoma skin 
cancers; 
13. Evidence of any other clinically significant non-cardiac disease or condition that, in the opinion 
of the Investigator, would preclude participation in the study; or 
14. Known ezetimibe or 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 
Participants who have screen-failed are permitted to rescreen once, following consultation with 
the Medical Monitor. Rescreening may be scheduled after at least 5 days have elapsed from the 
previous study visit. 


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4.5 
Withdrawal Criteria 
Participation in this clinical 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. 
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. The reason for participant withdrawal must be documented in the 
electronic case report form (eCRF). 
In the case of participants lost to follow-up, at least 3 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: 
 Combination therapy: 5 mg obicetrapib + 10 mg ezetimibe; 
 Obicetrapib monotherapy: 5 mg obicetrapib + placebo ezetimibe;  
 Ezetimibe monotherapy: placebo obicetrapib + 10 mg ezetimibe; or 
 Placebo: placebo obicetrapib + placebo ezetimibe. 
5.2 
Rationale for Dosing 
In previous multiple-dose clinical studies of obicetrapib in healthy subjects and patients, near 
maximal effects were observed with the 5 mg obicetrapib dose. At this dose level, CETP activity 
and concentrations were effectively reduced, and HDL-C levels were increased while LDL-C 
levels decreased. According to the Summary of Product Characteristics, the recommended daily 
dose of ezetimibe is 10 mg. Therefore, the present study will utilize a dose of 5 mg obicetrapib, 
administered with or without 10 mg ezetimibe, in participants with mild dyslipidemia following 
the TLC diet. 
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 combination therapy, obicetrapib monotherapy, ezetimibe 
monotherapy, or placebo treatment groups. At randomization, participants will be stratified 
according to their Screening Visit (Visit 1) LDL-C value (<3.5 mmol/L [<135 mg/dL] or 
3.5 mmol/L [135 mg/dL]). An automated interactive response technology (IRT) system will be 
used to assign the participant to 1 of the 4 treatment groups. 
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 through the PK Visit (Visit 6) for the 
last participant 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. 
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. 




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Participants will be randomized to receive 2 of the study drugs listed above for the duration of the 
study. 
At each appropriate visit (Visits 2 and 3), participants will receive a kit containing blister cards 
with the 2 study drugs appropriate for the participant’s treatment group. Participants will be 
instructed to take 2 units from the blister cards in the kit each day. The blister cards will be clearly 
labelled to indicate which blisters to use on each day. Each kit will provide a sufficient supply for 
1 month of dosing. Participants will be instructed to return all unused study drugs at the next visit. 
5.5.3 
Study Drug Administration 
Study drugs will be administered by the participant orally and once daily on Days 1 through 57. 
Study drugs should be administered at approximately the same time each morning, with food. On 
days with visits scheduled, study drugs should be administered with food following all fasted blood 
samples. 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 
Compliance to the study drug regimen will be evaluated by counting unused tablets and capsules. 
During the Treatment Period, if compliance is not between 80% and 120%, inclusive, the 
participant will be counselled about the importance of compliance to the regimen. If the limits are 
exceeded at 2 consecutive visits, a decision will be made by the Investigator and Sponsor as to 
whether the participant should be withdrawn from the study. 
5.5.5 
Storage and Accountability 
All study drugs must be stored 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 or capsule. 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 
Any lipid-altering therapy other than the investigational study drugs will be prohibited during the 
study. 
5.6.2 
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. 


