Clinical trial NCT02697136
Conditions: Familial Hypoalphalipoproteinemia
Keywords: Low HDL Low apoA-I ABCA-1 mutations ApoA-I mutations
Sponsor: Cerenis Therapeutics, SA
Start date: 2015-12-01; Completion date: 2018-12-21
Enrollment: 30 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the impact of 29 intravenous infusions of CER-001 vs. placebo, given at weekly (9 infusions) and biweekly (20 infusions) intervals on carotid vessel wall area as measured by 3TMRI, when administered to patients with familial primary hypoalphalipoproteinemia with proven CVD and appropriate background lipid-lowering therapy.

Detailed description:
Subjects will be required to have acceptable baseline 3TMRI imaging of carotid arteries. Subjects meeting all eligibility criteria will be randomized to receive CER-001 or placebo (2:1 randomization scheme). Randomized subjects will return weekly for a total of 9 infusions and then biweekly for an additional 20 infusions. 3TMRI imaging of the carotid and femoral arteries will be performed at Week 8, Week 24 (primary endpoint) and Week 48. The total study duration from randomization can range from 50 to 54 weeks for patients completing the study as designed.

Arms: arm 1: CER-001 infusion; 9 weekly infusions followed by 20 biweekly infusions arm 2: Saline infusion; 9 weekly infusions followed by 20 biweekly infusions
Interventions: intervention 1: CER-001 intervention 2: Placebo
Intervention descriptions: intervention 1: Recombinant human apoA-I/phospholipid complexes intervention 2: 0.9% Sodium Chloride Injection, USP

Protocol documents:
Prot_000.pdf: 
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TANGO 
Protocol n° CER-001-CLIN-009 
 
PHASE III, MULTI-CENTER, RANDOMIZED, 48 WEEKS, DOUBLE-BLIND, PARALLEL-
GROUP, PLACEBO-CONTROLLED STUDY TO EVALUATE EFFICACY AND SAFETY OF 
CER-001 ON VESSEL WALL AREA IN PATIENTS WITH GENETICALLY DEFINED 
FAMILIAL PRIMARY HYPOALPHALIPOPROTEINEMIA AND RECEIVING BACKGROUND 
OPTIMIZED LIPID THERAPY, WITH OPTIONAL OPEN-LABEL SAFETY EXTENSION 
 
 
CLINICAL PHASE : III 
EudraCT number  : 2015-003713-23 
 
 
 
PROTOCOL NUMBER: CER-001-CLIN-009 
 
Version: 3.0 of 13th of December 2016 
 
Revision History:  
Version 1.0 of 4th September 2015 
Version 1.1 of 19th October 2015 
Version 2.0 of 19th of November 2015 
 
Sponsor:  
 
CERENIS THERAPEUTICS SA 
265 Rue de la Découverte 
BAT.A 
31670 LABEGE  
France 
Telephone: +33 5 62 24 97 06  
 
 
This document is a confidential communication of Cerenis Therapeutics. The recipient should not share this 
information with any other party without the express and written consent of Cerenis Therapeutics. 


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SYNOPSIS 
TITLE OF STUDY:   
This is a Phase III, multi-center, randomized, 48 weeks, double-blind, parallel-group, placebo-
controlled study to evaluate efficacy and safety of CER-001 on vessel wall area in patients with 
genetically defined familial primary hypoalphalipoproteinemia and receiving background optimized 
lipid therapy, with optional open-label safety extension 
INVESTIGATIVE SITES:  
Approximately 15 sites from Europe, Canada, United States of America, Brazil and Israel to be 
determined based on availability of patients with this rare disease. 
ANTICIPATED STUDY DURATION: 
Anticipated Start Date for Study Enrollment: November 2015 
Anticipated Completion Date for Study Enrollment: First quarter 2017 
Anticipated Date for Last Patient Last Visit: First quarter 2018 
OBJECTIVES:   
Primary objectives: 
• To evaluate the effect of 24-week treatment with CER-001 on carotid Mean Vessel Wall Area 
(MVWA) as compared to placebo using 3T magnetic resonance imaging (3T-MRI); 
• To evaluate the safety and tolerability of CER-001 administered for 24 weeks 
Secondary objectives: 
• To evaluate the effect of 8-week and 48-week treatment with CER-001 on MVWA as 
compared to placebo using 3T-MRI;  
• To evaluate the effect of 8-week, 24-week and 48-week treatment with CER-001 on femoral 
artery as compared to placebo using 3T-MRI;  
• To evaluate the effect of 24-week treatment with CER-001 in the target (plaque) to 
background (blood) ratio (TBR) from an index vessel (either right carotid or left carotid) 
based on the standardized 18FDG uptake measured with PET/CT; 
• To evaluate safety and tolerability of CER-001 administered for 48 weeks  
Exploratory objectives: 
• To evaluate the effect of treatment with CER-001 with respect to other efficacy measurements 
including carotid artery and carotid normalized wall index using 3T-MRI;  
• To evaluate the effect of treatment with CER-001 with respect to potential surrogate markers 
on vessel wall biology including laboratory variables; 
• To evaluate the effect of treatment with CER-001 with respect to inflammation; 
• To evaluate plasma-mediated cellular cholesterol efflux capacity; 
• To measure ApoA-1 levels (pharmacokinetic parameters); 
• To measure cholesterol, triglycerides, lipids and lipoproteins levels.  


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Other objectives: 
• To evaluate safety and tolerability of 72 week treatment with CER-001. 
• To evaluate the effect of 72 week treatment with CER-001 on MVWA using 3T-MRI;  
• To evaluate the effect of 72 week treatment with CER-001 on femoral artery using 3T-MRI;  
 
 
BIOMARKER EVALUATION: 
Specimens for protein biomarker discovery and validation will be collected from all patients. These 
specimens could be used for research purposes to identify and/or verify biomarkers that are linked to 
CER-001 treatment and could help to understand the pathogenesis, course and outcome of the disease 
of the targeted patient population. 
METHODOLOGY:   
Patients with genetically defined familial primary hypoalphalipoproteinemia (FPHA – mutation in 
ApoA1 and/or ABCA1 gene), receiving background optimized lipid therapy AND with cardiovascular 
disease background will be enrolled in the study. 
 
Enrolled patient will receive 29 infusions of CER-001 or placebo over 48 weeks. 
 
After obtaining written informed consent and if the patient is eligible, he/she will receive twenty nine 
8 mg/kg doses of CER-001 or placebo, administered as a weekly infusion during the first 8 weeks (9 
doses) and then every two weeks during the following 40 weeks (20 doses). 
 
Patients will have a safety follow-up visit 4 weeks after the last dose administration. 
NUMBER OF PATIENTS:   
A total of 30 patients will be randomized. 
PRODUCT INFORMATION 
TREATMENT GROUPS: 
CER-001 is a negatively charged ApoA-1-containing lipoprotein/phospholipid complex mimicking 
natural HDL.   
 
COMPARATOR PRODUCT:  
Standard sodium chloride solution will be used as the placebo. 
ASSESSMENTS: 
• Vascular structural changes (atherosclerotic plaque burden assessed by 3T-MRI) 
• Vascular inflammation as measured by 18FDG-PET/CT 


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• Safety parameters (physical examination, vital signs, clinical laboratory measurements,  
electrocardiograms (ECGs), metabolic parameters, adverse events (AEs),  urine analyses and 
anti-ApoA-1 antibody development)   
• Pharmacokinetic (PK) parameters (assessed by ApoA-1 levels, cholesterol mobilization) 
• Pharmacodynamic parameters (lipids, lipoproteins and apolipoproteins) 
SAMPLE SIZE CALCULATION: 
The assumptions, upon which the power calculation are based, are data from the 7 patients 
completing the CER-001-CLIN-007 SAMBA study, given the similarity of the genetic mutations. 
Those patients presented with a median value for MVWA of 25.0 mm2 and had a follow-up median 
value at 6 months of 21.8 mm2. The mean percent reduction is reported as 6.7%, standard deviation = 
4.5%. These observed values would provide a conservative estimate of the effect of CER-001 in the 
more severe population for this FPHA study. 
 
Using these results from SAMBA (i.e. an assumed standard deviation of 4.5%) and a 2:1 
randomization scheme to maximize exposure to active drug, 16 completing patients in the CER-001 
group and 8 in the placebo group (24 total completers for mITT) would yield 90% power to detect a 
difference from baseline versus placebo of 6.7%, using two-tailed testing with α=0.05.  A total of 30 
patients are planned to be randomized that would provide a buffer such that a 20% discontinuation 
rate would still allow the study to retain sufficient power for a supporting per protocol efficacy 
analysis (MVWA). 
PRIMARY EFFICACY PARAMETER: 
The primary efficacy parameter of this study will be the change from baseline after 24 weeks 
treatment with CER-001 on carotid Mean Vessel Wall Area (MVWA) as compared to placebo using 
3T-MRI when administered to patients with genetically defined FPHA. 
SECONDARY EFFICACY PARAMETERS: 
• Change from baseline after 8-week and 48-week treatment with CER-001 on MVWA as compared 
to placebo using 3T-MRI when administered to patients with genetically defined FPHA.  
• Change from baseline after 8, 24 and 48 weeks treatment with CER-001 on femoral artery as 
compared to placebo using 3T-MRI when administered to patients with genetically defined FPHA. 
• Change from baseline at 24 weeks in the TBR from an index vessel (either right carotid or left 
carotid) based on the standardized 18FDG uptake measured with PET/CT in patients with 
genetically defined FPHA. 
SECONDARY SAFETY PARAMETERS: 
• Incidence and severity of AEs from routine monitoring. 
• Incidence of abnormalities and changes from baseline in clinical laboratory parameters from testing 
of blood and urine, including anti-ApoA-1 antibody.  
Incidence of cardiovascular events. 


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EXPLORATORY EFFICACY PARAMETERS: 
• Changes from Baseline in carotid normalized wall index assessed by 3T-MRI from baseline 
to week 24 and week 48. 
• Changes from baseline to week 24 and week 48 of potential markers on vessel wall biology 
including and not restricted to laboratory variables such as absolute and relative change in 
high sensitivity C-reactive protein (hs-CRP), MMP-9 and other selected inflammatory 
markers (TNFα, IL-6), soluble VCAM-1, PON-1 and sMCP1, plaque characterization indexes 
using 3T-MRI. 
• Cholesterol efflux capacity after CER-001 administration. 
• Changes from baseline of ApoA-1 level.  
• Changes from baseline in total cholesterol, unesterified cholesterol, esterified cholesterol, 
triglycerides, apolipoprotein B, other apolipoprotein and lipoprotein profiles for total and 
unesterified cholesterol by HPLC.  
OTHER EFFICACY PARAMETERS: 
• Change from baseline after 72 week treatment with CER-001 on carotid Mean Vessel Wall 
Area (MVWA) using 3T-MRI when administered to patients with genetically defined FPHA  
• 
Change from baseline after 72 week treatment with CER-001 on femoral artery using 3T-MRI 
when administered to patients with genetically defined FPHA 
 
SELECTION OF STUDY PATIENTS 
Patients with ApoA-1 ≤ 110mg/dL  and HDL≤ 35 mg/dL ,with suspected homozygous or heterozygous 
mutation in the ABCA1, and/or ApoA-1 genes confirmed by genetic testing, and background of 
symptomatic or asymptomatic cardiovascular disease, will be eligible for this study..  
Patients who fulfill all inclusion/exclusion criteria, including confirmation of a genetic defect, may be 
enrolled in the study.  
 
INCLUSION CRITERIA 
Eligible patients must meet the following criteria before they are enrolled in the study: 
1. Male and female patients, aged 18 and above. 
2. Female patients who are not either surgically sterile (e.g., tubal ligation or removal of ovaries 
or uterus) or post-menopausal (no spontaneous menstrual periods for at least one year) must 
agree to use one of the following forms of contraception from screening until 90 days after the 
completion of the study medication: (1) systemic hormonal treatment (2) an IUD which was 
implanted at least 2 months prior to screening or (3) "double-barrier" contraception (condom, 
diaphragm and spermicide are each considered a barrier), or (4) agree to remain sexually 
abstinent during the entire study period (when contraception is not acceptable for cultural or 
religious beliefs) 


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3. Sign written informed consent after the scope and nature of the investigation have been 
explained to them before screening evaluations and willing to comply with the study 
restrictions 
4. Are fluent in the language of the investigator, study staff (including raters), and the informed 
consent 
5. Diagnosis of genetically confirmed HDL-c deficiency due to defects in genes coding for e.g. 
ABCA1 and/or ApoA-1  
6. IF the subject is on lipid-lowering therapy or NEEDS to be treated with lipid-lowering therapy 
then the subject must be on a stable dose at least 6 weeks prior to the baseline procedures. 
7. Background symptomatic or asymptomatic cardiovascular disease should be present as such: 
- 
For symptomatic cardiovascular disease: i) history of cardio or cerebrovascular events, ii) 
diagnosed coronary artery disease (CAD), iii) diagnosed carotid or peripheral stenosis, iv) 
previous myocardial revascularisation - percutaneous coronary intervention (PCI), or coronary 
artery bypass graft (CABG). 
- 
For asymptomatic cardiovascular disease: patients with subclinical atherosclerosis diagnosed 
using imaging method such as i)vDoppler ultrasound, ii)vB-mode ultrasonography – 
measurement of carotid intima media thickness, iii)vintravascular ultrasonography, iv) 
Computed Tomography, v) Magnetic Resonance Imaging 
8. ApoA-1 ≤ 110 mg/dL 
9. HDL-cholesterol ≤ 35 mg/dL or 0.9 mmol/L 
 
EXCLUSION CRITERIA 
Patients meeting any one of the following criteria are not eligible for the study: 
1. Patient with LCAT mutation will be excluded 
2. Patient who experienced a cardiovascular event within 6 months prior to the start of screening 
3. Patient who experienced stroke or other cerebrovascular event within 1 year prior to the onset 
of screening 
4. Patients with triglycerides level above 500 mg/dL  
5. The patient has evidence of clinically significant, uncontrolled or unstable cardiovascular, 
renal, hepatic (incl. AST or ALT at or above 3x ULN, or bilirubin at or above 2x ULN), 
gastrointestinal, hematologic, immunological, neurological, endocrine, metabolic or 
pulmonary disease (as determined by medical history, clinical laboratory or ECG results, or 
physical examination) or any other medical disorder that would increase the risk associated 
with taking study medication or would confound the interpretation of study results. 
6. Patients with a body mass index (BMI) < 17 kg/m2 or > 40 kg/m2 
7. Patients with severe anemia defined as hemoglobin level below or equal to 10 g/dL 


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8. Any clinically significant abnormal laboratory data, vital signs, physical examination at 
screening or baseline, which in the opinion of the investigator, would interfere with safety 
assessments 
9. Clinically significant ECG abnormality at screening, including sinus bradycardia (resting 
heart rate < 50 beats per minute), 2nd or 3rd degree atrioventricular block, prolonged QTc 
(QTcF ≥ 450 ms in males and ≥ 470 ms in females) history of congenital long QT syndromes, 
or risk of Torsades de Pointes because of family history of sudden death, etc. 
10. Positive result on the serum pregnancy test or are breast feeding at screening, or intend to 
become pregnant during the course of the trial 
11. Male intending to father a child during the study 
12. Likely to be unreliable as a study participant based on the Investigator's (or designee’s) 
knowledge of the patient (e.g., alcohol or other drug abuse, inability or unwillingness to 
adhere to the protocol, or psychosis)  
13. Symptomatic (NYHA Class II or greater) congestive heart failure requiring and persisting 
despite appropriate medical treatment  
14. Uncontrolled blood pressure: systolic blood pressure ≥160 mmHg and/or diastolic blood 
pressure ≥100 mmHg at screening or any other pre-randomization visit 
15. Uncontrolled diabetes mellitus defined as HbA1c >10% 
16. Unexplained creatine phosphokinase level > 3 times the ULN  
17. History of malignancy during the 3 years prior to screening, with the exception of basal cell 
carcinoma of the skin 
18. Current alcohol or drug abuse or history thereof within 5 years prior to screening 
19. Contraindication to MRI scanning such as imbedded metal (e.g., schrapnel), implanted metal 
objects (e.g., pacemaker), claustrophobia 
20. Participated in any investigational study or taken an investigational drug within 30 days (or 5 
times the half-life of the investigational drug, whatever is longer) 
21. Ever received CER-001 within 6 months before the start of screening 
22. Medically non-compliant in the management of their disease in the investigator’s opinion 
SAFETY AND TOLERANCE  
• Incidence and severity of AEs from routine monitoring  
• Incidence of abnormalities and changes from baseline in clinical laboratory parameters from 
testing of blood and urine  
• Incidence of adverse changes from baseline vital sign values  
• Incidence of adverse changes from baseline physical examinations  
• Safety parameters will also be summarized by genetic subset to identify possible trends 


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SAFETY EVALUATION 
All patients who have received at least one dose, or any part of one dose, of study drug and have a 
subsequent safety evaluation will be included in the safety analyses. All adverse events reported 
during the study will be listed, documenting course, severity, relationship to study drug, and 
outcome. Adverse events will be coded to MedDRA terms.  
Adverse events will be summarized, giving the number of patients who experienced an adverse 
event, the maximum severity, relationship to study drug and body system. Laboratory parameters, 
vital signs, and physical exam results will be listed and summarized with the statistics of number of 
patients, mean, standard deviation, median and range or frequencies and percentages, as appropriate, 
from baseline to each subsequent visit. 
ASSESSMENT OF SAFETY 
Periodic safety review will be performed during the on-treatment period by a data and safety 
monitoring board (DSMB) to include surveillance of laboratory testing and on-treatment safety 
events so as to advise the study management team regarding potential changes in patients monitoring 
or treatment plans during the remaining treatment period. 


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PROTOCOL APPROVED BY COORDINATING INVESTIGATOR 
 
 
 
 
Investigator Name: 
 Professor Erik Stroes  
 
Investigator Address: AMC – Academic Medical Center  
Meibergdreef 9 
1105 AZ AMSTERDAM 
 
Telephone:  
 
+31-205665978 
 
Fax/Email:  
 
e.s.stroes@amc.uva.nl 
 
 
I have read this protocol and agree to conduct the study as outlined herein, in accordance with the 
Good Clinical Practices (cGCPs; ICH E6), the Declaration of Helsinki amended, Fortaleza, Brazil, 
October 2013, the standard operating procedures, local regulatory requirements and complying 
with the obligations and requirements of clinical Investigators and all other requirements listed in 
Code of Federal Regulations, FDA title 21 part 312 (21 CFR part 312). 
 
I agree to comply with procedures and all applicable regulations for data recording and reporting 
including Serious Adverse Event. 
 
I agree to authorize direct access to source data for monitoring, auditing and inspection. 
 
I agree to retain the trial-related essential documents until the Sponsor informs these documents 
are no longer needed.   
 
I agree to dispense, track and retain study drug in accordance with GCP & protocol. 
 
I agree to inform all patients in this study completely concerning the pertinent details and purpose 
of the study prior to their agreement to participate in the study in accordance with GCPs and 
Regulatory Authority requirements. 
 
I will be responsible for maintaining each patient’s consent form in the study file and providing 
each patient with a signed copy of the consent form. 
 
