Clinical trial NCT02586155
Conditions: Diabetes Mellitus, Type 2 Coronary Artery Disease
Sponsor: Resverlogix Corp
Start date: 2015-11-01; Completion date: 2021-06-21
Enrollment: 2425 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine whether bromodomain extraterminal domain (BET) inhibition treatment with RVX000222 in high-risk type 2 diabetes mellitus patients with coronary artery disease increases the time to major adverse cardiovascular events.

Detailed description:
The majority (75%) of deaths in subjects with diabetes mellitus (DM) are due to atherosclerotic cardiovascular disease (CVD). Recent studies suggest a major adverse cardiovascular event (MACE) rate of \>11% over 18 months in type 2 diabetes mellitus (T2DM) despite a baseline LDL-C of \<2.1 mmol/L. Bromodomains (BRDs) are a family of evolutionary conserved protein-interaction modules that play key functions in chromatin organization and regulation of gene transcription. One recognized family of bromodomain-containing proteins is the bromodomain and extra-terminal (BET) family. BET inhibition represents a novel, epigenetic approach to treat CAD.

RVX000222 affects biological processes important in atherosclerosis and acute coronary events via selective inhibition of BET proteins. RVX000222 is available as a capsule formulation with standard excipients and established stability.

The BETonMACE study will focus on prevention of subsequent MACE in subjects with CAD and DM with high intensity statin therapy as co-medication.

Arms: arm 1: Daily dose 100 mg capsule b.i.d. with high-intensity statin therapy (atorvastatin or rosuvastatin) arm 2: Placebo (for RVX000222 100 mg capsule) b.i.d. with high-intensity statin therapy (atorvastatin or rosuvastatin)
Interventions: intervention 1: Apabetalone intervention 2: Placebo intervention 3: Atorvastatin intervention 4: Rosuvastatin
Intervention descriptions: intervention 1: 100 mg capsule intervention 2: Capsule manufactured to mimic RVX000222 100 mg capsule intervention 3: High-Intensity Statin intervention 4: High-Intensity Statin

Protocol documents:
Prot_000.pdf: 
Version 3A / 31 October 2017 
 
CONFIDENTIAL  
 
 
 
 
 
BETonMACE 
A Phase III Multi-Center, Double-Blind, Randomized, Parallel Group, Placebo-Controlled Clinical Trial in 
High-Risk Type 2 Diabetes Mellitus (T2DM) Subjects with Coronary Artery Disease (CAD) to Determine 
Whether Bromodomain Extraterminal Domain (BET) Inhibition Treatment with RVX000222 Increases the 
Time to Major Adverse Cardiovascular Events (MACE) 
 
Protocol Number: 
RVX222-CS-015 
 
Investigational Product: 
RVX000222 Oral, 100 mg Capsule 
 
EudraCT Number: 
ClinicalTrials.gov Identifier: 
2015-002040-14  
NCT02586155 
 
Sponsor: 
Resverlogix Corp. 
300, 4820 Richard Road SW 
Calgary, Alberta, T3E 6L1 
CANADA 
Phone: 403.254.9252 
Fax: 403.256.8495 
 
Medical Monitor: 
Michael Sweeney, M.D. 
Resverlogix Corp. 
 
Protocol Version / Date: 
Version3A / 31 October 2017 
 
 
 
 
 
 
 
Clinical Development Approval: 
 
 
 
 
Michael Sweeney, M.D 
Senior VP of Clinical Development 
Resverlogix Corp. 
 
Date 
Resverlogix Confidential Information 
 
The information contained herein is the property of Resverlogix and may not be reproduced, published, or 
disclosed to others without written authorization of Resverlogix. This study will be conducted according to 
the principles of Good Clinical Practice (GCP) as described in International Conference on Harmonisation 
(ICH) guidelines, including the archiving of essential documents. 
 
 


Version 3A / 31 October 2017 
 
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Page 2 of 73 
PROTOCOL REVIEW AND SIGNATURE FORM 
Sponsor: 
Resverlogix Corp. 
 
 
Protocol Title: 
A Phase III Multi-Center, Double-Blind, Randomized, 
Parallel Group, Placebo-Controlled Clinical Trial in High-
Risk Type 2 Diabetes Mellitus (T2DM) Subjects with 
Coronary Artery Disease (CAD) to Determine Whether 
Bromodomain Extraterminal Domain (BET) Inhibition 
Treatment with RVX000222 Increases the Time to Major 
Adverse Cardiovascular Events (MACE) 
 
Protocol Number: 
 
Protocol Version / Date: 
RVX222-CS-015 
 
Version 3A / 31 October 2017 
 
 
 
I have read the above-mentioned protocol. I agree to conduct the study as detailed herein and in 
compliance with International Conference on Harmonisation (ICH) guidelines for Good Clinical Practice 
(GCP) and other applicable regulatory requirements, and to inform all who assist me in the conduct of this 
study of their responsibilities and obligations. 
 
 
 
 
 
Principal Investigator Signature 
 
 
Date 
Principal Investigator Name (print) 
 
 
 
 


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Page 3 of 73 
CLINICAL STUDY RVX222-CS-015 PROTOCOL SYNOPSIS 
Title 
BETonMACE:  A Phase III Multi-Center, Double-Blind, Randomized, Parallel Group, 
Placebo-Controlled Clinical Trial in High-Risk Type 2 Diabetes Mellitus (T2DM) Subjects 
with Coronary Artery Disease (CAD) to Determine Whether Bromodomain Extraterminal 
Domain (BET) Inhibition Treatment with RVX000222 Increases the Time to Major Adverse 
Cardiovascular Events (MACE) 
Protocol No. 
RVX222-CS-015 
Study Centers 
Multiple, global investigative sites  
Indication 
Secondary cardiovascular disease (CVD) prevention in type 2 diabetes mellitus (T2DM) 
subjects with low high-density lipoprotein cholesterol (HDL-C) at high risk for MACE.  
Objectives 
Primary Objective: 
To evaluate if treatment with RVX000222 as compared to placebo increases time to the 
first occurrence of narrowly defined MACE. Narrowly defined MACE is defined as a single 
composite endpoint of CV death or non-fatal MI or stroke. 
Secondary Objectives: 
• 
To evaluate if treatment with RVX000222 increases time to the first occurrence of 
broadly defined MACE in comparison to placebo 
Broadly defined MACE is the occurrence of any of the following events:  
• 
CV death 
• 
Non-fatal Myocardial Infarction (MI) 
• 
Hospitalization for CVD events including: 
• 
Unstable angina AND evidence of new or presumed new progressive 
obstructive coronary disease, OR 
• 
Emergency revascularization procedures at any time and urgent 
revascularization procedures ≥30 days after the index event as defined 
by Hicks et al. 
• 
Stroke 
• 
To evaluate if treatment with RVX000222 increases time to the first occurrence of 
fatal or non-fatal MI, or fatal or non-fatal stroke 
• 
To evaluate treatment group difference in all-cause mortality 
• 
To evaluate changes in lipoprotein concentrations including apoA-I, apolipoprotein B 
(apoB), low-density lipoprotein cholesterol (LDL-C), HDL-C, and triglyceride (TG) 
over time within and between treatment groups 
• 
To evaluate changes in diabetes mellitus variables including glycated hemoglobin 
(HbA1c), fasting glucose, and fasting insulin over time within and between treatment 
groups 
• 
To evaluate changes in alkaline phosphatase (ALP) over time within and between 
treatment groups including isoforms for whole population and quartiles of ALP 


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baseline concentration 
• 
Assess changes in kidney function in population with baseline estimated glomerular 
filtration rate (eGFR) <60 mL/min/1.7m2 
• 
To evaluate the safety and tolerability of RVX000222  
Exploratory Objectives: 
• 
To evaluate changes in inflammation variables including, but not limited to, high-
sensitivity C-reactive protein (hsCRP), fibrinogen, and inflammatory cytokines within 
and between treatment groups  
• 
To evaluate transcription (messenger RNA [mRNA]) change in whole blood from 
baseline to 6 weeks of treatment  
• 
To evaluate Health Related Quality of Life (HRQOL) as measured using the EQ-5D-
5L 
Study Design 
This design is a double-blind, placebo-controlled, 2-arm parallel-group (allocation ratio 
1:1), study of RVX000222 at a dose of 100 mg b.i.d. (total daily dose of 200 mg) or 
matching placebo in combination with high intensity statin therapy administered to T2DM 
subjects with history of recent CAD event and HDL-C level <40 mg/dL males or <45 
mg/dL females. High intensity statin therapy shall consist of a daily dose of either 
atorvastatin 40-80 mg or rosuvastatin 20-40 mg. [20 mg atorvastatin or 10 mg 
rosuvastatin is only acceptable in circumstances such as advanced age, low body mass, 
previous intolerance to higher doses or specific drug-drug interactions (e.g. anti-
retrovirals).] After an initial screening period of 1 to 2 weeks during which subjects will be 
treated with high intensity statin therapy, subjects will be randomized to either 
RVX000222 100 mg b.i.d. or matching placebo with continued statin treatment. This 
combination treatment period will continue until 250 narrowly defined MACE events have 
occurred in the study and all surviving patients have been followed for at least 24 weeks 
from randomization. Blinded treatment with RVX000222 or matching placebo will then be 
discontinued. Subjects will remain on high intensity statin therapy for 4 more weeks until 
the Follow-Up Visit.  
The study is an event-based trial and will continue until 250 narrowly defined MACE 
events have occurred.  The study will be monitored by a Data Safety Monitoring Board 
(DSMB). 
MACE will be adjudicated by an independent, treatment-blinded MACE Clinical Events 
Committee (CEC) in an ongoing manner.  
Target 
Population 
Male or female subjects with T2DM and high risk CAD treated with high intensity statin 
therapy and with a low level of HDL-C of <40 mg/dL males or <45 mg/dL females.  
Length of 
Study 
Total subject participation:  
• 
Screening period of 1-2 weeks 
• 
Treatment period of time until study reaches 250 narrowly defined MACE events 
or a minimum of 24weeks 
• 
Follow-up period of 4 weeks  
 
 


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Selection 
Criteria 
Inclusion Criteria: 
1. Male and female subjects age 18 and over with documented diagnosed T2DM and a 
CAD event of either unstable angina or myocardial infarction, not less than 7 days and 
no more than 90 days prior to Visit 1. In order to have sufficient number of clinical 
events, the number of subjects with unstable angina will be limited to 25% of the total 
number of subjects. 
• 
Unstable angina: for a qualifying unstable angina event, each of components (a), 
(b), and (c) must be satisfied:  
a. Characteristic ischemic pain or discomfort in chest or associated referral areas, 
occurring at rest or with minimal exertion 
b. ECG changes consistent with acute myocardial ischemia based upon at least 
one of the following: 
i. 
new or presumed new ST elevation 
ii. 
new or presumed new ST depression  
iii. 
new or presumed new T-wave inversion 
c. Objective evidence of obstructive coronary artery disease based upon at least 
one of the following: 
i. 
new or presumed new evidence of myocardial ischemia or infarction by 
perfusion imaging 
ii. 
new or presumed new regional wall motion abnormality 
iii. 
current evidence of at least one epicardial coronary artery stenosis ≥70% 
by coronary angiography 
iv. 
need for coronary revascularization for the index ACS event, including  a 
percutaneous coronary intervention (PCI) with or without coronary 
stenting 
• 
Previous MI 7-90 days before screening, treated with or without a percutaneous 
coronary intervention (PCI). For a qualifying event of MI, two of the following 
three criteria must be satisfied: 
a. Characteristic ischemic chest pain or pain in associated referral areas 
b. Dynamic elevation of troponin T or I or CKMB, if troponin T or I is unavailable 
at the local lab (at least above the upper limit of normal for the laboratory) 
c. Development of new Q-waves in at least two adjacent electrocardiogram 
(ECG) leads or development of a new dominant R wave in V1 
2. Documented diagnosis of T2DM (one or more of the following criteria must be met):  
• 
Documented history of T2DM  
• 
History of taking diabetes medication  
• 
HbA1c ≥6.5% at Visit 1 
3. For males HDL-C of <40 mg/dL (1.04 mmol/L) and for females HDL-C of <45 mg/dL 
(1.17 mmol/L) at Visit 1. 
4. In the opinion of the Investigator, subjects currently not on high intensity statin therapy 
will be able to start rosuvastatin according to the protocol at Visit 1. 


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5. In the opinion of the Investigator, subjects currently on statin therapy other than 
atorvastatin or rosuvastatin can be switched to rosuvastatin according to the protocol at 
Visit 1. High intensity statin therapy doses should remain unchanged during the study 
period if at all possible.    
6. Female subjects must meet one of the following: 
• 
If of childbearing potential, female subjects must have a negative urine pregnancy 
test and be willing and able to use medically acceptable non-hormonal method of 
birth control (non-hormonal intrauterine device, condom, or diaphragm) or remain 
abstinent from Screening until Follow-up Visit. 
• 
Be of non-child-bearing potential: post-surgical sterilization or post-menopausal.  
7. Have given signed informed consent to participate in this study. 
Exclusion Criteria:  
1. Heart disease which, in the opinion of the investigator, will within 90 days of Visit 1 
likely require coronary bypass, PCI, cardiac transplantation, surgical repair and/or 
replacement. 
2. Previous or current diagnosis of severe heart failure (New York Heart Association 
Class IV) or a documented left ventricular ejection fraction (LVEF) of <25% as 
determined by contrast left ventriculography, radionuclide ventriculography or 
echocardiography. The absence of a LVEF measurement in a subject without a 
previous or current diagnosis of heart failure does not prohibit entry into the study. 
3. Subjects with evidence of cardiac electrophysiologic instability including a history of 
uncontrolled ventricular arrhythmias, uncontrolled atrial fibrillation/flutter or uncontrolled 
supraventricular tachycardias with a ventricular response heart rate of >100 beats per 
minute at rest within 4 weeks prior to Visit 1. 
4. Coronary artery bypass grafting (CABG) within 90 days prior to Visit 1. 
5. Evidence of severe renal impairment as determined by any one of the following:  
• 
an eGFR <30 mL/min/1.7m2 at Visit 1 
• 
a current need for dialysis  
6. Uncontrolled hypertension defined as 2 consecutive measurements of sitting blood 
pressure of systolic >180 mm Hg or diastolic >100 mm Hg at Visit 1. 
7. Subjects at risk of immunosuppression, including current or recent (within 12 months 
prior to Visit 1) treatment with immunosuppressants (e.g., cyclosporine). 
8. Use of fibrates at any dose or niacin/nicotinic acid 250 mg or more within 30 days prior 
to Visit 1. 
9. A known allergy or sensitivity to any ingredient in the investigational medicinal product. 
10. History of intolerance to atorvastatin or rosuvastatin. This exclusion criterion applies 
to subjects with a history of intolerance to the statin to which they would be assigned 
at screening.  
11. Triglycerides >400 mg/dL (4.52 mmol/L) at Visit 1.  
12. Any medical or surgical condition which might significantly alter the absorption, 
distribution, metabolism or excretion of medication including, but not limited to any of 
the following: untreated or incompletely treated thyroid dysfunction, cholecystitis, 
Crohn’s disease, ulcerative colitis, or any gastric bypass alteration. 


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Page 7 of 73 
13. Evidence of cirrhosis from liver imaging or biopsy, a history of hepatic 
encephalopathy, esophageal or gastric varices, active hepatitis, or prior porta-caval 
shunt procedure, or a Child-Pugh score of at least 5 points (Appendix A).  
• 
Any one of the following liver enzymes that is >1.5x the upper limit of normal 
range (ULN) by central lab at Visit 1  
a. Alanine aminotransferase (ALT) 
b. Aspartate aminotransferase (AST) 
14. A total bilirubin that is >ULN by central lab at Visit 1.  
15. History of malignancy of any organ system, treated or untreated, within the past 2 
years whether or not there is evidence of local recurrence or metastases, with the 
exception of localized basal cell carcinoma of the skin.  
16. History or evidence of drug or alcohol abuse within 12 months of Visit 1, in the opinion 
of the investigator. 
17. Female subjects who are pregnant. 
18. Any condition which, in the opinion of the investigator, may place the subject at higher 
risk from his/her participation in the study, or is likely to prevent the subject from 
complying with the requirements of the study or completing the study, including 
subjects at risk of immunosuppression. 
19. Use of other investigational drugs and devices within 30 days or 5 half-lives of Visit 1, 
whichever is longer. 
20. History of noncompliance with medical regimens or unwillingness to comply with the 
study protocol. 
21. Any condition that, in the opinion of the investigator, would confound the evaluation 
and interpretation of efficacy and/or safety data. 
22. Persons directly involved in the execution of this protocol. 
Study 
Procedures 
After informed consent is signed at the Screening Visit (Visit 1), laboratory samples will be 
collected, and subjects currently receiving high intensity statin therapy of 40-80 mg 
atorvastatin or 20-40 mg rosuvastatin will continue on the same statin as they are 
currently receiving. Subjects who are currently receiving atorvastatin or rosuvastatin at 
doses other than the protocol-defined dosage will, if clinically appropriate in the 
investigator’s opinion, begin treatment with atorvastatin at the 40-80 mg dose or 
rosuvastatin at the 20-40 mg dose. [20 mg atorvastatin or 10 mg rosuvastatin is only 
acceptable in circumstances such as advanced age, low body mass, previous intolerance 
to higher doses or specific drug-drug interactions (e.g. anti-retrovirals).] Subjects not 
currently receiving high intensity statin therapy of atorvastatin or rosuvastatin, will begin 
treatment with 20-40 mg rosuvastatin and discontinue use of any other statin previously 
prescribed.  
Randomization will be stratified by the participating country and high intensity statin 
therapy (atorvastatin or rosuvastatin) within the country. Further, randomization will be 
dynamically restricted to assure that statin therapy imbalance is no greater than 60:40 (or 
40:60) within each country. 
After 1 to 2 weeks of study qualification and demonstrated tolerance of high intensity 
statin therapy treatment during screening phase, subjects will return to the clinic for Visit 2 
at which adverse events (AEs) will be recorded. Upon confirmation of tolerance of high 
intensity statin therapy and satisfaction of inclusion and exclusion criteria based on the 
Visit 1 central laboratory results, subjects will be randomized and treatment-blinded 
investigational drug will be dispensed. Atorvastatin or rosuvastatin dose may be adjusted 
if indicated clinically during the study. 


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Page 8 of 73 
Clinical safety will be evaluated at each visit. Assessments can include physical 
examinations, vital sign measurements and clinical laboratory measurements including 
lipid analysis, biomarkers of cardiovascular (CV) risk and safety laboratories. All CV 
events including hospitalizations and deaths will be adjudicated by a CEC. A DSMB will 
monitor the study regularly.   
After randomization to RVX000222 or placebo, visits will occur every 2 weeks until Week 
12. From Week 12 to 28, visits will occur every 4 weeks. From Weeks 28 until the Last 
Visit on Treatment visits will occur approximately every 12 weeks. Four to sixteen weeks 
after Last Visit on Treatment, patients will return for a final Follow-Up Visit. Study 
treatment will be terminated in all currently participating subjects when 250 narrowly 
defined MACE events have occurred in the study and all surviving patients have been 
followed for at least 24 weeks from randomization. At that time, all subjects will conduct 
their Last Visit on Treatment. Subjects will continue to take atorvastatin or rosuvastatin 
and will return 4 weeks after Last Visit on Treatment for the Follow-Up Visit. Procedures 
are defined in  
 
Screen 
Treatme
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Week 
- 2 to -1 
0 
2 
4 
6 
8 
10 
12 
16 
20 
24 
28 
± No. Day 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 


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Table 1: Schedule of Events.  The same visit schedule will apply to subjects who remain 
on assigned study treatment until the Last Visit on Treatment and to subjects who have 
prematurely discontinued study medication prior to the Last Visit on Treatment. 
Liver safety:  
a) If ALT increase of >3 and ≤5xULN is confirmed on repeat measurement (within 3-
4 days), subjects will be monitored every 3-4 days until the ALT is <1.5xULN.   
b) If ALT increase of >5xULN, investigational drug will be suspended. If confirmed 
on repeat measurement (within 3-4 days), investigational drug will be 
discontinued and subjects will be monitored every 3-4 days until ALT is 
<1.5xULN. 
c) If serum bilirubin increase of >2xULN, investigational drug will be suspended. If 
confirmed on repeat measurement (within 3-4 days), investigational drug will be 
discontinued and subjects will be monitored every 3-4 days until levels are within 
normal range.  
Subjects who have an ALT increase of >3xULN will be monitored by liver safety panels  
[ALT (SGPT), AST (SGOT), GGT, ALP, bilirubin (direct and total)] and have archival 
serum samples drawn every 3-4 days until ALT is <1.5xULN. Subjects who have an ALT 
increase of >5xULN or who have a serum bilirubin increase of >2xULN will be monitored 
by extended liver safety panels [ALT (SGPT), AST (SGOT), GGT, ALP, bilirubin (direct 
and total), as well osteopontin and PT INR] and have archival serum samples drawn 
every 3-4 days until ALT is <1.5xULN and serum bilirubin is within the normal range.  
If the ALT or serum bilirubin elevation has a likely cause other than investigational drug 
(e.g. trauma, infection-inflammation, surgery, acetaminophen, clavulanic acid, diclofenac), 
investigational drug may be restarted at 50 mg b.i.d. once ALT returns to 1.5xULN. 
Subjects should continue with all scheduled study visits with additional liver safety panel 
tests drawn as defined in Section 6.10.1. All re-initiations of study therapy must be 
discussed with and approved by the study medical monitor. 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion / Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
Medical History/Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
 
 
 
 
 
 
 
 
X 
 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
Central Laboratory: 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting Lipid profile 
X 
 
 
 
 
 
 
 
 
 
X 
 
Hematology, HbA1c 
X 
 
 
 
 
 
 
 
 
X 
 
Chemistry 
X 
 
 
 
 
 
 
 
X 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
X 
 
Hepatitis Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
Liver Safety Panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biomarker Laboratory Tests 
  
 
 
 
 
 
 
 
 
 
 
 
Lipoproteins, fasting insulin 
 
X 
 
 
 
 
 
 
 
 
X 
 
Inflammation Panel 
 
X 
 
 
 
 
 
X 
 
 
 
 
Serum/Plasma Archive 
 
X 
 
 
 
 
 
X 
 
 
 
 
Pharmacogenomic 
 
X 
 
 
X 
 
 
 
 
 
 
 
MOCA 
 
X 
 
 
 
 
 
 
 
 
 
 
EQ-5D-5L 
 
X 
 
 
 
 
 
 
 
 
X 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior / Con. Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug Dispense/Account. 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Page 10 of 73 
Investigational 
drug 
RVX000222 will be administered orally with food at a dose of 200 mg daily (100 mg b.i.d.). 
In certain situations the dose may be decreased to 100 mg daily (50 mg b.i.d.)  
Concomitant 
Statin Therapy 
Protocol-defined concomitant statin therapy in this study is a tolerable atorvastatin daily 
dose of 20-80 mg or rosuvastatin daily dose of 10-40 mg. [Doses of 20 mg atorvastatin 
and 10 mg rosuvastatin are only acceptable in circumstances such as advanced age, low 
body mass, previous intolerance to higher doses, or specific drug-drug interactions (e.g. 
anti-retrovirals).] 
Efficacy 
Assessments 
Primary Endpoint: 
Time from randomization to the first occurrence of adjudication-confirmed MACE narrowly 
defined as a single composite endpoint of CV Death or Non-fatal MI or Stroke.  
Key Secondary Endpoints: 
1. Time from randomization to the first occurrence of adjudication-confirmed MACE 
broadly defined between treatment groups.  
Broadly defined MACE is the occurrence of any of the following events:  
• 
CV death 
• 
Non-fatal MI 
• 
Hospitalization for CVD events which include:  
o 
Unstable angina AND evidence of new or presumed new progressive 
obstructive coronary disease, OR 
o 
Emergency 
revascularization 
procedures 
at 
any 
time 
and 
urgent 
revascularization procedures ≥30 days after the index events prior to 
randomization  
• 
 Stroke 
2. Time from randomization to fatal or non-fatal MI, or fatal or non-fatal stroke 
3. Time from randomization to CV Death or Non-fatal MI 
4. Time from randomization to Non-fatal MI 
5. Time from randomization to CV Death 
6. Time from randomization to Stroke 
7. All-cause mortality 
Other Secondary Endpoints:  
• 
The percent change in apoA-I, apoB, LDL-C, HDL-C, and TG over time within and 
between treatment groups 
• 
The change from baseline in HbA1c, fasting glucose, and fasting insulin within 
and between treatment groups 
• 
Changes in ALP within and between treatment groups for all subjects and 
according to quartiles of ALP baseline concentration 
• 
Changes from baseline in kidney function in subgroup population with estimated 
glomerular filtration rate <60 mL/min/1.7 m2 within and between treatment groups  
Exploratory Endpoints: 
• 
The percent change in hsCRP, fibrinogen, and inflammatory cytokines within and 
between treatment groups 
• 
Transcription/mRNA change in whole blood from baseline to 6 weeks treatment 


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Page 11 of 73 
within and between treatment groups 
• 
Change in Health Related Quality of Life (HRQOL) as measured using the EQ-
5D-5L 
Safety 
Assessments 
Safety assessments will include incidence of AEs, serious AEs (SAEs), vital sign 
measurements, clinical laboratory evaluations, and physical examination findings. For 
subjects ≥70 years at randomization, a Montreal Cognitive Assessment (MOCA) test will 
be completed. 
 
Data Safety 
Monitoring 
Board 
An independent DSMB will be appointed to monitor the subject safety data on an 
ongoing basis at quarterly meetings during the course of the study. The ongoing 
DSMB safety review will include review of adverse events of special interest, including 
all opportunistic infections and serious infections.  In addition to ongoing safety 
assessments, the DSMB will review and interpret the planned interim efficacy analysis 
to assess futility and sample size, if indicated, when 75% (i.e. 188) of the 250 narrowly 
defined MACE have been confirmed by CEC. 
The statistical methodology for SSA that preserves the overall Type I error will be 
described in greater detail in the DSMB interim futility / sample size adjustment 
analysis plan. 
Sample Size 
It is estimated that enrollment of approximately 2400 subjects will be needed to reach 
the 250 narrowly defined MACE in this event based trial. 
Statistical 
Consider-
ations  
Sample Size Justification: 
A sample size of 2400 randomized subjects will yield approximately 80% power for the 
primary analysis under the following assumptions: 
1. Total number of events: 250   
2. 2-sided type 1 error rate of α=5%   
3. 10.5% event rate in the placebo arm at 18 months 
4. 30% relative risk reduction (7.47% event rate at 18 months in the RVX000222 
arm)  
5. A cumulative drop-out rate of 10% per arm by the end of the study (5% drop out 
rate per arm by year 1) 
6. Provision for an interim analysis to terminate the trial for futility (non-binding) 
when approximately 75% of the 250 events have occurred 
Primary Analysis: 
The primary analysis of time to the first occurrence of MACE narrowly defined will be 
completed following the occurrence of the 250th adjudication-confirmed primary 
endpoint event. The RVX000222 and placebo groups will be compared using a two-
sided stratified log-rank test with an alpha = 0.05 level of significance. 
Secondary and Exploratory Analyses: 
Endpoints that are defined as time-to-event variables will be analyzed using the 
stratified log-rank test, as described for the primary analysis. Quantitative endpoints 
that are defined as a change from baseline will be analyzed using analysis of 


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Page 12 of 73 
covariance (ANCOVA) models with treatment group as a factor and the baseline value 
as a covariate.   
No adjustment for multiplicity is needed for the primary hypothesis as there is no 
provision to terminate the trial for efficacy. A sequential gate-keeping approach will be 
used to control the overall Type I error rate when testing for the key secondary 
endpoints only if superiority is established for primary efficacy endpoint. The key 
secondary endpoints will be tested sequentially following a pre-specified order. 
No multiplicity adjustment is planned to test the other secondary and exploratory 
endpoints. 