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6 
STUDY PROCEDURES 
A study visit schedule in tabular format is provided in Appendix A. 
6.1 
Informed Consent 
Signed informed consent must be obtained before any study-related procedures are performed. See 
Section 11.3 for details on informed consent. 
6.2 
Screening Visit (Visit 1, Day -14 to Day -1) 
The following procedures will be performed at the Screening Visit: 
 Obtain signed informed consent; 
 Confirm the participant meets the inclusion and exclusion criteria; 
 Record demographic information; 
 Record medical and surgical history; 
 Record prior and concomitant medications; 
 Record weight and height; 
 Perform physical examination; 
 Obtain vital signs; 
 Perform 12-lead ECG; 
 Perform urine pregnancy test for women of childbearing potential only; 
 Collect blood sample for FSH test for peri-menopausal women, defined as women <55 years 
of age for whom it has been 1 year since their last menstrual period; 
 Collect fasting (10 hours) blood samples for chemistry and hematology panels; 
Note: At Screening Visit only, hematology panel will include HbA1c. 
 Collect urine sample for urinalysis; 
 Collect fasting (10 hours) blood sample for lipid profile; 
 Counsel participant on TLC diet and instruct them to begin diet; and 
 Register visit in IRT. 
6.3 
Treatment Period – Visits 2 Through 4 
6.3.1 
Visit 2 (Day 1) 
The following procedures will be performed at Visit 2 (Day 1): 
 Confirm the participant continues to meet the inclusion and exclusion criteria and assess any 
updates since the Screening Visit; 
 Record concomitant medications; 


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 Obtain vital signs; 
 Collect fasting (10 hours) blood samples for chemistry and hematology panels; 
 Collect urine sample for urinalysis; 
 Collect fasting (10 hours) blood sample for lipid profile; 
 Collect blood samples for PK and CETP mass and store for future analysis;  
 Randomize the participant; 
 Dispense randomized study drugs, as appropriate; 
 Instruct the participant to self-administer the study drugs with food following all fasted blood 
samples; 
 Counsel participant on TLC diet; 
 Register visit in IRT; and 
 Assess AEs. 
6.3.2 
Visit 3 (Day 29 ±3 Days) 
The following procedures will be performed at Visit 3 (Day 29 ±3 days): 
 Record concomitant medications; 
 Obtain vital signs; 
 Collect fasting (10 hours) blood samples for chemistry and hematology panels; 
 Collect urine sample for urinalysis; 
 Collect fasting (10 hours) blood sample for lipid profile; 
 Perform study drug compliance check; 
 Dispense randomized study drugs, as appropriate; 
 Instruct the participant to self-administer the study drugs with food following all fasted blood 
samples; 
 Counsel participant on TLC diet; 
 Register visit in IRT; and 
 Assess AEs. 
6.3.3 
Visit 4 (Day 57 ±3 Days) 
The following procedures will be performed at Visit 4 (Day 57 ±3 days): 
 Record concomitant medications; 
 Record weight; 
 Perform physical examination; 


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 Obtain vital signs; 
 Collect fasting (10 hours) blood samples for chemistry and hematology panels; 
 Collect urine sample for urinalysis; 
 Collect fasting (10 hours) blood sample for lipid profile; 
 Collect blood samples for PK and CETP mass and store for future analysis;  
 Instruct the participant to self-administer the study drugs with food following all fasted blood 
samples; 
 Perform study drug compliance check; 
 Register visit in IRT; and 
 Assess AEs. 
6.4 
Safety Follow-up Visit (Visit 5, Day 85 ±3 Days) 
The following procedures will be performed at the Safety Follow-up Visit (Visit 5): 
 Record concomitant medications; 
 Obtain vital signs; 
 Collect fasting (10 hours) blood samples for chemistry and hematology panels; 
 Collect urine sample for urinalysis; 
 Collect blood samples for PK and CETP mass and store for future analysis; and 
 Assess AEs. 
6.5 
Pharmacokinetic Visit (Visit 6, Day 113 ±7 Days) 
The following procedures will be performed at the PK Visit (Visit 6): 
 Collect blood samples for PK and CETP mass and store for future analysis; and 
 Assess AEs. 
6.6 
Early Termination Visit and Withdrawal Procedures 
The end of the study for participants completing the study is Visit 6. For participants who are 
withdrawn from the study prior to completion, all of the following procedures will be performed 
at an Early Termination Visit:  
 Record concomitant medications; 
 Record weight; 
 Perform physical examination; 
 Obtain vital signs; 
 Collect fasting (10 hours) blood samples for chemistry and hematology panels; 
 Collect urine sample for urinalysis; 


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 Collect fasting (10 hours) blood sample for lipid profile; 
 Perform study drug compliance check; 
 Register visit in IRT; and 
 Assess AEs. 