Investigator Signature: ______________________________ Date: ______________ 
 
 
 
 


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PROTOCOL APPROVED BY PRINCIPAL INVESTIGATOR 
 
 
Site Number _______ 
 
 
 
 
Investigator Name: 
_________________________________________________________ 
 
Investigator Address:  ________________________________________________________ 
 
___________________________________________________________________________ 
 
 
Telephone: _________________________________________ 
 
Fax/Email: _________________________________________ 
 
 
I have read this protocol and agree to conduct the study as outlined herein, in accordance with the 
Good Clinical Practices (cGCPs; ICH E6), the Declaration of Helsinki amended, Fortaleza, Brazil, 
October 2013, the standard operating procedures, local regulatory requirements and complying 
with the obligations and requirements of clinical Investigators and all other requirements listed in 
Code of Federal Regulations, FDA title 21 part 312 (21 CFR part 312). 
 
I agree to comply with procedures and all applicable regulations for data recording and reporting 
including Serious Adverse Event. 
 
I agree to authorize direct access to source data for monitoring, auditing and inspection. 
 
I agree to retain the trial-related essential documents until the Sponsor informs these documents 
are no longer needed.   
 
I agree to dispense, track and retain study drug in accordance with GCP & protocol. 
 
I agree to inform all patients in this study completely concerning the pertinent details and purpose 
of the study prior to their agreement to participate in the study in accordance with GCPs and 
Regulatory Authority requirements. 
 
I will be responsible for maintaining each patient’s consent form in the study file and providing 
each patient with a signed copy of the consent form. 
 
 
 
Investigator Signature: ______________________________ Date: ______________ 
 
 


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Table of CONTENTS 
 
PART 1: STUDY DESIGN AND CONDUCT ................................................................ 15 
1 STUDY RESPONSIBILITIES ...................................................................................... 15 
2 LIST OF ABBREVIATIONS ........................................................................................ 17 
3 BACKGROUND ............................................................................................................. 19 
3.1 BACKGROUND ON DISEASE FAMILIAL PRIMARY HYPOLIPOPROTEINEMIA (FPHA) .............. 19 
3.2 ATHEROSCLEROSIS IN FPHA ................................................................................................ 20 
3.3 INVESTIGATIONAL PRODUCT ................................................................................................ 21 
3.3.1 Non-Clinical Findings for CER-001 .............................................................................. 21 
3.3.2 Clinical Findings for CER-001 ....................................................................................... 22 
3.3.3 Description and Mechanism of Action of CER-001 ...................................................... 24 
3.4 STUDY RATIONALE ............................................................................................................... 24 
4 TRIAL OBJECTIVES ................................................................................................... 25 
4.1 PRIMARY OBJECTIVES .......................................................................................................... 25 
4.2 SECONDARY OBJECTIVES ..................................................................................................... 25 
4.3 EXPLORATORY OBJECTIVES ................................................................................................. 25 
4.4 OTHER OBJECTIVES .............................................................................................................. 25 
5 RISK BENEFIT STATEMENT ................................................................................... 26 
6 STUDY DESIGN ............................................................................................................ 26 
6.1 OVERVIEW OF THE STUDY DESIGN AND DOSE REGIMEN ...................................................... 26 
6.1.1 Study periods .................................................................................................................. 27 
6.1.2 Rationale for the study design ........................................................................................ 27 
6.2 DOSE AND DOSE REGIMEN SELECTION ................................................................................ 28 
6.3 END OF THE STUDY ............................................................................................................... 28 
6.4 NUMBER OF PATIENTS AND ASSIGNMENT TO TREATMENT GROUP ....................................... 28 
6.5 CENTERS & COUNTRIES ........................................................................................................ 29 
6.6 SAFETY EXTENSION PROTOCOL ............................................................................................ 29 
7 STUDY POPULATION ................................................................................................. 29 
7.1 POPULATION TO BE STUDIED ................................................................................................ 29 
7.2 INCLUSION CRITERIA ............................................................................................................ 29 
7.3 EXCLUSION CRITERIA ........................................................................................................... 31 
7.4 CONCOMITANT TREATMENTS............................................................................................... 32 
7.5 PROHIBITED MEDICATION .................................................................................................... 32 
7.6 PERMITTED MEDICATION ..................................................................................................... 32 
7.7 MONITORING OF PATIENT COMPLIANCE .............................................................................. 33 
8 STUDY PROCEDURES ................................................................................................ 33 
8.1 SCREENING EXAMINATION AND ELIGIBILITY SCREENING FORM ........................................ 33 
8.2 PROCEDURES FOR ENROLLMENT OF ELIGIBLE PATIENTS AND ASSESSMENT AT VISIT 2..... 34 
8.3 CLINICAL ASSESSMENTS AND PROCEDURES DURING THE DOUBLE-BLIND TREATMENT PERIOD35 
8.4 CLINICAL ASSESSMENTS AND PROCEDURES DURING THE OPEN-LABELED TREATMENT PERIOD36 
8.5 SAFETY FOLLOW-UP ............................................................................................................. 36 
8.6 SPECIFIC IMAGING ASSESSMENTS ........................................................................................ 36 
8.6.1 Assessment of Vascular Structure of the Carotid and Femoral with 3T-MRI ............... 36 
8.6.2 Assessment of target (plaque) background (blood) ratio with PET/CT ......................... 37 
8.7 ASSESSMENTS AND PROCEDURES FOR PATIENTS WHO PREMATURELY DISCONTINUE STUDY 
MEDICATION DURING DOUBLE-BLIND TREATMENT PERIOD ...................................................... 37 
8.8 ASSESSMENT OF SAFETY ...................................................................................................... 37 
8.8.1 Physical Exam ................................................................................................................ 38 
8.8.2 Vital Signs ...................................................................................................................... 38 
8.8.3 Electrocardiograms ......................................................................................................... 39 
8.8.4 Clinical Laboratory Tests ............................................................................................... 39 
8.8.5 Immunogenicity Testing ................................................................................................. 41 


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8.9 ASSESSMENT OF LIPID PROFILES .......................................................................................... 41 
8.10 ASSESSMENT OF MARKERS OF VESSEL WALL BIOLOGY ................................................... 41 
8.11 ASSESSMENT OF CELLULAR CHOLESTEROL EFFLUX ......................................................... 42 
8.12 ASSESSMENT OF BIOMARKERS ........................................................................................... 42 
8.13 EFFICACY ASSESSMENT OF PROCEDURES .......................................................................... 42 
8.13.1 Primary Efficacy Parameters ........................................................................................ 42 
8.13.2 Secondary Efficacy Parameters .................................................................................... 42 
8.13.3 Exploratory Efficacy Parameters .................................................................................. 42 
8.13.4 Other Efficacy Parameters ............................................................................................ 43 
8.14 SAFETY ASSESSMENTS ....................................................................................................... 43 
8.14.1 Primary safety parameter .............................................................................................. 43 
8.14.2 Secondary safety parameters ........................................................................................ 43 
8.14.3 Other safety parameters ................................................................................................ 43 
8.15 PROTEIN BIOMARKER STUDY ............................................................................................. 43 
8.16 PHARMACOKINETIC (PK) PARAMETERS ............................................................................. 44 
9 INVESTIGATIONAL MEDICINAL PRODUCT ...................................................... 44 
9.1 DOSE AND SCHEDULE OF TEST “DRUG” AND PLACEBO ....................................................... 44 
9.2 PHARMACEUTICAL PROPERTIES AND FORMULATION .......................................................... 44 
9.3 PLACEBO ............................................................................................................................... 45 
9.4 PACKAGING AND LABELLING ............................................................................................... 45 
9.5 MEDICATION DISPENSING AND ADMINISTRATION ............................................................... 45 
9.6 METHOD OF ADMINISTRATION ............................................................................................. 46 
9.7 ADDITIONAL SUPPLIES PROVIDED BY SPONSOR .................................................................. 46 
9.8 INVESTIGATIONAL PRODUCT ACCOUNTABILITY .................................................................. 46 
9.9 RANDOMIZATION .................................................................................................................. 46 
9.10 TREATMENT BLINDING ....................................................................................................... 47 
9.11 MAINTAINING THE BLIND ................................................................................................... 47 
9.12 WITHDRAWAL FROM STUDY PARTICIPATION .................................................................... 47 
10 TREATMENT OF PATIENTS................................................................................... 48 
10.1 STUDY DRUG ADMINISTRATION ........................................................................................ 48 
10.2 INTERRUPTION OR DISCONTINUATION OF STUDY MEDICATION ........................................ 49 
10.3 DOSE ADJUSTMENTS OF STUDY MEDICATION ................................................................... 49 
11 SAFETY MONITORING ............................................................................................ 50 
11.1 DEFINITIONS ....................................................................................................................... 50 
11.2 ADVERSE EVENT SEVERITY RATING .................................................................................. 51 
11.3 RELATIONSHIP TO STUDY DRUG ........................................................................................ 51 
11.4 ADVERSE EVENT REPORTING ............................................................................................. 52 
11.5 SERIOUS ADVERSE EVENTS ................................................................................................ 53 
11.5.1 Definition ..................................................................................................................... 53 
11.5.2 Reporting ...................................................................................................................... 54 
11.5.3 Follow-up of Serious Adverse Events .......................................................................... 54 
11.5.4 Serious Adverse Events occurring after the study ........................................................ 55 
11.6 EXPECTED ADVERSE DRUG REACTIONS ............................................................................ 55 
11.7 LIVER AND KIDNEY EXPECTED ADVERSE REACTIONS WHICH MAY LEAD TO DRUG WITHDRAWAL
 .................................................................................................................................................... 55 
11.8 PREGNANCY ........................................................................................................................ 57 
11.9 DATA SAFETY MONITORING BOARD (DSMB) ................................................................... 57 
12 STATISTICS ................................................................................................................ 58 
12.1 STATISTICAL METHODS ...................................................................................................... 58 
12.2 EFFICACY ASSESSMENTS .................................................................................................... 58 
12.2.1 Primary Efficacy Analysis ............................................................................................ 58 
12.2.2 Secondary Efficacy Analysis ........................................................................................ 58 
12.2.3 Other Efficacy Analysis ............................................................................................... 59 
12.2.4 Exploratory Efficacy Analysis ..................................................................................... 59 


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12.3 SAFETY ASSESSMENTS ....................................................................................................... 60 
12.3.1 Safety and Tolerance Variables .................................................................................... 60 
12.3.2 Analysis of Safety and Tolerance Variables ................................................................ 60 
12.4 SAMPLE SIZE CALCULATION .............................................................................................. 60 
12.5 POPULATIONS FOR ANALYSIS ............................................................................................. 61 
13 REFERENCES ............................................................................................................. 62 
PART 2: ETHICS AND GENERAL STUDY ADMINISTRATION ETHICAL ASPECTS
 
63 
14 ETHICAL CONSIDERATIONS ................................................................................ 63 
14.1 INSTITUTIONAL REVIEW BOARD/ETHICS COMMITTEE....................................................... 63 
14.2 ETHICAL CONDUCT OF STUDY ........................................................................................... 63 
14.3 PATIENT INFORMATION AND CONSENT .............................................................................. 63 
14.4 PROTOCOL ADHERENCE ..................................................................................................... 63 
15 CONFIDENTIALITY AND ARCHIVING ............................................................... 64 
15.1 PERSONAL DATA PROTECTION AND CONFIDENTIALITY ..................................................... 64 
15.2 STUDY DOCUMENTATION KEEPING .................................................................................... 64 
16 DATA HANDLING AND RECORD KEEPING ...................................................... 65 
16.1 DATA COLLECTION ............................................................................................................. 65 
16.2 DATA CORRECTIONS .......................................................................................................... 65 
16.3 SOURCE DOCUMENTATION ................................................................................................. 65 
16.4 MONITORING, QUALITY CONTROL AND QUALITY ASSURANCE ........................................ 66 
16.5 RECORD RETENTION ........................................................................................................... 66 
17 FINANCING AND INSURANCE .............................................................................. 67 
18 PUBLICATION OF STUDY RESULTS ................................................................... 67 
19 CLINICAL STUDY REPORT (CSR) ........................................................................ 67 
20 OTHER INFORMATION ........................................................................................... 67 
APPENDIX A: SCHEDULE OF ASSESSMENTS IN DOUBLE-BLIND TREATMENT PHASE ............... 68 
APPENDIX B: SCHEDULE OF ASSESSMENTS IN OPEN-LABELED TREATMENT PHASE ............... 70 
APPENDIX C: DECLARATION OF HELSINKI.............................................................................. 72 
 
 


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PART 1: STUDY DESIGN AND CONDUCT 
1 STUDY RESPONSIBILITIES 
 
Sponsor 
Cerenis Therapeutics SA 
265 Rue de la Découverte 
BAT.A 
31670 Labège 
FRANCE 
 
CRO (operational management of the study)    
ICTA PM 
11 rue du Bocage 
21121 Fontaine les Dijon 
France 
Project Manager 
Banu Demirci-Guillermet 
Tel: +33.3.80.53.40.28 
 
3T-MRI and 18FDG-PET/CT Central Review 
Medpace 
5375 Medpace Way 
Cincinnati, OH 45227 
Farida Mostajabi, Ph.D 
Project Manager, Imaging Core Laboratory 
Tel:          +1.513.579.9911, ext. 2494 
Fax:         +1.513.579.0444 
e-mail:    f.mostajabi@medpace.com 
  
Central Laboratory 
Medpace 
5375 Medpace Way 
Cincinnati, OH 45227 
Kathleen Hammelrath, MHA 
Project Manager 
Medpace Reference Laboratories 
Tel:          +1.513.366.3270, ext. 2581 
e-mail: k.hammelrath@medpacelab.com 
 
 
 
 


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1 STUDY RESPONSIBILITIES  (cont.) 
 
Clinical Trial Material Labelling and Packaging 
Catalent Pharma Solutions 
Lancaster Way,  
Wingates Industrial Estate, Westhoughton, 
Bolton, BL5 3XX, UK 
  
Clinical Trial Material Distribution  
 
Catalent Pharma Solutions 
Lancaster Way,  
Wingates Industrial Estate, Westhoughton, 
Bolton, BL5 3XX, UK 
 
Study Drug Production 
14-7180 Seneffe 
BELGIUM 
Phone : +32 64 52 05 60  
 
 
 


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2 LIST OF ABBREVIATIONS 
ABCA1 
 
ATP Binding Cassette transporter A1 
ACS   
 
Acute Coronary Syndrome 
ADR  
 
Adverse Drug Reaction 
AE 
 
 
Adverse Event 
ANCOVA 
 
Analysis of Covariance 
ApoA-1 
 
Apolipoprotein A-1 
BMI 
 
 
Body Mass Index 
BP  
 
 
Blood Pressure 
BUN  
 
Blood Urea Nitrogen 
CABG  
 
Coronary Artery Bypass Graft 
CAD  
 
Coronary Arterial Disease 
CE  
 
 
Cholesterol Ester 
CER-001  
 
Experimental compound under study 
CHD   
 
Coronary Heart Disease 
CHO  
 
Chinese Hamster Ovary 
CK 
 
 
Creatine Kinase 
CRF   
 
Case Report Form 
CRO   
 
Clinical Research Organization 
CSR 
 
 
Clinical Study Report 
CVD   
 
Cardiovascular Disease 
DSMB  
 
Data Safety Monitoring Board 
ECG   
 
Electrocardiogram 
eCRF  
 
Electronic case report form 
ESF 
 
 
Eligilibity Screening Form 
FDA   
 
Food and Drug Administration 
18FDG-PET/CT 
18F-Fluorodeoxyglucose-Positron Emission Tomography/Computerized 
Tomography 
FH 
 
 
Familial Hypercholesterolemia 
FPHA  
 
Familial Primary Hypoalphalipoproteinemia 
HbA1c  
 
glycated Hemoglobin A1C 
HDL   
 
High density lipoprotein 
HDL/LDL RATIO  
High density lipoprotein/low density lipoprotein ratio 
HDL-C 
 
High density lipoprotein cholesterol 
HEENT 
 
Head, Ears, Eyes, Nose, Throat 
HPLC  
 
High-Pressure Liquid Chromatography 
HR  
 
 
Heart Rate 
hsCRP  
 
high sensitivity C-reactive protein 
ICH 
 
 
International Conference on Harmonization 
IL-6 
 
 
Interleukin 6 
IMP 
 
 
Investigational Medicinal Product 
IRB/IEC  
 
Institutional Review Board/Independent Ethics Committee 
ITT  
 
 
Intent-to-Treat  
 
 
IUD 
 
 
IntraUterin Device 
IVUS  
 
IntraVascular UltraSound 
IWRS  
 
Interactive Web Response System 
LCAT  
 
Lecithin Cholesterol AcylTransferase 
LDH   
 
Lactate dehydrogenase 
LDL 
 
 
Low density lipoprotein 
LDL-C  
 
Low density lipoprotein cholesterol 


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MACE  
 
Major adverse cardiovascular event 
Med-DRA  
 
Medical dictionary for regulatory activities 
MI  
 
 
Myocardial infarction 
mITT  
 
modified Intent To Treat 
MMP9  
 
Matrix Metallopeptidase 9  
MRI 
 
 
Magnetic Resonance Imaging 
MVWA 
 
Mean Vessel Wall Area 
NSF 
 
 
Nephrogenic Systemic Fibrosis 
PAV   
 
Percent Atheroma Volume 
PCI  
 
 
Percutaneous Coronary Intervention 
PET-CT 
 
Positron Emission Tomography–Computed Tomography 
PK  
 
 
Pharmacokinetic 
PL  
 
 
Phospholipid 
PON-1  
 
Serum paraoxonase/arylesterase 1 
RBC   
 
Red Blood Cells 
RLT 
 
 
Reverse Lipid Transport 
RR  
 
 
Respiratory Rate 
SAE 
 
 
Serious Adverse Effect 
SAP   
 
Statistical Analysis Plan 
SBP 
 
 
Systolic Blood Pressure 
SGPT (ALT)   
Serum glutamic-pyruvic transaminase/Alanine aminotransferase 
SGOT (AST)  
Serum glutamic-oxaloacetic transaminase/Aspartate amino transferase 
sMCP1 
Soluble monocyte chemoattractant protein 1 
SUSAR 
 
Suspected Unexpected SeriousAadverse Reaction 
TAV  
 
Total Atheroma Volume 
TBR 
 
 
Target to Background Ratio 
TEAE  
 
Treatment Emergent Adverse Events 
TNFα  
 
Tumor Necrosis Factor α 
3T-MRI 
 
3T- Magnetic Resonance Imaging 
UAP  
 
Unstable Angina Pectoris 
UC  
 
 
Unesterified cholesterol 
ULN  
 
Upper Limit of Normal 
VCAM-1 
 
Vascular cell adhesion protein 1 
WBC   
 
White Blood Cell 
 
 
 


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3 BACKGROUND 
 
3.1 Background on disease familial primary hypolipoproteinemia (FPHA) 
 
ATP binding cassette transporter A1 (ABCA1) and Apolipoprotein (ApoA-1) deficiencies are 
underlying causes of familial primary hypoalphalipoproteinemia (FPHA). FPHA is caused by 
genetic defect in one or more of the genes responsible for high-density lipoprotein (HDL) 
synthesis/maturation, such as ABCA1 and ApoA-1, and is associated with a very low number of 
HDL-particles, also reflected in a very low plasma concentration of ApoA-1. The disease is also 
generally associated with a positive family history of low HDL-cholesterol (HDL-C) or premature 
cardiovascular disease. 
 