 
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Page 13 of 73 
Table 1: Schedule of Events 
 
1Study treatment will be terminated in all currently participating subjects when the 250th event occurs and all surviving patients have been followed for at least 24 weeks from randomization. At that time all subjects actively treated will conduct their Last Visit on Treatment. 
2 4 weeks after Last Visit on Treatment (LVT). 
 
3 Physical Exam: height will be recorded only at Visit 1  
4 Lipid profile includes: TC, LDL-C, HDL-C, TG 
5 Hematology includes: platelet count, hemoglobin, hematocrit, RBC, WBC with differential  
6 Chemistry includes: albumin, blood urea nitrogen, creatine kinase, serum creatinine, fasting glucose,  calcium, phosphate, potassium, sodium, total protein  
7 Including urine HCG at screening for subjects of childbearing potential.  Dipstick tests performed and results maintained at investigational sites. 
8 Hepatitis Serology:  hepatitis A (IgM), B by HBs-Ag, Anti-HBs, Anti-HBc , C (HCV) 
9 Liver Safety Panel:  ALT (SGPT), AST (SGOT), GGT, ALP, bilirubin (direct and total)  
10 Additional biomarker laboratory test samples will be collected on a selected subset of subjects 
11 Lipoproteins include: apoA-I and apoB 
12Inflammation Panel includes: hsCRP, fibrinogen, and inflammatory cytokines 
13 Serum/plasma samples for future biomarker analysis in lipid/inflammation 
14 Optional:  whole blood will be collected for DNA analysis (Visit 2 only) and mRNA analysis (both Visit 2 and 5) if consent obtained. 
15 Montreal Cognitive Assessment (MOCA) will be performed on  subjects ≥70 years of age at randomization 
16 Only statin will be dispensed at screening visit and LVT.  
 
Screen 
Treatment 
Follow 
Up (ET) 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18  
19 to end of 
study 
LVT1 
FU 
Week 
- 2 to -1 
0 
2 
4 
6 
8 
10 
12 
16 
20 
24 
28 
40 
52 
64 
76 
88 
100  
112, then 
every 12wks 
end of 
study 
 LVT + 
4wks2 
± No. Day 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
Physical Exam3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
Central Laboratory: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting Lipid profile4 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
Hematology5, HbA1c 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
Chemistry6 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
Urinalysis7 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
Hepatitis Serology8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver Safety Panel9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biomarker Laboratory Tests10 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipoproteins11, fasting insulin 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
Inflammation Panel12 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Serum/Plasma Archive13 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Pharmacogenomic14 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MOCA15 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
EQ-5D-5L 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior / Con. Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug Dispense/Account. 
X16 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


 
Version3A / 31 October 2017 
 
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Page 14 of 73 
List of Abbreviations 
ACS 
Acute Coronary Syndrome 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
apoA-I 
Apolipoprotein A-I 
apoB 
Apolipoprotein B 
API 
active pharmaceutical ingredient 
AST 
Aspartate Aminotransferase 
ASSERT 
apoA-I Synthesis Stimulation Evaluation in Patients Requiring 
Treatment for Coronary Artery Disease 
ASSURE 
ApoA-I Synthesis Stimulation and Intravascular Ultrasound for 
Coronary Atheroma Regression Evaluation 
AUC 
Area under time curve 
BET 
Bromodomain and Extraterminal 
BID 
twice daily 
BMI 
Body Mass Index 
BRD 
Bromodomain 
BRD4 
BET protein 4 
CABG 
Coronary Artery Bypass Grafting  
CAD 
Coronary Artery Disease 
CEC 
Clinical Events Committee 
CI 
Confidence Interval 
CK 
Creatine Kinase 
CRO 
Contract Research Organization 


 
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Page 15 of 73 
CSC 
Clinical Steering Committee 
CV 
Cardiovascular 
CVD 
Cardiovascular disease 
CYP7A1 
cholesterol 7-alpha hydroxylase 
DM 
Diabetes Mellitus 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
eGFR 
Estimated Glomerular Filtration Rate 
EDC 
Electronic Data Capture 
EQ-5D-5L 
EuroQOL five dimensions questionnaire 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration, US 
FXR 
Farnesoid X Receptor 
GGT 
Gammaglutamyl Transferase 
HbA1c 
Glycated Hemoglobin 
HBcAb 
Hepatitis B Virus Core Protein Antibody 
HBsAb 
Hepatitis B Surface Antibody 
HBsAg 
Hepatitis B Surface Antigen 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HDL  
High-Density Lipoprotein  
HDL-C 
HDL cholesterol 
HIV 
Human Immunodeficiency Virus 
HRQOL 
Health Related Quality of Life  
hs-CRP 
high-sensitivity C-Reactive Protein 


 
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Page 16 of 73 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IgM 
Immunoglobulin M 
IND 
Investigational New Drug 
LDL 
Low-Density Lipoprotein  
LDL-C 
LDL Cholesterol 
LVEF 
Left Ventricular Ejection Fraction 
MACE 
Major Adverse Cardiac Events 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial Infarction 
MMRM 
Mixed Model Repeat Measures 
MOCA 
Montreal Cognitive Assessment 
mRNA 
Messenger RNA 
NOAEL 
No Observable Adverse Effect Level 
PCI 
Percutaneous Coronary Intervention 
PPS 
Per-Protocol Set 
RBC 
Red Blood Cells 
PT INR 
Prothrombin International Nomenclature Rate  
RCT 
Reverse Cholesterol Transport 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SmPC 
Summary of Product Characteristics 
SS 
Safety Set 
SSA 
Sample Size Adjustment 


 
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Page 17 of 73 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
SUSTAIN 
Study of qUantitative Serial Trends in lipids with ApoliproteIn A-I 
stimulatioN 
T2DM 
Type 2 Diabetes Mellitus 
TG 
Triglyceride 
ULN 
Upper Limit of Normal Range 
WBC 
White Blood Cells 
 
 
 


 
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Page 18 of 73 
TABLE OF CONTENTS 
 
 
BACKGROUND AND STUDY RATIONALE .................................................................. 22 
 
STUDY OBJECTIVES .................................................................................................... 25 
 
Primary Objective ........................................................................................................ 25 
 
Secondary Objectives ................................................................................................. 25 
 
Exploratory Objectives ................................................................................................ 25 
 
STUDY ENDPOINTS ...................................................................................................... 26 
 
Primary Endpoint ......................................................................................................... 26 
 
Key Secondary Endpoints ........................................................................................... 26 
 
Other Secondary Endpoints ........................................................................................ 26 
 
Exploratory Endpoints ................................................................................................. 26 
 
Safety Endpoints ......................................................................................................... 27 
 
STUDY DESIGN ............................................................................................................. 27 
 
STUDY POPULATION ................................................................................................... 27 
 
Number of Subjects ..................................................................................................... 27 
 
Inclusion Criteria.......................................................................................................... 27 
 
Exclusion Criteria ........................................................................................................ 29 
 
STUDY TREATMENT ..................................................................................................... 30 
 
Investigational Drug (RVX000222, Oral and Placebo for RVX000222, Oral) .............. 30 
6.1.1 RVX000222, Oral .................................................................................................... 30 
6.1.2 Placebo for RVX000222, Oral ................................................................................. 30 
 
Randomization ............................................................................................................ 30 
 
RVX000222 Treatment Blinding .................................................................................. 31 
 
Study Drug Supply, Storage, and Tracking ................................................................. 31 
 
RVX000222 Investigational Drug Administration ........................................................ 31 
 
Concomitant Statin Therapy ........................................................................................ 32 
 
Background Therapy ................................................................................................... 32 
 
Prohibited Concomitant Medications and Excluded Therapies ................................... 33 
 
Contraception / Hormone Replacement Therapy ........................................................ 33 
 
Study Drug Interruption/Discontinuation ...................................................................... 33 
6.10.1 
Additional Safety Lab Monitoring/Dose Adjustment ............................................ 34 
6.10.2 
Emergency Un-blinding of Treatment Assignment .............................................. 36 
6.10.3 
Subject Withdrawal / Discontinuation from Study ................................................ 36 
 
VISIT SCHEDULE AND ASSESSMENTS ..................................................................... 37 


 
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Safety Evaluations ....................................................................................................... 38 
7.1.1 Electrocardiograms ................................................................................................. 38 
7.1.2 Vital Signs ............................................................................................................... 38 
7.1.3 Physical Examinations ............................................................................................ 39 
7.1.4 Clinical Laboratory Tests ......................................................................................... 40 
7.1.4.1 
Fasting Lipid Profile ......................................................................................... 41 
7.1.4.2 
Hematology ..................................................................................................... 42 
7.1.4.3 
Chemistry ........................................................................................................ 43 
7.1.4.4 
Urinalysis ......................................................................................................... 44 
7.1.4.5 
Hepatitis Serology ........................................................................................... 45 
7.1.4.6 
Liver Safety Panel ........................................................................................... 45 
7.1.4.7 
Pregnancy Test ............................................................................................... 46 
7.1.5 Biomarker Laboratory Tests .................................................................................... 46 
7.1.5.1 
Lipoproteins ..................................................................................................... 47 
7.1.5.2 
Fasting Insulin ................................................................................................. 48 
7.1.5.3 
Inflammation Panel .......................................................................................... 49 
7.1.6 Serum and Plasma Archive Samples ...................................................................... 50 
7.1.7 Pharmacogenomic Testing (Optional) ..................................................................... 51 
7.1.8 Montreal Cognitive Assessment (MOCA) ................................................................ 52 
7.1.9 EuroQOL Five Dimensions Questionnaire (EQ-5D-5L) ........................................... 53 
 
Study Assessments ..................................................................................................... 55 
7.2.1 Screening/ Study Visit 1 (Week -2 to -1) ................................................................. 55 
7.2.2 Study Visit 2/Randomization (Week 0) .................................................................... 55 
7.2.3 Study Visits 3-4 (Weeks 2-4) ................................................................................... 56 
7.2.4 Study Visits 5 (Week 6) ........................................................................................... 56 
7.2.5 Study Visits 6-7 (Weeks 8-10) ................................................................................. 56 
7.2.6 Study Visits 8 (Weeks 12) ....................................................................................... 56 
7.2.7 Study Visits 9-10 (Weeks 16-20) ............................................................................. 56 
7.2.8 Study Visit 11 (Week 24) ......................................................................................... 56 
7.2.9 Study Visits 12-13 (Weeks 28, 40) .......................................................................... 57 
7.2.10 
Study Visit 14 (Week 52) ..................................................................................... 57 
7.2.11 
Study Visit 15 (Week 64) ..................................................................................... 57 
7.2.12 
Study Visit 16 (Week 76) ..................................................................................... 57 
7.2.13 
Study Visit 17 (Week 88) ..................................................................................... 57 


 
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Page 20 of 73 
7.2.14 
Study Visit 18 (Week 100) ................................................................................... 58 
7.2.15 
Study Visit 19 (Week 112) and additional visits until end of study (at 12 week 
intervals) 58 
7.2.16 
Last Visit on Treatment (at end of study)............................................................. 58 
7.2.17 
Follow-up Visit (4 weeks after Last Visit on Treatment) or Early Termination Visit
 
58 
 
SAFETY MONITORING .................................................................................................. 59 
 
Clinical Laboratory Tests ............................................................................................. 59 
 
Adverse Events ........................................................................................................... 59 
8.2.1 Definition of Adverse Events ................................................................................... 59 
8.2.2 Methods for Following and Documenting Adverse Events ...................................... 59 
8.2.2.1 
Follow-up on Adverse Events .......................................................................... 60 
8.2.2.2 
Rating Scale for Maximum Intensity ................................................................ 60 
8.2.2.3 
Rating Scale for Causality ............................................................................... 60 
8.2.2.4 
Follow-up Period After an Adverse Event ........................................................ 61 
8.2.2.5 
Coding of Adverse Events ............................................................................... 61 
8.2.3 Serious Adverse Events .......................................................................................... 61 
8.2.3.1 
Definition .......................................................................................................... 61 
8.2.3.2 
Hospitalization ................................................................................................. 61 
8.2.3.3 
SAE Reporting to Sponsor .............................................................................. 62 
8.2.3.4 
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities . 62 
8.2.3.5 
MACE Adjudication .......................................................................................... 63 
8.2.4 Pregnancies ............................................................................................................ 63 
 
STATISTICAL CONSIDERATIONS ............................................................................... 64 
 
General Considerations ............................................................................................... 64 
 
Sample Size ................................................................................................................ 64 
 
Analysis Sets ............................................................................................................... 64 
 
Baseline and Demographic Data ................................................................................. 65 
 
Subject Disposition ...................................................................................................... 65 
 
Efficacy Analysis ......................................................................................................... 65 
9.6.1 Multiplicity ................................................................................................................ 65 
 
Safety Analysis ............................................................................................................ 66 
 
Missing/Incomplete Subject Data ................................................................................ 66 
 
Interim Analysis ........................................................................................................... 66 


 
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Page 21 of 73 
 
REGULATORY AND PROCEDURAL REQUIREMENTS .............................................. 66 
 
Institutional Ethics Committee ..................................................................................... 66 
 
Ethical Conduct of the Study ....................................................................................... 67 
 
Informed Consent Document ...................................................................................... 67 
 
Responsibilities of the Investigator and IEC ................................................................ 67 
 
Monitoring the Study ................................................................................................... 67 
 
Protocol Adherence ..................................................................................................... 67 
 
Clinical Steering Committee ........................................................................................ 68 
 
Data and Safety Monitoring Board .............................................................................. 68 
 
Changes in the Conduct of the Study or Planned Analyses ........................................ 68 
 
Participant Recruitment ........................................................................................... 68 
 
Compensation, Insurance and Indemnity ................................................................ 68 
 
DATA COLLECTION ...................................................................................................... 68 
 
Recording of Data ....................................................................................................... 68 
 
Recordkeeping and Retention ..................................................................................... 69 
 
Data Collection ............................................................................................................ 69 
 
Efficacy ........................................................................................................................ 70 
 
Disclosure of Data ....................................................................................................... 70 
 
Confidentiality and Communication of Results ............................................................ 70 
 
REFERENCES ................................................................................................................ 72 
 
APPENDICES ................................................................................................................. 73 
Appendix A: Child-Pugh Classification9,10 ............................................................................... 73 
 
List of Figures 
 
Figure 1: MACE in Subjects Treated in RVX000222 Phase 2 Studies ....................................... 24 
 
List of Tables 
 
Table 1: Schedule of Events ....................................................................................................... 13 
Table 2: Effects of RVX000222 on Biomarkers of CV Risk – Lipids and Inflammation 
(ASSURE and SUSTAIN Trials) .......................................................................... 23 
Table 3: Investigational Drug Administration Schedule .............................................................. 32 
 
 


 
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Page 22 of 73 
 
BACKGROUND AND STUDY RATIONALE 
The majority (75%) of deaths in subjects with diabetes mellitus (DM) are due to atherosclerotic 
cardiovascular disease (CVD). In the United Kingdom Prospective Diabetes Study, after 9 years of follow-
up, fatal CVD events were 70 times more frequent than fatal microvascular complications.  High residual 
risk of CVD events remains, even in subjects with controlled low-density lipoprotein cholesterol (LDL-C). 
Recent studies suggest a major adverse cardiovascular event (MACE) rate of >11% over 18 months in 
type 2 diabetes mellitus (T2DM) despite a baseline LDL-C of <2.1 mmol/L. There is, therefore, an urgent 
need for new approaches to reduce MACE in subjects with CVD, especially for T2DM subjects.  
 
Bromodomains (BRDs) are a family of evolutionary conserved protein-interaction modules that play key 
functions in chromatin organization and regulation of gene transcription. One recognized family of 
bromodomain-containing proteins is the bromodomain and extra-terminal (BET) family.  BET inhibition 
represents a novel, epigenetic approach to treat CVD. RVX000222 is the first oral agent in the BET 
inhibitor class that preferentially targets BET protein 4 (BRD4) thereby regulating gene activity. 
RVX000222 affects biological processes important in atherosclerosis and acute coronary events via 
selective inhibition of BET proteins.  RVX000222 selectively binding to the bromodomains (BD1/2) of the 
BET proteins with a 20-fold higher affinity to the second domain (BD2) versus the first (BD1).  This feature 
of RVX000222 differentiates it from all other known BET inhibitors that have equal affinity of binding to 
either BD1/2.   RVX000222 affects a single target (the second domain [BD2] of the bromodomain system) 
with multiple biological actions. The discovery of RVX000222 in 2006 stemmed from the screening of 
chemical compounds that had the ability to increase apolipoprotein A-I (ApoA-I) gene expression when 
exposed to human hepatoma cells.  Initial cellular assays involving treatment with RVX000222 led to a 
rapid but direct effect in reducing IL-6 and VCAM-1 mRNA by 4 hours. In contrast, induction of ApoA-I 
mRNA and protein production required 24-48 hours suggesting an indirect effect. During the course of 
RVX000222 development, studies into the mechanism of action further demonstrated that its activity on 
atherosclerosis extended beyond its effects on ApoA-I/HDL.  We now know that the lipid modifying effects 
are likely a minor contributor to efficacy of the compound.  Indeed, current studies of RVX000222 show 
that it has effects on vascular inflammation, the complement and coagulation cascades, and acute phase 
response pathways all of which have known roles in cardiovascular disease and acute cardiac events. 
Gene expression regulation by BET proteins appears to be at the root of the pathogenesis of cardiac 
events.   The effect of selective BET inhibition on all of the pathways outlined above underlies the 
potential benefit of using RVX000222 in treating CVD risk and for the prevention of recurrent acute 
events. 
 
RVX000222 is available as a capsule formulation with standard excipients and established stability. 
 
A total of 985 subjects have participated in completed trials, of which 706 received treatment with 
RVX000222 including 130 healthy volunteers and 576 subjects with stable coronary artery disease (CAD) 
and/or dyslipidemia on standard of care therapy. Three Phase 2 studies in subjects with CVD have been 
completed: a 12-week study (RVX222-CS-005; ASSERT) in which 299 subjects with stable CAD on 
standard of care therapy were enrolled, coupled with 24-week (RVX222-CS-008; SUSTAIN) and 26-week 
(RVX222-CS-007; ASSURE) studies in statin treated subjects with stable CAD and/or dyslipidemia, with 
low baseline HDL-C concentrations. The latter two studies enrolled 176 and 323 subjects, respectively. 
An additional Phase 2 study in subject with pre-diabetes (RVX222-CS-010) that enrolled 20 subjects was 
also completed.  
 
The metabolism and disposition of RVX000222 after oral administration in humans, is similar to what 
occurs in animals. The parent molecule is metabolized to the same two inactive primary metabolites 
(RVX000288 [carboxylic acid] and RVX000404 [glucuronide]), with only about one-tenth of the dose 
excreted in the urine as a combination of parent and metabolite. It appears to be reasonably well 
absorbed, and exhibited dose-proportional increases in exposure (area under time curve [AUC]) between 
1 and 4 mg/kg. The terminal half-life of the drug is about 11 hours. An increase in bioavailability of 
approximately 60% when given with food led to a recommendation that dosing with meals is required for 
further clinical studies. On a b.i.d. treatment schedule, steady-state kinetics were achieved within about 1 


 
Version3A / 31 October 2017 
 
CONFIDENTIAL  
 
 
Page 23 of 73 
day of treatment. RVX000222 is expected to have low risk for producing drug-drug interactions, based on 
available data related to inhibition or induction of cytochrome P450 enzymes. 
 
Positive changes in CVD biomarkers were seen in both normal volunteer and subject studies and led to 
the identification of a total daily dose of 200 mg (100 mg b.i.d taken with meals) as the optimum balance 
of efficacy and adverse events (AEs). The changes in biomarkers observed in the longer term Phase 2 
studies are shown in Table 2. 
 
 Table 2: Effects of RVX000222 on Biomarkers of CV Risk – Lipids and 
Inflammation (ASSURE and SUSTAIN Trials) 
Biomarker 
Placebo (n=166) 
RVX000222 (n=331) 
p value vs. 
placebo 
Percent 
Change 
p value vs. 
baseline 
Percent 
Change 
p value vs. 
baseline 
HDL Cholesterol, 
(mg/dL) 
0 
0.59 
7.69 
<0.0001 
0.0003 
ApoA-I, (mg/dL) 
3.8 
0.0003 
10.3 
<0.0001 
0.005 
Total HDL particles, 
(µmol/L) 
0.4 
0.61 
6.51 
<0.0001 
0.07 
HDL particle size, 
(nm) 
0 
0.3 
1.16 
<0.0001 
0.049 
Large HDL particles, 
(µmol/L) 
4.11 
0.02 
30.71 
<0.0001 
0.03 
hs-CRP, (mg/L) 
-22.4 
0.0002 
-28.4 
<0.0001 
0.67 
ALP, (U/L) 
-3.23 
0.03 
-11 
<0.0001 
<0.001 
Results expressed as median percentage change from baseline. Source: RVX000222 data on file. Modified intention to treat 
population, 2-sided van Elteren test of RVX000222 vs. placebo, stratified by trial. Wilcoxon signed-rank test for within group 
comparison vs. baseline. 
The data from all three individual Phase 2 studies in CVD patients showed independent, consistent trends 
for fewer MACE in RVX000222-treated subjects versus subjects receiving placebo. In the ASSERT study, 
2.2% of subjects treated with RVX000222 experienced a MACE compared to 2.7% of placebo-treated 
subjects during 12 weeks of therapy.  In the SUSTAIN study, MACE occurred in 7.5% of placebo-treated 
subjects and only 0.4% of RVX000222-treated subjects (p <0.06) after 24 weeks of therapy. This trend 
was also observed in the ASSURE trial, with 14.3% of placebo-treated subjects experiencing MACE 
compared to 7.5% of subjects in the RVX000222-treated group after 26 weeks of therapy, an 
approximately 48% difference (p <0.1).   
  
Given the promising findings of reduced MACE from these three studies, a post-hoc meta-analysis was 
conducted using the pooled data (n = 798). Collectively, there was a statistically significant (p = 0.023) 
reduction in MACE as defined by death, myocardial infarction (MI), coronary revascularization, or 
cardiovascular hospitalization (CV) as shown in Figure 1. Subjects receiving RVX000222 were 44% less 
likely to experience a MACE compared to placebo with only 5.9% of RVX000222-treated subjects 
experiencing any MACE compared to 10.4% for placebo-treated subjects. Approximately 80% of subjects 
were treated with high intensity statin therapy (atorvastatin and rosuvastatin). 


 
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Page 24 of 73 
 
 
Figure 1: MACE in Subjects Treated in RVX000222 Phase 2 Studies 
Overall, RVX000222 was generally well tolerated and AEs were mild with little discernible difference 
between placebo- and the RVX000222-treated subjects. The dose-limiting toxicity for RVX000222 is a 
generally non-symptomatic elevation in serum transaminases (alanine aminotransferase [ALT] and in 
some cases aspartate aminotransferase [AST]), without adversely affecting total bilirubin values in any 
subject. There was no increase in alkaline phosphatase (ALP) observed. There was an overall incidence 
of 7-8% of subjects with ALT >3x the upper limit of normal range (ULN). There was often confounding 
with use of drugs known to increase ALT (diclofenac and clavulanic acid) or prior history of hepatitis. 
Raised enzymes return promptly to within the normal transaminase range (approximately 15 days for 
ALT >5xULN), suggesting that any hepatocellular effect can be reversed by suspending treatment with 
investigational drug. For subjects with elevations >3xULN and <5xULN, treatment was continued and all 
returned to normal levels. Subjects with ALT elevations >5x and <8xULN were dose interrupted, re-
challenged at a lower dose and the majority successfully completed the studies. Drug-induced ALT 
elevations >3xULN were observed between weeks 4-12 across all 4 completed Phase 2 trials, with one 
exception. One subject with elevated ALT and AST at Week 20 due to cholecystitis was noted in 
RVX222-CS-007. No cases of Hy’s Law have been detected.  
 
A possible mechanism implicated in the elevation of serum transaminases is the effect of BET inhibition 
on hepatic bile acids through changes in expression of the farsenoid X receptor (FXR) and cholesterol 7-
alpha hydroxylase (CYP7A1). Hepatocyte cell culture studies show that RVX000222 represses FXR 
expression.  Increased expression of CYP7A1, a rate limiting enzyme in bile acid synthesis, is observed 
in select donors of primary hepatocytes as a consequence of FXR repression.  Increased CYP7A1 
expression predicts increased bile acid synthesis.  Intracellular concentrations of bile acids may be further 
augmented through downregulation of BSEP, a bile acid export pump.  Increased bile acid synthesis, 
combined with a decrease in BSEP-mediated biliary excretion of bile acids, may mediate ALT elevations 
in select patients where CYP7A1 is induced.  In healthy volunteers or CVD patients taking RVX000222, 
serum bile acids appear to track with ALTs. Elevation of serum bile acids preceded serum ALT elevation, 
suggesting that the bile acid-mediated mechanism is plausible. However, other markers of liver damage 
such as bilirubin or LDH are not elevated and serum bile acids although increased from baseline remain 
in a normal range. 
 
Cummulative Event Rate (%)
   0%
   3%
   6%
   9%
  12%
Days Since Randomization
0
20
40
60
80
100
120
140
160
180
200
220
Placebo (n=242)
RVX000222 (n=556)


 
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Page 25 of 73 
Minimizing residual risk of MACE in T2DM subjects’ post-acute coronary syndrome (ACS) addresses an 
important unmet medical need. RVX000222 and BET inhibition represent a potential new treatment 
mechanism for subjects at high risk for CVD. Based on the data above, the BETonMACE study (RVX222-
CS-015) will focus on prevention of subsequent MACE in subjects with CAD and DM with high intensity 
statin therapy as co-medication.  
 