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7 
EFFICACY ASSESSMENTS 
The primary efficacy endpoint is percent change from Day 1 to Day 57 in LDL-C for the 
combination therapy group compared to the placebo group. 
The secondary efficacy endpoints include the following, in hierarchical order: 
 Percent change from Day 1 to Day 57 in LDL-C for the obicetrapib monotherapy group 
compared to the placebo group; 
 Percent change from Day 1 to Day 57 in ApoB for the combination therapy group compared 
to the placebo group; 
 Percent change from Day 1 to Day 57 in ApoB for the obicetrapib monotherapy group 
compared to the placebo group; 
 Percent change from Day 1 to Day 57 in LDL-C for the combination therapy group compared 
to the ezetimibe monotherapy group;  
 Percent change from Day 1 to Day 57 in LDL-C for the obicetrapib monotherapy group 
compared to the ezetimibe monotherapy group;  
 Percent change from Day 1 to Day 57 in LDL-C for the ezetimibe monotherapy group 
compared to the placebo group; and 
 Percent change from Day 1 to Day 57 in ApoB for the combination therapy group compared 
to the ezetimibe monotherapy group. 
The exploratory efficacy endpoints include the following: 
 Percent change from Day 1 to Day 57 in ApoB for the ezetimibe monotherapy group compared 
to the placebo group; 
 Pairwise comparisons among the various treatment groups for the percent change from Day 1 
to Day 57 in non-HDL-C, VLDL-C, HDL-C, TG, ApoE, and HDL-ApoE (with and without 
ApoC3); 
 Pairwise comparisons among the various treatment groups for the proportion of participants at 
Day 57 that achieve LDL-C <2.6 mmol/L (<100 mg/dL), LDL-C <1.8 mmol/L (<70 mg/dL), 
and LDL-C <1.3 mmol/L (<50 mg/dL); 
 Pairwise comparisons among the various treatment groups for the change from Day 1 to 
Day 57, Day 1 to Week 12, and Day 1 to Week 16 in the mean trough plasma levels of 
obicetrapib; and 
 Pairwise comparisons among the various treatment groups for the change from Day 1 to 
Day 57, Day 1 to Week 12, and Day 1 to Week 16 in CETP mass. 
Blood samples for lipid profile must be obtained under fasting conditions (ie, after the participant 
has fasted for 10 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 
will reschedule the visit as soon as possible. 


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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. 
All AEs, including observed or volunteered problems, complaints, or symptoms, are to be recorded 
on the appropriate eCRF. 
AEs, which include clinical laboratory test variables, will be monitored and documented from the 
time of first dose of study drug until 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 first dose of study drug, Investigators should make an assessment for 
AEs at each visit and record the event on the appropriate AE eCRF. 
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified by the Investigator and recorded on the eCRF. However, if an 
observed or reported sign or symptom is not considered a component of a specific disease or 
syndrome by the Investigator, it should be recorded as a separate AE on the eCRF. Additionally, 
the condition that led to a medical or surgical procedure (eg, surgery, endoscopy, tooth extraction, 
or transfusion) should be recorded as an AE, not the procedure itself.  
Any medical condition already present at the date of the first dose of study drug should be recorded 
as medical history and not be reported as an AE unless the medical condition or signs or symptoms 
present at baseline change in severity, frequency, or seriousness at any time during the study. In 
this case, it should be reported as an AE. 
Clinically significant abnormal laboratory or other examination findings that are detected during 
the study or are present at the date of the first dose of study drug 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 clinical study will be followed until repeat tests return to normal, stabilize, or 
are no longer clinically significant. Abnormal test results that are determined to be an error should 
not be reported as an AE. Laboratory abnormalities or other abnormal clinical findings 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 
relationship between a medicinal product and an AE is at least a reasonable possibility, ie, the 
relationship cannot be ruled out. 