The underlying aetiology for all clinical phenotypes of ABCA1 and ApoA-1 deficiencies is the 
imbalance in cholesterol metabolism. The major carriers for cholesterol in the blood are 
lipoproteins, including the low-density lipoprotein (or LDL) particles, and the HDL particles. In a 
healthy human body, there is a balance between the delivery and removal of cholesterol. The LDL 
particles deliver cholesterol to organs, where it can be used to produce hormones, maintain healthy 
cells, and be transformed into natural products that assist in the digestion of lipids. The HDL 
particles remove cholesterol from arteries and tissues to transport it back to the liver for storage, 
recycling, and elimination through a pathway called “reverse lipid transport (RLT)”. 
 
Mutations in the key HDL gene products, like ABCA1, ApoA-1 and lecithin:cholesterol 
acyltransferase (LCAT), result in low circulating levels of HDL particles in these patients and, as 
such, an absent or deficient RLT capacity which is insufficient to prevent the accumulation of 
cholesterol in the peripheral tissues and results in the development of premature cardiovascular 
disease. 
 
Current management of patients with FPHA is very limited and is focused on diet control and 
aggressive LDL-cholesterol (LDL-C)-directed pharmacotherapy that has proven useful adjuncts for 
managing overall cardiovascular risk. There is no treatment currently available, which can directly 
restore normal HDL levels/functioning. 
 
Epidemiological 
studies 
have 
consistently 
shown 
that 
decreased 
HDL-C 
levels 
(hypoalphalipoproteinemia) are strongly associated with an increased risk of developing Coronary 
Arterial Disease (CAD) (1, 2).  
 
Mutations in ApoA-1 
Several mutation variants of ApoA-1 have been identified. Homozygous patients have almost 
undetectable plasma ApoA-1 and HDL-C levels. Heterozygosity often results in approximately half-
normal plasma ApoA-1 and HDL-C concentrations (2). However, there are also many heterozygous 


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variants that do not seem to affect HDL-C levels. Class I mutations prevent the synthesis of ApoA-
1 and are associated with accumulation of cholesterol in tissues, manifesting clinically as 
xanthomatosis, corneal opacity and premature atherosclerosis in the affected individuals. Class II 
mutations lead to the production of truncated proteins and are variably associated with coronary 
risk. Class III mutations cause the synthesis of an ApoA-1 species with a grossly altered 
conformation that is not able to associate with LCAT, thus causing corneal opacity but not 
necessarily premature coronary heart disease (CHD). 
 
Approximately 25 patients with complete ApoA-1 deficiency have been reported by different 
authors (3-5). Almost all cases were characterized by the absence of or low levels of HDL-C, and 
coronary artery disease (CAD) was present in 11 of these patients; 13 of the remaining cases were 
below age 50, perhaps before clinical atherosclerosis could become manifest. A family clustering 
of ApoA-1 deficiency in Brazil caused by intermarriage has been reported (6), where a detailed 
description of two brothers indicated significant cardiovascular disease by their early 40s. One of 
these brothers was enrolled as the index patient in the CER-001 Phase II SAMBA study (CER-001 
CLIN-007) (7). 
 
Mutations in ATP-binding cassette transporter 1 (ABCA1) 
In humans, homozygous mutations in the ABCA1 gene leading to defective or non-functional 
ABCA1 receptors result in Tangier disease, characterized by profoundly decreased HDL-C, ApoA-
1 and ApoA-II levels, reduced total and LDL-C and ApoB, and elevated plasma triglyceride levels. 
With ABCA1 deficiency, ApoA-1 is rapidly cleared before it is able to acquire cholesterol. The 
cholesterol storage disorder that occurs with ABCA1 mutations might thus possibly be more a 
consequence of HDL deficiency than a direct consequence of dysfunctional ABCA1 (8). 
 
Homozygous (Tangier disease) patients develop peripheral neuropathy and premature CHD, caused 
by cholesteryl ester (CE) deposition in a variety of cell types, although the CHD risk differs from 
one kindred to another, probably because of the reported genetic heterogeneity of the disease (2). 
Even in heterozygote ABCA1 deficiency patients, radiolabeled HDL was more rapidly catabolized 
than in healthy controls. Therefore, the metabolic basis of Tangier disease is a rapid catabolism of 
ApoA-1 and HDL, rather than a defect in their biosynthesis (9). This condition results in an 
accumulation of CE in many tissues throughout the body, and fibroblasts are characterized by 
defective efflux capacity. The deposition of CE in the reticuloendothelial organs results in orange-
coloured tonsils. 
 
The overall data emerging from studies evaluating patients with ABCA1 mutations are indicative 
of a link with the development of atherosclerosis and increased vascular disease risk (10, 11). 
 
3.2 Atherosclerosis in FPHA  
 


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Atherosclerosis is thought to develop following an imbalance in which there is too much cholesterol 
delivery by LDL particles relative to the amount of removal by HDL particles.  
 
In animal studies, increasing HDL-C in transgenic mice and rabbits by overexpressing ApoA-1, a 
major protein in HDL-C, was associated with protection against diet-induced atherosclerosis (12-
14).  
 
In humans, FPHA has been reported as highly correlated with higher incidence of premature CAD 
(15, 16) and tissue cholesterol efflux was decreased in patients with FPHA which co-incided with 
accelerated and premature atherosclerosis (17).  
 
3.3 Investigational Product 
 
Cerenis Therapeutics has developed CER-001, a negatively charged lipoprotein complex mimicking 
natural, nascent discoidal pre-HDL, consisting of a combination of two naturally occurring 
phospholipids and recombinant human ApoA-1. The ApoA-1 protein component is expressed in 
mammalian CHO cells and purified by a three-step column chromatography process. This purified 
protein is also referred to as CT70246. The phospholipid component consists of egg sphingomyelin 
(Sph), and 1, 2-dihexadecanoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (Dipalmitoylphosphatidyl-
glycerol; DPPG) in a 97:3 weight ratio. The ratio of protein to total phospholipids in the CER-001 
complex is 1:2.7 weight/weight (w/w). The drug product, CER-001 Sterile Solution for Infusion, is 
a solution of the CER-001 complexes in phosphate buffered sucrose/mannitol solution (10 mM 
phosphate buffer, 4.0% sucrose, 2.0% mannitol, pH 8.0). The concentration of CER-001 complexes 
in the formulation is expressed as the concentration of the ApoA-1 protein component of the 
complex. CER-001 is intended for the treatment of complications due to atherosclerotic diseases. 
 
3.3.1 Non-Clinical Findings for CER-001 
 
CER-001, a recombinant human ApoA-1/phospholipid complex, was well-tolerated at the dose of 
100 mg/kg in rats and monkeys given intravenously (IV), every second day for 4 weeks. A dose of 
20 mg/kg, in both species, was considered a dose with no adverse effects in the 4-week dosing 
studies. CER-001 caused dose-dependent increase in total and free cholesterol, an expected 
pharmacodynamic effect, as a result of cholesterol mobilization, in both species. CER-001 also 
caused moderate-to-marked, but transient, increases in liver transaminases, ALT and AST, alkaline 
phosphatase, total bilirubin and triglycerides at higher doses of 100 mg/kg and above.   These 
changes were generally reversible within 24 to 48 hours post-dose. 
 
Pathological changes in rats included decreased red blood cell indices (evidence of anemia 
associated with reticulocytosis) consistent with regenerative anemia, dose-related mild-to-moderate 
hemopoiesis in spleen at 50 mg/kg and above and cholangitis or pericholangitis in liver at 100 
mg/kg. These changes were considered secondary to increased cholesterol mobilization and 
reversible during the treatment-free period. 
 


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Liver, spleen and bone marrow were considered target organs of toxicity effect of CER-001. Liver 
enzyme and renal parameter changes noted in single dose study in rat and rising dose study in 
monkey at doses 100 mg/kg and above were considered transient and secondary to exaggerated 
pharmacological effects. These changes were completely reversible within a short treatment-free 
period. 
 
CER-001 did not cause any treatment-related effects on neurobehavioral parameters and respiratory 
safety parameters in rats; cardiovascular and respiratory safety parameters evaluated in monkeys 
implanted with telemetry device at doses up to 100 mg/kg, except but small statistically significant 
increase in heart rate at 100 mg/kg. 
 
CER-001 did not induce any antibodies against human ApoA-1 in rats after alternate day dosing of 
CER-001 over a 4 week period. In monkeys, antibodies against human ApoA-1 were detected after 
alternate day dosing of CER-001 over a 4 week period as well as during the subsequent treatment 
free period. Further characterization of these antibodies in primates is still being conducted. 
 
3.3.2 Clinical Findings for CER-001 
 
A Phase I single dose tolerance study has been completed in 32 patients.  Single doses of 0.25, 0.75, 
2.0, 5.0, 10.0, 15.0, 30.0 and 45.0 mg/kg of CER-001 were administered to 32 healthy dyslipidemic 
volunteers in a randomized, double-blind, placebo-controlled, cross-over, single rising dose safety 
and tolerance study.  CER-001 was well-tolerated in all patients, with an adverse event profile 
similar to that observed with placebo.  CER-001 did not appear to affect clinical chemistry or 
hematology safety parameters differently than placebo.  No adverse effects of CER-001 on ECGs, 
vital signs, or physical findings were observed.  No antibodies against ApoA-1 developed following 
single doses. All related data can be found in the fifth version of the Investigational Brochure (7). 
 
One Phase II pilot study called EXPRESS, a small 12-patients study in Heterozygous Familial 
Hypercholesterolemia (FH) to assess MRI and IVUS imaging endpoints, has been completed.  The 
patients enrolled in the study were not representative of the typical high plaque burden/high risk 
heterozygous FH patient with clinically active atherosclerosis; mean baseline percent atheroma 
volume (PAV) was only 32% and ranged from 18% to 44%.  Non-representative sampling along 
the length of the coronary arteries by the MHI IVUS Core Lab has raised significant methodological 
concerns which call into question the appropriateness/applicability of the statistical analysis to the 
IVUS dataset and the validity of any interpretation of the analytical result relative to the vascular 
biology of the coronary arteries studied.  Given the small number of patients who contributed 
evaluable data due to measurement difficulties (n=9) and the subsequent methodological concerns, 
no meaningful conclusions could be drawn regarding the effects of CER-001 on atherosclerotic 
plaque volume in patients with heterozygous FH.  The absence of a detectable treatment response 
precludes the assessment of the association between the change from baseline in plaque burden 
measurements as assessed by IVUS and by 3T-MRI. Intravenous infusions of CER-001 
administered at a weekly dose of 8 mg/kg for six weeks were well tolerated in these patients with 
heterozygous FH (7). 
 


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A second Phase II study called CHI-SQUARE, in patients with Acute Coronary Syndrome has also 
been completed.  It was an ascending dose, placebo-controlled, double-blind, dose-response study 
that enrolled 507 patients (3:1 ratio active:placebo).  The full study report is still in preparation; 
however, preliminary results indicate that CER-001 did not meet its primary endpoint of a reduction 
in total atheroma volume (TAV) as measured by IVUS for the 12 mg/kg CER-001 treated patients 
compared to the placebo patients.  Methodological concerns regarding the IVUS analysis, as 
detected in the EXPRESS study, also pertain to CHI SQUARE.  An independent and blinded 
analysis of the IVUS images was conducted by a different IVUS core lab (SAHMRI, Adelaide 
Australia). In this post-hoc but blinded reanalysis, the 3 mg/kg treatment group showed consistent 
improvement relative to baseline and was numerically superior to placebo in all analysis 
populations.  In the Modified Per Protocol analysis, statistical significance of 3 mg/kg over placebo 
was achieved for some of the IVUS measurements (7).  
 
Figure 1.  Change in IVUS parameters by treatment group and analysis population 
(LS Means from ANCOVA modeling with nonparametric testing due to non-normality of data; mITT = modified 
intent-to-treat, mPP = modified per-protocol population; PPP = per protocol population) 
 
In general, CER-001 and placebo had a similar safety profile.  The incidence and type of SAEs were 
similar for CER-001 and placebo, with the possible exception of infusion reactions (drug 
hypersensitivity reactions, anaphylaxis, and adverse drug reactions).  
 
A Phase II study in Homozygous Familial Hypercholesterolemia (HoFH) called MODE has also 
been completed (18).  It was an open-label, single arm active treatment study that enrolled 23 
patients.  The primary efficacy endpoint was the percent change from baseline to follow-up in 
carotid artery mean vessel wall area (MVWA).  CER-001 produced a clinically meaningful and 
statistically significant decrease, from a mean of 17.23 mm2 at baseline to 16.75 mm2 at Month 6 
(2.53%; p=0.0124) in the mITT population (n=18: patients with baseline and follow-up 3T-MRI 
data).  Similar results were seen in the secondary efficacy parameters measuring the effect on the 
carotid artery.  CER-001, administered bi-weekly at a dose of 8 mg/kg for up to 12 months, was 
well tolerated in these patients.  There was only one report of a treatment-related SAE, an urticarial 
reaction which resolved rapidly with treatment (7). 
 


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Importantly, a Phase II study in Familial HDL-C Deficiency also referred to FPHA, called SAMBA, 
has also been completed.  It was an open-label, single arm active treatment study that enrolled nine 
patients with mutation in ApoA1 and/or ABCA1 gene. The primary study objective was to 
determine whether the pharmacokinetic and pharmacodynamics behavior of CER-001 was the same 
in patients with genetic defects affecting the reverse lipid transport pathway.  Secondary and 
exploratory efficacy parameters included measurements of carotid and aortic plaque structure by 
MRI, carotid plaque inflammation by PET-CT, and fecal elimination of sterols and bile acids.  
Results from the seven patients who had adequate collection of follow-up data have recently been 
published (17).  The encouraging trial data demonstrated that CER-001 regresses carotid artery 
inflammation and atherosclerosis and increased elimination of cholesterol from the body.  No SAEs 
were reported nor did any patient discontinue therapy due to an AE.  Blood chemistry and 
hematology findings were unremarkable for this patient population (7). 
 
Recently, the LOCATION study showed that CER-001 is able to target the atherosclerotic carotid 
plaques in patients with advanced carotid stenosis (manuscript under preparation).  
 
3.3.3 Description and Mechanism of Action of CER-001 
 
CER-001 is a complex consisting of recombinant human ApoA-1 and a proprietary combination of 
charged phospholipids. It is designed to mimic the action of natural nascent, discoidal pre-βHDL 
particles. When injected intravenously, CER-001 is likely to have properties that are similar to 
newly synthesized endogenous HDL, which is very effective in mobilizing cholesterol from 
peripheral tissues. More detailed information on CER-001 is provided in the Investigators’ Brochure 
(IB), 5th version, March 2015 (7). 
 
3.4 Study rationale 
 
The encouraging efficacy results seen to date from the CHI SQUARE (ACS), MODE (FH), 
LOCATION (carotid stenosis) and most importantly SAMBA (FPHA) studies indicate a potential 
for CER-001 to bring substantial benefit to patients with FHPA. Despite the efforts made on diet 
control and aggressive LDL-cholesterol (LDL-C)-directed pharmacotherapy, FHPA patients are 
remaining at high risk for developing cardiovascular event and there is no treatment currently 
available, which can directly restore functional HDL. Therefore CER-001 represents a potential 
treatment for those patients and warrant further clinical studies. 
 
This phase III study will confirm whether or not administration of CER-001 will benefit patients 
with FPHA.  
 
 


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4 TRIAL OBJECTIVES 
 
4.1 Primary Objectives  
 
The primary objectives of the study are: 
• To evaluate the effect of 24 week treatment with CER-001 on carotid Mean Vessel Wall 
Area (MVWA) as compared to placebo using 3T magnetic resonance imaging (3T-MRI); 
• To evaluate the safety and tolerability of CER-001 administered for 24 weeks. 
 
4.2 Secondary Objectives  
 
The secondary objectives of the study are: 
• To evaluate the effect of 8 week and 48 week treatment with CER-001 on MVWA as compared 
to placebo using 3T-MRI;  
• To evaluate the effect of 8 week, 24 week and 48 week treatment with CER-001 on femoral 
artery as compared to placebo using 3T-MRI;  
• To evaluate the effect of 24 week treatment with CER-001 in the target (plaque) to background 
(blood) ratio (TBR) from an index vessel (either right carotid or left carotid) based on the 
standardized 18FDG uptake measured with PET/CT. 
• To evaluate safety and tolerability of 48 week treatment with CER-001. 
 
4.3 Exploratory Objectives  
 
The exploratory objectives of the study include: 
• Evaluate the effect of treatment with CER-001 with respect to other efficacy measurements 
including carotid artery and carotid normalized wall index using 3T-MRI;  
• Evaluate the effect of treatment with CER-001 with respect to potential surrogate markers on 
vessel wall biology including laboratory variables; 
• Evaluate the effect of treatment with CER-001 with respect to inflammation; 
• Evaluate plasma-mediated cellular Cholesterol efflux capacity; 
• ApoA-1 levels (pharmacokinetic parameters); 
• Cholesterols, triglycerides, lipids, apolipoprotein and lipoprotein levels (pharmacodynamics 
parameters). 
 
4.4 Other Objectives  
 
Other objectives of the study include: 
• To evaluate safety and tolerability of 72 week treatment with CER-001. 
• To evaluate the effect of 72 week treatment with CER-001 on MVWA using 3T-MRI;  
• To evaluate the effect of 72 week treatment with CER-001 on femoral artery using 3T-MRI;  
 


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5 RISK BENEFIT STATEMENT 
 
All patients enrolled in this study will have four 3T-MRI measurements during a time period of 48 
weeks. 3T-MRI is a non-invasive imaging technique that does not involve exposure to ionizing 
radiation. The magnetic field itself is not harmful; however, imbedded metallic fragments such as 
shrapnel or implanted medical devices that contain metal such as pacemakers may malfunction or 
cause problems during an MRI exam.  
 
Patients in this study will have two 18FDG-PET scans during the study, the first one will be 
performed at baseline and the second and last assessment will be done at week 24. 18FDG-PET is 
routinely used in clinical practice. The total radiation exposure in the study corresponding to the 
two 18FDG-PET CT scans is 9.4 milli-Sievert. Labelled glucose, 18F-deoxyglucose, has no known 
side effects. No adverse effects are expected.  
 
Two thirds of the patients randomized in the trial will receive twenty-nine infusions of CER-001 
(8mg/kg) and one third will receive twenty-nine infusion of placebo.  More than 400 patients have 
been exposed to CER-001 in previous clinical trials including 122 patients exposed to 12 mg/kg 
CER-001 in phase II study. Overall CER-001 has been well tolerated. The incidence and type of 
SAEs were similar for CER-001 and placebo, with the possible exception of infusion reactions 
which occurred more frequently with CER-001 and may occur more frequently at higher doses. 
These reactions were reversible in all cases and either resolved spontaneously or after management 
with antihistamines, steroids and/or IV fluids. A phase II study (CARAT) aiming to enroll 292 
patients for evaluating the potential benefit of CER-001 in ACS patients is currently ongoing. 
6 STUDY DESIGN 
 
6.1 Overview of the study design and dose regimen  
 
This is a Phase III, multi-center, randomized, 48 weeks, double-blind, parallel-group, placebo-
controlled study to evaluate efficacy and safety of CER-001 on ApoA-1 and vessel wall area in 
patients with genetically defined familial primary hypoalphalipoproteinemia and receiving 
background optimized lipid therapy. 
 