 
STUDY OBJECTIVES 
 
Primary Objective 
• 
To evaluate if treatment with RVX000222 as compared to placebo increases time to the first 
occurrence of narrowly defined MACE. Narrowly defined MACE is defined as a single composite 
endpoint of CV death or Non-fatal MI or Stroke. 
 
Criteria for the evaluation of individual events will be defined in the MACE Clinical Events 
Committee (CEC) charter and will be based on the CDISC standardized definitions for 
Cardiovascular and Stroke Endpoint Events1. 
 
 
Secondary Objectives 
• 
To evaluate if treatment with RVX000222 increases time to the first occurrence of broadly defined 
MACE in comparison to placebo 
Broadly defined MACE is the occurrence of any of the following events:  
• 
CV death 
• 
Non-fatal MI 
• 
Hospitalization for CVD events including: 
o 
Unstable angina AND evidence of new or presumed new progressive obstructive 
coronary disease, OR 
o 
Emergency revascularization procedures at any time and urgent revascularization 
procedures ≥30 days after the index event as defined by Hicks et al. 
• 
Stroke 
• 
To evaluate if treatment with RVX000222 increases time to the first occurrence of fatal or non-
fatal MI, or fatal or non-fatal stroke 
• 
To evaluate treatment group difference in all-cause mortality  
• 
To evaluate changes in lipoprotein concentrations including apoA-I, apolipoprotein B (apoB), 
LDL-C, HDL-C, and triglyceride (TG) over time within and between treatment groups 
• 
To evaluate changes in DM variables including glycated hemoglobin (HbA1c), fasting glucose, 
and fasting insulin over time within and between treatment groups 
• 
To evaluate changes in ALP over time within and between treatment groups including  isoforms 
for whole population and quartiles of ALP baseline concentration 
• 
Assess changes in kidney function in population with baseline estimated glomerular filtration rate 
<60 mL/min/1.7m2 
• 
To evaluate the safety and tolerability of RVX000222  
 
 
Exploratory Objectives 
• 
To evaluate changes in inflammation variables including, but not limited to, high-sensitivity C-
reactive protein (hsCRP), fibrinogen, and inflammatory cytokines within and between treatment 
groups 
• 
To evaluate transcription (messenger RNA [mRNA]) change in whole blood from baseline to 6 
weeks of treatment  
• 
To evaluate Health Related Quality of Life (HRQOL) as measured using the EQ-5D-5L 


 
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Page 26 of 73 
 
STUDY ENDPOINTS 
 
Primary Endpoint   
The primary endpoint will be time from randomization to the first occurrence of adjudication-
confirmed MACE narrowly defined as a single composite endpoint of CV Death or Non-fatal MI or 
Stroke. 
 
 
Key Secondary Endpoints 
The key secondary endpoints will be:  
 
1. Time from randomization to the first occurrence of adjudication-confirmed MACE broadly 
defined between treatment groups.  
Broadly defined MACE is the occurrence of any of the following events:  
• 
CV death 
• 
Non-fatal MI 
• 
Hospitalization for CVD events which include:  
o 
Unstable angina AND evidence of new or presumed new progressive obstructive 
coronary disease, OR 
o 
Emergency 
revascularization 
procedures 
at 
any 
time 
and 
urgent 
revascularization procedures ≥30 days after the index events prior to 
randomization  
•  Stroke 
2. Time from randomization to fatal or non-fatal MI, or fatal or non-fatal stroke  
3. Time from randomization to CV Death or Non-fatal MI 
4. Time from randomization to Non-fatal MI 
5. Time from randomization to CV Death 
6. Time from randomization to Stroke 
7. All-cause mortality 
 
 
Other Secondary Endpoints 
• 
The percent change in apoA-I, apoB, LDL-C, HDL-C, and TG over time within and between 
treatment groups 
• 
The change from baseline in HbA1c, fasting glucose, and fasting insulin within and between 
treatment groups  
• 
Changes in ALP within and between treatment groups for all subjects and according to quartiles 
of ALP baseline concentration 
• 
Changes from baseline in kidney function in subgroup population with estimated glomerular 
filtration rate <60 mL/min/1.7m2 within and between treatment groups  
 
 
Exploratory Endpoints 
• 
The percent change in hsCRP, fibrinogen, and inflammatory cytokines within and between 
treatment groups 
• 
Transcription/mRNA change in whole blood from baseline to 6 weeks treatment within and 
between treatment groups  
• 
Change in Health Related Quality of Life (HRQOL) as measured using the EQ-5D-5L 
 


 
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Safety Endpoints 
• 
Safety assessments will include incidence of adverse events (AEs), serious adverse events 
(SAEs), vital sign measurements, clinical laboratory evaluations, Montreal Cognitive Assessment 
(MOCA) (for subjects ≥ 70 years of age at randomization) and physical examination findings 
 
 
 
STUDY DESIGN 
This is a double-blind, placebo-controlled, 2-arm parallel-group (allocation ratio 1:1), study of RVX000222 
at a daily dose of 100 mg b.i.d. (total daily dose of 200 mg) or matching placebo in combination with high 
intensity statin therapy administered to T2DM subjects with history of recent CAD event and HDL-C level 
<40 mg/dL in males or <45 mg/dL in females.  
 
After an initial screening period of 1 to 2 weeks during which subjects will demonstrate tolerance of high 
intensity statin therapy, subjects will be randomized to either RVX000222 100 mg b.i.d. or matching 
placebo with continued statin treatment. This combination treatment period will continue until 250 
narrowly defined MACE events have occurred in the study and all surviving patients have been followed 
for at least 24 weeks from randomization. Blinded treatment with RVX000222 or matching placebo will 
then be discontinued. Subjects will remain on high intensity statin therapy for 4 more weeks until the 
Follow-Up Visit. 
 
The study is an event-based trial and will continue until 250 primary endpoint events have occurred.   
Study treatment will be terminated after the 250th adjudicated event occurs. At that time, all subjects 
actively treated will conduct their Last Visit on Treatment and then be discontinued from investigational 
drug. Subjects will then return 4 weeks after last day of treatment for the Follow-Up Visit.  
 
A Clinical Steering Committee (CSC) will oversee the conduct of the study. A Data Safety Monitoring 
Board (DSMB) will oversee the safety data for this study and independent CEC will adjudicate all 
suspected MACE composite events in an ongoing manner. An independent team (including an 
independent statistician) will perform the prospective unblinded analyses described in Section 10.8 (Data 
Safety Monitoring Board) and will report the results to the DSMB. Each committee will develop a charter 
to describe their activities and responsibilities prior to initiation of the study. 
 
 
 
STUDY POPULATION  
 
Number of Subjects 
It is estimated that enrollment of approximately 2400 male or female subjects with T2DM and high-risk 
CAD treated with high intensity statin therapy (atorvastatin 20-80 mg or rosuvastatin 10-40 mg) and with a 
low level of HDL-C of <40 mg/dL in males or <45 mg/dL in females at multiple investigational sites 
globally will be needed to reach the 250 MACE needed for this event-based trial.    
 
 
Inclusion Criteria 
Subjects who meet the following criteria may be enrolled: 
1. Male and female subjects age 18 and over with documented diagnosed T2DM and a CAD event 
of either unstable angina or myocardial infarction, not less than 7 days and no more than 90 days 
prior to Visit 1. In order to have sufficient number of clinical events, the number of subjects with 
unstable angina will be limited to 25% of the total number of subjects. 


 
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CONFIDENTIAL  
 
 
Page 28 of 73 
• 
Unstable angina: for a qualifying unstable angina event, each of components (a), (b), and (c) 
must be satisfied: 
a. Characteristic ischemic pain or discomfort in chest or associated referral areas, occurring 
at rest or with minimal exertion 
b. ECG changes consistent with acute myocardial ischemia based upon at least one of the 
following: 
i. 
new or presumed new ST elevation  
ii. 
new or presumed new ST depression 
iii. 
new or presumed new T-wave inversion 
c. Objective evidence of obstructive coronary artery disease based upon at least one of the 
following: 
i. 
new or presumed new evidence of myocardial ischemia or infarction by perfusion 
imaging 
ii. 
new or presumed new regional wall motion abnormality 
iii. 
current evidence of at least one epicardial coronary artery stenosis ≥ 70% by 
coronary angiography 
iv. 
need for coronary revascularization for the index ACS event, including 
percutaneous coronary intervention (PCI) with or without coronary stenting  
• 
Previous MI 7-90 days before screening, treated with or without a percutaneous coronary 
intervention (PCI). For a qualifying event of MI, two of the following three criteria must be 
satisfied: 
a. Characteristic ischemic chest pain or pain in associated referral areas 
b. Dynamic elevation of troponin T or I or CKMB, if troponin T or I is unavailable at the local 
lab (at least above the upper limit of normal for the laboratory) 
c. Development of new Q-waves in at least two adjacent ECG leads, or development of a 
new dominant R wave in V1 
2. Documented diagnosis of T2DM (one or more of the following criteria must be met): 
• 
Documented history of T2DM  
• 
History of taking diabetes medication  
• 
HbA1c ≥6.5% at Visit 1 
3. For males HDL-C of <40 mg/dL (1.04 mmol/L) and for females HDL-C of <45 mg/dL (1.17 
mmol/L) at Visit 1. 
4. In the opinion of the Investigator, subjects currently not on high intensity statin therapy will be 
able to start rosuvastatin according to the protocol at Visit 1. 
5. In the opinion of the Investigator, subjects currently on statin therapy other than atorvastatin or 
rosuvastatin can be switched to rosuvastatin according to the protocol at Visit 1. High intensity 
statin therapy doses should remain unchanged during the study period if at all possible.   
6. Female subjects must meet one of the following: 
• 
If of childbearing potential, female subjects must have a negative urine pregnancy test and be 
willing and able to use medically acceptable non-hormonal method of birth control (non-
hormonal intrauterine device, condom, or diaphragm) or remain abstinent from Screening 
until Follow-up Visit. 
• 
Be of non-child-bearing potential: post-surgical sterilization or post-menopausal.  
7. Have given signed informed consent to participate in this study. 
 


 
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Page 29 of 73 
 
Exclusion Criteria 
Subjects who meet any of the following criteria will not be enrolled: 
1. Heart disease which, in the opinion of the investigator, will within 90 days of Visit 1 likely require 
coronary bypass, PCI, cardiac transplantation, surgical repair and/or replacement. 
2. Previous or current diagnosis of severe heart failure (New York Heart Association Class IV) or a 
documented left ventricular ejection fraction (LVEF) of <25% as determined by contrast left 
ventriculography, radionuclide ventriculography or echocardiography. The absence of an LVEF 
measurement in a subject without a previous or current diagnosis of heart failure does not prohibit 
entry into the study. 
3. Subjects with evidence of cardiac electrophysiologic instability including a history of uncontrolled 
ventricular arrhythmias, uncontrolled atrial fibrillation/flutter or uncontrolled supraventricular 
tachycardias with a ventricular response heart rate of >100 beats per minute at rest within 4 
weeks prior to Visit 1. 
4. Coronary artery bypass grafting (CABG) within 90 days prior to Visit 1. 
5. Evidence of severe renal impairment as determined by any one of the following:  
• 
an estimated Glomerular Filtration Rate less than 30 mL/min/1.7m2 at Visit 1 
• 
a current need for dialysis  
6. Uncontrolled hypertension defined as 2 consecutive measurements of sitting blood pressure of 
systolic >180 mm Hg or diastolic >100 mm Hg at Visit 1. 
7. Subjects at risk of immunosuppression, including current or recent (within 12 months prior to Visit 
1) treatment with immunosuppressants (e.g., cyclosporine). 
8. Use of fibrates at any dose or niacin/nicotinic acid 250 mg or more within 30 days prior to Visit 1. 
9. A known allergy or sensitivity to any ingredient in the investigational medicinal product. 
10. History of intolerance to atorvastatin or rosuvastatin. This exclusion criterion applies to subjects 
with a history of intolerance to the statin to which they would be assigned at screening. 
11. Triglycerides >400 mg/dL (4.52 mmol/L) at Visit 1.  
12. Any medical or surgical condition which might significantly alter the absorption, distribution, 
metabolism or excretion of medication including, but not limited to, any of the following: Untreated 
or incompletely treated thyroid dysfunction, cholecystitis, Crohn’s disease, ulcerative colitis, or 
any gastric bypass alteration.  
13. Evidence of cirrhosis from liver imaging or biopsy, a history of hepatic encephalopathy, 
esophageal or gastric varices, active hepatitis, or prior porta-caval shunt procedure, or a Child-
Pugh score of at least 5 points (Appendix A). 
• 
Any one of the following liver enzymes that is >1.5xULN by central lab at Visit 1  
a. ALT 
b. AST 
14. A total bilirubin that is >ULN by central lab at Visit 1. 
15. History of malignancy of any organ system, treated or untreated, within the past 2 years whether 
or not there is evidence of local recurrence or metastases, with the exception of localized basal 
cell carcinoma of the skin.  
16. History or evidence of drug or alcohol abuse within 12 months of Visit 1, in the opinion of the 
investigator. 
17. Female subjects who are pregnant. 
18. Any condition which, in the opinion of the investigator, may place the subject at higher risk from 
his/her participation in the study, or is likely to prevent the subject from complying with the 


 
Version3A / 31 October 2017 
 
CONFIDENTIAL  
 
 
Page 30 of 73 
requirements of the study or completing the study, including subjects at risk of 
immunosuppression. 
19. Use of other investigational drugs and devices within 30 days or 5 half-lives of Visit 1, whichever 
is longer. 
20. History of noncompliance to medical regimens or unwillingness to comply with the study protocol. 
21. Any condition that, in the opinion of the investigator, would confound the evaluation and 
interpretation of efficacy and/or safety data. 
22. Persons directly involved in the execution of this protocol. 
 
 
STUDY TREATMENT  
 
Investigational Drug (RVX000222, Oral and Placebo for RVX000222, Oral) 
6.1.1 
RVX000222, Oral 
RVX000222 is available as a capsule formulation with standard excipients and established stability. 
Active Pharmaceutical Ingredient (API) 
Chemical Structure 
 
Molecular Weight 
370.41 g/mol 
Molecular Formula 
C20H22N2O5 
Appearance 
White, off-white to tan solid 
Solubility 
RVX000222 has a solubility of 15-25 mcg/mL in water and 3-3.5 mg/mL in 
0.1 N HCl 
Capsule Formulation 
A free base immediate release capsule dosage form. This capsule 
formulation is a dry blend formulation comprised of Avicel, colloidal silicone 
dioxide, sodium starch glycolate and magnesium stearate. The capsule is a 
hard shell gelatin white, opaque size 1 capsule. 
 
6.1.2 
Placebo for RVX000222, Oral 
Placebo for RVX000222, Oral is available as a capsule formulation free of RVX000222 API. It is 
comprised of standard excipients and has established stability. The capsule formulation is the same as 
that used for RVX000222, Oral (described in Section 6.1.1). 
 
 
Randomization 
All qualified subjects will be randomly assigned in a ratio of 1:1 to one of the following two treatment 
arms: RVX000222 200 mg daily or matching placebo. Randomization will be stratified by country and high 
intensity statin therapy within the country (i.e. atorvastatin or rosuvastatin). Further, randomization will be 
dynamically restricted to assure that statin therapy imbalance is no greater than 60:40 (or 40:60) within 
NH
N
O
MeO
OMe
O
OH


 
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CONFIDENTIAL  
 
 
Page 31 of 73 
each country. Study participants will be directed (per informed consent) to switch their statin therapy to 
rosuvastatin or atorvastatin once randomization limits are reached on either statin to minimize enrollment 
impact. 
A randomization schedule will be generated for the IWRS and will be implemented by the IWRS prior to 
dosing at Visit 2. The IWRS will allocate the investigational drug via the prepared randomization scheme 
and will provide the randomization number and appropriate drug package numbers. The IWRS process to 
achieve an approximate even split of study participants across the statin levels per country will be 
described in greater detail in the IWRS specifications. The subject should always be provided 
investigational drug with the number allocated by the IWRS. Procedures for this will be described in the 
IWRS user manual. 
 
 
RVX000222 Treatment Blinding 
The blinding is ensured by using double-blind RVX000222 investigational drug. Placebo capsules will be 
equally matched in size, shape, and color to RVX000222 and will be packaged in the same manner. The 
investigational drug packaging will be labelled with unique identification numbers allocated from the 
IWRS.  
Subjects, investigative staff, persons performing the assessments, and data analysts will remain blind to 
the identity of the treatment from the time of randomization. No member of the CSC, the study team at 
Resverlogix, personnel at study centers, or any clinical research organization (CRO) handling data will 
have access to the randomization scheme during the course of the study, with the exception of the study 
personnel generating the randomization scheme, the personnel preparing DSMB unblinded analyses for 
review, the DSMB itself, the personnel providing IWRS and carrying out the packaging and labeling of 
investigational products. Unblinding will occur in the case of subject emergencies when knowledge of the 
treatment assignment would affect subject care (Section 6.10.2) and at the conclusion of the study.  
 
 
Study Drug Supply, Storage, and Tracking 
RVX000222 capsules, atorvastatin, and rosuvastatin will be shipped to the Investigator as labeled drug. 
All study drug must be received by a designated person at the study site, handled and stored safely and 
properly, and kept in a secured location to which only the investigator and qualified personnel have 
access. RVX000222 should be stored at ambient temperature, 15˚ to 30˚C (59˚ to 86˚F). Atorvastatin and 
rosuvastatin should be stored according to the respective SmPC (refer to the study manual for these 
documents). 
Study drug packaging will be subject-specific. Each subject will be allocated enough study drug at each 
visit to cover at least the time period until the next scheduled visit plus the visit window.  
Investigators must maintain an accurate record of the shipment and dispensing of study drug in a drug 
accountability ledger. Subjects will be asked to return all unused study drug and packaging, including 
concomitant statin therapy, if provided by sponsor, at each visit, the end of the study, or at the time of 
study drug discontinuation. 
At the conclusion of the study, and as appropriate during the course of the study, the investigator will 
return all used and unused study drug, packaging, drug labels, and a copy of the completed drug 
accountability ledger. 
Procedures for drug dispensing and drug accountability are described in the study manual.   
 
 
RVX000222 Investigational Drug Administration 
RVX000222 or matching placebo will be taken orally with meals in the morning and in the evening, 10-12 
hours apart. If a dose is missed, subject should take missed dose at the time it is remembered, unless it is 
within four hours of the next scheduled dose. If within four hours of the next schedule dose, missed dose 
should be skipped. Subjects will take their first dose of investigational drug while in clinic during Visit 2.  


 
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Table 3: Investigational Drug Administration Schedule 
Treatment 
Group 
Daily dose 
(mg) 
Dose administration 
b.i.d. (mg) 
AM 
Dose 
(mg) 
PM 
Dose 
(mg) 
No. of 
capsules/day 
A: RVX000222 
200 
100 
100 
100 
2 
B: Placebo 
0 
0 
0 
0 
2 
 
If subjects have elevated ALT values (see Section 6.10.1) they may be administered investigational drug 
or matching placebo at a reduced dose of 50 mg b.i.d, subject to confirmation by the medical monitor.  
 
 
Concomitant Statin Therapy  
Protocol defined concomitant treatment in this study is 40-80 mg atorvastatin or 20-40 mg rosuvastatin 
once daily orally. 20 mg atorvastatin or 10 mg rosuvastatin are only acceptable in circumstances such as 
advanced age, low body mass, or specific drug-drug interactions (e.g. anti-retrovirals).  
Subjects will receive concomitant statin therapy as follows:  
Subjects who, at Visit 1, are currently receiving high intensity statin therapy of atorvastatin 40-80 mg 
or rosuvastatin 20-40 mg will continue on the same statin as they are currently receiving.  
If clinically appropriate, in the investigator’s opinion, subjects who, at Visit 1, are currently receiving 
atorvastatin or rosuvastatin at doses other than the protocol-defined dosage (10 mg dose of 
atorvastatin or 5 mg dose of rosuvastatin) should be transitioned to a 40-80 mg dose of atorvastatin 
or 20-40 mg dose of rosuvastatin.  
Subjects not currently receiving high intensity statin therapy of atorvastatin or rosuvastatin will be 
prescribed rosuvastatin 20-40 mg as concomitant therapy at Visit 1 and will discontinue use of any 
other statin previously prescribed.  
A country level stratification will be applied to ensure that subjects are allocated evenly (no greater 
than 60:40 imbalance within each country) between atorvastatin and rosuvastatin. In the event that 
the atorvastatin or rosuvastatin strata is full, subjects may be transitioned at Visit 1 to the other 
protocol defined statin therapy.  
The dose and transition plan for statin administration will be monitored and accounted through the IWRS. 
High intensity statin therapy dose may be reduced if clinically indicated. Otherwise, dosing should remain 
unchanged during the course of the study if at all possible.  
Subjects will continue taking high intensity statin therapy until the Follow-Up Visit (final study visit). 
The statin dose shall be administered once daily at the same time as one of the two RVX000222 doses 
(or placebo) and within 30 minutes of completion of a meal. If a dose is missed, subject should take 
missed dose at the time it is remembered, unless it is within four hours of the next scheduled dose. If 
within four hours of the next schedule dose, missed dose should be skipped. 
 
 
Background Therapy 
The subject’s other background therapy for dyslipidemia and any coexisting conditions such as CAD, 
hypertension and diabetes, should in the investigator’s opinion, adhere to acceptable standards of care 
and preferably remain unaltered during the treatment period unless clinically indicated. 
Ezetimibe use is not prohibited at screening, randomization or during the study treatment phase. 
However, LDL-lowering should be addressed with high intensity statins. 


 
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Page 33 of 73 
 
 
Prohibited Concomitant Medications and Excluded Therapies 
The use of the following treatments is NOT allowed beginning at Visit 1 until the end of the study, as 
these medications may interfere with the evaluation of safety, tolerability and/or efficacy. Subjects who 
may require any of the following medication(s) during the course of the study should be excluded. 
1. Cyclosporine. The initiation of cyclosporine therapy during the study constitutes a mandatory 
reason for permanent discontinuation of investigational drug. 
2. Fibrates at any dose 
3. Niacin/nicotinic acid >250 mg per day 
4. Clavulanic acid 
5. Diclofenac (Topical diclofenac is acceptable with intermittent use, but not with daily use for any 
period >7 days.) 
6. Acetaminophen >1g/day 
7. Hormonal Contraceptives or Hormone Replacement Therapy (see Section 6.9) 
Patients whose clinical condition during the study warrants clavulanic acid, diclofenac, or 
acetaminophen >1g/day should suspend study medication from the day these treatments are initiated 
until three days after they are completed. 
The investigator should instruct the subject to notify the study site about any new medications he/she 
takes after the start of the study drug, including concomitant statin therapy. All medications (other than 
study drug) and significant non-drug therapies (including physical therapy and blood transfusions) 
administered after the subject starts treatment with study drug must be listed on the concomitant 
medications/significant non-drug therapies section of the electronic case report form (eCRF) after start of 
study drug. 
 
 
Contraception / Hormone Replacement Therapy 
Hormonal contraceptives are not allowed during study participation by study subjects. All female subjects 
of childbearing potential will be asked to practice appropriate non-hormonal contraception (non-hormonal 
intrauterine device, condom, or diaphragm) or practice abstinence for the duration of the study.  
Subjects who take hormone replacement therapy must be willing to discontinue their hormonal therapy if 
it is medically appropriate. To be eligible for study participation, they must agree to remain off their 
hormonal replacement therapy for the duration of the study. 
 
 Study Drug Interruption/Discontinuation 
Treatment may be interrupted or discontinued at the discretion of the Investigator and Sponsor, based on 
AEs, other clinical laboratory data, vital signs measurements, and/or electrocardiogram (ECG) findings.  
Subjects discontinuing study drug will continue participation in the study and will complete all remaining 
study visits. Discontinuation of assigned investigational drug (RVX000222 or placebo) or high intensity 
statin therapy should not result in study discontinuation. Subjects discontinuing investigational drug 
(RVX000222 or placebo) should be encouraged to continue on study-supplied high intensity statin 
therapy. For subjects who discontinue both investigational drug and study-supplied concomitant statin 
therapy, record alternative statin/lipid lowering therapy, if applicable.  
 


 
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Page 34 of 73 
6.10.1 
Additional Safety Lab Monitoring/Dose Adjustment 
Additional safety lab monitoring will occur and investigational drug (RVX000222 or placebo) may be 
interrupted, reduced, and/or discontinued if the subject meets following criteria. If ALT increases >3xULN 
or serum bilirubin increases >2xULN, subjects should be notified and repeat chemistries obtained as soon 
as possible. 
1. If ALT increase of >3 and ≤5xULN is confirmed on repeat measurement (within 3-4 days), 
subjects will be monitored every 3-4 days until the ALT is <1.5xULN.   
2. If ALT increase of >5xULN, investigational drug will be suspended. If confirmed on repeat 
measurement (within 3-4 days), investigational drug will be discontinued and subjects will be 
monitored every 3-4 days until the ALT is <1.5xULN. 
3. If serum bilirubin increase of >2xULN, investigational drug will be suspended. If confirmed on 
repeat measurement (within 3-4 days), investigational drug will be discontinued and subjects will 
be monitored every 3-4 days until levels are within normal range.  
Subjects who have an ALT increase of >3xULN will be monitored by liver safety panels [ALT (SGPT), 
AST (SGOT), GGT, ALP, bilirubin (direct and total)] and have archival serum samples drawn every 3-4 
days until ALT is <1.5xULN. 
Subjects who have an ALT increase of >5xULN or who have a serum bilirubin increase of >2xULN will be 
monitored by extended liver safety panels [ALT (SGPT), AST (SGOT), GGT, ALP, bilirubin (direct and 
total), as well as osteopontin and PT INR] and have archival serum samples drawn every 3-4 days until 
ALT is <1.5xULN and serum bilirubin levels are in within the normal range.  
Subjects should continue to follow the protocol-defined assessments according to the Schedule of Events 
( 
 
Screen 
Treatment 


 
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CONFIDENTIAL  
 
 
Page 35 of 73 
Table 1) until study completion.  
If the ALT or serum bilirubin elevation has a likely cause other than investigational drug (e.g. trauma, 
infection-inflammation, surgery, acetaminophen, clavulanic acid, diclofenac) investigational drug may be 
restarted at 50 mg b.i.d. once ALT returns to 1.5 xULN. Subjects should continue with all scheduled study 
visits according to the Schedule of Events ( 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18  
Week 
- 2 to -1 
0 
2 
4 
6 
8 
10 
12 
16 
20 
24 
28 
40 
52 
64 
76 
88 
100  
± No. Day 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Central Laboratory: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting Lipid profile 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Hematology, HbA1c 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Chemistry 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Hepatitis Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver Safety Panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biomarker Laboratory Tests 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipoproteins, fasting insulin 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Inflammation Panel 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Serum/Plasma Archive 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Pharmacogenomic 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
MOCA 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
EQ-5D-5L 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior / Con. Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug Dispense/Account. 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Screen 
Treatment 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18  
Week 
- 2 to -1 
0 
2 
4 
6 
8 
10 
12 
16 
20 
24 
28 
40 
52 
64 
76 
88 
100  
± No. Day 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Central Laboratory: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting Lipid profile 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Hematology, HbA1c 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Chemistry 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 


 
Version3A / 31 October 2017 
 
CONFIDENTIAL  
 
 
Page 36 of 73 
Table 1) and will have additional liver safety panel tests drawn according to the original study schedule:  
• Weeks 0-12 after investigational drug is reinitiated: liver safety panel every 2 weeks (Weeks 0, 2, 4, 
6, 8, 10, 12 after re-initiation) 
• Weeks 12-28 after investigational drug is reinitiated: liver safety panel every 4 weeks (Weeks 16, 
20, 24 after re-initiation) 
• Week 28 after investigational drug is reinitiated to end of treatment: liver safety panel approximately 
every 12 weeks (Weeks 40, 52, 64, 76, 88, 100) 
Any re-initiation of investigational drug must be discussed with and approved by the study medical 
monitor prior to dosing.  
 