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8.1.2 
Unexpected Adverse Drug Reaction 
An Unexpected Adverse Drug Reaction is defined as an adverse reaction, the nature or severity of 
which is not consistent with the applicable product information. For obicetrapib, the reference 
safety information is included in the Investigator’s Brochure currently in force. The reference 
safety information will be reviewed yearly and the periodicity of the review will be harmonized 
with the reporting period of the Development Safety Update Report. 
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, or unlikely to be related) – The time course between the administration 
of study drug and the occurrence or worsening of the AE rules out a causal relationship and another 
cause (concomitant drugs, therapies, complications, etc) is suspected. 
Yes (possibly, probably, or definitely related) – The time course between the administration of 
study drug and the occurrence or worsening of the AE is consistent with a causal relationship and 
no other cause (concomitant drugs, therapies, complications, etc) can be identified. 
The definition implies a reasonable possibility of a causal relationship between the event and the 
study drug. This means that there are facts (evidence) or arguments to suggest a causal relationship. 
The following factors should also be considered: 
 The temporal sequence from study drug administration- 
The event should occur after the study drug is given. The length of time from study drug 
exposure to event should be evaluated in the clinical context of the event. 
 Underlying, concomitant, intercurrent diseases- 
Each report should be evaluated in the context of the natural history and course of the disease 
being treated and any other disease the participant may have. 
 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. 
8.2 
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 an SAE under this criterion, nor will hospitalization for a procedure scheduled 
or planned before signing of informed consent, or elective treatment of a pre-existing condition 
that did not worsen from baseline. However, unexpected complications and/or prolongation of 
hospitalization that occur during elective surgery should be recorded as AEs and assessed for 
seriousness. Admission to the hospital for social or situational reasons (ie, no place to stay, live 
too far away to come for hospital visits, or 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 one 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. 


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8.3 
Serious Adverse Event Reporting − Procedures for Investigators 
Initial Reports 
All SAEs occurring from the time of the first dose of study drug until 30 days following the last 
administration of study drug must be reported to
 within 24 hours of the 
knowledge of the occurrence. After the 30-day reporting window, any SAE that the Investigator 
considers related to study drug must be reported to 
 or the 
Sponsor/designee. 
To report the SAE, complete the SAE form electronically in the 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 
 
 or call the 
 reporting line (telephone 
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 
(eg, participant discharge summary or autopsy reports) to 
 via fax or 
email. If it is not possible to access the EDC system, refer to the procedures outlined above for 
initial reporting of SAEs. 
8.4 
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 
should be withdrawn from the study. Early 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 (ie, postpartum complication, spontaneous abortion, stillbirth, neonatal 
death, or congenital anomaly), the Investigator should follow the procedures for reporting an SAE. 


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8.5 
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 applicable 
competent authorities in all the EU Member States concerned, to the Food and Drug 
Administration (FDA), and to the Central Ethics Committee/Institutional Review Board (IRB), 
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 8 days.  
All other SUSARs will be reported to the FDA, applicable competent authorities concerned, and 
to the Central Ethics Committee concerned 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 judgment should always be applied. In 
cases of a discrepancy in the drug accountability, overdose will be established only when it is 
clear that the participant has taken additional dose(s) or the Investigator has reason to suspect 
that the participant has taken additional dose(s).  
 Misuse: Refers to situations where the medicinal product is intentionally and inappropriately 
used in a way that is not in accordance with the protocol instructions or local prescribing 
information and may be accompanied by harmful physical and/or psychological effects.  
 Abuse: Is defined as persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects. 
 Medication error: Is any unintentional error in the prescribing, dispensing, or administration 
of a medicinal product by a healthcare professional, participant, or consumer, respectively. The 
administration or consumption of the unassigned treatment and administration of an expired 
product are always reportable as medication errors; cases of participants missing doses of 
investigational product are not considered reportable as medication errors. 
 Product complaint: Is defined as any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug or device after it is released for distribution. A special situations report 
form will only be completed if a complaint is associated with an adverse drug reaction.  
All special situation events as described above must be reported on the special situations report 
form and faxed/emailed to 
 (contact information listed below) within 
24 hours of knowledge of the event. All AEs associated with these special situation reports should 