Double-blind treatment phase: After obtaining written informed consent and provided the patient 
fulfills the selection criteria as defined in section 7, he/she will be randomized to receive twenty-
nine doses of CER-001 or placebo, weekly during the first 8 weeks (9 doses) and then every two 
weeks during the following 40 weeks (20 doses). Dosing visits will have a window of +/- 2 days 
around the strict weekly or biweekly date. 
 
Open-labeled treatment phase: After obtaining written informed consent, patient will receive twelve 
doses of CER-001, one every two weeks during 24 weeks following the last dose administered 
during double-blind treatment period. Dosing visits will have a window of +/- 2 days around the 
strict biweekly date. 


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Patients will have a safety follow-up visit at least 30 days after the last dose administered.  
 
 
 
Figure 1.  Schematic study design. 
 
 
6.1.1 Study periods 
 
The study duration can be up to 68 to 92 weeks in total: 
 
• Screening period: up to 16 weeks (+/-7 days) 
• Treatment period: the overall treatment period is 48 weeks (+/- 7 days) including an 
induction treatment phase of 8 weeks, followed by a 16 week maintenance treatment phase 
and a 24 week extension treatment phase. 
• Safety follow-up period: 4 weeks (+/- 7 days) after the end of treatment OR 
• Safety extension follow-up: 24 weeks (+/- 7 days) AND Safety follow-up period: 4 weeks 
(+/- 7 days) after the end of treatment 
 
6.1.2 Rationale for the study design 
 
In the present study, CER-001 will be evaluated at 8 mg/kg dose as its potential to induce regression 
of carotid atherosclerosis in patients with FPHA. As already described, both MODE (18) and 
SAMBA (17) studies have proven this dose as efficacious especially in the population addressed in 
this study (See section 3.3.2. Clinical Findings for CER-001).  
 
Overall study duration: 92 weeks
Screening period
CER-001 8mg/kg
CER-001 8mg/kg
Placebo
(N=20)
(N=10)
Double-blind treatment phase
Open-labeled treatment phase
9 doses
8 doses
12 doses
12 doses
Onsetof 
screening
End of FU 
(W76)
Randomization
End of 
treatment
(W72)
End of FU 
(W52)
End of 
treatment
(W48)
Up to 16 weeks
(+/- 7days)
Period 4: Safety
extension (optional)
(24 weeks)
Period 3: Extension 
(24 weeks)
Period 2: 
Maintenance
(16 weeks)
Period 1: 
Induction
(8 weeks)
Baseline
W8
W24
W48
W72
MRI
18FDG PET/CT
1
1
2
2
3
4
5


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Both previous trials mentioned above were designed to address the efficacy of CER-001 at 6 months. 
Indeed, even though infusion of CER-001 was leading to early positive effect on carotid 
atherosclerotic plaque burden as detected by a significant reduction of the mean carotid vessel wall 
area after 1 month treatment (17), it is of main interest to measure the longer lasting effect of the 
study drug and maintenance of its positive treatment outcome on atherosclerotic plaques. Therefore 
this study has been designed to confirm the previous clinical evaluation. Moreover, the 24 week 
extension treatment period (See Figure 1) will allow to assess even further beneficial effect of 8 
mg/kg dose of CER-001 as well as better evaluating the safety profile of the study drug by collecting 
safety data from the patients with FPHA exposed to CER-001 for 48 weeks. A final safety visit will 
occur at week 52. 
 
 6.2 Dose and Dose Regimen Selection  
 
Overall CER-001 has shown its potential benefit in various patient populations. Patients receiving 
8 mg/kg dose of CER-001 in the MODE study (18) indicate that six months biweekly infusion of 
CER-001 at 8 mg/kg is beneficial in regressing carotid plaque in patients with Homozygous FH who 
were receiving optimized LDL-lowering therapy.   
 
Moreover and remarkably CER-001 8 mg/kg transiently restored the population of HDL particles 
in patients with FPHA in the SAMBA study (17). Cholesterol mobilization was consequently 
increased along with fecal sterol excretion. CER-001 decreased inflammation in the carotid arteries. 
CER-001 treatment resulted in plaque regression in the carotids and aorta after 4 weeks of induction 
therapy and the effect was maintained over six months.  
 
The present study will evaluate the efficacy of 8 mg/kg dose of CER-001 as assessed by 3T-MRI 
aiming to confirm and validate the benefit on atherosclerosis previously observed in patients with 
FPHA.  
 
The dose and the dose regimen of the TANGO study are based on the previous positive SAMBA 
study that included an induction and a maintenance phase. 
 
6.3 End of the study 
 
The study will end when the last randomized patient completes the last assessment 4 weeks after 
the end of the treatment period. 
 
 
6.4 Number of patients and assignment to treatment group 
 
A total of 30 patients are planned to be randomized. Treatment groups include 8 mg/kg dose of 
CER-001 and placebo. Patients will be recruited over a planned recruitment period of 9 months. 
FPHA is a rare disease explaining the small number considered for this clinical study. The number 
of patients may slightly increase depending on the ability to find patients with FPHA and a clinical 
profile matching with the inclusion and exclusion criteria as defined in Section 7.  
 


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Considering the profile of patients targeted in this study, twice more patients will be randomized 
into the active 8 mg/kg dose of CER-001 group as compared to those patients who will be 
randomized into the placebo group - randomization in a 2:1 ratio.  
 
6.5 Centers & countries 
 
Approximately 15 sites from Europe, Canada, United States of America, Brazil and Israel will be 
involved in this study based on availability of identified patients with this rare disease. 
 
6.6 Safety extension protocol  
 
Patients having completed their last infusion 48 weeks after the first one will be offered to 
continue in the study for 6 months for safety follow-up.  
All patients who accept to continue will be treated with CER-001 8mg/kg whatever the 
randomization arm. A total of 12 infusions will be administered bi-weekly until week 72. A 3T-
MRI scan assessing the carotid and femoral artery will be optimally performed at this visit. 
A final safety visit will occur at week 76, 4 weeks after the last infusion. 
 
7 STUDY POPULATION 
7.1 Population to be studied 
 
Patients with ApoA-1 ≤ 110 mg/dL and HDL≤ 35 mg/dL with suspected homozygous or 
heterozygous mutation in the ABCA1, and/or ApoA-1 genes confirmed by genetic testing and 
background of symptomatic or asymptomatic cardiovascular disease, will be eligible for this study.  
Patients, who fulfill all inclusion/exclusion criteria, including confirmation of a genetic defect, may be 
enrolled in the study. 
7.2 Inclusion criteria 
 
A patient may be randomized if the answer to all of the following statements is “yes”. 
Demographic 
1. Male and female patients, aged 18 and above 
2. Female patients who are not either surgically sterilized (e.g., tubal ligation or removal of ovaries 
or uterus) or post-menopausal (no spontaneous menstrual periods for at least one year) must 
agree to use one of the following forms of contraception from screening until 90 days after the 
completion of the study medication: (1) systemic hormonal treatment (2) an IUD which was 
implanted at least 2 months prior to screening or (3) "double-barrier" contraception (condom, 
diaphragm and spermicide are each considered a barrier), or (4) agree to remain sexually 
abstinent during the entire study period (when contraception is not acceptable for cultural or 
religious beliefs) 
 


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Procedural 
3. Sign written informed consent after the scope and nature of the investigation have been 
explained to them before screening evaluations and willing to comply with the study restrictions 
4. Are fluent in the language of the investigator, study staff (including raters), and the informed 
consent 
 


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Clinical 
5. Diagnosis of genetically confirmed HDL-c deficiency due to defects in genes coding for e.g. 
ABCA1 and/or ApoA-1 
6.  
IF the subject is on lipid-lowering therapy or NEEDS to be treated with lipid-lowering therapy then 
the subject must be on a stable dose at least 6 weeks prior to the baseline procedures. 
7. Background symptomatic or asymptomatic cardiovascular disease should be present as such: 
- 
For symptomatic cardiovascular disease: i) history of cardio or cerebrovascular events, ii) 
diagnosed coronary artery disease (CAD), iii) diagnosed carotid or peripheral stenosis, iv) 
previous myocardial revascularisation - percutaneous coronary intervention (PCI), or 
coronary artery bypass graft (CABG). 
- 
For asymptomatic cardiovascular disease: patients with subclinical atherosclerosis 
diagnosed using imaging method such as i)vDoppler ultrasound, ii)vB-mode 
ultrasonography – measurement of carotid intima media thickness, iii)vintravascular 
ultrasonography, iv) Computed Tomography, v) Magnetic Resonance Imaging 
8. ApoA-1 ≤ 110 mg/dL 
9. HDL-cholesterol ≤ 35 mg/dL or 0.9 mmol/L 
 
7.3 Exclusion criteria 
 
Patients meeting any one of the following criteria are not eligible for the study: 
 
Medical Status 
1. Patient with LCAT mutation will be excluded  
2. Patient who experienced a cardiovascular event within 6 months prior to the onset of screening 
3. Patient who experienced stroke or other cerebrovascular event within 1 year prior to the onset 
of screening 
4. Patient with triglycerides level above 500 mg/dL 
5. The patient has evidence of clinically significant, uncontrolled or unstable cardiovascular, renal, 
hepatic (incl. AST or ALT at or above 3x ULN, or bilirubin at or above 2x ULN), 
gastrointestinal, hematologic, immunological, neurological, endocrine, metabolic or pulmonary 
disease (as determined by medical history, clinical laboratory or ECG results, or physical 
examination) or any other medical disorder that would increase the risk associated with taking 
study medication or would confound the interpretation of study results 
6. Patients with a body mass index (BMI) < 17 kg/m2 or > 40 kg/m2 
7. Patients with severe anemia defined as hemoglobin level below or equal to 10 g/dL 
8. Any clinically significant abnormal laboratory data, vital signs, physical examination at 
screening or baseline, which in the opinion of the investigator, would interfere with safety 
assessments 


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9. Clinically significant electrocardiogram (ECG) abnormality at screening, including sinus 
bradycardia (resting heart rate < 50 beats per minute), 2nd or 3rd degree atrioventricular block, 
prolonged QTc (QTcF ≥ 450 ms in males and ≥ 470 ms in females) history of congenital long 
QT syndromes, or risk of Torsades de Pointes because of family history of sudden death, etc. 
10. Positive result on the serum pregnancy test or are breast feeding at screening, or intend to 
become pregnant during the course of the trial 
11. Male intending to father a child during the study 
12. Likely to be unreliable as a study participant based on the Investigator's (or designee’s) 
knowledge of the patient (e.g., alcohol or other drug abuse, inability or unwillingness to adhere 
to the protocol, or psychosis)  
13. Symptomatic (NYHA Class II or greater) congestive heart failure requiring and persisting 
despite appropriate medical treatment  
14. Uncontrolled blood pressure: systolic blood pressure ≥160 mmHg and/or diastolic blood 
pressure ≥100 mmHg at screening or any other pre-randomization visit 
15. Uncontrolled diabetes mellitus defined as HbA1c >10% 
16. Unexplained creatine phosphokinase level > 3 times the ULN  
17. History of malignancy during the 3 years prior to screening, with the exception of basal cell 
carcinoma of the skin 
18. Current alcohol or drug abuse or history thereof within 5 years prior to screening 
19. Contraindication to MRI scanning such as imbedded metal (e.g., schrapnel), implanted metal 
objects (e.g., pacemaker), claustrophobia 
20. Participated in any investigational study or taken an investigational drug within 30 days (or 5 
times the half-life of the investigational drug, whatever is longer) 
21. Ever received CER-001within 6 month from the onset of screening 
22. Medically non-compliant in the management of their disease in the investigator’s opinion 
 
7.4 Concomitant Treatments 
 
Any medication the patient takes, other than study drugs specified by the protocol, is considered a 
concomitant medication. All concomitant medications must be recorded in the electronic case report 
form (eCRF). 
 
7.5 Prohibited Medication 
 
There are no excluded medications other than any other investigational drugs. 
 
7.6 Permitted Medication 
 
All medications that are considered medically necessary for maintenance of patient health are 
permitted during the study. Details of their use must be recorded on the concomitant medication 
page of the eCRF. 
 


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7.7 Monitoring of Patient Compliance 
 
All study therapy will be administered under direct observation. 
 
8 STUDY PROCEDURES 
 
A detailed schedule of assessments by visit is shown in Appendix A and Appendix B and a detailed 
description of assessments and procedures during screening, double-blind and open-labeled 
treatment is given below. 
 
8.1 Screening Examination and Eligibility Screening Form  
 
All patients must provide written informed consent before any study specific assessments or 
procedures are performed. An Eligibility Screening Form (ESF) documenting the investigator’s 
assessment of each screened patient with regard to the protocol’s inclusion and exclusion criteria is 
to be completed by the investigator. A screen failure log must be maintained by the investigator. 
 
Visit 1  
This is the first visit of the study. This visit will be performed after obtaining written informed 
consent. The investigator will advise the patient on heart healthy diet and life style. 
Screening assessments include: 
• 
Informed Consent 
• 
Inclusion/exclusion criteria 
• Demographic information 
• 
Smoking status 
• Measurement of height and body weight 
• Medical history/surgical history and concomitant diseases 
• 
Previous and concomitant treatments 
• Physical exam (See Section 8.8.1) 
• 
Vital Signs (See Section 8.8.2) 
• 
Blood Pressure and Heart Rate  
• 
ECG (See Section 8.8.3) 
• 
Serum biochemistry (See Section 8.8.4) 
• 
Hematology and coagulation (See Section 8.8.4) 
• Urinalysis (See Section 8.8.4) 
• 
Fasting lipid profile (See Section 8.9), including Apolipoprotein profile.  
• Anti-ApoA-1 antibody (See Section 8.8.5) 
• Markers of inflammation, oxidation, lipid metabolism and CV risk (See Section 8.10) 
• Serum pregnancy test in female patients (See Section 11.8) 
• 
FSH (only for women whose last menstrual period was between 6 and 12 months before 
screening) 
• 
Fasting blood glucose and HbA1c  
• Creatinine and/or BUN testing to determine GFR 


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Patient must have fasted (ie not to take any food or liquids other than water) for 8 hours prior to 
blood sampling. 
 
A DNA sample will be taken ONLY for determination of the presence of HDL gene mutations 
specifically for ABCA1 and/or ApoA-1 mutation(s) to ensure that the patient was to satisfy all 
inclusion and exclusion. Genotyping will be performed at the Robarts Research Institute, London, 
Canada. 
 
Following visit 1, if a patient is eligible according to all of the inclusion and exclusion criteria, 
he/she will be instructed to come in fasted for the randomization visit 2. 
 
8.2 Procedures for Enrollment of Eligible Patients and Assessment at Visit 2 
 
Once a patient has fulfilled all inclusion and exclusion criteria, he/she will be randomized at visit 2 
to receive CER-001 or placebo using an interactive voice response system (IVRS/IWRS). The 
investigator/designee will contact the IVRS/IWRS to randomize a patient for this study and will be 
given a patient number and a randomization number. The investigator or designee will use the eCRF 
with the assigned patient number and the IVRS/IWRS will automatically download the treatment 
allocation and randomization number as well as the patient number for the patient into the eCRF.  
The following assessments will be performed at visit 2 (V2): 
• Physical exam (See Section 8.8.1) 
• 
Blood Pressure and Heart Rate  
• 
Measurement of weight and vital signs (See Section 8.8.2) 
• ECG (See Section 8.8.3) 
• Blood samples for  
- 
Hematology and coagulation (See Section 8.8.4) 
- 
Serum chemistry (See Section 8.8.4) 
- 
Fasting lipid profile (See Section 8.9) 
- 
Markers of inflammation, oxidation, lipid metabolism and CV risk (See Appendix A) 
- 
Fasting blood glucose and HBA1c  
- 
Protein biomarker assessment  
• Urinalysis (See Section 8.8.4) 
• Pregnancy test 
• Previous and concomitant medication 
• Adverse events 
• Creatinine and/or BUN testing to determine GFR 
Patient must have fasted (ie not to take any food or liquids other than water) for 8 hours prior to 
blood sampling. 
 
The first 3T-MRI and the first 18FDG-PET/CT scan assessing the carotid and femoral artery will be 
optimally performed at this visit prior to the first infusion.  


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After all assessments have been performed the patient will be administered the first infusion as 
described in Section 9.6.   
 
He/she will stay for an additional hour after the infusion to ensure completion of the overall 
examination. A blood sample will be drawn two hours after initiation of the infusion to assess the 
pharmacokinetics of the study drug. 
 
8.3 Clinical Assessments and Procedures during the Double-blind Treatment Period  
 
Patients will visit the clinic each week for the first 8 weeks and every 2 weeks thereafter until the 
end of the treatment period (week 48) as described in Appendix A. At each visit, the patient will 
receive an infusion and will be checked for: 
• Adverse events 
• Previous and concomitant medications 
 
Complete assessments as described for visit 2 (see Section 8.2 above) will be performed 4 weeks 
and 8 weeks after randomization (at visit 6 and visit 10). Thereafter, patients will have complete 
assessments every 8 weeks until the end of the week 48 treatment period (at week 16, 24, 32, 40 and 
48).  Unless otherwise specified, blood and urine specimens will be collected prior to study drug 
dosing. 
 
Markers of inflammation, oxidation, lipid metabolism and CV risk (See Section 8.10) will be 
assessed at baseline, week 8, week 24 and week 48 (end of treatment). 
 
HBA1c assessment will be performed only at baseline (See Appendix A). 
 
Anti-ApoA-1 antibody assessment will be performed at week 8, week 24 and week 48 (end of 
treatment). 
 
Blood samples will be collected for biomarkers assessments at week 24. 
 
A blood sample will also be drawn two hours after initiation of the infusion to assess the PK, at 
week 24. 
 
Follow-up 3T-MRI will be done at the end of the induction treatment phase (week 8), week 24 and 
at the end of the overall week 48 treatment period. 
 
Follow-up  18FDG-PET/CT will be performed only once 24 weeks after randomization.  
 


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8.4 Clinical Assessments and Procedures during the Open-labeled Treatment Period  
 
Patients will visit the clinic every 2 weeks until the end of the treatment period (week 72) as 
described in Appendix B. At each visit, the patient will receive an infusion and will be checked for: 
• Adverse events 
• Previous and concomitant medications 
 
Follow-up 3T-MRI will be done at the end of the open-labeled phase (week 72). 
 