6.10.2 
Emergency Un-blinding of Treatment Assignment 
Emergency un-blinding should only be undertaken when it is essential for effective treatment of the 
subject. Most often, investigational drug discontinuation and knowledge of the possible treatment 
assignments are sufficient to treat a study subject who presents with an emergency condition. Individual 
treatment codes indicating the treatment randomization for each randomized subject will be available to 
the investigator. Procedures for this will be described in the IWRS user manual. The Investigator will 
notify the Medical Monitor as soon as possible of any situation resulting in treatment un-blinding of any 
subject.  
 
6.10.3 
Subject Withdrawal / Discontinuation from Study 
Subjects are free to discontinue participation in the study at any time. A subject’s participation may also 
be discontinued at any time at the discretion of the Investigator. Withdrawn subjects will not be replaced. 
However, discontinuation of study drug should not result in discontinuation of study participation.  
 
A subject’s participation in the study will be discontinued if any of the following applies: 
 
• 
Withdrawal of informed consent 
• 
Subject experiences AEs sufficiently severe to contraindicate continuing the study 
• 
Subject’s general condition, in the opinion of the Investigator, contraindicates continuing in 
the study 
• 
Subject refuses to cooperate; or 
• 
Sponsor elects to end the study, or any portion thereof, for any reason 
 
When a subject decides to discontinue participation in the study, or is lost to follow-up (those subjects 
whose status is unclear because they fail to appear for study visits without stating an intention to 
withdraw), a reasonable attempt will be made to contact the subject about the reasons for discontinuation 
and any AEs. All AEs will be followed until resolved or a stable condition has been established. Subjects 
withdrawn due to an AE or abnormal laboratory test will be followed until the AE or abnormal laboratory 
Hepatitis Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver Safety Panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biomarker Laboratory Tests 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipoproteins, fasting insulin 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Inflammation Panel 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Serum/Plasma Archive 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Pharmacogenomic 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
MOCA 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
EQ-5D-5L 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior / Con. Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug Dispense/Account. 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


 
Version3A / 31 October 2017 
 
CONFIDENTIAL  
 
 
Page 37 of 73 
test resolves, or there is an adequate explanation that the AE or abnormal laboratory test was not related 
to study drug.  
 
For subjects who are lost to follow-up, the Investigator should show “due diligence” by documenting in the 
source documents the steps taken to contact the subject.  
 
Should a subject request to be withdrawn from the study, the following options should be offered to 
him/her regarding continued participation:  
 
1. Continued study site visits and procedures following the visit schedule, without medication being 
dispensed.  
2. Telephone (or other communication) contact at regular scheduled study visits. Last visit on treatment 
and follow-up visit would be at clinic, if at all possible.  Concomitant medications, updated contact 
information, and SAE assessments should be collected at each telephone visit.  
3. On-site and/or telephone (or other communication) contact at less than scheduled visit intervals (at a 
minimum, at least approximately at the calculated timeframe for the follow-up visit). If telephone 
contact, collect concomitant medications, update contact information, and SAEs at each telephone 
visit. 
4. Indirect Method: Subject is not willing to have Principal Investigator or staff contact them. However, 
allows Primary Care Physician/Designated Contact at approximately the calculated timeframe for the 
follow-up visit.  
5. Indirect Method: Subject is not willing to have Principal Investigator or staff contact them. However, 
allows review of vital status checks throughout the study. Vital status will be checked using 
appropriate available information sources such as public records or contact with family members. 
6. No further contact/full withdrawal of consent, in writing. 
 
The subject’s continued level of participation should be clearly documented and updated in the subject’s 
source documents. Should a subject no longer wish any further contact, the primary reason for 
termination must be recorded as well. In addition, efforts should be made to perform all procedures 
scheduled for the last visit on treatment and follow-up visit. 
 
The Investigator, in discussion with the Sponsor, may decide to withdraw a subject or prematurely end 
the study for clinical safety reasons.  
 
 
VISIT SCHEDULE AND ASSESSMENTS 
 
 
Screen 
Treatment 


 
Version3A / 31 October 2017 
 
CONFIDENTIAL  
 
 
Page 38 of 73 
Table 1: Schedule of Events lists all of the assessments and indicates with an “x” the visits when they are 
performed. 
 
Subjects should be seen for all visits on the designated day. Visit dates should be adhered to as closely 
as possible. Target visit dates will be generated for each subject based on the Visit 2 date.  
 
 
Safety Evaluations 
Safety and tolerability will be determined by symptoms, signs, severity, and causality of AEs, clinical 
laboratory test results, vital sign measurements, and changes in physical examination findings.  
 
7.1.1 
Electrocardiograms 
A standard 12-lead ECG will be performed at Screening (Visit 1). Each ECG tracing should be kept in the 
source documents at the study site. Interpretation of the tracing must be made by a qualified physician 
and documented in the source documentation. This interpretation will be collected in the eCRF. Only 
clinically significant abnormalities should be reported on this page. Clinically significant abnormalities 
should also be recorded on the relevant medical history/current medical conditions eCRF page.  
 
7.1.2 
Vital Signs 
Vital signs (systolic/diastolic blood pressure, heart rate, respiratory rate, and temperature) will be 
measured according to the Schedule of Events ( 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18  
Week 
- 2 to -1 
0 
2 
4 
6 
8 
10 
12 
16 
20 
24 
28 
40 
52 
64 
76 
88 
100  
± No. Day 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Central Laboratory: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting Lipid profile 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Hematology, HbA1c 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Chemistry 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Hepatitis Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver Safety Panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biomarker Laboratory Tests 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipoproteins, fasting insulin 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Inflammation Panel 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Serum/Plasma Archive 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Pharmacogenomic 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
MOCA 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
EQ-5D-5L 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior / Con. Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug Dispense/Account. 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Screen 
Treatment 


 
Version3A / 31 October 2017 
 
CONFIDENTIAL  
 
 
Page 39 of 73 
Table 1). All measurements will be recorded in the subject’s source documents and eCRF.  
Blood pressure will be measured in the sitting position at all time points. Blood pressure will be measured 
in the subject’s dominant arm (if possible), with the arm supported at the level of the heart, and recorded 
to the nearest 1 mm Hg. Screening blood pressure may be retested up to 3 times at intervals of no less 
than 5 minutes between each measurement. The final blood pressure measurement should be recorded 
in the eCRF.  
The use of automated devices for measuring blood pressure and heart rate is acceptable. When done 
manually, heart rate will be measured in the brachial or radial artery for at least 30 seconds. 
 
7.1.3 
Physical Examinations 
Physical examinations will occur as shown in the Schedule of Events ( 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18  
Week 
- 2 to -1 
0 
2 
4 
6 
8 
10 
12 
16 
20 
24 
28 
40 
52 
64 
76 
88 
100  
± No. Day 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Central Laboratory: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting Lipid profile 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Hematology, HbA1c 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Chemistry 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Hepatitis Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver Safety Panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biomarker Laboratory Tests 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipoproteins, fasting insulin 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Inflammation Panel 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Serum/Plasma Archive 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Pharmacogenomic 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
MOCA 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
EQ-5D-5L 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior / Con. Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug Dispense/Account. 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Screen 
Treatment 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18  
Week 
- 2 to -1 
0 
2 
4 
6 
8 
10 
12 
16 
20 
24 
28 
40 
52 
64 
76 
88 
100  
± No. Day 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Version3A / 31 October 2017 
 
CONFIDENTIAL  
 
 
Page 40 of 73 
Table 1). Height will be measured at screening only. Weight will be measured during each physical exam. 
Physical examinations will include but not be limited to the examination of general appearance, skin, 
head, eyes, ears, nose, throat, respiratory, cardiovascular, gastrointestinal, endocrine metabolic, genito-
urinary, blood/lymphatic, and musculoskeletal systems.   
 
Information for all physical examinations must be included in the source documentation at the study site. 
Significant findings that are present prior to the start of study drug must be included in the relevant 
Medical History/Current Medical Conditions screen on the subject’s eCRF. Significant findings after 
signing of the informed consent, which meet the definition of an AE, must be recorded on the AE eCRF. 
 
7.1.4 
Clinical Laboratory Tests 
Clinical laboratory samples (fasting lipid panel, hematology, chemistry, infectious serology, and urinalysis) 
will be collected as shown in the Schedule of Events ( 
Medical History/Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Central Laboratory: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting Lipid profile 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Hematology, HbA1c 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Chemistry 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Hepatitis Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver Safety Panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biomarker Laboratory Tests 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipoproteins, fasting insulin 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Inflammation Panel 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Serum/Plasma Archive 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Pharmacogenomic 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
MOCA 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
EQ-5D-5L 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior / Con. Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug Dispense/Account. 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Screen 
Treatment 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18  
Week 
- 2 to -1 
0 
2 
4 
6 
8 
10 
12 
16 
20 
24 
28 
40 
52 
64 
76 
88 
100  
± No. Day 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Central Laboratory: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting Lipid profile 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Hematology, HbA1c 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Chemistry 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 


 
Version3A / 31 October 2017 
 
CONFIDENTIAL  
 
 
Page 41 of 73 
Table 1).  
 
A central laboratory will be used for analysis of all specimens collected, except dipstick tests for 
urinalysis. Details on the collections, shipment of samples and reporting of results by the central 
laboratory are provided to the investigators in the laboratory manual. All laboratory results (excluding 
biomarker and pharmacogenomics results) will be communicated to the investigators.  Dipstick tests for 
urinalysis will be performed and results maintained at investigational sites. 
 
For fasting laboratory tests, blood should be collected after a period of 9 to 12 hours with no oral intake 
except for water and medications. If a subject attends a study visit in a non-fasting state, labs should be 
collected nonetheless and the non-fasting condition should documented.  
 
7.1.4.1 
Fasting Lipid Profile 
Fasting bloodwork will be collected for lipid profile (total cholesterol, LDL-C, HDL-C, and TGs), at visits 
indicated on the Schedule of Events ( 
Hepatitis Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver Safety Panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biomarker Laboratory Tests 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipoproteins, fasting insulin 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Inflammation Panel 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Serum/Plasma Archive 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Pharmacogenomic 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
MOCA 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
EQ-5D-5L 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior / Con. Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug Dispense/Account. 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Screen 
Treatment 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18  
Week 
- 2 to -1 
0 
2 
4 
6 
8 
10 
12 
16 
20 
24 
28 
40 
52 
64 
76 
88 
100  
± No. Day 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Version3A / 31 October 2017 
 
CONFIDENTIAL  
 
 
Page 42 of 73 
Table 1). 
 
7.1.4.2 
Hematology 
Hemoglobin, Hematocrit, red blood cell count (RBC), white blood cell count (WBC) with differential, 
platelet count, and HbA1c will be measured at visits indicated on Schedule of Events ( 
Vital Signs 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Central Laboratory: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting Lipid profile 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Hematology, HbA1c 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Chemistry 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Hepatitis Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver Safety Panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biomarker Laboratory Tests 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipoproteins, fasting insulin 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Inflammation Panel 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Serum/Plasma Archive 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Pharmacogenomic 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
MOCA 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
EQ-5D-5L 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior / Con. Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug Dispense/Account. 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Screen 
Treatment 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18  
Week 
- 2 to -1 
0 
2 
4 
6 
8 
10 
12 
16 
20 
24 
28 
40 
52 
64 
76 
88 
100  
± No. Day 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Central Laboratory: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting Lipid profile 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Hematology, HbA1c 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Chemistry 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 


 
Version3A / 31 October 2017 
 
CONFIDENTIAL  
 
 
Page 43 of 73 
Table 1). 
 
7.1.4.3 
Chemistry 
Albumin, blood urea nitrogen, creatine kinase (CK), serum creatinine, fasting glucose, ALP, calcium, 
phosphate, potassium, sodium, and total protein will be measured at visits indicated on the Schedule of 
Events ( 
Hepatitis Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver Safety Panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biomarker Laboratory Tests 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipoproteins, fasting insulin 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Inflammation Panel 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Serum/Plasma Archive 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Pharmacogenomic 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
MOCA 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
EQ-5D-5L 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior / Con. Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug Dispense/Account. 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Screen 
Treatment 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18  
Week 
- 2 to -1 
0 
2 
4 
6 
8 
10 
12 
16 
20 
24 
28 
40 
52 
64 
76 
88 
100  
± No. Day 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Central Laboratory: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting Lipid profile 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 


 
Version3A / 31 October 2017 
 
CONFIDENTIAL  
 
 
Page 44 of 73 
Table 1). 
Estimated glomerular filtration rate will be calculated by the lab using serum creatinine values and the 
Cockcroft-Gault formula. 
 
7.1.4.4 
Urinalysis  
Urinalysis consisting of visual description, a dipstick test (specific gravity, pH, protein [qualitative], 
glucose, ketones, bilirubin, and blood) will be done at visits indicated on Schedule of Events ( 
Hematology, HbA1c 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Chemistry 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Hepatitis Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver Safety Panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biomarker Laboratory Tests 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipoproteins, fasting insulin 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Inflammation Panel 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Serum/Plasma Archive 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Pharmacogenomic 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
MOCA 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
EQ-5D-5L 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior / Con. Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug Dispense/Account. 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Screen 
Treatment 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18  
Week 
- 2 to -1 
0 
2 
4 
6 
8 
10 
12 
16 
20 
24 
28 
40 
52 
64 
76 
88 
100  
± No. Day 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Central Laboratory: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting Lipid profile 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 


 
Version3A / 31 October 2017 
 
CONFIDENTIAL  
 
 
Page 45 of 73 
Table 1). Dipstick tests will be performed and results maintained at investigational sites. 
 
7.1.4.5 
Hepatitis Serology 
Blood samples will be collected at Screening to test for antibody to hepatitis A (IgM), hepatitis B surface 
antigen (HBsAg), hepatitis B surface antibody (HBsAb), hepatitis B virus core protein antibody (HBcAb), 
hepatitis C (HCV). Subjects with evidence, in the opinion of the Investigator, of active hepatitis will be 
excluded from participation in this study.  
 
7.1.4.6 
Liver Safety Panel 
ALT (SGPT), AST (SGOT), gammaglutamyl transferase (GGT), ALP, and bilirubin (direct and total) will be 
measured at each visit as indicated on the Schedule of Events ( 
Hematology, HbA1c 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Chemistry 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Hepatitis Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver Safety Panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biomarker Laboratory Tests 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipoproteins, fasting insulin 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Inflammation Panel 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Serum/Plasma Archive 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Pharmacogenomic 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
MOCA 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
EQ-5D-5L 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior / Con. Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug Dispense/Account. 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Screen 
Treatment 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18  
Week 
- 2 to -1 
0 
2 
4 
6 
8 
10 
12 
16 
20 
24 
28 
40 
52 
64 
76 
88 
100  
± No. Day 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Central Laboratory: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Version3A / 31 October 2017 
 
CONFIDENTIAL  
 
 
Page 46 of 73 
Table 1). 
 
As defined in Section 6.10.1, subjects  who have an ALT increase of ≥3xULN will be monitored by liver 
safety panels and have archival serum samples drawn every 3-4 days until ALT values return to 
<1.5xULN and subjects who have an ALT increase of >5xULN or who have a serum bilirubin increase 
of >2xULN will be monitored by extended liver safety panels and have archival serum samples drawn 
every 3-4 days until ALT values return to <1.5xULN or serum bilirubin values return to within normal 
range.  
The Extended Liver Panel includes ALT (SGPT), AST (SGOT), GGT, ALP, bilirubin (direct and total), as 
well as osteopontin and PT INR  
 
7.1.4.7 
Pregnancy Test 
All pre-menopausal women who are not surgically sterile will have a dipstick urine pregnancy test at 
Screening (Visit 1). Dipstick tests will be performed and results maintained at investigational sites. 
 
7.1.5 
Biomarker Laboratory Tests  
A subset of up to 600 subjects in selected countries will have additional biomarker samples collected for 
lipoprotein, fasting insulin, and an inflammation panel analysis as described below (Sections 7.1.5.1, 
7.1.5.2, and 7.1.5.3) at visits indicated on the Schedule of Events ( 
Fasting Lipid profile 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Hematology, HbA1c 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Chemistry 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Hepatitis Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver Safety Panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biomarker Laboratory Tests 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipoproteins, fasting insulin 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Inflammation Panel 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Serum/Plasma Archive 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Pharmacogenomic 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
MOCA 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
EQ-5D-5L 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior / Con. Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug Dispense/Account. 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Screen 
Treatment 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18  
Week 
- 2 to -1 
0 
2 
4 
6 
8 
10 
12 
16 
20 
24 
28 
40 
52 
64 
76 
88 
100  
± No. Day 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Central Laboratory: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Version3A / 31 October 2017 
 
CONFIDENTIAL  
 
 
Page 47 of 73 
Table 1).  
 
7.1.5.1 
Lipoproteins 
Fasting bloodwork will also be collected from a selected subset of subjects for apoA-I and apoB at visits 
indicated on the Schedule of Events ( 
Fasting Lipid profile 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Hematology, HbA1c 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Chemistry 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Hepatitis Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver Safety Panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biomarker Laboratory Tests 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipoproteins, fasting insulin 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Inflammation Panel 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Serum/Plasma Archive 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Pharmacogenomic 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
MOCA 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
EQ-5D-5L 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior / Con. Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug Dispense/Account. 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Screen 
Treatment 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18  
Week 
- 2 to -1 
0 
2 
4 
6 
8 
10 
12 
16 
20 
24 
28 
40 
52 
64 
76 
88 
100  
± No. Day 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Central Laboratory: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting Lipid profile 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 


 
Version3A / 31 October 2017 
 
CONFIDENTIAL  
 
 
Page 48 of 73 
Table 1). 
 
7.1.5.2 
Fasting Insulin 
Fasting insulin will be measured in a selected subset of subjects at visits indicated on Schedule of Events 
( 
Hematology, HbA1c 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Chemistry 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Hepatitis Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver Safety Panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biomarker Laboratory Tests 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipoproteins, fasting insulin 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Inflammation Panel 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Serum/Plasma Archive 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Pharmacogenomic 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
MOCA 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
EQ-5D-5L 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior / Con. Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug Dispense/Account. 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Screen 
Treatment 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18  
Week 
- 2 to -1 
0 
2 
4 
6 
8 
10 
12 
16 
20 
24 
28 
40 
52 
64 
76 
88 
100  
± No. Day 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Central Laboratory: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting Lipid profile 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Hematology, HbA1c 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 


 
Version3A / 31 October 2017 
 
CONFIDENTIAL  
 
 
Page 49 of 73 
Table 1). 
 
7.1.5.3 
Inflammation Panel 
hsCRP, fibrinogen, and inflammatory cytokines will be measured in a selected subset of subjects at visits 
indicated on Schedule of Events ( 
Chemistry 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Hepatitis Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver Safety Panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biomarker Laboratory Tests 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipoproteins, fasting insulin 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Inflammation Panel 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Serum/Plasma Archive 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Pharmacogenomic 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
MOCA 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
EQ-5D-5L 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior / Con. Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug Dispense/Account. 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Screen 
Treatment 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18  
Week 
- 2 to -1 
0 
2 
4 
6 
8 
10 
12 
16 
20 
24 
28 
40 
52 
64 
76 
88 
100  
± No. Day 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Central Laboratory: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting Lipid profile 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Hematology, HbA1c 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 


 
Version3A / 31 October 2017 
 
CONFIDENTIAL  
 
 
Page 50 of 73 
Table 1). 
 
7.1.6 
Serum and Plasma Archive Samples 
Serum and plasma samples will be collected in subjects at visits indicated on the Schedule of Events ( 
Chemistry 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Hepatitis Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver Safety Panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biomarker Laboratory Tests 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipoproteins, fasting insulin 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Inflammation Panel 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Serum/Plasma Archive 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Pharmacogenomic 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
MOCA 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
EQ-5D-5L 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior / Con. Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug Dispense/Account. 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Screen 
Treatment 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18  
Week 
- 2 to -1 
0 
2 
4 
6 
8 
10 
12 
16 
20 
24 
28 
40 
52 
64 
76 
88 
100  
± No. Day 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Central Laboratory: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting Lipid profile 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Hematology, HbA1c 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Chemistry 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 


 
Version3A / 31 October 2017 
 
CONFIDENTIAL  
 
 
Page 51 of 73 
Table 1). The serum and plasma samples will be stored for future exploratory biomarker analysis relevant 
to lipid and inflammatory pathways.  
 
Details on the collection and shipment of samples and archiving will be provided to investigators in the 
laboratory manual.  
 
7.1.7 
Pharmacogenomic Testing (Optional) 
Pharmacogenomics is the study of how drug response is affected by genetic variation. An individual’s 
genotype may impact the pharmacokinetics, pharmacodynamics, and/or the clinical response to a 
medicine2-5. The objective of this research is to investigate a possible genetic relationship to the handling 
or response to RVX000222. If at any time during this clinical study or after a multiple studies with 
RVX000222 there appears to be variability in response to the investigational drug, the relationship 
between genetic variants and the pharmacokinetics, pharmacodynamics, safety, tolerability, and/or 
efficacy of RVX000222 may be investigated. Pharmacogenomic research generally relies on two 
approaches: 
 
1) Analyzing specific sections of the DNA (i.e., candidate genes) known to encode the drug target 
and metabolic enzymes or analyzing areas of the genome known to be associated with adverse 
events and diabetes. Note: this could include genes relevant to disease or drug response 
identified in the future. 
2) Evaluation of polymorphisms (e.g., single nucleotide polymorphisms) throughout the genome to 
identify markers that potentially correspond to response. 
 
Subjects will be asked to provide additional whole blood samples for anonymized phamacogenomic 
analysis of both DNA and mRNA expression. Collection of these samples will be optional to the subjects 
and will require a separate informed consent. Subjects may opt not to provide these samples and still 
participate in the study.  
 
The need for a pharmacogenomic analysis may not be identified until after the completion of this study. 
Therefore, samples will be stored securely for up to 15 years after the last subject has completed the 
study; however, the sponsor may destroy the samples sooner. The sponsor (or sponsor’s designee) will 
use the samples only for the purpose stated in this protocol and the informed consent. Subjects can 
request that their samples be destroyed at any time prior to anonymization. 
 
Where required, the IEC and applicable regulatory agency must approve the pharmacogenomic 
assessment before these can be conducted at a site. The written approval must clearly indicate approval 
of the pharmacogenomic assessment. When the pharmacogenomic assessments are not approved, the 
approval for the rest of the study must clearly indicate this and the pharmacogenomics portion will not be 
conducted at that site. 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Hepatitis Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver Safety Panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biomarker Laboratory Tests 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipoproteins, fasting insulin 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Inflammation Panel 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Serum/Plasma Archive 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Pharmacogenomic 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
MOCA 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
EQ-5D-5L 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior / Con. Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug Dispense/Account. 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


 
Version3A / 31 October 2017 
 
CONFIDENTIAL  
 
 
Page 52 of 73 
 
Instructions for sampling, preparation, storage, dispatch and shipment of samples will be provided in the 
laboratory manual.  
 
7.1.8 
Montreal Cognitive Assessment (MOCA)  
The MOCA6 will be performed on subjects ≥70 years of age at randomization.  It will be performed at the 
visits indicated on the Schedule of Events ( 
 
Screen 
Treatment 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18  
Week 
- 2 to -1 
0 
2 
4 
6 
8 
10 
12 
16 
20 
24 
28 
40 
52 
64 
76 
88 
100  
± No. Day 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Central Laboratory: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting Lipid profile 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 


 
Version3A / 31 October 2017 
 
CONFIDENTIAL  
 
 
Page 53 of 73 
Table 1) to measure any cognitive changes from baseline.  
 
7.1.9 
EuroQOL Five Dimensions Questionnaire (EQ-5D-5L) 
The EQ-5D-5L7,8 will be used to measure Health Related Quality of Life (HRQOL) at the visits indicated 
on the Schedule of Events ( 
Hematology, HbA1c 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Chemistry 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Hepatitis Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver Safety Panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biomarker Laboratory Tests 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipoproteins, fasting insulin 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Inflammation Panel 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Serum/Plasma Archive 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Pharmacogenomic 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
MOCA 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
EQ-5D-5L 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior / Con. Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug Dispense/Account. 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Screen 
Treatment 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18  
Week 
- 2 to -1 
0 
2 
4 
6 
8 
10 
12 
16 
20 
24 
28 
40 
52 
64 
76 
88 
100  
± No. Day 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Central Laboratory: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting Lipid profile 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Hematology, HbA1c 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 


 
Version3A / 31 October 2017 
 
CONFIDENTIAL  
 
 
Page 54 of 73 
Table 1). 
 
 
Chemistry 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Hepatitis Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver Safety Panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biomarker Laboratory Tests 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipoproteins, fasting insulin 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Inflammation Panel 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Serum/Plasma Archive 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Pharmacogenomic 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
MOCA 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
EQ-5D-5L 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior / Con. Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug Dispense/Account. 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


 
Version3A / 31 October 2017 
 
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Page 55 of 73 
 
Study Assessments 
For all study days, if a subject has any clinically significant, study-related abnormalities, additional 
evaluations may be performed at the discretion of the Investigator. 
 
7.2.1 
Screening/ Study Visit 1 (Week -2 to -1) 
Before any study-specific procedures are performed, the subject must receive an explanation of all study 
procedures, have an opportunity to ask questions, and must sign and date an Institutional Ethics 
Committee (IEC) approved written informed consent form. 
 