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8.10 
Electrocardiograms 
A single, standard 12-lead ECG will be performed by the Investigator or trained site personnel at 
the Screening Visit and centrally read by 
.  
8.11 
Physical Examinations 
Physical examinations 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 after a participant receives a restricted lipid-altering therapy, 
outside of the current study design, 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 57 value for the LDL-C assessment, and 
who did not experience a major protocol deviation that potentially impacted the primary efficacy 
endpoint. The PP Population, along with the reason for exclusion, will be finalized prior to study 
unblinding. 
The 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 
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 57 in LDL-C will be 
performed using a mixed model for repeated measures (MMRM) 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, for the pairwise comparisons of the 
combination therapy, obicetrapib monotherapy, and ezetimibe monotherapy to placebo, and for 
the pairwise comparisons of combination therapy and obicetrapib monotherapy versus ezetimibe 
monotherapy will be provided. The treatment comparison will be performed using a 2-sided test 
at the  = 0.05 level of significance. 


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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 Statistical 
Analysis Plan (SAP). 
9.2.1.2 
Secondary and exploratory efficacy analysis 
A similar MMRM model will be used for the analysis of the secondary and exploratory efficacy 
endpoints corresponding to the percent change from baseline. For the binary efficacy endpoints, a 
logistic regression analysis will be performed with model covariates of treatment group and 
baseline LDL-C.  
In order to maintain the overall Type I error rate, the secondary efficacy endpoints will be tested 
sequentially at the 0.05 significance level according to the pre-specified order of hierarchy. No 
adjustment will be made for multiplicity in testing the exploratory efficacy endpoints. Nominal 
p-values will be provided when applicable. Descriptive and graphical summaries by treatment 
group will also be presented. 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 (MedDRA) category designations. Summaries of 
AEs, including the number and percentage of participants who experience an AE, will be provided. 
Laboratory values will be summarized descriptively, including the change from baseline, by 
treatment group, and overall. In addition, shift tables will be presented to describe the change in 
laboratory parameter values at post-baseline visits using normal range categories (low, normal, 
and high). 
9.2.3 
Pharmacokinetic Analysis 
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 (ie, 25 participants per treatment group) will 
provide >90% power to detect a 30% difference in LDL-C reduction at Day 57 (SD 15%) for the 
combination therapy group 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 (>80%) for the 
analyses of the primary efficacy endpoint and secondary efficacy endpoints described in Section 7. 
The sample size calculations used values reported from a previous clinical trial involving 
obicetrapib (TA-8995) as a starting point for the assumptions of the treatment difference and 


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standard deviation.13 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 value 
(<3.5 mmol/L [<135 mg/dL] or 3.5 mmol/L [135 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 have been accounted for. 
10.1.2 
Computer Systems 
Data will be processed using a validated computer system conforming to regulatory requirements. 
10.1.3 
Data Entry 
Data must be recorded using the EDC system as the study is in progress. All site personnel must 
login to the system using their secure user name and password in order to enter, review, or correct 
study data. These procedures must comply with Title 21 of the Code of Federal Regulations 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: 
 MedDRA (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. 
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 is defined as all information in original 
records and certified copies of original records of clinical findings, observations, or other activities 
in a clinical study necessary for the evaluation and reconstruction of the clinical study. Source data 
are contained in source documents (original records or certified copies). These records will be 
retained in a secure file for the period as set forth in the Clinical Study Agreement. Prior to transfer 
or destruction of these records, the Sponsor must be notified in writing and be given the 
opportunity to further store such records.  