8.5 Safety Follow-up 
 
For patients treated until week 48:  
Patients will be instructed to fast prior to the visit. A safety follow-up for all patients will be 
conducted 4 weeks (+/- 7 days) after the final dose of study medication and will include, 
• Physical exam (See Section 8.8.1) 
• Blood Pressure and Heart Rate 
• Vital signs (See Section 8.8.2) 
• ECG (See Section 8.8.3) 
• Previous and concomitant treatments 
• Adverse Events 
• Urinalysis (See Section 8.8.4) 
• Blood samples for 
- 
Serum biochemistry (See Section 8.8.4) 
- 
Hematology and coagulation (See Section 8.8.4) 
 
For patients treated until week 72:  
A safety follow-up for the patients will be conducted by phone 4 weeks (+/- 7 days) after the final 
dose of study medication and will include:  
• Previous and concomitant treatments 
• Adverse Events 
 
 
8.6 Specific Imaging Assessments  
 
8.6.1 Assessment of Vascular Structure of the Carotid and Femoral with 3T-MRI 
 
Patients will have 3T-MRI imaging performed at Baseline, Week 8, Week 24, Week 48 and Week 
72 (optional) for carotid and femoral Mean Vessel Wall Area (MVWA) and carotid normalized wall 
index (NVWI) measurements. 
 
The baseline 3T-MRI can be done anytime during the screening period, before the randomization 
provided all other selection criteria are satisfied. 
 
All images will be collected for their review by an imaging expert, with a window of +/-7 days 
around the strict date. 
 


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The detailed procedure for performing and collecting of 3T-MRI images will be outlined in the 
Imaging Manual. 
 
8.6.2 Assessment of target (plaque) background (blood) ratio with PET/CT 
 
Patients will have two PET/CT scans with labelled glucose 18F-deoxyglucose at Baseline and Week 
24 only at the sites appropriately equipped.  
 
The baseline PET/CT scan can be done anytime during the screening period, before the 
randomization. 
 
All images will be collected for their review by an expert, with a window of +/-7 days around the 
strict date. 
 
The detailed procedure for performing and collecting PET/CT scans will be outlined in the Imaging 
Manual. 
 
8.7 Assessments and Procedures for Patients who Prematurely Discontinue Study 
Medication during double-blind treatment period 
Patients who withdraw from study medication should come to the site for a safety follow-up, 4 
weeks after the last dose: the same safety assessments as the ones planned for study completer’s 
week 52 visit (V31) should be performed.   
Additionally: 
• In case the study medication is stopped prematurely prior to week 24 (V18), a 3T-MRI 
should be performed as soon as possible after study drug discontinuation. If the patient 
agrees to stay in the study, he/she will be asked to come back at the site for full 
assessments as per protocol every 8 weeks until visit V30 and a last 3T-MRI will be 
performed at visit V30. 
• In case the study drug is stopped during the extension treatment period (i.e. after week 24 
(visit V18), patient should come back to the site for full assessments as per protocol every 
8 weeks until week 48 , a last 3T-MRI will be done at week 48. 
All AEs (related or not related) must be reported until the final study evaluation at visit V30 and 
thereafter only the SAEs likely to be related to the study drug or study procedures must be 
notified.   
8.8 Assessment of Safety  
 
During double-blind treatment period, all patients who receive at least one dose of study medication 
and have a subsequent safety evaluation will be included in the safety analyses.   
 
Safety assessments will include: 
• Physical exam 
• Vital signs assessments 
• Electrocardiogram (ECG) assessments  


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• Laboratory tests 
• Adverse events (AEs) 
• Metabolic parameters  
• Urinalysis 
• Anti-ApoA-1 antibody 
 
During open-labeled treatment period, all patients who receive at least one dose of CER-001 and 
have a subsequent safety evaluation will be included in the safety analyses.   
 
Safety assessments will include Adverse Events (AEs).  
 
8.8.1 Physical Exam 
 
The Investigator or qualified designee will perform a complete physical examination at Screening, 
Baseline, week 4, week 8 and every 8 weeks until the end of treatment. Additionally, a last physical 
examination will be done at the end of follow-up visit. Height will be collected at the screening visit 
only. The complete physical examination should include assessment of general appearance, 
HEENT/neck, pulmonary system, cardiovascular system, abdomen, extremities, musculoskeletal 
system, neurological system, and skin. Any findings that differ from the screening visit will be noted 
and if adverse and clinically significant, in the judgment of the Investigator, will be reported on the 
adverse event form. 
 
8.8.2 Vital Signs 
 
Temperature in degree centigrade and respiratory rate (RR) should be measured at the screening 
visit, randomization, at week 4, week 8 and every 8 weeks until the end of treatment. Additionally, 
assessment of vital signs will be done at the end of follow-up visit. Respiratory rate should be 
measured by counting the number of respirations for 30 seconds, and then multiplying by 2 in order 
to obtain the RR per minute. The patient’s pulse should be measured for 30 seconds, and then 
multiplied by 2 in order to obtain HR per minute. 
 
Blood pressure (BP) and heart rate (HR) should be measured at screening visit, randomization, pre-
infusion and post-infusion (after the post-infusion observation period prior to the patient leaving the 
clinic) at week 4, week 8 and every 8 weeks until the end of treatment. Additionally, a last BP 
assessment will be done at the end of follow-up visit. BP and HR measurements should be 
determined after the patient has been seated for at least 5 minutes. At the screening visit, the BP will 
be measured twice in each arm in order to determine the arm to use for subsequent measurement 
(unless a concomitant condition favors the use of a particular arm), using an appropriately sized 
cuff. The second BP measure should be taken at least 2 minutes following the first measure. The 
arm with the higher average systolic reading will then be used for single determinations of BP 
throughout the remainder of the study. If patient has a systolic blood pressure (SBP) reading of 
>160mmHg at time of randomization the Investigator, in consultation with the patient may measure 
again if able to randomize within the allowed window. 
 


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8.8.3 Electrocardiograms 
 
Protocol-specified ECGs will be acquired. 12 lead ECGs will be performed using equipment on site 
at screening visit, randomization, week 4, week 8 and every 8 weeks until the end of treatment. 
Additionally, a last ECG will be done at the end of follow-up visit. The Investigator will perform 
standard interpretations of all tracings with results documented in the appropriate source documents 
and CRFs.  
 
It is the responsibility of the Investigator to obtain additional ECGs required for the clinical 
management of the patient. All ECGs supporting any suspected MACE or other SAE/AE during the 
course of the study period, wherever performed, will be reported in the eCRF. 
 
8.8.4 Clinical Laboratory Tests 
 
Laboratory tests should be measured at the screening visit, randomization, at week 4, week 8 and 
every 8 weeks thereafter until the end of treatment. Additionally, laboratory tests will be done at the 
follow-up visit. Any blood sample collected according to the Schedule of Assessments (Appendix A) 
may be analyzed for any of the tests outlined in the protocol. This may also include, but is not limited 
to, investigation of unexpected results and incurred sample reanalysis. 
 
Clinical laboratory safety testing during the screening and treatment periods will be performed by a 
central laboratory. Collection kits, shipment instructions, and a detailed clinical laboratory manual 
will be provided to the study sites. Investigators are required to review the labs upon receipt and 
make a determination of clinical significance for labs outside of the normal range. All laboratory 
reports must be reviewed, signed and dated by a medically trained investigator. Clinical laboratory 
safety testing will consist of the following panels of laboratory tests. The details of which tests are 
performed at each visit can be found in Appendix A.  
 
CHEMISTRY PROFILE 
 
Glucose 
Blood Urea Nitrogen (BUN) 
Creatinine 
Total Bilirubin 
Indirect Bilirubin 
Aspartame Aminotransferase (AST/SGOT) 
Alanine Aminotransferase (ALT/SGPT) 
Alkaline Phosphatase 
Total Protein 
Albumin 
Lactate Dehydrogenase (LDH) 
Creatine Kinase (CK) 
Sodium 
Potassium 


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Chloride 
Carbon dioxide 
Uric Acid 
Calcium 
Phosphorous 
 
HEMATOLOGY 
 
White Blood Count 
Red Blood Count 
Hemoglobin 
Hematocrit 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Platelets 
 
URINALYSIS 
 
Microalbuminuria 
Specific Gravity 
pH 
Glucose 
Total Protein 
Ketones 
Total Bilirubin 
WBC 
RBC 
Casts 
 
The results of all laboratory tests required by the protocol will be documented and will be transferred 
to the study database via 21 CFR 11 compliant methodology. All clinically important abnormal 
laboratory tests occurring during the study will be repeated at appropriate intervals until they return 
either to baseline or to a level deemed acceptable by the Investigator and the Medical Monitor, or 
until a diagnosis that explains them is made.  
 
The criteria for determining whether an abnormal objective test finding should be reported as an 
adverse event are described in section 11.1. 
 
A serum pregnancy test will be done at screening visit only. Urinary pregnancy test will be used 
during the course of the study. 
 


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8.8.5 Immunogenicity Testing 
 
Specimen will be collected for anti-ApoA-1 antibody testing at the screening visit, week 8, 24 and 
end of treatment period. If patients have a positive result for the presence of neutralizing anti-ApoA1 
antibody at the end of treatment period visit, the patients must return monthly for testing until the 
antibodies return to screening value. Collection tubes will be supplied by the central laboratory as 
part of the visit specific kits for these visits. Collection, processing and shipment instructions will 
be located in the Laboratory Manual provided to the study sites. The clinical sites will send batch 
shipments of samples to the central laboratory monthly or sooner depending on local site 
requirements.  An aliquot for specimens that test positive for Anti-ApoA-1 antibody testing will be 
analyzed for neutralizing antibody activity.  
 
8.9 Assessment of Lipid Profiles   
 
Fasting* samples for the following lipid profile tests will be obtained at screening visit, baseline, 
week 8, week 24 and week 48: 
• Total Cholesterol 
• Unesterified Cholesterol 
• Esterified Cholesterol 
• LDL Cholesterol  
• HDL Cholesterol  
• Triglycerides 
• Phospholipids 
• Apolipoprotein A-1, Apolipoprotein B 
• Apolipoprotein profile 
 
*Patient must have fasted (ie not to take any food or liquids other than water) for 8 hours prior to 
blood sampling. 
Assessment of Lipid Profiles will be performed by a central laboratory. Instructions for the 
collection, storage and shipment of lipid profile samples will be included in the laboratory manual. 
There will be no data reporting to the Investigator or the Sponsor for lipid profiles prior to database 
lock with the exception of screening triglyceride values and any triglyceride value greater than 1000 
mg/dL. 
 
8.10 Assessment of Markers of Vessel Wall Biology  
 
Blood samples will be obtained at screening visit, baseline, week 8, week 24 and week 48 visits to 
analyse markers on vessel wall biology including and not restricted to laboratory variables such as 
absolute and relative change in high sensitivity C-reactive protein (hs-CRP), PON-1, MMP-9 and 
other selected inflammatory markers (TNFα, IL-6), soluble VCAM-1 , sMCP1, Oxysterols (FACS 
Analysis), ABCA1 mRNA and protein levels (Monocytes).   
Instructions for the collection, storage and shipment of samples will be included in the laboratory 
manual. 


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8.11 Assessment of Cellular Cholesterol Efflux  
 
Blood samples will be obtained at screening visit, baseline, week 8, week 24 and week 48.  At 
infusion visits, samples should be drawn 2 hours after the start of the infusion. 
 
8.12 Assessment of Biomarkers   
 
Plasma samples will be obtained at baseline and week 24. 
 
Instructions for the collection, storage and shipment of samples will be included in the laboratory 
manual. 
 
8.13 Efficacy Assessment of Procedures   
 
8.13.1 Primary Efficacy Parameters 
 
The primary efficacy parameter of this study will be the change from baseline after 24 weeks 
treatment with CER-001 on carotid Mean Vessel Wall Area (MVWA) as compared to placebo using 
3T-MRI when administered to patients with FPHA. 
 
8.13.2 Secondary Efficacy Parameters 
 
The secondary efficacy parameters will be to evaluate the:  
• Change from baseline after 8 week and 48 week treatment with CER-001 on carotid Mean 
Vessel Wall Area (MVWA) as compared to placebo using 3T-MRI when administered to 
patients with genetically defined FPHA  
• Change from baseline after 8, 24 and 48 week treatment with CER-001 on femoral artery as 
compared to placebo using 3T-MRI when administered to patients with genetically defined 
FPHA 
• Change from baseline at 24 weeks in the target (plaque) to background (blood) ratio (TBR) 
from an index vessel (either right carotid or left carotid) based on the standardized 18FDG 
uptake measured with PET/CT in patients with genetically defined FPHA. 
8.13.3 Exploratory Efficacy Parameters 
 
• 
Evaluate the effect of treatment with CER-001 in patients with genetically defined Familial 
Primary Hypoalphalipoproteinemia (FPHA) with respect to other efficacy measurements 
including carotid artery and carotid normalized wall index using 3T-MRI 
• 
Evaluate the effect of treatment with CER-001 in patients with genetically defined Familial 
Primary Hypoalphalipoproteinemia (FPHA) with respect to potential markers on vessel wall 
biology including and not restricted to laboratory variables such as absolute and relative 
change in high sensitivity C-reactive protein (hs-CRP), MMP-9 and other selected 


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inflammatory markers (TNFα, IL-6), PON-1, soluble VCAM-1 and sMCP1, plaque 
characterization indexes using 3T-MRI 
• 
Evaluate Plasma-mediated cellular Cholesterol efflux capacity. 
 
8.13.4 Other Efficacy Parameters 
 
• Change from baseline after 72 week treatment with CER-001 on carotid Mean Vessel Wall 
Area (MVWA) using 3T-MRI when administered to patients with genetically defined FPHA  
• Change from baseline after 72 week treatment with CER-001 on femoral artery using 3T-
MRI when administered to patients with genetically defined FPHA 
 
 
8.14 Safety Assessments 
 
8.14.1 Primary safety parameter 
 
The primary safety parameter will be to: 
• Evaluate safety and tolerability of CER-001 administered for 24 weeks 
 
8.14.2 Secondary safety parameters 
 
The secondary safety parameter will be to: 
• 
Evaluate safety and tolerability of CER-001 administered for 48 weeks 
 
Safety parameters will also be evaluated as secondary endpoints and will include: 
• Incidence and severity of AEs from routine monitoring 
• Incidence of abnormalities and changes from baseline in clinical laboratory parameters 
from testing of blood and urine, including antibody development 
 
8.14.3 Other safety parameters 
 
Other safety parameter will be to: 
• 
Evaluate safety and tolerability of CER-001 administered for 72 weeks 
 
Safety parameters will include: 
• Incidence and severity of AEs from routine monitoring. 
 
 
8.15 Protein Biomarker Study   
 
Specimens for protein biomarker discovery and validation will be collected from all patients. These 
specimens will be used for research purposes ONLY to identify and/or verify biomarkers that are 


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linked to CER-001 treatment and could help to understand the pathogenesis, course and outcome of 
the disease of the targeted patient population. These samples will be used to measure soluble serum 
proteins that could potentially correlate with response to treatment with CER-001. Identification of 
patient subgroups with an increased or decreased response to therapy (homozygous versus 
heterozygous mutations in ABCA1 and/or APOA-1 gene) may provide information of significant 
clinical value to guide treatment decisions and aid in the appropriate use of the therapy.  
 
For sampling procedures, storage conditions and shipment instructions see laboratory instruction 
manual. These specimens will be stored for 5 years and then destroyed.  
 
8.16 Pharmacokinetic (PK) parameters    
 
Two PK samples will be taken 2h after starting the infusion administration, after the first infusion 
administration (V2) and at Week 24 (V18). 
 
9 INVESTIGATIONAL MEDICINAL PRODUCT 
 
9.1 Dose and Schedule of Test “Drug” and Placebo 
 
Patients will be administered 8 mg/kg dose of CER-001 or a matching placebo infusion once weekly 
for 8 weeks and every 2 weeks thereafter. Study medication will be administered at the site by 
qualified staff.  
 
9.2 Pharmaceutical Properties and Formulation 
 
The study drug, CER-001 Sterile Solution for Infusion, is a solution of the ApoA-1/phospholipid 
complexes in phosphate-buffered solution with sucrose and mannitol. The calculated concentration 
of CER-001 complexes is based on protein content (8 mg/mL). The CER-001 Sterile Solution for 
Infusion is filled into 20 mL glass serum vials (17.2 mL minimum extractable volume), stoppered 
with grey butyl rubber stoppers and sealed with aluminium crimp seals. 
 
Study drug product will be diluted with normal saline to accommodate the dosing range. CER-001 
solution will be supplied and stored frozen, to be thawed and diluted prior to administration at the 
study site. Thawing and dilution procedures will be detailed in a Pharmacy Manual for the study. A 
general description of CER-001 product is provided in Table 1. 
 


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Table 1 Pharmaceutical Properties of CER-001 
International Non-Proprietary Name 
(INN) 
Recombinant human apolipoprotein A-1 
United States Adopted Name (USAN) 
To be determined 
CAS Number 
1383435-67-3 
Laboratory Code 
CER-001 
Description (Drug Substance) 
 
Protein/phospholipid complex containing a 
1:2.7 weight to weight ratio of recombinant 
human ApoA-1 to phospholipids (97% 
Sph, 3% DPPG) 
Physical Form (Drug Product) 
Solution of the ApoA-1/phospholipid 
complexes in phosphate buffered solution 
with sucrose and mannitol (10 mM 
phosphate buffer, 4 % sucrose, 2% 
mannitol, pH 8.0). Protein content 
8mg/mL. 
External Appearance 
Frozen solution (17.2mL extractable 
volume) in 20 mL glass vials with 20 mm 
gray butyl rubber stoppers, sealed with 
20mm aluminium crimp seals with red flip-
off caps 
Storage Conditions 
Store frozen at -15C to -25C; thaw before 
administration.  A matching placebo of 
normal saline will also be supplied. 
 
9.3 Placebo  
 
Placebo, standard sodium chloride solution, is provided as a 250 mL solution for infusion similar in 
volume to the active treatment solution study.  
 
9.4 Packaging and Labelling  
 
The packaging and labelling for all study medication will be performed by Catalent Pharma 
Solutions for Cerenis Therapeutics and will comply with local applicable regulations. Labelling 
requirements for the dispensed IV containers will be specified in the Pharmacy Manual. 
 
9.5 Medication Dispensing and Administration  
 
The Investigator will administer the study medication only to patients included in this study 
following the procedures set out in the study protocol. Each patient will be given only the study 
medication assigned by the randomization system. All dispensing will be documented in the eCRF 
and other study drug records. 


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9.6 Method of Administration  
 
CER-001 is provided as a frozen solution in 20 mL vials containing at least 17.2 mL of product at 
a concentration of 8 mg/mL (ApoA-1 content).  
 
CER-001 will be constituted into an IV dosing solution by the Study Pharmacist or designee by 
diluting with normal saline. All doses will be diluted with normal saline to a volume of 250 mL and 
will be administered over a one-hour period using an infusion pump at a fixed rate of 250 mL/hr. 
Study drug administration may be extended up to a period of 120 minutes if deemed medically 
necessary for the patient by the Investigator (e.g. concern for fluid overload). Reasons for 
administration periods greater than 60 minutes must be properly documented. Patients should be 
observed for a minimum of 15 minutes following the infusion. 
 
Placebo, standard 250 mL sodium chloride solution, is provided and will be administered over a 
one-hour period using an infusion pump at a fixed rate of 250 mL/hr.  
 
Patients should be observed for a minimum of 15 minutes following the infusion. 
 