The following will be conducted at Screening: 
 
• 
Assess inclusion/exclusion criteria 
• 
Document in the subject’s medical records the participation in this clinical trial, that informed 
consent has been obtained, and that a copy of the signed informed consent form has been given 
to the subject.  
• 
Prepare subjects for the first treatment period participation by informing them of study restrictions 
and study procedures 
• 
Record demographics 
• 
Measure height and weight  
• 
Review and record complete medical history (including CV history)  
• 
Record prior and concomitant medications (including all CV medications), including detailed 
information related to the dose, starting and end dates for all medications. Prior medications 
taken during the 30 day period before Visit 1 will be collected 
• 
Measure vital signs  
• 
Perform a physical examination  
• 
Perform a standard 12-lead ECG 
• 
Collect clinical laboratory samples:  fasting lipid profile, hematology, HbA1c, chemistry, urinalysis, 
liver safety panel 
• 
Perform serology for hepatitis A, B, and C viruses 
• 
Perform urine pregnancy test (female subjects of childbearing potential only) 
• 
Subjects will continue or begin high intensity statin therapy as described in Section 6.6.  
 
7.2.2 
Study Visit 2/Randomization (Week 0) 
• 
Review inclusion and exclusion criteria 
• 
Record any AEs 
• 
Record concomitant medications 
• 
If subject satisfies all inclusion and exclusion criteria, randomization may occur  
• 
Measure vital signs  
• 
Collect clinical laboratory test samples: liver safety panel  
• 
Collect biomarker laboratory test samples in a selected subset of subjects: lipoproteins, fasting 
insulin, and inflammation panel  
• 
Collect serum/plasma archive samples 
• 
Collect blood samples for phamacogenomic testing (DNA and RNA) if subject consent received 
• 
Perform MOCA test for any subjects ≥ 70 years of age at randomization 
• 
Administer EQ-5D-5L 
• 
Dispense investigational drug  
• 
Dispense high intensity statin  
 


 
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7.2.3 
Study Visits 3-4 (Weeks 2-4) 
• 
Collect clinical laboratory test samples: liver safety panel 
• 
Record concomitant medications 
• 
Monitor AEs 
• 
Perform drug accountability; dispense investigational drug; dispense high intensity statin  
 
7.2.4 
Study Visits 5 (Week 6) 
• 
Collect clinical laboratory test samples: liver safety panel 
• 
Collect blood samples for phamacogenomic testing (RNA only) if subject consent received 
• 
Record concomitant medications 
• 
Monitor AEs 
• 
Perform drug accountability; dispense investigational drug; dispense high intensity statin 
 
7.2.5 
Study Visits 6-7 (Weeks 8-10) 
• 
Collect clinical laboratory test samples: liver safety panel 
• 
Record concomitant medications 
• 
Monitor AEs 
• 
Perform drug accountability; dispense investigational drug; dispense high intensity statin 
 
7.2.6 
Study Visits 8 (Weeks 12) 
• 
Collect clinical laboratory test samples: liver safety panel 
• 
Collect biomarker laboratory test samples in a selected subset of subjects: inflammation panel 
• 
Collect serum/plasma archive samples 
• 
Record concomitant medications 
• 
Monitor AEs 
• 
Perform drug accountability; dispense investigational drug; dispense high intensity statin 
 
7.2.7 
Study Visits 9-10 (Weeks 16-20) 
• 
Collect clinical laboratory test samples: liver safety panel 
• 
Record concomitant medications 
• 
Monitor AEs 
• 
Perform drug accountability; dispense investigational drug; dispense high intensity statin 
 
7.2.8 
Study Visit 11 (Week 24) 
• 
Measure vital signs  
• 
Collect clinical laboratory test samples: fasting lipid profile, hematology, HbA1c, chemistry, 
urinalysis, liver safety panel 
• 
Collect biomarker laboratory test samples in a selected subset of subjects: lipoproteins, fasting 
insulin 
• 
Administer EQ-5D-5L 
• 
Record concomitant medications 
• 
Monitor AEs 
• 
Perform drug accountability; dispense investigational drug; dispense high intensity statin 
 


 
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Page 57 of 73 
7.2.9 
Study Visits 12-13 (Weeks 28, 40) 
• 
Collect clinical laboratory test samples: liver safety panel  
• 
Record concomitant medications 
• 
Monitor AEs  
• 
Perform drug accountability; dispense investigational drug; dispense high intensity statin  
 
7.2.10 
Study Visit 14 (Week 52) 
• 
Measure vital signs  
• 
Collect clinical laboratory test samples: fasting lipid profile, hematology, HbA1c, chemistry, 
urinalysis, liver safety panel 
• 
Collect biomarker laboratory test samples in a selected subset of subjects: lipoproteins, fasting 
insulin, and inflammation panel 
• 
Collect serum/plasma archive samples 
• 
Perform MOCA test for any subjects ≥ 70 years of age at randomization  
• 
Administer EQ-5D-5L 
• 
Record concomitant medications 
• 
Monitor AEs  
• 
Perform drug accountability; dispense investigational drug; dispense high intensity statin 
 
7.2.11 
Study Visit 15 (Week 64) 
• 
Collect clinical laboratory test samples: liver safety panel 
• 
Record concomitant medications 
• 
Monitor AEs 
• 
Perform drug accountability; dispense investigational drug; dispense high intensity statin 
 
7.2.12 
Study Visit 16 (Week 76) 
• 
Measure vital signs  
• 
Collect clinical laboratory test samples: fasting lipid profile, hematology, HbA1c, chemistry, 
urinalysis, liver safety panel 
• 
Collect biomarker laboratory test samples in a selected subset of subjects: lipoproteins, fasting 
insulin  
• 
Administer EQ-5D-5L 
• 
Record concomitant medications 
• 
Monitor AEs 
• 
Perform drug accountability; dispense investigational drug; dispense high intensity statin 
 
7.2.13 
Study Visit 17 (Week 88) 
• 
Collect clinical laboratory test samples: liver safety panel 
• 
Record concomitant medications 
• 
Monitor AEs 
• 
Perform drug accountability; dispense investigational drug; dispense high intensity statin  
 
 


 
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Page 58 of 73 
7.2.14 
Study Visit 18 (Week 100) 
• 
Measure vital signs  
• 
Perform a physical examination  
• 
Collect clinical laboratory test samples: fasting lipid profile, hematology, HbA1c, chemistry, 
urinalysis, liver safety panel 
• 
Collect biomarker laboratory test samples in a selected subset of subjects: lipoproteins, fasting 
insulin  
• 
Perform MOCA test for any subjects ≥ 70 years of age at randomization 
• 
Administer EQ-5D-5L 
• 
Record concomitant medications 
• 
Monitor AEs  
• 
Perform drug accountability; dispense investigational drug; dispense high intensity statin 
 
7.2.15 
Study Visit 19 (Week 112) and additional visits until end of study (at 
12 week intervals)  
• 
Collect clinical laboratory test samples: liver safety panel 
• 
Record concomitant medications 
• 
Monitor AEs 
• 
Perform drug accountability; dispense investigational drug; dispense high intensity statin  
 
7.2.16 
Last Visit on Treatment (at end of study) 
• 
Measure vital signs  
• 
Perform a physical examination  
• 
Collect clinical laboratory test samples: fasting lipid profile, hematology, HbA1c, chemistry, 
urinalysis, liver safety panel 
• 
Collect biomarker laboratory test samples in a selected subset of subjects: lipoproteins, fasting 
insulin  
• 
Perform MOCA test for any subjects ≥ 70 years of age at randomization 
• 
Administer EQ-5D-5L 
• 
Record concomitant medications 
• 
Monitor AEs  
• 
Perform final drug accountability for RVX000222; dispense high intensity statin 
 
7.2.17 
Follow-up Visit (4 weeks after Last Visit on Treatment) or Early 
Termination Visit 
• 
Measure vital signs  
• 
Perform a physical examination  
• 
Collect clinical laboratory test samples: fasting lipid profile, hematology, HbA1c, chemistry, 
urinalysis, liver safety panel 
• 
Collect biomarker laboratory test samples in a selected subset of subjects: lipoproteins, fasting 
insulin  
• 
Record concomitant medications 
• 
Monitor AEs 
• 
Perform final drug accountability for high intensity statin 
• 
Discharge from study 
 


 
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Page 59 of 73 
 
SAFETY MONITORING 
 
Clinical Laboratory Tests 
Clinical laboratory blood and urine samples will be collected as described in Section 7.1.4. The 
Investigator will monitor the laboratory test findings. If any laboratory test on or after first dose is 
abnormal, it will be followed at the discretion of the Investigator. If the laboratory abnormality induces 
clinical signs or symptoms, or requires therapeutic intervention, then the diagnosis or medical condition 
must be entered on the AE eCRF. If the laboratory abnormality is the primary reason for an unforeseen 
hospitalization or otherwise fulfills the seriousness category of an AE, then the procedure for rapid 
notification of SAEs must be followed. Likewise, if the laboratory abnormality leads to discontinuation from 
the study, then the subject must be followed until the abnormality resolves or until it is judged to be 
permanent. 
 
 
Adverse Events 
Adverse events that are reported, observed, or elicited by indirect questioning will be collected throughout 
the study beginning at the time of informed consent and continuing for the duration of the study. Ongoing 
AEs will be followed to resolution, whenever possible. 
 
8.2.1 
Definition of Adverse Events 
An AE is any untoward medical occurrence in a subject, which does not necessarily have a causal 
relationship with study treatment.  It includes the appearance or worsening of any undesirable sign, 
symptom, or medical condition occurring after informed consent even if the event is not considered to be 
related to study drug. Study drug includes the investigational drug under evaluation and the concomitant 
statin therapy that is given during any phase of the study. 
 
8.2.2 
Methods for Following and Documenting Adverse Events 
All subjects are carefully monitored for the occurrence of any AE. The safety variables comprise physical 
examination findings, vital signs, ECGs, and clinical laboratory tests. Additional safety evaluations 
considered necessary might be performed at the discretion of the Investigator.  
Medical conditions/diseases present before starting study drug are only considered AEs if they worsen 
after starting study drug. Abnormal laboratory values or test results constitute AEs only if they induce 
clinical signs or symptoms, are considered clinically significant, or require therapy. Wherever possible, the 
underlying cause for signs or symptoms should be considered the AE and not the observed signs and 
symptoms (e.g., pneumonia is preferable to cough, fever, and chest pain). Laboratory values that 
precipitate dose interruption or discontinuation will be captured as AEs. 
The occurrence of AEs should be sought by non-directive questioning of the subject at each visit during 
the study. Adverse events also may be detected when they are volunteered by the subject during or 
between visits or through physical examination, laboratory test, or other assessments. All reported AEs 
are to be recorded in the subject’s medical record and in the eCRF. If no AE has occurred during the 
study period, this should also be indicated in the study documents. The severity and causal relationship to 
study treatment should be assessed. 
Characteristics of the AE are to be recorded including: 
• 
Nature (brief description) 
• 
Time and date of onset 
• 
Time and date of resolution 
• 
Maximum intensity (mild, moderate, severe) 
• 
Seriousness 


 
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Page 60 of 73 
• 
Treatment given 
• 
Relationship (causality) to the investigational drug (scale: not related, possibly related, probably 
related, and related) 
• 
Action taken (investigational drug) 
• 
Relationship (causality) to the concomitant statin therapy 
• 
Action taken (concomitant statin therapy) 
• 
Outcome 
 
8.2.2.1 
Follow-up on Adverse Events 
Adverse events, abnormal clinical laboratory test results, changes in physical examination findings, or 
changes in vital sign measurements or ECGs that the Investigator considers to be clinically significant will 
be followed until resolution or a until a stable condition has been established. Subjects withdrawn for 
safety reasons will be followed until the AE or abnormal laboratory test has been normalized, or until 
there is an adequate explanation for the AE or laboratory test that is unrelated to the study drug. 
 
8.2.2.2 
Rating Scale for Maximum Intensity 
Maximum intensity of an AE is the accumulated degree of discomfort, or if the AE is life threatening. 
Intensity should be assessed according to the following definitions: 
Mild: 
Awareness of signs or symptoms, but these are easily tolerated (acceptable) 
Moderate: 
Discomfort enough to interfere with usual activity (disturbing) 
Severe: 
Incapacity to work or to do usual activity (unacceptable) 
 
8.2.2.3 
Rating Scale for Causality 
Assessment of causality of suspected AEs is based on associative connections (time or place), 
pharmacological explanations, previous knowledge of the drug, presence of characteristic clinical or 
pathological phenomena, exclusion of other causes, and absence of alternative explanations. The 
Investigator will be asked to assess the causal relationship to the study drug according to the following 
classifications: 
 
Not related: 
Time relationship with study drug administration is nonexistent or doubtful, or other 
factors, certain or probable, to have been causative. 
Possible: 
Time relationship with study drug administration exists. Other possible causative factors 
may exist (e.g., concurrent disease or concomitant medication). Improvements on 
dechallenge or dose reduction (if performed) may or may not have been seen. 
Probable: 
Time relationship with study drug administration exists. No other possible causative 
factors may exist (not reasonably explained by the subject’s known clinical state or 
concomitant medication). Improvements on dechallenge or dose reduction (if performed) 
have occurred. Recurrence of symptoms on rechallenge (if performed) has occurred. A 
specific laboratory investigation (if performed) has confirmed the relationship. 
Definite: 
Those events for which there is no shadow of doubt that they are a consequence of 
administration of the study drug. It is likely that such events will be widely documented 
and generally accepted as having association with the study drug or that they 
reoccurred after rechallenge (if performed). 


 
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8.2.2.4 
Follow-up Period After an Adverse Event 
If clinically significant findings are present at the study termination (Follow-Up Visit), a determination will 
be made about each persistent clinically significant finding. If not clinically important (i.e., does not pose a 
health risk to the subject), the findings will be labeled ongoing and follow-up will cease. If clinically 
important, follow-up will continue on a case-by-case basis until satisfactory resolution. 
 
8.2.2.5 
Coding of Adverse Events 
Adverse events will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA). 
Coding will be performed after the eCRFs have been completed by the Investigative Sites. 
 
8.2.3 
Serious Adverse Events 
8.2.3.1 
Definition 
An SAE or reaction is any untoward medical occurrence that at any dose: 
 
• 
Results in death; 
• 
Is life threatening (life threatening refers to an event in which the subject was at immediate risk of 
death at the time of the event; it does not refer to an event that hypothetically might have caused 
death if it were more severe); 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization; 
• 
Results in persistent or significant disability or incapacity; 
• 
Is a congenital anomaly or birth defect; or 
• 
Is medically significant, and though not included in the above list, is an important medical event 
that may jeopardize the subject or require medical intervention to prevent one of the outcomes 
listed above. Discontinuation of study drug or conduct of additional diagnostic evaluations, will 
not, by themselves, satisfy the criterion for a medically significant event. 
 
Medical judgment should be exercised in deciding whether expedited reporting is appropriate in other 
situations, such as important medical events that may not be immediately life threatening or result in 
death or hospitalization, but that may jeopardize the subject or may require intervention to prevent one of 
the other outcomes listed in the definition above. These events should also usually be considered 
serious. Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias, or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse. 
 
8.2.3.2 
Hospitalization 
Adverse events reported from clinical trials associated with hospitalization or prolongation of 
hospitalization are considered serious. Any initial admission to a healthcare facility meets these criteria. 
Hospitalization does not include the following: 
• 
Rehabilitation facilities 
• 
Hospice facilities 
• 
Respite care 
• 
Skilled nursing facilities 
• 
Nursing home 
• 
Routine emergency room admission 
• 
Same day surgeries (as outpatient/same day/ambulatory procedures) 
 


 
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Hospitalizations or prolongation of hospitalization in the absence of precipitating clinical AE is not in itself 
an SAE. Examples include: 
 
• 
Routine treatment or monitoring of the studied indication, not associated with any deterioration in 
condition 
• 
Elective or pre-planned treatment for a pre-existing condition that is unrelated to the indication 
under study and has not worsened since the start of study drug 
• 
Treatment on an emergency outpatient basis for an event not fulfilling any of the definitions of a 
SAE given above and not resulting in hospital admission 
• 
Social reasons and respite care in the absence of any deterioration in the subject’s general 
condition 
 
8.2.3.3 
SAE Reporting to Sponsor 
All SAEs must be reported, whether or not considered attributable to the study drug, on a separate SAE 
report form. As much information as possible should be supplied at the time of the initial report with at 
least the following information: 
 
• 
Subject, treatment, and study identifiers; 
• 
Investigator’s name and address; 
• 
Description of the event, action taken, and outcome; 
• 
Date of onset and current status; 
• 
Any suspect (study) drug, with its start date, dose, and form of administration; 
• 
Reason the AE is regarded as serious; 
• 
Current assessment or opinion of causality; 
• 
Any other available diagnostic information that will contribute to the understanding of the event; 
and 
• 
If applicable, whether the randomization code has been broken because of the SAE. 
 
The Investigator must inform the Sponsor or Sponsor’s designee within 24 hours of when the Investigator 
is aware of the occurrence of the SAE, whether or not the SAE is related to the study drug. A written 
report should be submitted, consisting of the SAE report form accompanied by the demographics, 
medical history, AE, and the concomitant medications pages from the study documents. All pertinent 
information must be followed by a full follow-up report to the Sponsor within 3 calendar days. As complete 
a report as possible, (e.g., results of any additional tests) should be forwarded within 8 additional calendar 
days to the Sponsor. Any significant new information on the SAE and final outcome must be supplied 
promptly to the Sponsor. 
 
SAEs will be collected throughout the study beginning at Screening and continuing for the duration of the 
study. Ongoing SAEs will be followed to resolution, whenever possible. 
 
8.2.3.4 
Safety Reporting to Investigators, IRBs or IECs, and Regulatory 
Authorities 
The Sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) which do not represent a protocol-defined MACE endpoint (see Section 8.2.3.5), and any other 
applicable SAEs to regulatory authorities, investigators and IRBs or IECs as applicable, in accordance 
with national regulations in the countries where the study is conducted.  
 


 
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Relative to the first awareness of the event by/or further provision to the sponsor or sponsor’s designee, 
SUSARs will be submitted to the regulatory authorities as expedited report within 7 days for fatal and life-
threatening events and 15 days for other serious events, unless otherwise required by national 
regulations. The sponsor will also prepare an expedited report for other safety issues where these might 
materially alter the current benefit-risk assessment of an investigational medicinal product or that would 
be sufficient to consider changes in the investigational medicinal products administration or in the overall 
conduct of the trial.  
 
The Investigator should comply with the applicable regulatory requirements related to the reporting of 
SAEs to the local IEC. 
 
8.2.3.5 
MACE Adjudication  
All potential primary and secondary MACE events will be reported as SAEs as noted in Section 8.2.3.3. 
The coronary revascularization cases collected in the eCRF will also be forwarded for adjudication.  
 
An independent, treatment-blinded CEC will be appointed to adjudicate CV events. The Committee will 
confirm all primary and secondary MACE events as defined below: 
 
Primary and Secondary MACE events will include: 
 
• 
CV death 
• 
Non-fatal MI 
• 
Hospitalization for CVD events including:  
o 
Unstable angina 
o 
Congestive heart failure 
o 
Any revascularization procedure 
• 
Stroke  
 
All deaths will be adjudicated for CV deaths. 
 
A Charter will be prepared to detail precise responsibilities and procedures applicable to this committee.  
Adjudications will be based on events as defined in the CEC charter and will be based on the CDISC 
standardized definitions for Cardiovascular and Stroke Endpoint Events1. 
 
8.2.4 
Adverse Events of Special Interest  
Adverse events of special interest (AESIs) in this study are AEs which could be associated with 
immunosuppression, including all opportunistic infections and any serious infections that occur during the 
AE reporting period.  The study Medical Monitor will review AESIs on an ongoing basis in a blinded 
fashion, and the DSMB will periodically review unblinded AESIs at their regular meetings. 
 
8.2.5 
Pregnancies 
Pregnancies during the study and within 4 weeks after end of treatment will be reported and tracked 
according to Safety monitoring documentation.  
 


 
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STATISTICAL CONSIDERATIONS 
 
General Considerations 
A statistical analysis plan (SAP) will be prepared and finalized prior to the first unblinded interim analysis. 
This document will provide further details regarding the definition of analysis variables and analysis 
methodology to address all study objectives.  This document may modify the analysis plans outlined in 
the protocol and supersede the statistical methods described in the protocol. 
 
Blinded data review meetings will be conducted prior to unblinding. This blinded review will assess the 
accuracy and completeness of the study database, subject evaluability, and appropriateness of the 
planned statistical methods. 
 
Any change to the data analyses methods described in the protocol will require a protocol amendment 
only if it changes one or more of the principal features of the protocol. Any other change to the statistical 
analysis methods described in the protocol and the justification for making the change will be described in 
the clinical study report. 
 
Additional exploratory analyses of the data will be conducted as deemed appropriate. 
 
 
Sample Size 
Assuming a design with a provision for futility at 75% adjudicated events will provide approximately 80% 
power to declare superiority of RVX000222 arm over Placebo with a hazard ratio of 0.7, a true hazard 
ratio of 1.0 and at an overall 2-sided 5% significance level. 
To calculate the sample size, the following additional information was assumed: 
• 
Total number of narrowly defined MACE events needed:  250  
• 
10.5% event rate in the placebo arm at 18 months 
• 
30% relative risk reduction (7.47% event rate at 18 months in the RVX000222 arm)  
• 
A cumulative drop-out rate of 10% per arm by the end of the study (5% drop out rate per arm by year 
one) 
With the above design and assumptions, a sample size of 2400 randomized subjects enrolled uniformly 
over 1.7 years with subjects followed until failure, drop out or end of study will provide the 250 events 
needed. 
The power and sample size for this study was calculated using East 6.2. 
 
 
Analysis Sets 
Full Analysis Set (FAS): The FAS will include all randomized subjects who receive any amount of study 
therapy and have at least one measurement of the assessment of interest.  All efficacy analyses will be 
conducted for the FAS set. Subjects will be analyzed based on randomized treatment group. 
Per-protocol Set (PPS): The PPS will consist of all FAS subjects who fulfill all inclusion/exclusion criteria, 
and have no other major protocol violations.  The major protocol violation criteria will be finalized by the 
Clinical Science and Biostatistics teams as part of the treatment-blinded data review prior to the interim 
and final database locks. Likewise, whenever possible, subjects belonging to the PPS will be determined 
prior to the interim and final database locks.   
Safety Set (SS): The SS will include all subjects who took at least one dose of double-blind study therapy. 
In safety summaries, subjects will be analyzed according to the actual treatment received.  All safety 
analyses will use the SS. 
 


 
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Baseline and Demographic Data 
Baseline and demographic information will be listed and summarized by group and overall Continuous 
demographic variables will be summarized using number of observations, mean and standard deviation, 
median and minimum and maximum values. Categorical values will be summarized using number of 
observations and percentages. 
 
 
Subject Disposition 
Subject disposition (analyses of randomized, treated, discontinued with primary reason for 
discontinuation) will be summarized using frequency and percentage by treatment group. 
 
 
Efficacy Analysis 
All efficacy analyses will use the FAS set. Key efficacy analyses will also be performed on the PPS as 
supportive evidence and to assess the robustness of the efficacy findings. Subjects will be analyzed 
according to randomized treatment group.  
Time to event analyses for primary and secondary endpoints will use a Kaplan-Meier method to estimate 
the median onset time and its 2-sided 95% confidence intervals (CIs). A stratified log rank test will be 
used for calculating the 2-sided p-value for treatment comparisons. 
Quantitative endpoints that are defined as a change from baseline will be analyzed using analysis of 
covariance (ANCOVA) models with strata and treatment group as factors and the baseline value as 
covariate. Mixed model repeated measurements (MMRM) will be used to analyse all assessments of 
continuous outcomes over time. 
For continuous endpoints pertaining liver function, lipid profile, kidney function, HbA1c, fasting glucose, 
and insulin, descriptive statistics (N, mean, median, standard deviation, quartiles, minimum and 
maximum) will be provided by treatment group at specified visits. 
Efficacy results will be considered statistically significant after consideration of the control of multiplicity as 
specified in Section 9.6.1. All statistical tests will be conducted at alpha = 0.05 (2-sided) level, and a 2 
sided p-values and CIs will be reported.  
 
9.6.1 
Multiplicity 
Statistical tests for comparing RVX000222 arm with Placebo will be conducted for the primary endpoint 
and other efficacy endpoints as listed in Section 3.0. 
The multiplicity of the analyses of the primary and key secondary endpoints will be adjusted using a 
Sequential Gate-Keeping Procedure. This procedure will preserve the Family Wise Error Rate in light of 
multiple analyses being performed. The analyses will be performed in sequence until one of the analyses 
has failed to show the significance level of p = 0.05.  
The key secondary endpoints will be tested for superiority in order only if superiority is established for 
primary efficacy endpoint. The key secondary endpoints will be tested sequentially following a pre-
specified order as seen in Section 3.0. 
No multiplicity adjustment is planned to test the other secondary and exploratory endpoints as these 
endpoints are considered supportive. 
Subjects will continue to be followed for both primary and secondary endpoints until 250 primary endpoint 
events have been observed. Other than the pre-specified sequential testing, no additional alpha 
adjustments for multiplicity will be made. 
 


 
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Page 66 of 73 
 
Safety Analysis 
Drug administration, disposition data, medical history and prior medications will be summarized by 
treatment group using descriptive statistics. Safety data such as clinical laboratory results, vital signs, 
findings from physical examinations, and MOCAs will be listed and summarized by treatment group where 
appropriate. For continuous variables, these summaries will include sample size, mean, median, standard 
deviation, minimum, and maximum. For categorical variables, these summaries will include frequencies 
and corresponding percentages. No inferential hypothesis testing will be performed on the safety 
variables. 
The assessment of safety will be based on the frequency, intensity, and types of AEs and for change and 
shift from Baseline in the clinical laboratory variables, and vital sign measurements. Baseline values for 
clinical laboratory variables, and vital sign measurements are defined as the last non-missing values 
obtained prior to dosing. Clinical laboratory variables outside reference ranges will be flagged in clinical 
laboratory listings. 
Adverse events will be summarized using the safety set. Adverse events will be coded using MedDRA 
(version 17.0 or higher), summarized by frequency, severity, relationship to study drug, and number of 
subjects per treatment and by the preferred term and system organ class.  Data will be summarized using 
preferred term and primary system organ class. The coded events will be summarized by treatment 
group, in subsets of all treatment-emergent AEs, all treatment-related AEs, non-serious treatment 
emergent AEs and serious treatment emergent AEs. Adverse events of special interest (opportunistic 
infections and all serious/severe infections) will be analyzed as a subset of the overall AEs. Treatment-
emergent AEs will be defined as any AEs, regardless of relationship to study drug, that occur after the 
first dose of double-blind investigational drug and within 14 days after the last dose of double-blind 
investigational drug. Treatment-related AEs will be defined as any AEs that are considered by the 
investigator to be either possibly, probably, or definitely related to study drug. In addition, if relationship 
information is missing, the AE will be considered treatment-related. Listings for the subsets of SAEs and 
treatment-related SAEs will be provided. 
 