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


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11 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL  
11.1 
Ethical Conduct of the Study 
Good Clinical Practice (GCP) is an international ethical and scientific quality standard for 
designing, conducting, recording, and reporting studies that involve human participants. 
Compliance with this standard provides public assurance that the rights, safety, and wellbeing of 
study participants are protected, consistent with the principles that have their origin in the 
Declaration of Helsinki, and that the clinical study data are credible. 
11.2 
Institutional Review Board/Independent Ethics Committee 
It is the responsibility of the Sponsor or their designee (ie, 
) to ensure the 
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 written 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 patients 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 drug will be released to the site for dosing until written IRB/IEC authorization has been 
received by the Sponsor. 
11.3 
Informed Consent 
The ICF and any changes to the ICF made during the course of the study must be agreed to by the 
Sponsor or designee and the IRB/IEC prior to its use and must be in compliance with all ICH GCP, 
local regulatory requirements, and legal requirements. 
The Investigator must ensure that each study participant is fully informed about the nature and 
objectives of the study and possible risks associated with participation and must ensure that the 
participant has been informed of his/her rights to privacy. The Investigator will obtain written 
informed consent from each participant before any study-specific activity is performed and should 
document in the source documentation that consent was obtained prior to enrollment in the study. 
The original signed copy of the ICF must be maintained by the Investigator and is subject to 
inspection by a representative of the Sponsor, their representatives, auditors, the IRB/IEC, and/or 
regulatory agencies. A copy of the signed ICF will be given to the participant. 
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 taking part in a clinical research study, type of 
treatment, number of treatment packs 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, ICH GCP, Directive 2001/20/EC, applicable regulatory requirements, and the 
Declaration of Helsinki 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-specific monitoring log. 
11.6 
Disclosure of Data 
Data generated by this study must be available for inspection by 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, 
eg, eCRFs and hospital records), all original signed ICFs, copies of all eCRFs, SAE forms, source 
documents, and detailed records of treatment disposition. The records should be retained by the 
Investigator according to specifications in the ICH guidelines, local regulations, or as specified in 
the Clinical Study Agreement, whichever is longer. The Investigator must obtain written 
permission from the Sponsor before disposing of any records, even if retention requirements have 
been met. 
If the Investigator relocates, retires, or for any reason withdraws from the study, the Sponsor should 
be prospectively notified. The study records must be transferred to an acceptable designee, such 
as another Investigator, another institution, or to the Sponsor. 


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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 
Insurance and Indemnity 
In accordance with the relevant national regulations, the Sponsor has taken out participant liability 
insurance for all participants who have given their consent to the clinical study. This cover is 
designed for the event that a fatality, physical injury, or damage to health occurs during the clinical 
study’s execution. 
11.10 
Legal Aspects 
The clinical study is submitted to the relevant national competent authorities in all participating 
countries to achieve a clinical trial authorisation (CTA). 
The study will commence (ie, initiation of study centers) when the CTA and favorable Ethics 
opinion have been received.  