The Study Pharmacist or designee will dispense the appropriate concentration and volume of 
solution for each patient, based on his/her weight at Screening. The infusion bag and drip set will 
be sent from the pharmacy with the infusion bag shrouded with a bag to maintain the blind.  
 
9.7 Additional Supplies Provided by Sponsor 
 
IV bags, tubing and infusions pumps will be supplied by the sponsor as necessary. 
 
 9.8 Investigational Product Accountability  
 
The Investigator or designee must maintain accurate and adequate records including dates of receipt 
and return of drug shipments, lot number (if available), and quantities received/returned, as well as 
dates and amounts administered, and returned by the study site. 
 
All vials, empty, partial, or full, must be returned. The study site must ensure that unused supplies 
remain in their original containers as provided by Catalent Pharma Solutions for Cerenis 
Therapeutics and that the label is intact and unobliterated. The “Clinical Returns Authorization 
Form” contains a specific return shipping address and instructions. 
 
9.9 Randomization 
 
After obtaining written informed consent, completing screening procedures, and ensuring the patient 
meets all of the inclusion criteria and none of the exclusion, the patient will then be randomized. 
Stratification according to the genetic mutation will be done to ensure appropriate balanced 


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distribution of the mutations across treatment groups. The patient will be randomized to receive 29 
infusions of either active drug or placebo; 2:1 randomization scheme will be used as indicated in 
section 6.1. 
 
9.10 Treatment Blinding 
 
Study drug will be dispensed by an unblinded Study Pharmacist or designee. Study drug blinding 
to the Investigator and all other staff at site will be achieved by shrouding the IV container with an 
opaque bag, sealed by the pharmacist. Any labelling necessary for administration will be affixed 
both to the IV container and to the shroud itself. The Study Pharmacist will be responsible for 
ensuring consistency of the labels. After administration, the infusion bag will be returned within its 
shroud to the pharmacy. After the last patient completes the final visit, the database will be cleaned 
and locked after this data is entered, and the data will be unblinded and analyzed for all primary and 
secondary efficacy and safety parameters.  
 
9.11 Maintaining the Blind 
 
Study drug will be dispensed by an unblinded Study Pharmacist or designee who will be unblinded 
as described in Section above (Section 9.10). The study patients, Investigator, sponsor and study site 
personnel and site monitors will remain blinded to the treatment. During the study, and prior to 
database lock, no lipid profile data will be reported to the Investigator or to the Sponsor. Data will 
be reviewed in a blinded manner. 
 
Randomization list is kept strictly confidential, accessible only to authorized persons, until the time 
of unblinding. It is the responsibility of the Pharmacist to maintain the blind throughout the study.  
 
The randomization code may be broken if an emergency situation arises that in the Investigator’s 
opinion requires the knowledge of the code (for example, life threatening situation or necessity to 
know the product administered to provide with the best medical care). The investigator must do 
his/her very best to contact the Sponsor before unblinding the code using an Interactive Web 
Response System (IWRS). Date, time, and reason(s) for breaking the code must be recorded by the 
Investigator in IWRS.  
 
At the conclusion of the trial, the occurrence of any emergency code breaks will be verified after 
return of all code break reports and unused drug supplies to the packaging supplier.  
 
The CRO mandated for pharmacovigilance reserves the right to break the blind for SAEs which are 
considered as related to the study drug and unexpected, which could require an expedited report to 
the regulatory authorities. 
 
9.12 Withdrawal From Study Participation 
 
Reasons for withdrawal from study drug may include, but are not limited to, the following: 


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• Investigator's request, for safety reasons, such as severe adverse reactions 
• Investigator’s request, for other reasons, such as patient non-compliance 
• Patient’s request, for tolerability reasons 
• Patient’s request, for other reasons, such as withdrawal of informed consent 
 
Discontinuation of study drug alone does not constitute discontinuation or withdrawal from the 
study. 
 
Patients should continue to be followed as though they had completed the treatment phase. Patients 
who prematurely discontinue study medication are to be followed as described in the section 8.7. 
 
All premature study discontinuations and their causes must be carefully documented by the 
Investigator. 
 
A discontinuation occurs when an enrolled patient ceases participation in the study, regardless of 
the circumstances, prior to completion of the final protocol procedures. The Investigator must 
determine the primary reason for discontinuation. Withdrawal due to an adverse event should be 
distinguished from withdrawal due to other reasons according to the definition of adverse event (See 
Section 11.1). A discontinuation must be reported immediately to the Sponsor (or designated 
representative) if it is due to a serious adverse event (see Section 11.5). 
 
If a patient discontinues treatment, the Investigator will record the reason for study drug 
discontinuation, provide or arrange for appropriate follow up for such patients, and document the 
course of the patient's condition during the appropriate follow up period on the follow up contact 
eCRF. 
 
Patients who withdraw consent and refuse to return for subsequent visits, if consent to, will 
be contacted by telephone within 30 days following last study drug administration to assess 
their current health status. It is imperative that all patients are accounted for at the conclusion 
of the trial. 
10 TREATMENT OF PATIENTS 
 
10.1 Study Drug Administration 
 
The first dose administration will occur at the randomization, first infusion visit (visit 2), and weekly 
scheduled visits for the first nine doses induction period. During the maintenance and extension 
periods, dosing will occur every 2 weeks for the following twenty doses until the end of the week 
48 treatment period.  
 
At each of these visits, patient will be given a single intravenous infusion of either placebo or CER-
001 (8mg/kg) over a one hour period. Dosing procedures are specified in Section 9.6 (Method of 
Administration). 


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10.2 Interruption or Discontinuation of Study Medication 
 
Patients may be interrupted or discontinued from study medication if any of the following occur: 
1. Any drug-related adverse event or other reason which, in the Investigator's opinion, will 
jeopardize the patient's participation in the trial or the interpretation of trial data (e.g., severe 
inter-current illness requiring additional care measures or preventing further dosing)  
2. Significant tolerability issues 
 
At the time of study medication interruption, the study site will document in the eCRF the reason 
for drug discontinuation. The patient should continue to be followed clinically and all attempts 
should be made to re-institute study medication within 21 days of the study drug interruption if not 
otherwise contraindicated. Study medication may be re-instituted at the initial dose level, or by using 
a dose reduction scheme as outlined in the following section. 
 
10.3 Dose Adjustments of Study Medication 
 
The Principal Investigator will liaise with the Medical Monitor in relation to potential dose 
reductions. At the discretion of the Medical Monitor, the dose of study medication may be 
temporarily or permanently reduced any time after administration of the initial dose (Visit 2). 
Reasons for dose reduction may include but are not limited to significant tolerability issues. 
 
Dose reductions will always be 50% of the previously administered dose level. Dose reduction may 
be performed up to two times, i.e. 25% of the original dose. 
 
Dose reduction will be accomplished by preparation of a reduced dose by the Study Pharmacist. 
Reduced doses will still consist of a total of 250 mL of study drug solution to be administered over 
60 minutes. Complete instructions for preparation of reduced doses will be contained in the 
Pharmacy Manual. 
 
The investigator may increase the patient dose back up to the prescribed dose in consultation with 
the studies medical monitor. All dose increases should be accomplished by doubling the previously 
administered dose. In no case should the patient receive a dose greater than the prescribed dose. 
 
 


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11 SAFETY MONITORING 
 
11.1 Definitions 
 
Adverse Event (AE):  An adverse event is any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily have a 
causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom or disease temporally associated with the use 
of a medicinal (investigational) product, whether or not considered related to the medicinal 
(investigational) product. Pre-existing conditions which worsen during a study are to be reported as 
AEs. 
 
In clinical studies, an AE can include an undesirable medical condition occurring at any time, 
including screening or wash-out periods, even if no experimental treatment has been administered.  
 
Treatment Emergent Adverse Events (TEAE): Treatment emergent adverse events are defined 
as adverse events which occur during or after the administration of the first dose of the 
investigational medicinal product (IMP) or if present before the first administration of IMP, worsen 
on study treatment. 
 
Adverse Drug Reaction (ADR): An adverse drug reaction is any untoward and unintended 
response to a medicinal product related to any dose administered. 
 
Unexpected Adverse Drug Reaction: Any adverse drug reaction the nature, severity or outcome 
of which is not consistent with the applicable product information. 
 
In this study, the reference document to be used to evaluate the unexpectedness of the adverse drug 
reactions consists in section 5.7 Possible Adverse Reactions” of the Investigator's Brochure (most 
recent version). 
 
Events involving illnesses with onset during the study, or exacerbation of pre-existing illnesses 
should be recorded as adverse events. Exacerbation of pre-existing illness is defined as a 
manifestation (sign or symptom) of the illness that indicates a significant increase in the severity of 
the illness as compared to the severity noted at the start of the trial. It may include worsening or 
increase in severity of signs and symptoms of the illness, increase in frequency of signs and 
symptoms of an intermittent illness, or the appearance of a new manifestation/complication. 
Exacerbation of a pre-existing illness should be considered when a patient requires new or additional 
concomitant drug or non-drug therapy for the treatment of that illness during the trial. In addition, 
clinically significant changes in physical examination findings and abnormal objective test findings 
(e.g., laboratory, x-ray, ECG) should also be recorded as adverse events. 
 


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Laboratory test abnormalities & follow-up 
Laboratory test results will be recorded on the laboratory results eform of the eCRF, or appear on 
electronically produced laboratory reports submitted directly from the central laboratory, if 
applicable.  
Any treatment-emergent abnormal laboratory result which is clinically significant, i.e., meeting one 
or more of the following conditions, should be recorded as a single diagnosis on the AE form in the 
eCRF: 
• Accompanied by clinical symptoms 
• Test result requiring additional diagnostic testing or medical/surgical intervention,  
• Leading to a change in study medication (e.g. interruption or permanent discontinuation) 
• Requiring a change in concomitant therapy (e.g. addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy or treatment). 
  
This applies to any protocol and non-protocol specified safety and efficacy laboratory result from 
tests performed after the first dose of study medication, which falls outside the laboratory reference 
range and meets the clinical significance criteria. 
This does not apply to any abnormal laboratory result which falls outside the laboratory reference 
range but which does not meet the clinical significance criteria (these will be analyzed and reported 
as laboratory abnormalities); those which are considered AEs of the type explicitly exempted by the 
protocol; or those which are a result of an AE which has already been reported. 
In the event of medically significant unexplained abnormal laboratory test values, the tests should 
be repeated and followed up until they have returned to the normal range and/or an adequate 
explanation of the abnormality is found. If a clear explanation is established it should be recorded 
on the eCRF. 
 
11.2 Adverse Event Severity Rating  
 
The severity of an AE will be assessed according to the following scale: 
• Mild: Awareness of sign or symptom, but easily tolerated 
• Moderate: Discomfort enough to cause interference with usual activity 
• Severe: Incapacitating with inability to work or perform usual activity 
 
11.3 Relationship to Study Drug 
 
The Investigator should assess the relationship of an AE to study drug according to the following 
definitions: 
 
Not related: 
1. The existence of a clear alternative explanation (e.g., mechanical bleeding at surgical site) 
or  
2. Non-plausibility, e.g., the patient is struck by an automobile or cancer developing a few days 
after drug administration.  
 


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Unlikely (remote):  
A clinical event, including laboratory test abnormality (if applicable), with an improbable time 
sequence to drug administration and in which other drugs, chemicals or underlying disease provide 
plausible explanations. 
 
Possible:  
A clinical event, including laboratory test abnormality (if applicable), with a reasonable time 
sequence to administration of the drug, which could also be explained by concurrent disease or other 
drugs or chemicals.  
 
Probable: 
 A clinical event, including laboratory test abnormality (if applicable), with a reasonable time 
sequence to administration of the drug, unlikely to be attributed to concurrent disease or other drugs 
or chemicals, and which follows a clinically reasonable response on withdrawal.  
 
Definite: 
 A clinical event, including laboratory test abnormality (if applicable), for which there is no 
uncertainty in the relationship to test product administration (e.g., positive recalling). 
 
11.4 Adverse Event Reporting 
 
All observed or volunteered adverse events occurring during the study period, at any time from the 
signature of the informed consent until the final study evaluation, regardless of treatment group or 
suspected causal relationship to study drug, will be recorded on the adverse event page(s) of the 
eCRF.  
 
The need to capture this information is not dependent upon whether the adverse event is considered 
to be related to the use of the study drug. Also, adverse events resulting from concurrent illnesses 
and reactions to concurrent medications must be reported. In order to avoid vague, ambiguous, or 
colloquial expressions, the AE will be recorded using standard medical terminology rather than the 
patient’s own words. 
 
Each AE should be described in detail in the eCRF: nature of the event (a sign, a symptom or a 
diagnosis preferably), onset and stop dates, severity, relationship to study drug, seriousness (see 
below Section 11.5), action taken including corrective therapy and outcome.  
 
AEs that are believed to be at least possibly related to study drug should be followed until 
satisfactory resolution or acceptable stabilization. 
 
For all AEs, the Investigator must pursue and obtain the necessary information both to determine 
the outcome of the adverse event and to assess whether it meets one of the criteria for classification 
as a serious adverse event requiring immediate notification to the PV Department of ICTA PM 
(see Section 11.5). For all AEs, sufficient information should be obtained by the Investigator to 
determine the causality of the adverse event (e.g., study drug or other illness).  


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11.5 Serious Adverse Events  
 
11.5.1 Definition 
 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 
1. Results in death; 
2. Is life-threatening; 
3. Results in patient’s hospitalization or prolongation of existing hospitalization; 
4. Results in a persistent or significant disability/incapacity; or 
5. Results in congenital anomaly/birth defect 
6. Is a medically significant event 
 
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is a suspected adverse event 
considered as related to the study drug and which is both unexpected and serious. 
 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered as serious adverse events when, based upon appropriate medical judgment, they 
may jeopardize the patient or may require medical or surgical intervention to prevent one of the 
outcomes listed above. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in patient hospitalization, or the development of drug dependency or drug abuse.  
 
A life-threatening adverse event is any adverse event that places the patient at immediate risk of 
death from the reaction as it occurred (e.g., it does not include a reaction that, had it occurred in a 
more severe form, might have caused death). 
 
Initial hospitalization is defined as any inpatient admission (even if less than 24 hours). For chronic 
or long-term in patients, inpatient admission also includes transfer within the hospital to an 
acute/intensive care inpatient unit (e.g., from the psychiatric wing to a medical floor, from a medical 
floor to the coronary care unit, from the neurological floor to the tuberculosis unit). 
 
Inpatient admission in the absence of a precipitating, treatment-emergent, clinical adverse event 
may meet criteria for “seriousness”, is not considered as an adverse event and thus is not subject to 
immediate reporting. For example: 
 
1. Admission for treatment of a pre-existing condition not associated with the development of 
a new adverse event or with a worsening of the pre-existing condition (e.g., for work-up of 
persistent pre-treatment lab abnormality) 
2. Social admission (e.g., patient has no place to sleep) 
3. Administrative admission (e.g., for yearly physical exam) 
4. Protocol-specified admission during a clinical trial (e.g., for a procedure required by the 
study protocol) 


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5. Optional admission not associated with a precipitating clinical adverse event (e.g., for 
elective cosmetic surgery). 
 
The following events are neither considered as inpatient admission nor serious adverse events: 
1. Emergency Room/Accident and Emergency/Casualty Department visits 
2. Outpatient/same-day/ambulatory procedures 
3. Observation/short-stay units 
4. Rehabilitation facilities 
5. Hospice facilities 
6. Respite care (e.g., caregiver relief) 
7. Skilled nursing facilities 
8. Nursing homes 
 
11.5.2 Reporting 
 
Any SAE, occurring during the study period, at any time from the signature of the informed consent 
until the final study evaluation, regardless of treatment group or suspected causal relationship to 
study drug, must be reported by the investigator within 24 hours from the date of the first awareness 
to: 
the PV Department of ICTA PM 
by email to pharmacovigilance@icta.fr (or by fax: +33 380 539 110) 
 
The Investigator (principal investigator or any other investigator designed by the principal 
investigator as authorized to notify safety issues) will be requested to complete and sign a separate 
SAE report form in addition to the information recorded on the adverse event page of the eCRF.  
All available information concerning the SAE (copies of laboratory results, other exams, 
hospitalization reports, autopsy report and other appropriate documents) will be transmitted 
anonymously with the SAE report form. 
 
Any laboratory result abnormality fulfilling the criteria for a SAE should be reported as such, in 
addition to being recorded as an AE in the eCRF. As soon as the diagnostic term for the laboratory 
result abnormality is available, the SAE report should be updated to include the diagnosis as event 
term, if possible. 
 
In case of SUSAR, the Sponsor or its representative will be responsible for their notification to the 
relevant regulatory authorities as outlined in the ICH Guidelines. All investigators participating in 
studies of CER-001 will also be informed as required by regulations.  
 
11.5.3 Follow-up of Serious Adverse Events 
 
For any new information relating to an already notified SAE, the investigator will have to complete 
a SAE Follow-up report which will be transmitted by fax/email, within 24 hours, to the PV 
Department of ICTA PM to pharmacovigilance@icta.fr (or by fax: + 33 380 539 110) 


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accompanied with anonymized copies of the applicable laboratory results, other exams and/or the 
hospitalization reports. 
The reporting of the follow-up information will be done in the same manner as initial SAE reports. 
Any SAE, regardless of the causal relationship to the study drug, must be followed until satisfactory 
resolution or stabilization (in case of sequelae) of the event. This can sometimes mean that the 
follow-up continues after the patient study termination. Satisfactory resolution may include referral 
to the patients usual care provider. 
 
11.5.4 Serious Adverse Events occurring after the study 
 
All SAEs occurring at any time after the end of the study, likely to be related to the study drug or to 
a study procedure, according to the investigator, must be notified according to the process for SAE 
reporting described above. 
 
11.6 Expected Adverse Drug Reactions 
 
CER 001 has previously been administered to humans in single doses ranging from 0.25 to 45 
mg/kg.  No treatment related AE were reported in that single dose study.  In the completed multiple 
dose studies the adverse event profile has been consistent with what would be expected from the 
experience of Phase I and Phase II studies and from treating these populations of patients.  
 
AEs that would be reasonable to expect based on repeat dosing in animal toxicity studies include 
increased liver enzymes, and changes to red blood cell indices although these have not been 
observed with single or multiple human doses at a rate higher than that observed with placebo.  
Other AEs that may be anticipated are local injection site reactions and allergic responses.  These 
reactions may include one or more of the following symptoms: wheezing, eye itching, eye swelling, 
facial swelling, rash , feeling cold, decrease in body temperature, cold sweat, cold shivers , chest 
pressure, chest pain, jaw pain, decreased blood pressure, increased blood pressure, fatigue, 
dizziness, headache, nausea, vomiting, stomach pains, and diarrhea.  
 
11.7 Liver and kidney expected adverse reactions which may lead to drug withdrawal 
 
To date, there have been no significant laboratory abnormalities associated with the use of CER-
001 in humans, however toxicology studies in mice and monkeys indicate that liver and kidney are 
possible target organs for toxicity.   
 
Specific requirements for hepatic and renal abnormalities are detailed below. 
 