 
Missing/Incomplete Subject Data 
Missing values will not be imputed. 
 
 
Interim Analysis 
Prospective unblinded analyses for safety, futility, and sample size adjustment (SSA) if indicated will be 
conducted by an independent statistician as part of the study design as described in Section 10.8 (Data 
and Safety Monitoring Board). An interim analysis is planned to assess futility at 75% adjudication of 
primary endpoint events. 
The statistical methodology for futility and SSA that preserves the overall Type I error will be described in 
greater detail in the DSMB interim futility / sample size adjustment plan.  
 
 REGULATORY AND PROCEDURAL REQUIREMENTS 
It is the responsibility of the Investigator to assure that the study is conducted in accordance with current 
local and national regulations, International Conference on Harmonisation (ICH) and other applicable 
requirements governing the conduct of human clinical trials. 
 
 Institutional Ethics Committee 
The study protocol, including final version of the subject information and informed consent form, must be 
approved by the IEC prior to enrolment of any subject. The approval of the IEC should be dated and 


 
Version3A / 31 October 2017 
 
CONFIDENTIAL  
 
 
Page 67 of 73 
given in writing. A list of those present at the committee meeting (names and positions) should be 
attached whenever possible. 
 
The Investigator is responsible for informing the IEC of any SAE or amendments to the protocol as 
specified in the local requirements. All correspondence with the IEC should be filed by the Investigator. 
 
 Ethical Conduct of the Study 
The study will be performed in accordance with the principles stated in the Declaration of Helsinki and 
subsequent revisions, the ICH E6, FDA regulations, and applicable local regulations. 
 
 Informed Consent Document 
At the Screening visit, and before any study-related procedures, the IEC-approved informed consent form 
will be provided to the subject. The Investigator, or a qualified designee, will fully inform the subject of all 
pertinent aspects of the study. Before informed consent is given, the Investigator or a designee should 
provide the subject ample time and opportunity to inquire about details of the study. All questions about 
the study should be answered to the subject’s satisfaction.  
 
Before participation in the study, the written informed consent form will be signed and personally dated by 
the subject and by the person who conducted the informed consent discussion. Both the informed 
consent discussion and the written informed consent form will include clear explanations of the 
recommended elements of informed consent. No subject is to participate in study activities until informed 
consent has been obtained. Subjects will be given a copy of their signed informed consent form. 
 
 Responsibilities of the Investigator and IEC 
The protocol and the proposed informed consent form must be reviewed and approved by a properly 
constituted IEC before study start. A signed and dated statement that the protocol and informed consent 
have been approved by the IEC must be given to the Sponsor or Sponsor’s designee before study 
initiation.  
 
Prior to study start, the investigator is required to sign a protocol signature page confirming his/her 
agreement to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to the Sponsor or 
Sponsor’s designee, IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform the Sponsor immediately that this 
request has been made. 
 
 Monitoring the Study 
Site visits and inspections will be conducted by the Sponsor or Sponsor’s designee at regular intervals in 
accordance with the applicable health authority and ICH guidelines. The Investigator will permit 
representatives of the Sponsor’s monitoring team and health authority auditors to inspect relevant 
facilities and records. 
 
 Protocol Adherence 
The Investigator will not deviate from the protocol without prior written approval from Sponsor or its 
designee, except in medical emergencies. In the event of a medical emergency, the Medical Monitor must 
be notified as soon as possible. Any other change to the protocol must be implemented as an 
amendment to the protocol and must be approved by the IEC and Sponsor before implementation. 
 


 
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The governing IEC will be informed of all protocol changes by the Investigator in accordance with the 
IEC’s established procedure. No deviations from the protocol of any type will be permitted without 
complying with established IEC procedures. 
 
 Clinical Steering Committee  
An independent CSC will serve to oversee and guide the conduct of the study. The CSC will be blinded to 
the study data while the study is ongoing. 
 
 Data and Safety Monitoring Board  
An independent DSMB will be appointed. The committee will not include any investigators involved with 
the study. The DSMB will monitor the un-blinded subject safety data on an ongoing basis at quarterly 
meetings during the course of the study. The ongoing DSMB safety review will also include review of 
adverse events of special interest, as defined in Section 8.2.4.   
 
The DSMB charter will be prepared to detail precise roles and responsibilities and procedures to ensure 
maintenance of the blinding to those not part of the DSMB and the integrity of the study in the review of 
accumulating data and interactions with the CSC and protocol management team. The DSMB will also be 
involved in the monitoring unblinded efficacy data generated from interim analyses planned to assess 
futility at 75% adjudication of events. A DSMB futility / sample size adjustment analysis plan will contain 
more detail.  
 
 Changes in the Conduct of the Study or Planned Analyses 
Only the Sponsor, on the recommendation of the CSC, may modify the protocol. Amendments to the 
protocol will be made only after consultation and agreement between the Sponsor and the Investigator. 
The only exception is when the Investigator considers that a subject’s safety is compromised without 
immediate action. In these circumstances, the Investigator takes the appropriate action, documents the 
action taken, and informs the Sponsor and the IEC as soon as possible or within 5 working days after the 
emergency occurred. All amendments that have an impact on subject risk or the study objectives, or 
require revision of the informed consent form, must receive approval from the IEC before being 
implemented. 
 
 Participant Recruitment 
If an Investigator chooses to advertise for subjects, whether in professional or consumer publications, 
radio, or television, Sponsor and the IEC must approve all advertising before it begins. 
 
 Compensation, Insurance and Indemnity 
These elements will be covered in the contractual agreements between the Sponsor, the site and the 
Investigator. 
 
 
 DATA COLLECTION 
 Recording of Data 
An electronic data capture (EDC) system will be used for data collection and query handling. The 
investigator will ensure that data are accurately entered into the eCRF as specified in the protocol and 
respond to any reported discrepancies rapidly. 
 


 
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The eCRFs allow data entry by authorized personnel, who can add and edit data, add new subjects, 
identify and resolve discrepancies, and view records. Each person involved with the study will have an 
individual identification code and password that allows for record traceability. Thus, the system, and 
subsequently any investigative reviews, can identify coordinators, Investigators, and individuals who have 
entered or modified records, as well as the time and date of any modifications. There is an internal quality 
review audit of the data and additional reviews by the Clinical Monitor. 
 
The Investigator will sign the completed CRF. The Investigator’s signature will be applied as specified in 
the Data Management Plan. 
 
All suspected events included in the composite endpoint of CV death, non-fatal MI, stroke, or secondary 
CV endpoints will be recorded in the respective appropriate modules of the eCRF. Investigators are also 
required to provide the CEC copies of source documents (e.g., medical records, discharge summary, 
death certificate, autopsy report, etc.) Refer to the study manual for procedures regarding Events to be 
Adjudicated.  
 
 Recordkeeping and Retention 
The Investigator must maintain adequate records for the study, including completed study documents, 
medical records, laboratory reports, signed informed consent documents, drug disposition records, AE 
reports, information regarding subjects who discontinued, all correspondence with the IEC and the 
Sponsor (or designee), and other pertinent data.  
 
Source documents should be completed for each included subject. It is the Investigator's responsibility to 
ensure completion and to review and approve these source documents.  Source documents must be 
signed/initialed by the investigator or by an authorized staff member. These signatures/initials serve to 
attest that the information contained on the source documents is true. At all times, the Investigator has 
final personal responsibility for the accuracy and authenticity of all clinical and laboratory data entered on 
the source documents.  
 
The Investigator will retain all records for a minimum of 2 years after the health authority approves the 
marketing application for the drug, or for a minimum of 2 years after the termination or withdrawal of the 
health regulatory agency exemption (e.g., Investigational New Drug [IND] or clinical trial application) 
under which the study was conducted. To avoid any possible errors, the Investigator must contact 
Sponsor or its designee before the destruction of any study records. The Investigator will also notify 
Sponsor or its designee of accidental loss or destruction of any study records. 
 
 Data Collection 
Study data as indicated on the Schedule of Events ( 
 
Screen 
Treatment 


 
Version3A / 31 October 2017 
 
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Page 70 of 73 
Table 1) will be collected at each study visit and recorded in the appropriate sections of the eCRF.  
 
 Efficacy 
The primary and secondary CV efficacy variables will be adjudicated by the independent, treatment-
blinded CEC. For documents to be sent to the CEC, refer to the study manual.  
 
 Disclosure of Data 
A subject’s medical information obtained as a result of this study is confidential. Disclosure to third parties 
other than those noted below is prohibited. Subject confidentiality will be further assured by using subject 
identification code numbers to correspond to treatment data in the computer files. If results of this study 
are reported in medical journals or at meetings, the subject’s identity will remain confidential. 
 
Medical information may be provided to the subject’s personal physician or to other appropriate medical 
personnel responsible for the subject’s welfare. Data generated as a result of this study are to be 
available for inspection on request by health authority auditors, the sponsor’s monitors, and by the IEC. If 
the health authority or other regulatory agency should schedule an inspection, the medical monitor should 
be advised immediately. 
 
 Confidentiality and Communication of Results 
All information concerning this study and Sponsor, including patent applications and manufacturing 
processes not previously published, is considered confidential and shall remain the sole property of 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18  
Week 
- 2 to -1 
0 
2 
4 
6 
8 
10 
12 
16 
20 
24 
28 
40 
52 
64 
76 
88 
100  
± No. Day 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Central Laboratory: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting Lipid profile 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Hematology, HbA1c 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Chemistry 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Hepatitis Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver Safety Panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biomarker Laboratory Tests 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipoproteins, fasting insulin 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Inflammation Panel 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Serum/Plasma Archive 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Pharmacogenomic 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
MOCA 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
EQ-5D-5L 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior / Con. Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug Dispense/Account. 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


 
Version3A / 31 October 2017 
 
CONFIDENTIAL  
 
 
Page 71 of 73 
Sponsor. Confidential information may be published only in collaboration with participating personnel from 
the Sponsor. 
 
 


 
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Page 72 of 73 
 REFERENCES 
1. Hicks HM, Hung J, Mahaffey KW, Mehran R, Nissen SE, Stockbridge NL, Targum SL, Temple R. 
Standardized Definitions for Cardiovascular and Stroke Endpoint Events in Clinical Trials, Draft 
Definitions for CDISC August 20, 2014. 
2. Drazen JM, Yandava CN, Dube L, Szczerback N, Hippensteel R, Pillari A, Israel E, Schork N, 
Silverman ES, Katz DA, Drajesk J. Pharmacogenetic association between ALOX5 promoter 
genotype and the response to anti-asthma treatment. Nat Genet. 1999;22:168-70. 
3. Hetherington S, Hughes AR, Mosteller M, Shortino D, Baker KL, Spreen W, Lai E, Davies K, 
Handley A, Dow DJ, Fling ME, Stocum M, Bowman C, Thurmond LM, Roses AD. Genetic 
variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet. 2002;359:1121-2. 
4. Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, Sayer D, Castley A, Mamotte C, 
Maxwell D, James I, Christiansen FT. Association between presence of HLA-B*5701, HLA-DR7, 
and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet. 
2002;359:727-32. 
5. Roses AD. Genome-based pharmacogenetics and the pharmaceutical industry. Nat Rev Drug 
Discov. 2002;1:541-9. 
6. Nasreddine ZS., Phillips NA, Bédirian V, Charbonneau S, Whitehead V, Collin I, Cummings JL, & 
Chertkow H. (2005). The Montreal Cognitive Assessment, MoCA: A brief screening tool for mild 
cognitive impairment. JAGS, 53, 695–699. 
7. The EuroQol Group. EuroQol-a new facility for the measurement of health-related quality of life. 
Health Policy. 1990; 16(3):199-208. 
8. Brooks R. EuroQol: the current state of play. Health Policy. 1996; 37(1):53-72. 
9. Child CG, Turcotte JG. Surgery and portal hypertension. The liver and portal hypertension. 
Philadelphia: Saunders. 1964; 50-64. 
10. Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus 
for bleeding oesophageal varices. British Journal of Surgery. 1973; 60 (8): 646–9. 
 
 


 
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Page 73 of 73 
 APPENDICES 
APPENDIX A: CHILD-PUGH CLASSIFICATION9,10 
 
Child- Turcotte-Pugh (CTP) classification of the severity of cirrhosis 
 
  
Points* 
  
1 
2 
3 
Encephalopathy 
None 
Grade 1-2 
(or precipitant-induced) 
Grade 3-4 
(or chronic) 
Ascites 
None 
Mild/Moderate  
(diuretic-responsive) 
Severe 
(diuretic-refractory) 
Bilirubin (mg/dL) 
<2 
2-3 
>3 
Albumin (g/dL) 
>3.5 
2.8-3.5 
<2.8 
PT (sec prolonged) 
or INR 
<4 
<1.7 
4-6 
1.7-2.3 
>6 
>2.3 
 
CTP score is obtained by adding the score for each parameter 
CTP class:  
A = 5-6 points 
 
B = 7-9 points 
 
C = 10-15 points 
 

SAP_001.pdf: 
 
Confidential 
 
 
 
 
Resverlogix Corp. 
 
Protocol Number: RVX222-CS-015 
 
 
 
A Phase III Multi-Center, Double-Blind, Randomized, Parallel Group, 
Placebo-Controlled Clinical Trial in High-Risk Type 2 Diabetes Mellitus 
(T2DM) Subjects with Coronary Artery Disease (CAD) to Determine 
Whether Bromodomain Extraterminal Domain (BET) Inhibition Treatment 
with RVX000222 Increases the Time to Major Adverse Cardiovascular 
Events (MACE) 
 
EudraCT Number: 
ClinicalTrials.gov Identifier: 
2015-002040-14 
NCT02586155 
 
 
 
Statistical Analysis Plan 
 
Final Version 3.0 
Date: 10 June 2019 
 
 
Prepared by: 
 
PPD 
on behalf of Resverlogix Corp. 
 
 
 
CONFIDENTIAL PROPERTY OF RESVERLOGIX 
This document is a confidential communication of Resverlogix. Acceptance of this document constitutes the 
agreement by the recipient that no information contained herein will be published or disclosed without written 
authorization from Resverlogix.


Resverlogix Corp. 
 
Statistical Analysis Plan, Final Version 3.0 
RVX222-CS-015 
 
Date Issued: 10 June 2019 
 
 
 
 
2
APPROVAL SIGNATURES 
 
Study Title: 
A Phase III Multi-Center, Double-Blind, Randomized, Parallel Group, 
Placebo-Controlled Clinical Trial in High-Risk Type 2 Diabetes Mellitus 
(T2DM) Subjects with Coronary Artery Disease (CAD) to Determine 
Whether Bromodomain Extraterminal Domain (BET) Inhibition Treatment 
with RVX000222 Increases the Time to Major Adverse Cardiovascular 
Events (MACE) 
Prepared by: 
 
 
LieLing Wu (with follow up by Dan Conroy) 
Project Statistician / Biostatistics Project Lead 
Principal Biostatistician 
Biostatistics, PPD 
 
 
 
 
 
 
 
Resverlogix Approvals: 
 
 
 
 
 
Mike Sweeney, MD 
Senior Vice President, Clinical Development 
 
 
 
Date 
Jan Johansson, MD 
Senior Vice President, Medical Affairs 
 
 
 
Date 
 
 
 
 
PPD Review and Approvals: 
 
 
 
 
Tingting Li 
Sr. Manager, Biostatistics 
BIOSTATISTICS, PPD 
  
Date 
 
 


Resverlogix Corp. 
 
Statistical Analysis Plan, Final Version 3.0 
RVX222-CS-015 
 
Date Issued: 10 June 2019 
 
 
 
 
3
TABLE OF CONTENTS: 
 
LIST OF ABBREVIATIONS ..................................................................................................... 5 
1. 
INTRODUCTION ........................................................................................................... 7 
2. 
OBJECTIVES.................................................................................................................. 8 
2.1. 
PRIMARY OBJECTIVE .................................................................................................. 8 
2.2. 
SECONDARY OBJECTIVES ............................................................................................ 8 
2.3. 
EXPLORATORY OBJECTIVES ........................................................................................ 8 
3. 
INVESTIGATIONAL PLAN ......................................................................................... 9 
3.1. 
OVERALL STUDY DESIGN AND PLAN .......................................................................... 9 
3.2. 
STUDY ENDPOINTS ...................................................................................................... 9 
3.2.1. 
PRIMARY ENDPOINT ................................................................................................... 9 
3.2.2. 
KEY SECONDARY ENDPOINTS ..................................................................................... 9 
3.2.2.1. 
OTHER SECONDARY ENDPOINTS ............................................................................... 10 
3.2.3. 
EXPLORATORY ENDPOINTS ....................................................................................... 10 
3.2.4. 
SAFETY ENDPOINTS .................................................................................................. 10 
3.3. 
STUDY DRUGS .......................................................................................................... 10 
3.4. 
STUDY DRUG INTERRUPTION/DISCONTINUATION ..................................................... 11 
3.5. 
CONCOMITANT STATIN THERAPY ............................................................................. 11 
3.6. 
BACKGROUND THERAPY ........................................................................................... 11 
3.7. 
STUDY VISITS ........................................................................................................... 11 
3.8. 
DOSE ADJUSTMENT/MODIFICATIONS ........................................................................ 11 
4. 
GENERAL STATISTICAL CONSIDERATIONS ...................................................... 13 
4.1. 
REPORTING CONVENTIONS AND DATES HANDLING .................................................. 13 
4.2. 
SAMPLE SIZE JUSTIFICATION: ................................................................................... 13 
4.3. 
RANDOMIZATION, STRATIFICATION, AND BLINDING ................................................. 14 
4.3.1. 
RANDOMIZATION ...................................................................................................... 14 
4.3.2. 
RVX000222 TREATMENT BLINDING ........................................................................ 14 
4.4. 
ANALYSIS SET .......................................................................................................... 15 
4.4.1. 
FULL ANALYSIS SET (FAS) ...................................................................................... 15 
4.4.2. 
PER-PROTOCOL SET (PPS) ........................................................................................ 15 
4.4.3. 
SAFETY SET (SS) ...................................................................................................... 15 
4.5. 
DEFINITION OF TIME POINTS, STUDY DATES, VISIT WINDOWS, AND DURATION ...... 15 
Table 1: Visit Windows for Efficacy and Safety Variables .................................. 16 
5. 
SUBJECT DISPOSITION............................................................................................. 18 
5.1. 
DISPOSITION ............................................................................................................. 18 
5.2. 
SIGNIFICANT PROTOCOL DEVIATIONS ....................................................................... 18 
6. 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ...................... 19 
6.1. 
DEMOGRAPHICS ........................................................................................................ 19 
6.2. 
BASELINE DISEASE CHARACTERISTICS AND MEDICAL HISTORY .............................. 19 
7. 
TREATMENTS AND MEDICATIONS ...................................................................... 20 
7.1. 
STUDY TREATMENTS ................................................................................................ 20 
7.1.1. 
STUDY DRUG EXPOSURE .......................................................................................... 20 
Table 2: Study Drug Administration Schedule...................................................... 20 
7.2. 
PRIOR AND CONCOMITANT MEDICATIONS ................................................................ 20 
7.2.1. 
CONCOMITANT STATIN THERAPY ............................................................................. 21 


Resverlogix Corp. 
 
Statistical Analysis Plan, Final Version 3.0 
RVX222-CS-015 
 
Date Issued: 10 June 2019 
 
 
 
 
4
8. 
EFFICACY ANALYSIS ............................................................................................... 22 
8.1. 
ADJUDICATION PROCESS OF THE KEY ENDPOINTS .................................................... 22 
8.2. 
PRIMARY ANALYSIS .................................................................................................. 23 
8.3. 
KEY SECONDARY ANALYSIS ..................................................................................... 24 
8.4. 
OTHER SECONDARY AND EXPLORATORY ANALYSIS................................................. 25 
9. 
SAFETY ANALYSIS ................................................................................................... 26 
9.1. 
ADVERSE EVENTS ..................................................................................................... 26 
9.1.1. 
INCIDENCE OF ADVERSE EVENTS .............................................................................. 26 
9.1.2. 
RELATIONSHIP OF ADVERSE EVENTS TO STUDY DRUG ............................................. 26 
9.1.3. 
INTENSITY OF ADVERSE EVENT ................................................................................ 27 
9.1.4. 
SERIOUS ADVERSE EVENTS ...................................................................................... 27 
9.1.5. 
HOSPITALIZATION ..................................................................................................... 27 
9.1.6. 
ADVERSE EVENTS LEADING TO STUDY DRUG DISCONTINUATION ............................ 27 
9.1.7. 
DEATH ...................................................................................................................... 28 
9.2. 
CLINICAL LABORATORY EVALUATIONS .................................................................... 28 
9.2.1. 
FASTING LIPID PROFILE ............................................................................................ 28 
9.2.2. 
HEMATOLOGY ........................................................................................................... 28 
9.2.3. 
CHEMISTRY ............................................................................................................... 28 
9.2.4. 
HEPATITIS SEROLOGY ............................................................................................... 29 
9.2.5. 
LIVER SAFETY PANEL ............................................................................................... 29 
9.2.6. 
BIOMARKER LABORATORY TESTS ............................................................................ 29 
9.2.6.1 
LIPOPROTEINS ........................................................................................................... 29 
9.2.6.2 
FASTING INSULIN ...................................................................................................... 29 
9.2.6.3 
INFLAMMATION PANEL ............................................................................................. 29 
9.3 
MONTREAL COGNITIVE ASSESSMENT (MOCA)........................................................ 30 
9.4 
VITAL SIGN MEASUREMENTS ................................................................................... 30 
9.5 
ELECTROCARDIOGRAM ............................................................................................. 30 


Resverlogix Corp. 
 
Statistical Analysis Plan, Final Version 3.0 
RVX222-CS-015 
 
Date Issued: 10 June 2019 
 
 
 
 
5
List of Abbreviations 
 
ACS 
Acute Coronary Syndrome 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
apoA-I 
Apolipoprotein A-I 
apoB 
Apolipoprotein B 
API 
active pharmaceutical ingredient 
AST 
Aspartate Aminotransferase 
BET 
Bromodomain and Extraterminal 
BID 
twice daily 
BMI 
Body Mass Index 
CAD 
Coronary Artery Disease 
CEC 
Clinical Events Committee 
CI 
Confidence Interval 
CK 
Creatine Kinase 
CRO 
Contract Research Organization 
CSC 
Clinical Steering Committee 
CV 
Cardiovascular 
CVD 
Cardiovascular disease 
DM 
Diabetes Mellitus 
DSMB 
Data Safety Monitoring Board 
EAC 
Event Adjudication Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EQ-5D / EQ-5D-5L 
EuroQOL five dimensions questionnaire 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration, US 
GGT 
Gammaglutamyl Transferase 
HbA1c 
Glycated Hemoglobin 
HBcAb 
Hepatitis B Virus Core Protein Antibody 
HBsAb 
Hepatitis B Surface Antibody 
HBsAg 
Hepatitis B Surface Antigen 
HCV 
Hepatitis C Virus 
HDL  
High-Density Lipoprotein  
HDL-C 
HDL cholesterol 
HRQOL 
Health Related Quality of Life  
hs-CRP/hsCRP 
high-sensitivity C-Reactive Protein 
IgM 
Immunoglobulin M 
LDL 
Low-Density Lipoprotein  
LDL-C 
LDL Cholesterol 
LVT 
Last Visit on Treatment 
MACE 
Major Adverse Cardiac Events 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial Infarction 
MMRM 
Mixed-effect Model Repeat Measures 
MOCA/MoCA 
Montreal Cognitive Assessment 
mRNA 
Messenger RNA 
PCI 
Percutaneous Coronary Intervention 
PPS 
Per-Protocol Set 
RBC 
Red Blood Cells 


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PT INR 
Prothrombin International Nomenclature Rate  
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SS 
Safety Set 
T2DM 
Type 2 Diabetes Mellitus 
TG 
Triglyceride 
ULN 
Upper Limit of Normal Range 
WBC 
White Blood Cells 
WHO 
World Health Organization 
 
 


Resverlogix Corp. 
 
Statistical Analysis Plan, Final Version 3.0 
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Date Issued: 10 June 2019 
 
 
 
 
7
 
1. Introduction 
 
This statistical analysis plan (SAP) describes the analyses and data presentation for Resverlogix’s 
protocol RVX222-CS-015 “A Phase III Multi-Center, Double-Blind, Randomized, Parallel Group, 
Placebo-Controlled Clinical Trial in High-Risk Type 2 Diabetes Mellitus (T2DM) Subjects with 
Coronary Artery Disease (CAD) to Determine Whether Bromodomain Extraterminal Domain (BET) 
Inhibition Treatment with RVX000222 Increases the Time to Major Adverse Cardiovascular Events 
(MACE).” It contains definitions of analysis populations and statistical methods for the efficacy and 
safety analysis.  
 
The study is an event-based trial and will continue until 250 narrowly defined MACE events (primary 
events; defined in section 3.2) have occurred. Throughout this SAP, the treatment arms will be referred to 
as RVX000222 and placebo.   
 
This SAP prospectively lays out statistical approaches in the analysis of study data. All statistical analyses 
detailed in this SAP will be conducted using Statistical Analysis Software (SAS)® Version 9.2 or higher.  
 
 
 


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Statistical Analysis Plan, Final Version 3.0 
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Date Issued: 10 June 2019 
 
 
 
 
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2. Objectives 
 
2.1. Primary Objective 
 
• 
To evaluate if treatment with RVX000222 as compared to placebo increases time to the first 
occurrence of narrowly defined MACE. Narrowly defined MACE is defined as a single 
composite endpoint of CV death or Non-fatal MI or Stroke. 
 