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


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13 
REFERENCES 
1. 
World 
Health 
Organization. 
Cardiovascular 
diseases 
(CVDs). 
http://www.who.int/mediacentre/factsheets/fs317/en/. Accessed 02 December 2019. 
2. 
Go AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke statistics--2014 update: 
a report from the American Heart Association. Circulation. 2014;129(3):e28-e292. 
3. 
Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the 
National Cholesterol Education Program Adult Treatment Panel III guidelines. 
Circulation. 2004;110(2):227-239. 
4. 
Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering 
treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised 
trials of statins. Lancet. 2005;366(9493):1267-1278. 
5. 
Lansberg P, Lee A, Lee ZV, et al. Nonadherence to statins: individualized intervention 
strategies outside the pill box. Vasc Health Risk Manag. 2018;14:91-102. 
6. 
Banach M, Rizzo M, Toth PP, et al. Statin intolerance - an attempt at a unified definition. 
Position paper from an International Lipid Expert Panel. Arch Med Sci. 2015;11(1):1-23. 
7. 
Toth PP, Patti AM, Giglio RV, et al. Management of statin intolerance in 2018: still more 
questions than answers. Am J Cardiovasc Drugs. 2018;18(3):157-173. 
8. 
Ference BA, Kastelein JJP, Ginsberg HN, et al. Association of genetic variants related to 
CETP inhibitors and statins with lipoprotein levels and cardiovascular risk. JAMA. 
2017;318(10):947-956. 
9. 
Ference BA, Kastelein JJP, Ray KK, et al. Association of triglyceride-lowering LPL 
variants and LDL-C-lowering LDLR variants with risk of coronary heart disease. JAMA. 
2019;321(4):364-373. 
10. 
Tall AR, Rader DJ. Trials and tribulations of CETP inhibitors. Circ Res. 
2018;122(1):106-112. 
11. 
American Heart Association Scientific Sessions, 2019. MDP477. The effects of 
anacetrapib therapy on occlusive vascular events during post-trial follow-up of the 
REVEAL randomized trial. 
12. 
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. 
13. 
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. 
14. 
Pandor A, Ara RM, Tumur I, et al. Ezetimibe monotherapy for cholesterol lowering in 
2,722 people: systematic review and meta-analysis of randomized controlled trials. J Intern 
Med. 2009;265(5):568-580. 
15. 
Morrone D, Weintraub WS, Toth PP, et al. Lipid-altering efficacy of ezetimibe plus statin 
and statin monotherapy and identification of factors associated with treatment response: a 
pooled analysis of over 21,000 subjects from 27 clinical trials. Atherosclerosis. 
2012;223(2):251-261. 
16. 
Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute 
coronary syndromes. N Engl J Med. 2015;372(25):2387-2397. 
 


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APPENDIX A: SCHEDULE OF PROCEDURES 
 
Screening 
Treatment Period 
Safety 
Follow-up  
PK 
Early 
Termination 
Visit 
Visit 
1 
2 
3 
4 
5 
6 
Week 
Up to -2 
0 
4 
8 
12 
16 
Day (Visit Window) 
-14 to -1 
1 
29 (3) 
57 (3) 
85 (3) 
113 (7) 
Unscheduled 
Informed consenta 
X
 
Inclusion/exclusion criteria 
X
Xb
 
Demographic information 
X
 
Medical/surgical history 
X
 
Prior/concomitant medications 
X
X
X
X 
X
X
Weight and heightc 
X
X 
X
Physical examination 
X
X 
X
Vital signsd 
X
X
X
X 
X
X
12-lead ECGe 
X
 
Urine pregnancy testf 
X
 
FSH testg 
X
 
Fasting (10 hours) chemistry and hematologyh
X
X
X
X 
X
 
X
Urinalysis 
X
X
X
X 
X
X
Fasting (10 hours) lipid profilei 
X
X
X
X 
 
X
PK samplej 
X
X 
X
X
CETP mass samplej 
X
X 
X
X
Randomization 
X
 
Dispense study drugs, as appropriate 
X
X
 
Study drug administrationk 
X
X
X 
Study drug compliance check 
X
X 
X
TLC diet counselingl 
X
X
X
 
Register visit in IRT 
X
X
X
X 
X
Adverse event assessment 
X
X
X 
X
X
X
 
 
 
 


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a. Signed informed consent must be obtained before any study-related procedures are performed. 
b. Any updates since the Screening Visit will be assessed. 
c. Height and weight will be measured at the Screening Visit and will be used to calculate body mass index. Weight only will be measured at all other visits as indicated. Measurement 
of weight should be performed with the participant dressed in indoor clothing, with shoes removed, and bladder empty. 
d. Vital signs will include body temperature, heart rate, and triplicate blood pressure (systolic and diastolic) measurements.  
e. A single, standard 12-lead ECG will be performed by the Investigator or trained site personnel at the Screening Visit and centrally read by 
 