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Hepatic Stopping Criteria: 
In the case of Liver Function Test elevation > 3xULN, additional workup may be required within 
24 hours of the event by the investigator in close consultation with the Sponsor according to 
established protocols. This is to rule out possible cases of Hy’s law. 
Patients should have dosing withheld if the most recently obtained serum ALT or AST exceeds five 
times the upper limit of normal.  If the most recently obtained serum ALT or AST elevation is 
greater than the upper limit of normal but less than five times the upper limit of normal, the patients 
may receive their next dose, which may be reduced in consultation with the Sponsor (see Section 
10.3 for more details). 
Discontinuation criteria: 
Any of the following findings should prompt discontinuation from study drug: 
- First observation of ALT or AST >8xULN 
- ALT or AST >5xULN for more than 2 weeks 
- Any case of Hy's Law (i.e., ALT or AST >3xULN and TBL >2xULN or jaundice) 
All Hy's Law cases (i.e., ALT or AST >3xULN and TBL >2xULN or jaundice) have to be reported 
as adverse events.  
 
Re-challenge following discontinuation of study drug for either aminotransferase elevations or for 
potential or confirmed Hy's Law cases must not be attempted under any circumstances, unless a 
decision about re-challenge has been endorsed by the Sponsor. 
 
Renal Stopping Criteria: 
Special attention will be paid to: 
1. Unexplained serum creatinine values greater than: 
a. two times the upper limit of the normal range at two consecutive test points following 
dosing; or 
b. one and one half (1.5) times the upper limit of the normal range at three consecutive 
test points following dosing or 
2. Creatinine Clearance ≤ 30mL/min. 
 
Creatinine clearance will be measured from serum creatinine based on the Cockcroft-Gault formula: 
 
CrCl = [ 140 – age (years)] x weight (kg) (x 0.85 for female patient) 
[72 x serum creatinine (mg/dL)] 
 
If the study drug is thought to have caused the abnormalities, the Investigator may elect to 
discontinue study drug dosing. The cause should be thoroughly documented in the patient record. 
Such renal impairments should be reported as adverse events. 
 


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11.8 Pregnancy  
 
If a patient becomes pregnant during the treatment period of the study or within 15 weeks after the 
last dose of study drug, the pregnancy must be reported.  
 
If the pregnancy occurs during the treatment period, the study drug should be discontinued. 
Pregnancy itself is not an AE; however pregnancies must always be followed until completion or 
until pregnancy termination (i.e. induced abortion) and the outcome must be notified to the Sponsor 
or its representative.  
 
The Investigator will be provided with a Pregnancy Report Form. This form must be completed and 
sent to the PV Department of ICTA within 24 hours of awareness. If the outcome of the 
pregnancy meets the criteria for a SAE (i.e. spontaneous miscarriage, congenital anomaly) the 
investigator must follow the procedures for SAEs reporting. Any complications occurring during 
pregnancy will be recorded as AEs and/or SAEs. 
 
If the partner of a male patient becomes pregnant during the treatment period of the study or within 
the 15 weeks following the last dose of study drug, this should be reported to the investigator.  
 
A specific informed consent will be provided to allow the collection of data concerning the follow-
up and outcome of the pregnancy of the patient’s partner.  
 
Reporting and follow-up of the partner pregnancy will be done as mentioned above. 
 
11.9 Data Safety Monitoring Board (DSMB) 
 
The Data Safety Monitoring Board (DSMB) will formally review study safety data to ensure there 
is no avoidable increased risk for harm to patients. The DSMB will meet no less frequently than 3 
times per year, with additional meetings at the discretion of the DSMB based on the review of 
ongoing data and observations. Analyses for the DSMB will be provided by the CRO mandated by 
Cerenis.  
 


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12 STATISTICS 
 
12.1 Statistical Methods 
 
Data will be analyzed by the mandated CRO.  All cases will be checked for consistency and 
completeness by the Data Management Department of the mandated CRO. 
 
Demographic and other baseline characteristics will be summarized across all randomized patients. 
Baseline is defined as the last observation for any given parameter prior to the first infusion of study 
drug.  Comparability at baseline among treatment groups will be assessed using descriptive statistics 
without formal statistical tests. 
 
The statistical techniques that are proposed in the sections below require certain assumptions.  These 
assumptions will be checked for validity, and if they are not tenable, then appropriate statistical 
procedures will be utilized to complement the proposed procedures.  Further detail on the statistical 
analysis is provided in the TANGO Statistical Analysis Plan (SAP) and decisions about analysis 
methods based on distribution assumptions will be documented in a review of the data before 
unblinding. 
 
12.2 Efficacy Assessments 
 
12.2.1 Primary Efficacy Analysis  
 
The primary efficacy parameter of this study will be the change from baseline to 24 weeks in carotid 
MVWA in all randomised patients. 
The primary efficacy endpoint, difference in the change from baseline in carotid artery Mean Vessel 
Wall Area (MVWA) at 24 weeks in patients treated with CER-001 compared to patients treated 
with placebo, will be analysed by an analysis of covariance (ANCOVA) model that includes 
treatment group and baseline MVWA as well as ABCA-1 or ApoA-1 genetic mutation as a 
covariate. Adjusted means for the change in MVWA in each treatment group and the difference 
between CER-01 and placebo will be provided, along with a 95% confidence interval.  
Results (in terms of 95% confidence intervals for treatment effects) will also be presented for each 
of the ABCA-1 and ApoA-1 subgroups. 
 
12.2.2 Secondary Efficacy Analysis  
 
The secondary efficacy endpoints of this study will include the following:  
Change from baseline MVWA by 3T-MRI:  
• In the carotid artery at 8 and 48 weeks versus placebo 
• In the femoral artery at 8, 24 and 48 weeks versus placebo 


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• 
Change from baseline in target (plaque) to background (blood) ratio based on standardised 
18FDG uptake measured with 18FDG-PET/CT. 
 
All the above secondary endpoints will be analysed using similar ANCOVA model as for the 
primary endpoint. 
There is only one primary endpoint; no multiplicity adjustments will be made for the secondary 
endpoints. 
 
12.2.3 Other Efficacy Analysis  
 
The other efficacy endpoints of this study will include the following:  
Change from baseline MVWA by 3T-MRI:  
• In the carotid artery at 72 weeks  
• In the femoral artery at 72 weeks  
All the above endpoints will be analysed using similar ANCOVA model as for the primary endpoint. 
 
12.2.4 Exploratory Efficacy Analysis  
 
Change from baseline in carotid MVWA at six months will be examined in each genetic subset as 
a sensitivity analysis; the study is not powered to detect a difference between CER- 001 and placebo 
for individual genetic subgroups, this analysis is performed to assess whether trends in the 
subgroups are directionally consistent with the results of the total study population. The genetic 
subsets will also be examined for the other secondary endpoints listed above.  
Other efficacy endpoints for the study will include the following and will be examined both for the 
full study population and for each genetic subset:  
• The percent change in femoral artery MVWA versus placebo  
• The percent change in maximum vessel wall thickness (MaxVWT) versus placebo  
• The percent change in mean vessel wall thickness (MVWT) versus placebo  
• The percent change in carotid mean vessel wall volume (MVWV) versus placebo  
• The absolute change in carotid MVWV versus placebo  
• The percent change in the mean of the carotid normalized wall index (NVWI) versus placebo  
• The percent change in femoral artery MVWV versus placebo  
• The absolute change in femoral MVWV versus placebo  
These exploratory efficacy biomarkers will be summarized by treatment group using descriptive 
statistics (n, mean, standard deviation, median and range), or frequencies and percentages, as 
appropriate. 


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12.3 Safety Assessments 
 
Safety will be assessed based on reporting of adverse events, physical examinations, clinical 
laboratory test results, vital sign measurements, and electrocardiogram (ECG) measures.  
12.3.1 Safety and Tolerance Variables 
 
Safety and tolerance variables will include: 
• Incidence, severity and causality of AEs and particularly coronary events 
• Change from baseline in physical examinations, clinical laboratory tests, vital signs and 
ECGs  
12.3.2 Analysis of Safety and Tolerance Variables 
 
Descriptive statistics will be provided for all safety parameters. 
Adverse events will be coded by body system and preferred term based on the Med-DRA dictionary 
of standardized terminology.  All AEs reported during the study will be listed, documenting course, 
severity, relationship to study drug and outcome.  Adverse events will be tabulated by study 
treatment.  
Summary tables will give the number and proportion of patients who experienced an AE, broken 
down by body system, preferred term and maximum severity.  Related adverse events, defined as 
those adverse events that are possibly, probably or definitely related to study drug, will be 
summarized similarly. 
Laboratory parameters, vital signs, physical exam results, and ECG findings will be summarized by 
treatment group and time point using descriptive statistics (n, mean, standard deviation, median and 
range), or frequencies and percentages, as appropriate. Results will be classified as normal or 
abnormal at screening and at on-treatment and follow-up visits.  Shift tables of these values will be 
provided to summarize the change between screening and on-treatment / follow-up for each 
treatment group.  
12.4 Sample Size Calculation 
 
The assumptions upon which the power calculations are based are data from the 7 patients 
completing the CER-001-CLIN-007 SAMBA study, given the similarity of the genetic mutations. 
Those patients presented with a median value for MVWA of 25.0 mm2 and had a follow-up median 
value at 6 months of 21.8 mm2. The mean percent reduction is reported as 6.7%, standard deviation 
= 4.5%. These observed values would provide a conservative estimate of the effect of CER-001 in 
the more severe population for this FPHA study. 
 
Using these results from SAMBA (i.e. an assumed standard deviation of 4.5%) and a 2:1 
randomization scheme to maximize exposure to active drug, 16 completing patients in the CER-001 
group and 8 in the placebo group (24 total completers for mITT) would yield 90% power to detect 
a difference from baseline versus placebo of 6.7%, using two-tailed testing with α=0.05. A total of 


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30 patients are planned to be randomized that would provide a buffer such that a 20% 
discontinuation rate would still allow the study to retain sufficient power for a supporting per 
protocol efficacy analysis (MVWA). 
 
12.5 Populations for Analysis 
 
The objectives of this study will be addressed primarily through the modified Intention-to-Treat 
(mITT) approach.  In this approach all randomized patients with at least one valid, post 
randomization efficacy measurement, i.e., a follow up evaluation, will be included in the efficacy 
assessments, irrespective of their protocol adherence.  Additionally, a per-protocol analysis will be 
performed which will only include patients who received all infusions of study drug (up to the time 
of each analysis), at the planned dosage and have no major protocol violations.  Documentation of 
patients included / excluded from analysis populations will be completed before the study is 
unblinded. 
 
For safety evaluations, all randomized patients who received at least one dose of study medication 
will be included. 
 
 
 
 


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13 REFERENCES 
 
1. 
Vega GL, Grundy SM. Hypoalphalipoproteinemia (low high density lipoprotein) as a risk factor for 
coronary heart disease. Curr Opin Lipidol. 1996 Aug;7(4):209-16.  
2. 
Calabresi L, Franceschini G. High density lipoprotein and coronary heart disease: insights from 
mutations leading to low high density lipoprotein. Curr Opin Lipidol. 1997 Aug;8(4):219-24.  
3. 
Ikewaki K, Matsunaga A, Han H, Watanabe H, Endo A, Tohyama J, et al. A novel two nucleotide 
deletion in the apolipoprotein A-I gene, apoA-I Shinbashi, associated with high density lipoprotein 
deficiency, corneal opacities, planar xanthomas, and premature coronary artery disease. 
Atherosclerosis. 2004 Jan;172(1):39-45.  
4. 
Yokota H, Hashimoto Y, Okubo S, Yumoto M, Mashige F, Kawamura M, et al. Apolipoprotein A-I 
deficiency with accumulated risk for CHD but no symptoms of CHD. Atherosclerosis. 2002 
Jun;162(2):399-407.  
5. 
Pisciotta L, Miccoli R, Cantafora A, Calabresi L, Tarugi P, Alessandrini P, et al. Recurrent mutations 
of the apolipoprotein A-I gene in three kindreds with severe HDL deficiency. Atherosclerosis. 2003 
Apr;167(2):335-45.  
6. 
Santos RD, Schaefer EJ, Asztalos BF, Polisecki E, Wang J, Hegele RA, et al. Characterization of 
high density lipoprotein particles in familial apolipoprotein A-I deficiency. J Lipid Res. 2008 
Feb;49(2):349-57.  
7. 
Investigational Brochure version 5.0; March 2015. 
8. 
Attie AD, Kastelein JP, Hayden MR. Pivotal role of ABCA1 in reverse cholesterol transport 
influencing HDL levels and susceptibility to atherosclerosis. J Lipid Res. 2001 Nov;42(11):1717-26.  
9. 
Puntoni M, Sbrana F, Bigazzi F, Sampietro T. Tangier disease: epidemiology, pathophysiology, and 
management. Am J Cardiovasc Drugs. 2012 Oct 1;12(5):303-11.  
10. 
Clee SM, Kastelein JJ, van Dam M, Marcil M, Roomp K, Zwarts KY, et al. Age and residual 
cholesterol efflux affect HDL cholesterol levels and coronary artery disease in ABCA1 
heterozygotes. J Clin Invest. 2000 Nov;106(10):1263-70.  
11. 
van Dam MJ, de Groot E, Clee SM, Hovingh GK, Roelants R, Brooks-Wilson A, et al. Association 
between increased arterial-wall thickness and impairment in ABCA1-driven cholesterol efflux: an 
observational study. Lancet. 2002 Jan 5;359(9300):37-42.  
12. 
Paszty C, Maeda N, Verstuyft J, Rubin EM. Apolipoprotein AI transgene corrects apolipoprotein E 
deficiency-induced atherosclerosis in mice. J Clin Invest. 1994 Aug;94(2):899-903.  
13. 
Plump AS, Scott CJ, Breslow JL. Human apolipoprotein A-I gene expression increases high density 
lipoprotein and suppresses atherosclerosis in the apolipoprotein E-deficient mouse. Proc Natl Acad 
Sci U S A. 1994 Sep 27;91(20):9607-11.  
14. 
Duverger N, Kruth H, Emmanuel F, Caillaud JM, Viglietta C, Castro G, et al. Inhibition of 
atherosclerosis development in cholesterol-fed human apolipoprotein A-I-transgenic rabbits. 
Circulation. 1996 Aug 15;94(4):713-7.  
15. 
Genest JJ, Jr., Martin-Munley SS, McNamara JR, Ordovas JM, Jenner J, Myers RH, et al. Familial 
lipoprotein disorders in patients with premature coronary artery disease. Circulation. 1992 
Jun;85(6):2025-33.  
16. 
Genest J, Jr., Bard JM, Fruchart JC, Ordovas JM, Schaefer EJ. Familial hypoalphalipoproteinemia 
in premature coronary artery disease. Arterioscler Thromb. 1993 Dec;13(12):1728-37.  
17. 
Kootte RS, Smits LP, van der Valk FM, Dasseux JL, Keyserling CH, Barbaras R, et al. Effect of 
open-label infusion of an apoA-I-containing particle (CER-001) on RCT and artery wall thickness 
in patients with FHA. J Lipid Res. 2015 Mar;56(3):703-12.  
18. 
Hovingh GK, Smits LP, Stefanutti C, Soran H, Kwok S, de Graaf J, et al. The effect of an 
apolipoprotein A-I-containing high-density lipoprotein-mimetic particle (CER-001) on carotid 
artery wall thickness in patients with homozygous familial hypercholesterolemia: The Modifying 
Orphan Disease Evaluation (MODE) study. Am Heart J. 2015 May;169(5):736-42 e1.   
 
 


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PART 2: ETHICS AND GENERAL STUDY ADMINISTRATION ETHICAL 
ASPECTS 
 
14 ETHICAL CONSIDERATIONS 
14.1 Institutional Review Board/Ethics Committee 
 
This protocol and all appropriate amendments will be properly reviewed and approved by an Ethics 
Committee (IEC) or Institutional Review Board (IRB). Signed and dated notification of the 
IRB/IEC’s approval must be made to the Sponsor and Investigator prior to study initiation. 
 
14.2 Ethical Conduct of Study 
 
This study will be conducted in accordance with the ethical principles originating from the 
Declaration of Helsinki amended, Fortaleza, Brazil, October 2013, (Appendix B) , GCPs (ICH E6) 
and in compliance with the standard operating procedures, local regulatory requirements and 
complying with the obligations and requirements of clinical Investigators and all other requirements 
listed in Code of Federal Regulations, FDA title 21 part 312 (21 CFR part 312). 
Patient identity will be kept confidential, and to the extent permitted by the applicable laws and/or 
regulations, will not be made publicly available. If the results of the trial are published, the patient 
identity will remain confidential. 
 
14.3 Patient Information and Consent 
 
Informed consent will be obtained in accordance with ICH/GCP Guidelines and The Declaration of 
Helsinki and will be implemented before protocol specific procedures are carried out. The risks and 
benefits of participating in the study will be verbally explained to each potential patient prior to 
signing the consent form. Prior to the conduct of any screening tests or procedures, the patient must 
sign and date the written informed consent (which also defines the risks and benefits of participating 
in the study) in accordance with local regulatory and legal requirements. The Sponsor will provide 
a sample informed consent to the Investigators. The final form must be approved by the 
Sponsor/CRO and an IRB/IEC. It must contain all the elements in the sample form using language 
readily understood by the patients. 
 
The date of receipt of written informed consent must be recorded in each patient's CRF and medical 
records. The signed consent form will be retained by the Investigator and a copy will be provided 
to each participant. 
 
14.4 Protocol Adherence 
 
The Investigators must read the protocol thoroughly and must follow the instructions exactly. Any 
protocol deviations will be documented and will be reviewed during the data review meeting. 
 


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Investigators must ensure that any amendment containing major modifications (particularly if it may 
involve an increased risk to the patients) is approved by the IRB/IEC before it is implemented. 
15 CONFIDENTIALITY AND ARCHIVING 
 
15.1 Personal data protection and Confidentiality 
 
The investigator must assure that the personal data of patients, including their identity and all other 
personal medical information, will be kept confidential at any time. 
 
Patient number and initials will identify the patients in the eCRF. On other documents or 
photographic materials (including the results of imaging) submitted to the sponsor, patients will not 
be identified by their names but by an identification code (e.g. initials and patient number). 
 
By signing this protocol, the investigator undertakes that the protocol and all attached information 
are and will remain confidential. The investigator agrees that after providing the protocol and all 
information necessary for the personnel involved, he remains responsible for their total 
confidentiality. Such obligation is detailed in the confidentiality agreement signed by the 
investigator before the initiation of the study. 
 
The investigator agrees that, subject to local regulations and ethical considerations, a sponsor 
representative or any regulatory agency may consult directly and/or copy study documents in order 
to verify a case report, provided that the subject's identity remains anonymous. 
 
The investigator undertakes to treat all subjects data used or disclosed in connection with the 
conduct of study in compliance with European and local applicable laws relating to data protection. 
 
The investigator will be responsible for keeping a list of all enrolled patients including patient 
numbers, full names and date of birth. 
 
15.2 Study documentation keeping 
 
The investigator must maintain adequate and accurate records to enable the conduct of the study to 
be fully documented and the study data to be subsequently verified. The study documents, including 
patient CRFs, should be classified in the investigator's file. 
 
The investigator's file will contain the protocol/amendments, independent Ethics Committee and 
Health Authorities with correspondence, sample informed consent, IMP records, staff curriculum 
vitae and authorization forms, correspondence, etc. 
 