2.2. Secondary Objectives 
 
• 
To evaluate if treatment with RVX000222 increases time to the first occurrence of broadly 
defined MACE in comparison to placebo 
 
Broadly defined MACE is the occurrence of any of the following events:  
• 
CV death 
• 
Non-fatal MI 
• 
Hospitalization for CVD events including: 
o Unstable angina AND evidence of new or presumed new progressive obstructive 
coronary disease, OR 
o Emergency revascularization procedures at any time and urgent revascularization 
procedures ≥30 days after the index events prior to randomization 
• 
Stroke 
• 
To evaluate if treatment with RVX000222 increases time to the first occurrence of fatal or non-
fatal MI, or fatal or non-fatal stroke. 
• 
To evaluate treatment group difference in all-cause mortality 
• 
To evaluate changes in lipoprotein concentrations including apoA-I, apolipoprotein B (apoB), 
LDL-C, HDL-C, and triglyceride (TG) over time within and between treatment groups 
• 
To evaluate changes in DM variables including glycated hemoglobin (HbA1c), fasting glucose, 
and fasting insulin over time within and between treatment groups 
• 
To evaluate changes in ALP over time within and between treatment groups including isoforms 
for whole population and quartiles of ALP baseline concentration 
• 
Assess changes in kidney function in population with baseline estimated glomerular filtration rate 
<60 mL/min/1.7m2 
• 
To evaluate the safety and tolerability of RVX000222  
 
2.3. Exploratory Objectives 
 
• 
To evaluate changes in inflammation variables including, but not limited to, high-sensitivity C-
reactive protein (hsCRP), fibrinogen, and inflammatory cytokines within and between treatment 
groups 
• 
To evaluate transcription (messenger RNA [mRNA]) change in whole blood from baseline to 6 
weeks of treatment  
• 
To evaluate Health Related Quality of Life (HRQOL) as measured using the EQ-5D-5L 
• 
To evaluate cognition changes in subject >= 70 years as measured using the MoCA scale 
 
 


Resverlogix Corp. 
 
Statistical Analysis Plan, Final Version 3.0 
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Date Issued: 10 June 2019 
 
 
 
 
9
3. Investigational Plan 
 
The sub-sections below re-iterate salient features of the investigational plan from the protocol as 
necessary context prior to the description of general statistical considerations, definitions of analysis 
populations and the proposed statistical approaches for the analyses of efficacy and safety data.  
 
3.1. Overall Study Design and Plan 
  
This is a double-blind, placebo-controlled, 2 arm parallel-group (allocation ratio 1:1), study of 
RVX000222 at a dose of 100 mg b.i.d. (total daily dose of 200 mg) or matching placebo in combination 
with high potency statin therapy administered to T2DM subjects with history of recent CVD event and 
HDL-C level < 40 mg/dL males or <45 mg/dL females. The high potency statin therapy shall consist of 
daily dose of either atorvastatin 20-80 mg or rosuvastatin 10-40 mg [20 mg atorvastatin or 10 mg 
rosuvastatin is only acceptable in circumstances such as advanced age, low body mass, previous 
intolerance to higher doses or specific drug-drug interactions (e.g. anti-retrovirals).  
 
After an initial screening period of 1 to 2 weeks during which subjects will be treated with standard of 
care high potency statin therapy, subjects will be randomized to either RVX000222 100 mg b.i.d. or 
matching placebo with continued statin treatment. This combination treatment period will continue until 
250 narrowly defined MACE events have occurred in the study and all surviving subjects have been 
followed for at least 24 weeks from randomization. Blinded treatment with RVX000222 or matching 
placebo will then be discontinued. Subjects will remain on standard of care high potency statin therapy 
for 4 more weeks until the Follow-Up Visit.  
 
The study is an event-based trial and will continue until 250 narrowly defined MACE events have 
occurred.  The study will be monitored by a Data Safety Monitoring Board (DSMB).  MACE will be 
adjudicated by an independent MACE Adjudication Committee (EAC) in an ongoing manner.  Study data 
as indicated on the Schedule of Events (See the study protocol) will be collected at each study visit and 
recorded in the appropriate sections of the eCRF. 
 
3.2. Study Endpoints 
 
3.2.1. Primary Endpoint 
 
The primary endpoint will be time from randomization to the first occurrence of adjudication 
confirmed MACE narrowly defined as a single composite endpoint of CV Death or Non-fatal MI 
or Stroke. 
 
3.2.2. Key Secondary Endpoints 
 
The key secondary endpoints will be:  
 
1. Time from randomization to the first occurrence of adjudication-confirmed MACE broadly 
defined between treatment groups.  
Broadly defined MACE is the occurrence of any of the following events:  
• 
CV death Non-fatal MI 
• 
Hospitalization for CVD events which include:  
o Unstable angina AND evidence of new or presumed new progressive obstructive 
coronary disease, OR 


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Statistical Analysis Plan, Final Version 3.0 
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o Emergency revascularization procedures at any time and urgent revascularization 
procedures ≥30 days after the index events prior to randomization  
•  Stroke 
2. Total incidence of Narrow MACE 
3. Time from randomization to CV Death or Non-fatal MI 
4. Time from randomization to coronary heart disease (CHD) death or Non-fatal MI 
5. Time from randomization to Non-fatal MI 
6. Time from randomization to CV Death 
7. Time from randomization to Stroke 
8. All-cause mortality 
9. Incidence of hospitalization for congestive heart failure (CHF)  
 
 
3.2.2.1. Other Secondary Endpoints 
 
• 
The percent change in apoA-I, apoB, LDL-C, HDL-C, and TG over time within and 
between treatment groups 
• 
The change from baseline in HbA1c, fasting glucose, and fasting insulin within and 
between treatment groups  
• 
Changes in ALP within and between treatment groups for all subjects and according to 
quartiles of ALP baseline concentration 
• 
Changes from baseline in kidney function in subgroup population with estimated 
glomerular filtration rate <60 mL/min/1.7m2 within and between treatment groups 
  
3.2.3. Exploratory Endpoints 
 
• 
The percent change in hsCRP, fibrinogen, and inflammatory cytokines within and between 
treatment groups 
• 
Change in MoCA score in all and those with baseline MoCA <26 within and between 
treatment groups 
• 
Transcription/mRNA change in whole blood from baseline to 6 weeks treatment within and 
between treatment groups  
• 
Change in Health Related Quality of Life (HRQOL) as measured using the EQ-5D-5L 
 
3.2.4. Safety Endpoints 
 
• 
Safety assessments will include incidence of adverse events (AEs), serious adverse events 
(SAEs), vital sign measurements, clinical laboratory evaluations, and physical examination 
findings. 
 
3.3. Study Drugs 
 
RVX000222 is available as a capsule formulation with standard excipients and established stability.  
Placebo for RVX000222 is available as a capsule formulation free of RVX000222 API. It is comprised of 
standard excipients and has established stability.  
 
RVX000222 (200 mg BID) will be taken orally with food in the morning and evening, approximately 10-
12 hours apart.  In certain situations the dose may be decreased to 100 mg daily (50 mg b.i.d.; refer to the 
protocol). Per protocol, if a dose is missed, subject should take missed dose at the time it is remembered, 
unless it is within four hours of the next scheduled dose. If within four hours of the next schedule dose, 


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Statistical Analysis Plan, Final Version 3.0 
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the missed dose should be skipped. Subjects will take their first dose of study drug while in clinic during 
Visit 2.   
 
3.4. Study Drug Interruption/Discontinuation 
 
Treatment may be interrupted or discontinued at the discretion of the Investigator and Sponsor, based on 
AEs, other clinical laboratory data, vital signs measurements, and/or electrocardiogram (ECG) findings. 
 
Subjects discontinuing study drug will continue participation in the study and will complete all remaining 
study visits. Discontinuation of assigned study drug (RVX000222 or placebo) or high intensity statin 
therapy should not result in study discontinuation. 
 
3.5. Concomitant Statin Therapy 
 
Protocol defined concomitant treatment in this study is 20-80 mg atorvastatin or 10-40 mg rosuvastatin 
once daily orally. 20 mg atorvastatin or 10 mg rosuvastatin are acceptable in circumstances such as 
advanced age, low body mass, or specific drug-drug interactions (e.g. anti-retrovirals).   
 
Subjects will receive concomitant statin therapy as stated in section 6.6 in the protocol. 
 
The statin dose shall be administered daily in the morning at the same time as the RVX000222 dose (or 
placebo) and within 30 minutes of completion of a meal. Per protocol, if a dose is missed, subject should 
take missed dose at the time it is remembered, unless it is within four hours of the next scheduled dose. If 
within four hours of the next schedule dose, missed dose should be skipped. 
 
3.6. Background Therapy 
 
The subject’s other background therapy for dyslipidemia and any coexisting conditions such as CAD, 
hypertension and diabetes should, in the investigator’s opinion, adhere to acceptable standards of care and 
preferably remain unaltered during the treatment period unless clinically indicated. 
 
3.7. Study Visits 
 
After randomization to RVX000222 or placebo, visits will occur every 2 weeks until Week 12. From 
Week 12 to Week 28, visits will occur every 4 weeks. From Week 28 until the Last Visit on Treatment, 
visits will occur approximately every 12 weeks. Four weeks after the Last Visit on Treatment, subjects 
will return for a final Follow-Up Visit. The Schedule of Events can be found in the study protocol.  Study 
treatment will be terminated in all currently participating subjects when it is estimated that 250 subjects 
have experienced a narrowly defined MACE event.  At that time, all subjects actively treated will conduct 
their Last Visit on Treatment as soon after as possible while ensuring at least 6 months of study therapy 
and then return 4 weeks after last day of treatment for the Follow-Up Visit. Procedures are defined in the 
Schedule of Events.  
 
 
3.8. Dose Adjustment/Modifications 
 
Additional safety lab monitoring will occur and study drug may be interrupted, reduced, and/or 
permanently discontinued if the subject meets following criteria. If ALT increases >3xULN or serum 
bilirubin increases >2xULN, subjects will be notified and repeat chemistries obtained as soon as possible. 
 


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1. If ALT increase of 3-5xULN is confirmed on repeat measurement (within 3-4 days), subjects 
will be monitored every 3-4 days until the ALT is <1.5xULN.   
2. If ALT increase of >5xULN, study drug will be suspended. If confirmed on repeat 
measurement (within 3-4 days), study drug will be permanently discontinued and subjects 
will be monitored every 3-4 days until the ALT is <1.5xULN. 
3. If serum bilirubin increase of >2xULN is confirmed on repeat measurement (within 3-4 days), 
then study drug will be permanently discontinued and subjects will be monitored every 3-4 
days until levels are within normal range.  
 
Subjects who have an ALT increase of ≥3xULN will be monitored by liver safety panels [ALT (SGPT), 
AST (SGOT), GGT, ALP, bilirubin (direct and total)] and have archival serum samples drawn every 3-4 
days until ALT is <1.5xULN. 
 
Subjects who have an ALT increase of >5xULN or who have a serum bilirubin increase of >2xULN will 
be monitored by extended liver safety panels [ALT (SGPT), AST (SGOT), GGT, ALP, bilirubin (direct 
and total), as well as osteopontin and PT INR] and have archival serum samples drawn every 3-4 days 
until ALT is <1.5xULN and serum bilirubin levels are in within the normal range. 
  
Per protocol, subjects should continue to follow the protocol-defined assessments according to the 
Schedule of Events in the protocol until study completion.  
 
If the ALT elevation has cause (e.g. trauma, infection-inflammation, surgery, acetaminophen, clavulanic 
acid, diclofenac) treatment may be restarted at 50 mg b.i.d. once ALT returns to 1.5 xULN and subjects 
should continue with all scheduled study visits according to the Schedule of Events and will have 
additional liver safety panel tests drawn according to the original study schedule:  
 
• Weeks 0-12 after study drug is reinitiated: liver safety panel every 2 weeks (Weeks 0, 2, 4, 6, 8, 
10, 12 after re-initiation) 
• Weeks 12-28 after study drug is reinitiated: liver safety panel every 4 weeks (Weeks 16, 20, 24 
after re-initiation) 
• Weeks 28 after investigational drug is reinitiated to end of treatment: liver safety panel 
approximately every 12 weeks (Weeks 40, 52, 64, 76, 88, 100) 
 
Re-initiation of study drug will be discussed with and approved by the study medical monitor prior to 
dosing.  
 
 
 


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4. General Statistical Considerations 
 
4.1. Reporting Conventions and Dates Handling 
 
Derived analysis data sets will be produced from the electronic case report form (eCRF) data, central 
laboratory data and the electronic adjudication data (EAS) to assist with analysis and summary of both 
efficacy and safety endpoints. Derived data sets will identify observations selected according to the study 
window convention described in section 4.5 and values that will be summarized.   
 
The number and percentage of subjects will be used to summarize categorical variables. When count data 
are presented and the count is zero, the percentage will be suppressed.  Unless otherwise specified, the 
denominator for percentages will be the number of subjects in a given treatment group within the analysis 
set of interest.  Descriptive statistics (number of subjects with non-missing values, mean, standard 
deviation, minimum, 25th percentile, median, 75th percentile, and maximum) will be used to summarize 
continuous variables unless otherwise noted. 
 
In summary tables for categorical data, all categories will be presented if they are specified on the eCRF 
(eg, discontinuation reason), or if categories are ordered intervals (eg, age groups), regardless of whether 
or not a subject is found in a given category.  For other categorical data (eg, AEs and medications), only 
categories with at least 1 subject will be presented.  A row denoted “Missing” will be included in count 
tabulations where specified on the shells to account for dropouts and missing values.  When no data are 
available for a table or listing, an empty page with the title will be produced with suitable text (eg, “There 
are no observations for this table/listing.”). 
 
Means and percentiles will be presented to 1 more decimal place than the recorded data. Standard 
deviations and standard errors will be presented to 2 more decimal places than the recorded data. 
Minimum and maximum values will be presented using the same number of decimal places as the 
recorded data. Percentages will be presented to 1 decimal place.  Hazard ratios will be presented with 3 
decimal places. Confidence intervals (CIs) will be presented using the same number of decimal places as 
the parameter estimate (eg, LS mean or hazard ratio).  
 
Subjects are uniquely identified by a concatenation of study center number and subject number. All data 
available from the eCRFs along with some derived variables will be listed.  For relevant dates, the actual 
day relative to start of double-blind treatment will also be listed. Dates will be presented in the format of 
“DDMMMYYYY.”. 
 
4.2. Sample Size Justification: 
 
The study design will provide approximately 80% power to declare superiority of RVX000222 arm over 
Placebo with a hazard ratio of 0.7, a true hazard ratio of 1.0 and at an overall 2-sided 5% significance 
level. 
To calculate the sample size (number of subjects), the following additional information was assumed: 
• 
Total number of narrowly defined MACE events needed:  250  
• 
10.5% event rate in the placebo arm at 18 months 
• 
30% relative risk reduction (7.47% event rate at 18 months in the RVX000222 arm) 
• 
Accrual period of 1.7 years (20 months) and a total study duration (including follow-up) of 2.75 years 
(143 weeks)  
• 
A cumulative drop-out rate of 10% per arm by the end of the study (5% drop out rate per arm by year 
one) 


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With the above design and assumptions, a sample size of approximately 2400 randomized subjects 
enrolled uniformly over 1.7 years with total study duration of 143 weeks and subjects followed until 
failure, drop out or end of study is estimated to provide the 250 events needed. 
 
The power and sample size for this study was calculated using East 6.2.  
 
 
 
4.3. Randomization, Stratification, and Blinding 
 
4.3.1. Randomization 
 
All qualified subjects will be randomly assigned in a ratio of 1:1 to one of the following two 
treatment arms: RVX000222 200 mg daily or matching placebo. Randomization will be stratified by 
country and high intensity statin therapy within the country (i.e. atorvastatin or rosuvastatin). Further, 
randomization will be dynamically restricted to assure that statin therapy imbalance is no greater than 
60:40 (or 40:60) within each country. Study participants will only be directed (per informed consent) 
to switch their statin therapy to rosuvastatin or atorvastatin once randomization limits are reached on 
either statin to minimize enrollment impact. 
 
A randomization schedule will be generated for the IWRS and will be implemented by the IWRS 
prior to dosing at Visit 2. The IWRS will allocate the study drug via the prepared randomization 
scheme and will provide the randomization number and appropriate drug package numbers. The 
IWRS process to achieve an approximate even split of study participants across the statin levels per 
country will be described in greater detail in the IWRS specifications. The subject should always be 
provided study drug with the number allocated by the IWRS.  
 
4.3.2. RVX000222 Treatment Blinding 
 
The blinding is ensured by using double-blind RVX000222 study drug. Placebo capsules will be 
equally matched in size, shape, and color to RVX000222 and will be packaged in the same manner. 
The study drug packaging will be labeled with unique identification numbers allocated from the 
IWRS.  
 
Subjects, investigative staff, persons performing the assessments, and data analysts will remain blind 
to the identity of the treatment from the time of randomization. No member of the CSC, the study 
team at Resverlogix, personnel at study centers, or any clinical research organization (CRO) handling 
data will have access to the randomization scheme during the course of the study, with the exception 
of the study personnel generating the randomization scheme, the personnel preparing DSMB data for 
review, the DSMB itself, the personnel providing IWRS and carrying out the packaging and labelling 
of investigational products. Unblinding will occur in the case of subject emergencies when 
knowledge of the treatment assignment would affect subject care and at the conclusion of the study. 
 
 


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4.4. Analysis Set 
 
The following 3 analysis sets will be used. 
 
4.4.1. Full Analysis Set (FAS) 
 
The FAS will include all randomized subjects who receive any amount of study therapy and have at 
least one measurement of the assessment of interest.  All efficacy analyses will be conducted for the 
FAS. Subjects will be analyzed based on randomized treatment group. Subjects experienced study 
drug dose adjustment will be included in the FAS and their data will be analyzed according to the 
randomized treatment group. 
 
4.4.2. Per-protocol Set (PPS) 
 
The PPS will consist of all FAS subjects who fulfill all inclusion/exclusion criteria, and have no 
major protocol violations.  The major protocol violation criteria will be finalized by the Clinical 
Science and Biostatistics teams as part of the masked data reviews prior to the interim and final 
database locks. Likewise, whenever possible, subjects belonging to the PPS will be determined prior 
to the interim and final database locks. Subjects will be analyzed based on the treatments received 
most often. The list of major protocol violations is provided in section 5.2 of this statistical analysis 
plan. 
 
4.4.3. Safety Set (SS) 
 
The SS will include all subjects who took at least one dose of double-blind study therapy. In safety 
summaries, subjects will be analyzed according to the actual treatment received.  All safety analyses 
will use the SS. 
 
 
4.5. Definition of Time Points, Study Dates, Visit Windows, and Duration 
 
Study Day 1 is defined as the day of randomization when subjects will receive the first dose.  Other study 
days are defined relative to Study Day 1, e.g. the day prior to Study Day 1 is Day -1 and the day after 
Study Day 1 is Day 2.  Study days will not be computed for subjects who are not randomized.  
 
All scheduled study visits will be defined relative to Study Day 1. For example, the appropriate day for 
the scheduled Week 2 visit should be: Day 1 + 14 = Day 15.  A windowing convention which will be 
used to determine the analysis value for a given study visit will be applicable for all by-visit summaries 
and analyses.  The study visit window can be found in the “Schedule of Events” in the study protocol and 
also presented in the following table below: 


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Statistical Analysis Plan, Final Version 3.0 
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Table 1: Visit Windows for Efficacy and Safety Variables 
Study Week 
Scheduled Day 
Study Day Range 
0 
Baseline (Day 1) 
<=1 
  
2 
15 
12 
18 
4 
29 
26 
32 
6 
43 
40 
46 
8 
57 
54 
60 
10 
71 
68 
74 
12 
85 
82 
88 
16 
113 
110 
116 
20 
141 
138 
144 
24 
169 
166 
172 
28 
197 
194 
200 
40* 
281 
274 
288 
52 
365 
358 
372 
64 
449 
442 
456 
76 
533 
526 
540 
88 
617 
610 
624 
100 
701 
694 
708 
112 
785 
778 
792 
 
 
 
 
*Visits to occur with +/- 7-day window past week 40 every 12 weeks 
 
Study treatment will be terminated in all currently participating subjects when the 250th event occurs and 
all surviving patients have been followed for at least 24 weeks from randomization. At that time all 
subjects actively treated will conduct their Last Visit on Treatment. Follow up visit is to be scheduled 4 
weeks after last visit on treatment. Last visit on treatment and follow up are subject to +/-7 day window. 
 
The baseline value for a variable is defined as the last observation collected on or before Study Day 1/first 
dose date & time; it cannot be substituted for any post-baseline value.  Unscheduled visits or Study visits 
that are outside the protocol defined windows will be mapped to the closest study visits.  All safety data 
with incomplete dates will be forwarded to Data Management for query. 
   
One or more results for a particular variable may be obtained in the same visit window due to 
unscheduled or repeated measurements. In such events, the result with the date closest to the expected 
visit date (scheduled day) will be used.  In the event that 2 observations equidistant from the expected 
visit date are available, the later observation will be used. 
 
If the CRF dates are needed for variable derivation or calculation and they are missing after querying the 
sites, the imputation rules below will be employed.  However, no results or outcomes will be imputed.   
 
• 
If the day is missing in the interim data cut, impute missing day as 15th of the month.   
• 
If the month is missing, impute the month as July. 
• 
Additionally, if both day and month are missing, impute to 15JUL. 


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• 
If month/year of the onset date is on or after the month/year of Study Day 1, the AE will be 
considered on-study; 
• 
If month/year of the onset date is equal to the month/year of Study Day 1, and the end date is 
present, the end date will be used to determine when the AE resolved. If the end date is on or after 
Study Day 1, the AE will be considered on-study; otherwise, if the AE stopped before Study 
Day 1, then it will not be on-study; If month/year of the onset date is equal to the month/year of 
Day 1, and the end date is a partial date, the AE will be considered on-study. 
 
In addition, durations (e.g. treatment duration) will be measured in weeks and will be calculated as: 
(End Date – Start Date + 1)/7. 
• 
Intervals that are presented in weeks will be transformed from days to weeks by using (without 
truncation) the following conversion formula: 
WEEKS = DAYS /7. 
• 
Intervals that are presented in months will be transformed from days to months by using (without 
truncation) the following conversion formula: 
MONTHS = DAYS /30.4375. 
 
 
 


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Statistical Analysis Plan, Final Version 3.0 
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5. Subject Disposition 
 
5.1. Disposition 
 
Subjects in the analysis sets (FAS, PPS, and SS) and within each of the stratification factors, namely 
statin use and country, will be presented. Subject disposition (analyses of randomized, treated, 
discontinued with primary reason for discontinuation) for FAS will be summarized using frequency and 
percentage by treatment group. 
 
Subjects are free to discontinue participation in the study at any time. A subject’s participation may also 
be discontinued at any time at the discretion of the Investigator. Withdrawn subjects will not be replaced.  
 
Per protocol, discontinuation of study drug should not result in discontinuation of study participation. The 
frequency and percentage of randomized subjects who were not treated, who discontinued study drug, and 
who terminated the study early by reason will be summarized. Such subjects will be still included in the 
study analysis and final vital status will be ascertained if at all possible using recognized methods. 
 
A subject’s participation in the study will be discontinued if any of the following applies: 
 
• 
Adverse Event 
• 
Withdrawn Consent 
• 
Abnormal Lab Value 
• 
Lost to Follow-up 
• 
Protocol Violation 
• 
Death 
• 
Other 
 
Possible reasons for discontinuation of study drug and discontinuation of study include consent 
withdrawal, AEs, lost to follow-up or safety labs. 
 
Disposition data, inclusion and exclusion criteria, subject eligibility, as well information on stratification 
will be displayed.  
  
5.2. Significant Protocol Deviations 
 
The Investigator will not deviate from the protocol without prior written approval from Sponsor or its 
designee, except in medical emergencies.  In the instances that protocol deviations do occur, these will be 
documented and reviewed as stated in generation of the per-protocol set and displayed. The list of major 
protocol violations is expected to be as follows: 
 
- 
Patients who had only an elective PCI (percutaneous coronary intervention) as their index 
event instead of an urgent one that was performed for the presentation of unstable angina 
or myocardial infarction 
- 
Acute Coronary Syndrome outside the protocol-specified window 
- 
No evidence of T2DM Diabetes recorded in the case report forms 
- 
Use of immunosuppressants as identified in the exclusion criteria of the protocol and 
other clinical documentation. 
 


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6. Demographics and Other Baseline Characteristics 
 
6.1. Demographics 
 
Baseline and demographic information will be summarized for each treatment group and overall. 
Demographic and baseline characteristics are age in years, age categories (<=65 vs >65 and by quartiles), 
sex, race, country, height (cm), weight (kg), and body mass index (BMI) (kg/m2). Summaries of 
demographic and baseline characteristics will be based on the FAS. No inferential statistics will be 
presented. 
 
For subjects not in the United States, age in years will be collected directly from the eCRF. Otherwise, 
age will be calculated as the integer part of 
(
)
365.25
1 
birth 
 
of
 
date
  
-
consent 
 
informed
 
of
 
date
+
 
and will be summarized using descriptive statistics. The numbers and percentages of subjects in 2 age 
categories (<=65 vs >65) and by quartiles will also be reported. 
 
The number and percentage of male and female subjects will be summarized. 
 
The number and percentage of subjects in each race category (American Indian or Alaska Native, Asian, 
Black or African American, Native Hawaiian or Other, Pacific Islander, White and Other) will be 
presented. 
 
Height will be measured at screening only. Weight will be measured during each physical examination.  
BMI will be calculated using weight and height collected at Screening as follows: 
2
100)
 / 
cm)
in 
((height 
kg
in 
weight 
. 
 
Height, weight, and BMI at Baseline will be summarized using descriptive statistics. 
 
6.2. Baseline Disease Characteristics and Medical History 
 
Baseline disease characteristics such as time since diagnosis of T2DM to randomization, index ACS event 
type, and time from ACS to randomization will be calculated or extracted from medical history and 
presented by treatment group. 
Medical history will consist of any significant conditions or diseases that stopped at or prior to the date of 
informed consent. Ongoing conditions will be considered concurrent medical conditions.  
 
Concurrent medical conditions are significant ongoing conditions or diseases present at time of informed 
consent. These include clinically significant laboratory findings, ECG, or physical examination 
abnormalities.  Summaries of medical history and concurrent medical conditions will be based on the 
FAS. 
 
Medical history and concurrent medical conditions will be coded using the latest possible version of 
Medical Dictionary for Drug Regulatory Activities (MedDRA).  
 
 
 


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7. Treatments and Medications 
 
7.1. Study Treatments 
 
7.1.1. Study Drug Exposure 
 
RVX000222 or matching placebo will be taken orally with meals in the morning and in the evening, 
10-12 hours apart.  
 
Table 2: Study Drug Administration Schedule 
Treatment 
Group 
Daily dose 
(mg) 
Dose administration 
b.i.d. (mg) 
AM 
Dose 
(mg) 
PM 
Dose 
(mg) 
No. of 
capsules/day 
A: 
RVX000222 
200 
100 
100 
100 
2 
B: Placebo 
0 
0 
0 
0 
2 
 
As described in section 3.8, if subjects have elevated ALT values they may be administered study 
drug or matching placebo at a reduced dose of 50 mg b.i.d. This dose change information is to be 
collected in the eCRF as action taken with study drug when reporting elevated ALT values as an 
adverse event and subject to confirmation by the medical monitor. Subjects with at least one study 
treatment dose reduction and those with none will be represented by treatment group on FAS. 
Information on number of subjects by number of dose reductions will also be summarized by 
treatment group.  
 
Study drug exposure will begin on the day of the first dose of study drug and end on the day of the 
last dose of study drug. Duration of study drug exposure in months will be defined as (date of last 
dose - date of first dose + 1)/30.4.  
 