f. For women of childbearing potential only. 
g. FSH test will be performed in peri-menopausal women, defined as women <55 years of age for whom it has been 1 year since their last menstrual period. 
h. At Screening Visit only, hematology panel will include HbA1c. 
i. At all visits, LDL-C will be calculated using the Friedewald formula. In addition, at Visit 2 and Visit 4, LDL-C will also be measured by preparative ultracentrifugation, also 
referred to as beta quantification. 
j. Samples will be stored for future analysis. 
k. Study drugs will be administered by the participant orally and once daily on Days 1 through 57. Study drugs should be administered at approximately the same time each morning, 
with food. On days with visits scheduled, study drugs should be administered with food following all fasted blood samples. 
l. Participants will be instructed to begin the TLC diet at the Screening Visit. 
CETP = cholesteryl ester transfer protein; ECG = electrocardiogram; FSH = follicle-stimulating hormone; HbA1c = glycosylated hemoglobin; IRT = interactive response technology; 
PK = pharmacokinetic; TLC = Therapeutic Lifestyle Changes. 
 
 


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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) 
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: 
https://www.mdcalc.com/ckd-epi-equations-glomerular-filtration-rate-gfr. 
 
Endocrinology 
Follicle-stimulating hormone [1] 
 
[1] Follicle-stimulating hormone test will be performed in peri-menopausal women, defined as 
women <55 years of age for whom it has been 1 year since their last menstrual period. 
 
Hematology 
Glycosylated hemoglobin (HbA1c) [1] 
Hematocrit 
Hemoglobin 
Platelets 
Red blood cell count 
White blood cell count and differential [2] 
[1] Screening Visit only. 
[2] Manual microscopic review is performed only if white blood cell count and/or differential 
values are out of reference range. 
 
Urinalysis 
Bilirubin 
Blood 
Glucose 
Ketones 
Leukocyte esterase 
Microscopy [1] 
Nitrite 
pH 
Protein 
Specific gravity 
Urobilinogen 
 
[1] Microscopy is performed only as needed based on positive dipstick test results. 
 


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Pregnancy Test 
Urine 
 
 
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] At all visits, LDL-C will be calculated using the Friedewald formula. In addition, at Visit 2 
and Visit 4, LDL-C will also be measured by preparative ultracentrifugation, also referred to as 
beta quantification. 
 
 


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APPENDIX C: DIET GUIDELINES 
The table below describes guidelines for the Therapeutic Lifestyle Changes diet: 
Component 
Recommendation 
Saturated fats 
<7% of total calories
Total fat 
25% to 35% of total calories
Dietary cholesterol 
<200 mg/day
Sodium 
<2400 mg/day
Total calories 
Adjust total caloric intake to maintain desirable body weight and/or prevent 
weight gain
Adapted from the United States National Institutes of Health Therapeutic Lifestyle Changes [TLC] diet. 
 

SAP_001.pdf: 
MEDPCE 
STATISTICAL ANALYSIS PLAN 
Protocol Title: 
A Placebo-Controlled, Double-Blind, Randomized Phase 2 
Study to Evaluate the Effect of Obicetrapib in Combination 
with Ezetimibe in Participants with Mild Dyslipidemia 
Protocol Number: 
TA-8995-303 
Protocol Version/Date: 
V4.0 / 14 January 2021 
lnvestigational Product: 
Obicetrapib 
Sponsor: 
SAP Version/Date: 
NewAmsterdam Pharma BV 
Gooimeer 2-35 
1411 DC 
Naarden 
The Netherlands 
Telephone: +31 35 699 30 00 
Fax: +31 20 240 07 79 
V2.0 / 24 June 2021 
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 or Independent Ethics Committee and study personnel directly involved with 
conducting this protocol. Persons to whom the information is disclosed must be informed that the 
information is confidential and proprietary to NewAmsterdam Pharma BV and that it may not be 
further disclosed to third parties. 
NCT number: NCT04770389
This NCT number has been applied to the document for the purposes of 
posting on clinicaltrials.gov