Study participation will begin on the day of randomization and end on the day of last contact. 
Duration of study participation in months will be defined as (date of last contact – date of 
randomization +1)/30.4.  
 
Duration of exposure to study drug and duration of study participation will be summarized for the 
FAS using descriptive statistics.  Duration of study drug exposure and duration of study participation 
will also be categorically summarized by number and percentage of subjects who had at least 12-
weeks, greater than 12 weeks up to 24 weeks, greater than 24 weeks up to 52 weeks, and greater than 
52 weeks of study drug exposure and study participation. Duration of drug exposure on subjects with 
at least one dose reduction will be summarized by the aforementioned categories.  
 
7.2. Prior and Concomitant Medications 
 
Prior and concomitant medications, including antidiabetic medications, will be coded using the latest 
WHO Drug dictionary Version June, 2010 or higher and classified into the default anatomical therapeutic 
chemical (ATC) classification system codes provided by the system (the first ATC code by alphabetic 
order).  
 
Any medication that was stopped prior to the treatment start date will be considered a prior medication. 
Medication taken at any time between the treatment start date and the date of last contact, inclusive, will 
be considered concomitant medication. If the medication start or stop dates are missing or partially 


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missing and the medication is not checked as ongoing, general imputation rules from section 4.5 will be 
applied. Subject data including prior and concomitant medications including antidiabetic medications will 
be presented.  
 
7.2.1. Concomitant Statin Therapy 
 
The high potency statin therapy administered to the study participants will be summarized on FAS 
including the type of statin (Atorvastatin or Rosuvastatin) and doses. Dose adjustments (increase or 
decrease dose after first dose administered) will be summarized in a manner similar to study drug 
dose reduction.  
 
 
 


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8. Efficacy Analysis 
 
All efficacy analyses will use the FAS set. Subjects will be analyzed according to randomized treatment 
group.  Key efficacy analyses will also be performed on the PPS as supportive evidence and to assess the 
robustness of the efficacy findings. Each table presents the population that the analysis was conducted on. 
Time to event analyses for primary and secondary endpoints will use the Kaplan-Meier method to 
estimate the median survival time and its 2-sided 95% confidence intervals (CIs). A stratified log rank test 
will be used for calculating the 2-sided p-value for treatment comparisons. 
Primary and key secondary endpoint analyses will include presentation of estimated hazard ratios and 
associated 2-sided CI obtained from a stratified Cox Proportional Hazards (CPH) model. Assessment of 
proportional hazards assumption for treatment will be assessed through diagnostic checks involving plots 
of Schoenfeld residuals obtained from CPH model that fit the primary endpoint of narrowly defined 
MACE.  
For the primary, secondary, and exploratory endpoints, time to event will be the time from the date of 
randomization to the date of first occurrence of any event in the respective endpoint. A subject who did 
not have an episode of an event for a given endpoint throughout the study, will be censored for that 
endpoint at the day of last contact. For any interim database cut, a subject who has not discontinued from 
the study and did not have an episode of an event for a given endpoint will be censored for that endpoint 
at the date of the interim cutoff.  
Statistical tests for comparing RVX000222 arm with Placebo will be conducted for the primary endpoint 
and other efficacy endpoints described in Section 3.2.  The key secondary endpoints will be tested for 
superiority in order only if superiority is established for primary efficacy endpoint. The key secondary 
endpoints will be tested sequentially following a pre-specified order as seen in Section 3.2.2. 
The multiplicity of the analyses of the primary and key secondary endpoints will be adjusted using a 
Sequential Gate-Keeping Procedure. This procedure will preserve the Family Wise Error Rate in light of 
multiple analyses being performed. The analyses will be performed in sequence until one of the analyses 
has failed to show the significance level of p = 0.05.   That is, in order to preserve the overall alpha level 
at 0.05 across the narrowly defined MACE and broadly defined MACE endpoints, formal statistical 
inference for the broadly defined MACE can only be made if superiority of RVX222 is demonstrated for 
the primary efficacy endpoint, narrowly defined MACE, at the two-sided 0.05 significance level. 
For continuous endpoints pertaining to liver function, lipid profile, kidney function, HbA1c, fasting 
glucose, and insulin, descriptive statistics (N, mean, median, standard deviation, quartiles, minimum and 
maximum) will be provided by treatment group at specified visits. 
Quantitative endpoints that are defined as a (percent) change from baseline will be analyzed using 
analysis of covariance (ANCOVA) models with treatment group as a factor and the baseline value as a 
covariate. Mixed-effect model repeated measurements (MMRM) will be used to analyse a subset of 
secondary outcomes over time.  
Subjects will continue to be followed for both primary and secondary endpoints until 250 adjudicated 
primary endpoints have been observed. Other than the pre-specified sequential testing, no additional alpha 
adjustments for multiplicity will be made.  That is, no multiplicity adjustment is planned for testing 
regarding the other secondary and exploratory endpoints as these endpoints are considered supportive. 
 
8.1. Adjudication Process of the Key Endpoints 
 
Potential CV events will be identified by comparing all SAE preferred terms to a pre-established list of 
MedDRA preferred terms.  The terms included in the pre-established list are designed to broadly capture 


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potential CV events from MedDRA SMQs, system organ classes, preferred terms, and lower-level terms 
specified in the FDA draft guidance document “Endpoints and Standardized Data Collection for 
Cardiovascular Outcomes Trials”, issued July 22, 2009.  All reported terms that code to a listed preferred 
term will be forwarded to the Clinical Events Committee (CEC) for adjudication.  The details of CEC 
operations and the clinical definitions of the CV outcomes are specified in the CEC charter (v3.0 / 
08JUN2017).   
 
 
High level results of the CEC adjudication of potential CV events as entered into PPD PVG EAS 
(Electronic Adjudication System) will be transferred and maintained in a SAS dataset.  All potential CV 
events and corresponding adjudication outcomes will be summarized.  In addition, association of these 
events with respect to the primary and key secondary endpoints will be flagged for the analyses.  The 
possible adjudication outcomes are categorized as follows: 
 
 
• 
Deaths  
o Cardiovascular deaths (including coronary heart disease (CHD) deaths) 
o Non cardiovascular deaths  
o Undetermined cause of death  
• 
Non‐fatal cardiovascular events  
o Acute myocardial infarction  
o Hospitalization for unstable angina and evidence of new or progressive obstructive 
coronary disease. 
o Hospitalization for other angina 
o Hospitalization for heart failure  
o Non‐ Elective (Urgent/Emergency/Salvage) Coronary Revascularization 
o Stroke 
 
 
8.2. Primary Analysis 
 
The primary analysis will be a time-to-event analysis. The distributions of the primary endpoint within 
the RVX000222 and placebo groups will be compared using a two-sided stratified log-rank test (LRT) 
with an alpha = 0.05 level of significance (two sided). Time to first narrowly defined MACE, defined as a 
single composite endpoint of CV Death or Non-fatal MI or Stroke, will be calculated using randomization 
date and date of the confirmed event, or date of last contact for censored subjects.  For the purpose of the 
primary analysis and all subsequent analyses involving CV deaths, events within the undetermined cause 
of death category will be considered CV deaths. All subjects will be followed until drop-out, death, or 
study closure.   Drop-out may be due to withdrawal of consent from further data collection or lost to 
follow-up. Subjects who drop-out or are alive at study closure will have their event times censored at the 
time of last contact.   
 
The primary efficacy analysis will be performed on the FAS. The number and percentage of subjects who 
experienced the narrowly defined MACE, median survival time and corresponding 95% confidence 
intervals (CIs) will be tabulated and presented by treatment group. A stratified log-rank test and 
corresponding test statistic, stratifying by country of enrollment and prescribed statin therapy (atorvastatin 
or rosuvastatin), at a two-sided alpha level of 0.05, will be used to compare the survival rate between the 
two treatment groups.  If stratifying by country results in too many empty cells, stratifying by geographic 
region may be considered.  
 


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As supportive analyses, the primary efficacy analysis will be  
1. 
repeated for the PPS set  
2. 
repeated for FAS set but using just events adjudicated as CV deaths excluding 
“undetermined cause of death events”. This analysis will be outside the analysis 
hierarchy of the study and will not influence secondary endpoint analyses. 
3. 
performed on the FAS using an unstratified LRT as a supportive analysis.  
 
Kaplan-Meier plots for the primary and key secondary endpoints by treatment groups will be presented. 
Presentation of primary analyses will include estimated hazard ratios and associated 2-sided CI obtained 
from Cox Proportional Hazard (CPH) models with treatment as the single factor, stratified by country of 
enrollment and prescribed statin therapy (atorvastatin or rosuvastatin).  
 
Subgroup analyses will be conducted for the primary endpoint based on the following categorizations: 
 
• 
Subjects receiving rosuvastatin and those receiving atorvastatin 
• 
Index acute coronary syndrome < 30 days and > 30 days pre randomization 
• 
LDL/HDL/TG’s above and below median value for the study sample 
• 
HbA1c above and below median value for the study sample 
• 
GFR >60 mL/min and < 60 mL/min as calculated at baseline 
• 
hs-CRP > and below the median, as collected at Visit 2 
• 
ALP above and below median as collected at screening,  
• 
Males and Females 
 
 
 
8.3. Key Secondary Analysis 
 
Similar to the primary analysis, the key secondary endpoints (listed in section 3.2.2) are also time-to-
event variables and will be analyzed using time-to-event models and the stratified log rank test, as 
described for the primary analysis. 
 
The key secondary analysis will be performed on FAS. The number and percentage of subjects 
experienced the broadly defined MACE, median survival time and corresponding 95% confidence 
intervals (CI) will be tabulated and presented by treatment group. A stratified log-rank test and 
corresponding test statistic, stratifying for country of enrollment and prescribed statin therapy 
(atorvastatin or rosuvastatin), at a two-sided alpha level of 0.05, will be used to compare the survival rate 
between the two treatment groups. For the purpose of all subsequent analyses listed below involving CV 
deaths, events within the “undetermined cause of death” category will be considered CV deaths. 
 
No adjustment for multiplicity is needed for the primary hypothesis as there is no provision to terminate 
the trial for efficacy.  A sequential gate-keeping approach will be used to control the overall Type I error 
rate when testing for the key secondary endpoints only if superiority is established for primary efficacy 
endpoint.  
The key secondary endpoints will be tested sequentially following a pre-specified order as stated in 
section 3.2.2 and re-emphasized below:  
 
1. Time from randomization to the first occurrence of adjudication-confirmed MACE broadly 
defined between treatment groups.  


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2. Total incidence in narrow MACE (CV Death or Non-fatal MI or Stroke) 
3. Time from randomization to CV Death or Non-fatal MI 
4. Time from randomization to coronary heart disease (CHD) death or Non-fatal MI 
5. Time from randomization to Non-fatal MI 
6. Time from randomization to CV Death 
7. Time from randomization to Stroke 
8. All-cause mortality 
9. Incidence of hospitalization for congestive heart failure (CHF)  
 
The analysis of the key secondary endpoint will be repeated for the PPS set as the supportive analysis. 
Presentation of key secondary analyses will include estimated hazard ratios and associated 2-sided CI 
obtained from Cox Proportional Hazards (CPH) model with treatment as a factor, stratified by country of 
enrollment and prescribed statin therapy (atorvastatin or rosuvastatin).  
 
Endpoints such as incidence of narrow MACE or incidence of CHF will allow consideration of recurrent 
events and will be evaluated using Andersen-Gill methodology in a proportional hazards model.  Hazard 
ratios, confidence intervals, and p values will be presented as appropriate. Event rate and corresponding 
hazard ratios will be provided for all-cause mortality. 
 
8.4. Other Secondary and Exploratory Analysis 
 
Other secondary and exploratory endpoints are listed in sections 3.2.2.1 and 3.2.3.  Quantitative endpoints 
that are defined as a (percent) change from baseline will be analyzed using analysis of covariance 
(ANCOVA) models with treatment group, baseline value, and strata as covariates. Descriptive statistics 
for (percent) change from baseline at each post-baseline visit will be summarized using the FAS. 
 
Descriptive statistics (number of subjects with non-missing values, mean, standard deviation, minimum, 
25th percentile, median, 75th percentile, and maximum) will be used to summarize continuous variables by 
treatment group for the FAS set. 
 
Least squares (LS) means and difference in LS means between RVX000222 and Placebo with standard 
errors (SEs) and 2-sided 95% CI and p-values obtained from ANCOVA model will be presented at each 
applicable post baseline visit.   
 
Mixed-effects model repeated measures analysis will be used to model percent change in measurements 
over time at the last visit on treatment (LVT). An unstructured covariance matrix will be used to fit the 
underlying MMRM model. Subject and error will be considered random effects; all effects that include 
treatment, strata and baseline value will be considered fixed. 
 
The pattern of change from baseline over time will also be displayed graphically in Figures for some 
endpoints.  No multiplicity adjustment is planned to test the other secondary and exploratory endpoints.  
Since most of the other secondary endpoints are clinical laboratory tests, they are also summarized under 
safety analysis in section 9. 
 
Analyses will summarize EQ-5D-5L scale and subscale scores at each visit and change from baseline at 
each visit. 
 
Analyses will address mean differences by treatment group on MOCA scale and differences for subjects 
with a baseline score indicative of cognitive impairment (Baseline MoCA < 26) 
 
 


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9. Safety Analysis 
 
Safety data such as clinical laboratory results, vital signs, findings from physical examinations will be 
listed and/or summarized by treatment group where appropriate. No inferential hypothesis testing will be 
performed on the safety variables. 
 
The assessment of safety will be based on the frequency, intensity, and types of AEs and for change and 
from Baseline in the clinical laboratory variables, and vital sign measurements.  
 
9.1. Adverse Events 
 
Adverse events will be summarized using the safety set. Adverse events will be coded using MedDRA 
(version 17.0 or higher), summarized by frequency, severity, relationship to study drug, and number of 
subjects per treatment and by the preferred term and system organ class.  Data will be summarized using 
preferred term and primary system organ class. The coded events will be summarized by treatment group, 
in subsets of all treatment-emergent AEs, all treatment-related AEs, and serious treatment emergent AEs.   
 
9.1.1. Incidence of Adverse Events 
 
A Treatment-Emergent AE (TEAE) will be defined as any AEs, regardless of relationship to study 
drug, that occur after the first dose of double-blind study drug and within 14 days after the last dose 
of double-blind study drug.  An AE with a reported onset date after the subject has signed the 
informed consent document and before the date of randomization (or the date of first dose of study 
drug if a subject was treated but no randomized) will be considered a pre-study event. AEs with 
missing onset dates will be considered on-study events.  
 
If the day of onset of an AE is missing, and if the month and year of an onset date are on or after 
Day 1, general imputation rules from section 4.5 will be applied.  
 
If, despite implementing the above conventions, the onset date of the AE cannot be placed before, on, 
or after Day 1, then the event will be considered on-study. 
 
All AEs will be coded using the MedDRA Version 17.0 or higher coding system. In this dictionary, 
each diagnosis is mapped to a lower level term and then to a preferred MedDRA term, which is then 
mapped to a system organ class. 
 
TEAEs will be summarized by treatment group and overall for the SS. Summaries of TEAEs will be 
displayed by descending overall frequency for system organ class and preferred term.  Treatment-
Emergent AEs and SAEs will include events per 100 subject-years of study drug exposure.  In 
addition, TEAEs leading to Study Drug Discontinuation, Serious TEAEs and TEAEs resulting in 
Deaths will be presented.   
 
9.1.2. Relationship of Adverse Events to Study Drug 
 
Numbers and percentages of subjects with TEAEs by causality and study drug-related TEAEs will be 
summarized by system organ class and preferred term; TEAE with missing relationship to study drug 
will be considered as study drug-related and included. However, the TEAE will be presented with a 
missing relationship. Drug-related TEAEs will be defined as any TEAE that the investigator 
considers related to study drug. If a subject reported multiple occurrences of the same AE, only the 


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related occurrence will be presented. Therefore, these summaries will not include events per 
100 subject-years of study exposure.  
 
9.1.3. Intensity of Adverse Event 
 
Numbers and percentages of subjects with TEAEs by intensity, system organ class and preferred term 
will be summarized; AEs with missing intensity will be imputed. If a subject reported multiple 
occurrences of the same AE, only the most severe occurrence will be presented. Therefore, these 
summaries will not include events per 100 subject-years of study exposure.  
 
9.1.4. Serious Adverse Events 
 
An SAE or reaction is any untoward medical occurrence that at any dose: 
 
• Results in death; 
• Is life threatening (life threatening refers to an event in which the subject was at immediate risk 
of death at the time of the event; it does not refer to an event that hypothetically might have 
caused death if it were more severe); 
• Requires inpatient hospitalization or prolongation of existing hospitalization; 
• Results in persistent or significant disability or incapacity; 
• Is a congenital anomaly or birth defect; or 
• Is medically significant, and though not included in the above list, is an important medical 
event that may jeopardize the subject or require medical intervention to prevent one of the 
outcomes listed above. Discontinuation of study drug or conduct of additional diagnostic 
evaluations, will not, by themselves, satisfy the criterion for a medically significant event. 
 
9.1.5. Hospitalization 
 
Adverse events reported from clinical trials associated with hospitalization or prolongations of 
hospitalization are considered serious and will be included in SAEs. 
 
Hospitalization does not include the following: 
 
• Rehabilitation facilities 
• Hospice facilities 
• Respite care 
• Skilled nursing facilities 
• Nursing home 
• Routine emergency room admission 
• Same day surgeries (as outpatient/same day/ambulatory procedures) 
 
9.1.6. Adverse Events Leading to Study Drug Discontinuation 
 
AEs leading to study drug withdrawal will be recorded on the eCRF with a study drug action taken as 
“Drug Withdrawn”. Numbers and percentages of subjects with AEs leading to study drug withdrawal 
will be summarized by system organ class and preferred term. All AEs leading to study drug 
withdrawal will also be summarized. 
 


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9.1.7. Death 
 
All deaths during this study will be reported. Data presented will include, where applicable, date of 
first dose, AE type, date of death, days relative to the date of randomization, date of last dose, study 
day, cause of death, and relationship of cause of death to study drug. 
 
9.2. Clinical Laboratory Evaluations 
 
Clinical laboratory samples (fasting lipid panel, hematology, chemistry, hepatitis serology, liver safety, 
lipoproteins, and inflammation panel) will be collected according to the study Schedule of Events shown 
in the protocol. 
 
Evaluation of clinical laboratory samples collected for safety will include standard hematology, serum 
chemistry, and urinalysis.  All summaries of clinical laboratory variables will be performed using the SS.  
No inferential statistics will be provided. 
 
Change from baseline in continuous safety laboratory variables will be summarized by treatment group. 
Standard units will be reported for all lab tests.  
 
In the event that 2 or more observations equidistant from the expected visit date are available, the later 
observation will be used. A subject who has multiple test results for a particular test at a particular visit 
and at least 1 of them is markedly abnormal; the subject will be classified as having a markedly abnormal 
result at that visit and values from all visits will be listed. All descriptive statistics will be based on data 
selected according to the window convention outlined in Section 4.5. 
 
9.2.1. Fasting Lipid Profile 
 
Fasting blood work will be collected for lipid profile (total cholesterol, LDL-C, HDL-C, and TGs), at 
visits indicated on the Schedule of Events in the study protocol. 
 
A summary of descriptive statistics of lipid profile values for baseline, each post-baseline scheduled 
visit, and change from baseline to each post-baseline scheduled visit will be presented.  
 
9.2.2. Hematology 
 
Hemoglobin, hematocrit, red blood cell count (RBC), white blood cell count (WBC) with differential, 
platelet count, and HbA1c will be measured at visits indicated on Schedule of Events in the study 
protocol. 
 
A summary of descriptive statistics of hematology values for baseline, each post-baseline scheduled 
visit, and change from baseline to each post-baseline scheduled visit will be presented.  
 
9.2.3. Chemistry 
 
Albumin, blood urea nitrogen, creatine kinase (CK), serum creatinine, fasting glucose, ALP, calcium, 
phosphate, potassium, sodium, and total protein will be measured at visits indicated on the Schedule 
of Events in the study protocol. 
 
Estimated glomerular filtration rate will be calculated by the lab using serum creatinine values and the 
Cockcroft-Gault formula. 


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A summary of descriptive statistics of serum chemistry values for baseline, each post-baseline 
scheduled visit, and change from baseline to each post-baseline scheduled visit will be presented.  
 
9.2.4. Hepatitis Serology 
 
Blood samples will be collected at Screening to test for antibody to hepatitis A (IgM), hepatitis B 
surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), hepatitis B virus core protein 
antibody (HBcAb), hepatitis C (HCV). Subjects with evidence, in the opinion of the Investigator, of 
active hepatitis will be excluded from participation in this study. Since these tests are only collected at 
screening only, the data will be available upon request. 
 
9.2.5. Liver Safety Panel 
 
ALT (SGPT), AST (SGOT), gammaglutamyl transferase (GGT), ALP, and bilirubin (direct and total) 
will be measured at each visit as indicated on the Schedule of Events in the study protocol. 
 
As defined in the protocol, subjects who have an ALT increase of ≥3xULN will be monitored by liver 
safety panels and have archival serum samples drawn every 3-4 days until ALT values return to 
<1.5xULN and subjects who have an ALT increase of >5xULN or who have a serum bilirubin 
increase of >2xULN will be monitored by extended liver safety panels and have archival serum 
samples drawn every 3-4 days until ALT values return to <1.5xULN or serum bilirubin values return 
to within normal range.  
 
The Extended Liver Panel includes ALT (SGPT), AST (SGOT), GGT, ALP, bilirubin (direct and 
total), as well as osteopontin and PT/INR.  
 
9.2.6. Biomarker Laboratory Tests 
 
A subset of up to 600 subjects in selected countries will have additional biomarker samples collected 
for lipoprotein, fasting insulin, and an inflammation panel analysis as described below 
(Sections 9.2.6.1 through 9.2.6.3) at visits indicated on the Schedule of Events in the study protocol. 
9.2.6.1 Lipoproteins 
Fasting blood work will also be collected from a selected subset of subjects for apoA-I and apoB 
at visits indicated on the Schedule of Events in the study protocol. Summary statistics for apoA-I 
and apoB values at baseline, each post-baseline scheduled visit, and change from baseline to each 
post-baseline scheduled visit will be presented. 
9.2.6.2 Fasting Insulin 
Fasting insulin will be measured in a selected subset of subjects at visits indicated on Schedule of 
Events in the study protocol.  A summary of descriptive statistics for fasting insulin values at 
baseline, each post-baseline scheduled visit, and change from baseline to each post-baseline 
scheduled visit will be presented. 
9.2.6.3 Inflammation Panel 
hsCRP, fibrinogen, and inflammatory cytokines will be measured in a selected subset of subjects 
at visits indicated on Schedule of Events in the study protocol.  Summary statistics of hsCRP, 
fibrinogen, and inflammatory cytokines values at baseline, each post-baseline scheduled visit, and 
change from baseline to each post-baseline scheduled visit will be presented.  


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9.3 Montreal Cognitive Assessment (MOCA). 
 
The MOCA will be performed on subjects 70 years of age and older at visits indicated on the Schedule of 
Events to measure any cognitive changes from baseline.  Descriptive statistics of the assessment and 
changes from baseline at visits will be presented. Analyses will also address mean differences for subjects 
with a baseline score indicative of cognitive impairment (Baseline MoCA < 26). 
 
9.4 Vital Sign Measurements 
 
Vital signs (systolic/diastolic blood pressure, heart rate, respiratory rate, and temperature) will be 
measured according to the Schedule of Events in the study protocol.  
 
Vital signs measured are systolic and diastolic blood pressure in mmHg, pulse rate in beats per minute, 
and weight in kg. A summary of descriptive statistics for vital sign measurements at baseline, each post-
baseline scheduled visit, interim last value, and the last observed value, and change from baseline to each 
post-baseline scheduled visit using the SS will be presented. 
 
9.5 Electrocardiogram 
 
A standard 12-lead ECG will be performed at Screening (Visit 1).  
 
The number and percentage of subjects in each overall ECG interpretation category (normal, clinically 
significant abnormal, non-clinically significant abnormal) will be summarized using the SS.  Percentages 
will be based on the number of subjects with values at each visit. 
 
 


 
 
 
Schedule of Events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1Study treatment will be terminated in all currently participating subjects when the 250th event occurs and all surviving patients have been followed for at least 24 weeks from randomization. At that time all subjects actively treated will conduct their Last Visit on Treatment. 
2 4 weeks after Last Visit on Treatment (LVT). 
 
3 Physical Exam: height will be recorded only at Visit 1  
4 Lipid profile includes: TC, LDL-C, HDL-C, TG 
5 Hematology includes: platelet count, hemoglobin, hematocrit, RBC, WBC with differential  
6 Chemistry includes: albumin, blood urea nitrogen, creatine kinase, serum creatinine, fasting glucose,  calcium, phosphate, potassium, sodium, total protein  
7 Including urine HCG at screening for subjects of childbearing potential.  Dipstick tests performed and results maintained at investigational sites. 
8 Hepatitis Serology:  hepatitis A (IgM), B by HBs-Ag, Anti-HBs, Anti-HBc , C (HCV) 
9 Liver Safety Panel:  ALT (SGPT), AST (SGOT), GGT, ALP, bilirubin (direct and total)  
10 Additional biomarker laboratory test samples will be collected on a selected subset of subjects 
11 Lipoproteins include: apoA-I and apoB 
12Inflammation Panel includes: hsCRP, fibrinogen, and inflammatory cytokines 
13 Serum/plasma samples for future biomarker analysis in lipid/inflammation 
14 Optional:  whole blood will be collected for DNA analysis (Visit 2 only) and mRNA analysis (both Visit 2 and 5) if consent obtained. 
15 Montreal Cognitive Assessment (MOCA) will be performed on  subjects ≥70 years of age at randomization 
16 Only statin will be dispensed at screening visit and LVT.  
 
Screen 
Treatment 
Follow 
Up (ET) 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18  
19 to end of 
study 
LVT1 
FU 
Week 
- 2 to -1 
0 
2 
4 
6 
8 
10 
12 
16 
20 
24 
28 
40 
52 
64 
76 
88 
100  
112, then 
every 12wks 
end of 
study 
 LVT + 
4wks2 
± No. Day 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
Physical Exam3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
Central Laboratory: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting Lipid profile4 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
Hematology5, HbA1c 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
Chemistry6 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
Urinalysis7 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
Hepatitis Serology8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver Safety Panel9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biomarker Laboratory Tests10 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipoproteins11, fasting insulin 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
Inflammation Panel12 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Serum/Plasma Archive13 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Pharmacogenomic14 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MOCA15 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
EQ-5D-5L 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior / Con. Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug Dispense/Account. 
X16 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X