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The investigator must keep the Study File until the Sponsor authorization of destruction and by 
default during at least 15 years after completion or discontinuation of the study. 
Should the investigator wish to assign the study records to another party or move them to another 
location, the sponsor must be notified in advance. 
 
16 DATA HANDLING AND RECORD KEEPING 
 
16.1 Data Collection 
 
An electronic data capture system will be used in the clinical study. The Investigator will ensure the 
accuracy, completeness, and timeliness of the data reported to the Sponsor. Data collection 
processes and procedures will be reviewed and validated to ensure completeness, accuracy, 
reliability, and consistency. A complete audit trail will be maintained of all data changes. The 
Investigator or designee will cooperate with the Sponsor/CRO’s representative(s) for the periodic 
review of study documents to ensure the accuracy and completeness of the data capture system at 
each scheduled monitoring visit. 
 
Any source data that is not captured electronically will be captured on paper source documents. The 
appropriate data from these paper source documents will then be manually entered into an electronic 
data capture system according to the data entry guidelines. 
 
16.2 Data Corrections 
 
Electronic consistency checks and manual review will be used to identify any errors or 
inconsistencies in the data. Any missing, impossible or inconsistent data will be referred back to the 
Investigator. This information will be provided to the respective study sites by means of electronic 
or manual queries, using a data query form and be documented for each individual patient before 
clean file status is declared. 
 
Any changes made to the data after approval by the site monitor will be discussed with and approved 
by the Investigator. 
 
16.3 Source Documentation 
 
The Investigator will keep accurate separate records (other than the CRFs) of all patients' visits, 
being sure to include all pertinent study related information. A statement will be made in the patient 
chart indicating that the patients have been enrolled in Protocol CER-001-CLIN-009 and the visit 
dates. Thoroughly document all side effects and AEs in the patient chart. Include results of any 
diagnostic tests conducted during the study in the source documentation. Record any telephone 
conversations with the patient and/or Sponsor concerning the study. 
 


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16.4 Monitoring, Quality Control and Quality Assurance 
 
The Sponsor/CRO will be responsible for monitoring the study, data entry and data management. If 
designated by the Sponsor, the CRO will also perform quality control of the study and database. 
 
The CRAs will be trained prior to study initiation. This training will include an overview of the 
study disease and study drug background. Specific monitoring guidelines and procedures will be 
reviewed. 
 
A pre-study/initiation visit will be conducted with all Principal Investigators, Study Coordinators, 
and Study Pharmacists. During this meeting, an extensive review and discussion of the protocol and 
associated procedures will be conducted, including the procedures for study drug preparation and 
dosing. The conduct of the study will be closely monitored by representatives of CRO and the 
Sponsor following GCP guidelines. The reports of these verifications will also be archived with the 
study report.  
 
In addition, inspections or on-site audits may be carried out by local authorities or by CRO and the 
Sponsor's independent Quality Assurance Department or designee. The Investigators will allow 
CRO and the Sponsor's representatives and any regulatory agency to examine all study records, 
CRFs, corresponding patient medical records, clinical drug dispensing records and drug storage 
area, and any other documents considered source documentation. The Investigators also agree to 
assist the representative, if required. 
 
16.5 Record Retention 
 
Maintain all CRFs and pertinent data, correspondence, original or amended protocol, all reports and 
all other material relating to the study securely in the Investigator's files for one of the following 
two periods: 
• a period of at least two years following the date on which the study drug is approved by FDA 
for marketing for the purposes that were the indication studied; or 
• If no application is to be filed or if the application is not approved for the indication studied, 
a period of at least two years after the date on which the entire investigation (all clinical 
studies) is terminated and the FDA is notified. 
 
In any event, do not destroy study documentation without the express written permission of 
Cerenis™ Therapeutics. If the Investigator retires, relocates, or for other reasons withdraws from 
the responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. The Sponsor and IRB/IEC must be notified in writing of the name and 
address of the new custodian. 
 
 


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17 FINANCING AND INSURANCE 
The contractual details between the Investigator and the Sponsor are contained in a separate 
agreement. During the study, the Sponsor will hold Clinical Trial Insurance with coverage 
commensurate to the risks associated with the study. 
18 PUBLICATION OF STUDY RESULTS 
The TANGO Steering Committee is responsible for preparing the manuscripts and presentations 
and will publish the results of this study after providing a draft manuscript to the Sponsor for review 
and comment at least 45 days prior to submission. 
19 CLINICAL STUDY REPORT (CSR) 
A clinical study report will be written and distributed to Health Authorities as required by applicable 
regulatory requirements.   
The sponsor will designate a principal coordinating investigator (who will sign the final study 
report) based on their contribution to the conduct of the study, and/or their expertise employed in 
the interpretation of the overall study results. 
20 OTHER INFORMATION 
This study will be registered on the clinicaltrials.gov website. 


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APPENDIX A: Schedule of Assessments in double-blind treatment phase 
Screening 
Randomization 
Period 1 
Period 2 
Period 3 
Period 3 
Final 
safet
y 
V1 
Baseline 
Induction 
Maintenance 
Extension
Extension 
V2 
Infusion every week 
Infusion every two weeks 
V3 to V5 
V6 
V7 to V9 
V10 
V11 to V13 
V14 
V15 to V17 
V18 
V19 to V21 
V22 
V23 to V25 
V26 
V27 to V29 
V30 
V31 
W0 
W1 to W3 
W4 
W5 to W7 
W8 
W10 to W14 
W16 
W18 to W22 
W24 
W26 to W30 
W32 
W34 to W38 
W40 
W42 to W46 
W48 
W52 
Informed consent 
X 
Selection criteria 
X 
Demography 
X 
Medical history (smoking status) 
X 
Counseling on heart healthy diet and lifestyle 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood pressure & heart rate assessment 
X 
X 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
X 
*BP and HR should be measured pre-infusion and post-infusion 
Heigh 
X 
Weigh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Previous and concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FSH2 
X 
Serum Pregnancy Test 
X 
Urinary Pregnancy Test 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology/coagulation3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistry4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Markers of inflammation, oxidation and CV risk6 
X 
X 
X 
X 
X 
X 
Anti-ApoA-1  antibody 
X 
X 
X 
X 
Fasting plasma glucose7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HBA1c 
X 
X 
Biomarkers sample 
X 
X 
Lipid & Lipoprotein profile8 
X 
X 
X 
X 
X 
(from fasting samples) 
Cholesterol Efflux9 
X 
X 
X 
X 
X 
Genotyping10 
X 
Study drug infusion11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetics12 
X 
X 
(2 hours after starting the infusion) 
3TMRI (MVWA)  
X 
X 
X 
X 
18FDG-PET/CT (if site equipped to do it) 
X 
X 
1. AEs and SAEs (related or not related) to be recorded at each visit until the final study evaluation. After the end of the study, only the SAEs likely to be related to the study medication or study procedures must be notified. 
2. FSH in women whose last menstrual period was between 6 and 12 months before screening 
3. White blood count, red blood count, hemoglobin, hematocrit, neutrophlis, lymphocytes, monocytes, eosinophils, basophils, platelets, differential 
4. Glucose, Blood Urea Nitrogen (BUN), Creatinine, Total Bilirubin, Indirect Bilirubin, Aspartame Aminotransferase 5AST/SGOT), Alanine Aminotransferase (ALT/SGPT), Alkaline Phosphatase, Total Protein, Albumin, Lactate Dehydrogenas (LDH), Creatinine Kinase 
(CK), Sodium, Potassium, Chloride, Carbon dioxide, Uric Acid, Calcium, Phosphorous 
5. Microalbuminuria, Specific Gravity, pH, Glucose, Total Protein, Ketones, Total Bilirubin, WBC, RBC, Casts. 


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6. Markers of inflammation, oxidation and CV risk and other markers (hsCRP, TNFα, IL6, sVCAM, PON-1, MMP-9, Oxysterols (FACS Analysis), sMCP1, ABCA1 mRNA, protein levels (Monocytes)) 
7. Patient must have fasted (ie not to take any food or liquids other than water) for 8 hours prior to blood sampling. 
8. Patient must have fasted (ie not to take any food or liquids other than water) for 8 hours prior to blood sampling. Total cholesterol, unesterified cholesterol, esterified cholesterol, apolipoprotein A-1, apolipoprotein B, other apolipoprotein, Apolipoprotein profil, 
triglycerides, HDL-C, LDL-C + subfractions. HDL-C particles assessment including pre- analyzed by NMR and 2D-gel. Additionally, oxPhopholipids (OxPL) will be assessed. 
9. At infusion visits, samples should be drawn 2 hours after the start of the infusion. 
10. Mandatory assessment of the genetic mutation at screening. A DNA sample will be taken ONLY for determination of the presence of HDL gene mutations specifically for ABCA1 and ApoA-1 mutation(s) in case the patient was to satisfy all other selection 
criteria and would not have a confirmed related genetic mutation. Genotyping will be performed centrally. 
11. Visits may be scheduled +/- 2days from target weekly or biweekly date. 
12. PK assessment including 2D-gel. 
13. 3T-MRI and 18FDG-PET/CT should be collected with a window of +/- 7 days around the strict date. 
14. Safety follow-up visit will be performed 4 weeks +/- 7 days after the last dose of study medication for all patients. 
 
 
 
 


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APPENDIX B: Schedule of Assessments in open-labeled treatment phase 
 
 
V31 to V41  
V42 
V43 FU 
 
W50 to W70 
W72 
W76 
 
Informed Consent 
X 
 
 
Selection criteria (Inclusion/Exclusion) 
 
 
 
Medical history 
 
 
 
Demography 
 
 
 
12-Lead ECG 
 
 
 
Height 
 
 
 
Weight 
 
 
 
Pregnancy Test 
 
 
 
Physical Exam 
 
 
 
Vital Signs 
 
 
 
Blood Pressure (BP) & Heart Rate (HR) 
assessment 
 
 
 
Hematology/coagulation 
 
 
 
Serum Chemistry 
 
 
 
Urinalysis 
 
 
 
Adverse Events 
X 
X 
X 
Previous and concomitant medications 
X 
X 
X 
FSH 
 
 
 
Counseling on heart healthy diet and lifestyle 
 
 
 
Genotyping 
 
 
 
Markers of inflammation, oxidation and CV 
risk 
 
 
 
Biomarkers sample 
 
 
 
HBA1c 
 
 
 
Fasting  blood glucose 
 
 
 
Lipid & Lipoprotein Profile 
 
 
 
Anti-ApoA1 antibody 
 
 
 
Creatinine and/or BUN testing to determine 
GFR 
 
 
 
Cellular Cholesterol Efflux 
 
 
 
Study drug infusion 
X 
X 
 
Pharmacokinetics (PK)  
 
 
 
3TMRI (MVWA)  
 
X 
 
18FDG-PET/CT 
 
 
 
 


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APPENDIX C: Declaration of Helsinki 
 
 
 
WORLD MEDICAL ASSOCIATION - DECLARATION OF HELSINKI 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 
and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000  
53rd WMA General Assembly, Washington DC, USA, October 2002 (Note of Clarification 
added) 
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
Preamble 
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including 
research on identifiable human material and data. 
The Declaration is intended to be read as a whole and each of its constituent paragraphs 
should be applied with consideration of all other relevant paragraphs. 
2. Consistent with the mandate of the WMA, the Declaration is addressed primarily to 
physicians. The WMA encourages others who are involved in medical research involving 
human subjects to adopt these principles.  
General Principles 
3. The Declaration of Geneva of the WMA binds the physician with the words, “The health of 
my patient will be my first consideration,” and the International Code of Medical Ethics 
declares that, “A physician shall act in the patient's best interest when providing medical 
care.” 
4. It is the duty of the physician to promote and safeguard the health, well-being and rights 
of patients, including those who are involved in medical research. The physician's knowledge 
and conscience are dedicated to the fulfilment of this duty. 
5. Medical progress is based on research that ultimately must include studies involving human 
subjects. 
6. The primary purpose of medical research involving human subjects is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and 


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therapeutic interventions (methods, procedures and treatments). Even the best proven 
interventions must be evaluated continually through research for their safety, effectiveness, 
efficiency, accessibility and quality. 
7. Medical research is subject to ethical standards that promote and ensure respect for all 
human subjects and protect their health and rights. 
8. While the primary purpose of medical research is to generate new knowledge, this goal can 
never take precedence over the rights and interests of individual research subjects. 
9. It is the duty of physicians who are involved in medical research to protect the life, health, 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal 
information of research subjects. The responsibility for the protection of research subjects 
must always rest with the physician or other health care professionals and never with the 
research subjects, even though they have given consent. 
10. Physicians must consider the ethical, legal and regulatory norms and standards for 
research involving human subjects in their own countries as well as applicable international 
norms and standards. No national or international ethical, legal or regulatory requirement 
should reduce or eliminate any of the protections for research subjects set forth in this 
Declaration. 
11. Medical research should be conducted in a manner that minimizes possible harm to the 
environment. 
12. Medical research involving human subjects must be conducted only by individuals with 
the appropriate ethics and scientific education, training and qualifications. Research on 
patients or healthy volunteers requires the supervision of a competent and appropriately 
qualified physician or other health care professional. 
13. Groups that are underrepresented in medical research should be provided appropriate 
access to participation in research. 
14. Physicians who combine medical research with medical care should involve their patients 
in research only to the extent that this is justified by its potential preventive, diagnostic or 
therapeutic value and if the physician has good reason to believe that participation in the 
research study will not adversely affect the health of the patients who serve as research 
subjects. 
15. Appropriate compensation and treatment for subjects who are harmed as a result of 
participating in research must be ensured. 
 
 
Risks, Burdens and Benefits  


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16. In medical practice and in medical research, most interventions involve risks and burdens. 
Medical research involving human subjects may only be conducted if the importance of the 
objective outweighs the risks and burdens to the research subjects. 
17. All medical research involving human subjects must be preceded by careful assessment 
of predictable risks and burdens to the individuals and groups involved in the research in 
comparison with foreseeable benefits to them and to other individuals or groups affected by 
the condition under investigation. 
Measures to minimize the risks must be implemented. The risks must be continuously 
monitored, assessed and documented by the researcher.  
18. Physicians may not be involved in a research study involving human subjects unless they 
are confident that the risks have been adequately assessed and can be satisfactorily managed. 
When the risks are found to outweigh the potential benefits or when there is conclusive proof 
of definitive outcomes, physicians must assess whether to continue, modify or immediately 
stop the study.  
Vulnerable Groups and Individuals 
19. Some groups and individuals are particularly vulnerable and may have an increased 
likelihood of being wronged or of incurring additional harm. 
All vulnerable groups and individuals should receive specifically considered protection. 
20. Medical research with a vulnerable group is only justified if the research is responsive to 
the health needs or priorities of this group and the research cannot be carried out in a non-
vulnerable group. In addition, this group should stand to benefit from the knowledge, 
practices or interventions that result from the research. 
Scientific Requirements and Research Protocols  
21. Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant 
sources of information, and adequate laboratory and, as appropriate, animal 
experimentation. The welfare of animals used for research must be respected. 
22. The design and performance of each research study involving human subjects must be 
clearly described and justified in a research protocol. 
The protocol should contain a statement of the ethical considerations involved and should 
indicate how the principles in this Declaration have been addressed. The protocol should 
include information regarding funding, sponsors, institutional affiliations, potential conflicts 
of interest, incentives for subjects and information regarding provisions for treating and/or 


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compensating subjects who are harmed as a consequence of participation in the research 
study. 
In clinical trials, the protocol must also describe appropriate arrangements for post-trial 
provisions. 
Research Ethics Committees 
23. The research protocol must be submitted for consideration, comment, guidance and 
approval to the concerned research ethics committee before the study begins. This 
committee must be transparent in its functioning, must be independent of the researcher, 
the sponsor and any other undue influence and must be duly qualified. It must take into 
consideration the laws and regulations of the country or countries in which the research is to 
be performed as well as applicable international norms and standards but these must not be 
allowed to reduce or eliminate any of the protections for research subjects set forth in this 
Declaration.  
The committee must have the right to monitor ongoing studies. The researcher must provide 
monitoring information to the committee, especially information about any serious adverse 
events. No amendment to the protocol may be made without consideration and approval by 
the committee. After the end of the study, the researchers must submit a final report to the 
committee containing a summary of the study’s findings and conclusions.  
Privacy and Confidentiality  
24. Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information. 
Informed Consent  
25. Participation by individuals capable of giving informed consent as subjects in medical 
research must be voluntary. Although it may be appropriate to consult family members or 
community leaders, no individual capable of giving informed consent may be enrolled in a 
research study unless he or she freely agrees. 
26. In medical research involving human subjects capable of giving informed consent, each 
potential subject must be adequately informed of the aims, methods, sources of funding, any 
possible conflicts of interest, institutional affiliations of the researcher, the anticipated 
benefits and potential risks of the study and the discomfort it may entail, post-study 
provisions and any other relevant aspects of the study. The potential subject must be 
informed of the right to refuse to participate in the study or to withdraw consent to 
participate at any time without reprisal. Special attention should be given to the specific 
information needs of individual potential subjects as well as to the methods used to deliver 
the information. 


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After ensuring that the potential subject has understood the information, the physician or 
another appropriately qualified individual must then seek the potential subject’s freely-given 
informed consent, preferably in writing. If the consent cannot be expressed in writing, the 
non-written consent must be formally documented and witnessed.  
All medical research subjects should be given the option of being informed about the general 
outcome and results of the study. 
27. When seeking informed consent for participation in a research study the physician must 
be particularly cautious if the potential subject is in a dependent relationship with the 
physician or may consent under duress. In such situations the informed consent must be 
sought by an appropriately qualified individual who is completely independent of this 
relationship. 
28. For a potential research subject who is incapable of giving informed consent, the physician 
must seek informed consent from the legally authorized representative. These individuals 
must not be included in a research study that has no likelihood of benefit for them unless it 
is intended to promote the health of the group represented by the potential subject, the 
research cannot instead be performed with persons capable of providing informed consent, 
and the research entails only minimal risk and minimal burden. 
29. When a potential research subject who is deemed incapable of giving informed consent 
is able to give assent to decisions about participation in research, the physician must seek 
that assent in addition to the consent of the legally authorised representative. The potential 
subject’s dissent should be respected. 
30. Research involving subjects who are physically or mentally incapable of giving consent, 
for example, unconscious patients, may be done only if the physical or mental condition that 
prevents giving informed consent is a necessary characteristic of the research group. In such 
circumstances the physician must seek informed consent from the legally authorised 
representative. If no such representative is available and if the research cannot be delayed, 
the study may proceed without informed consent provided that the specific reasons for 
involving subjects with a condition that renders them unable to give informed consent have 
been stated in the research protocol and the study has been approved by a research ethics 
committee. Consent to remain in the research must be obtained as soon as possible from the 
subject or a legally authorised representative. 
31. The physician must fully inform the patient which aspects of their care are related to the 
research. The refusal of a patient to participate in a study or the patient’s decision to 
withdraw from the study must never adversely affect the patient-physician relationship. 
32. For medical research using identifiable human material or data, such as research on 
material or data contained in biobanks or similar repositories, physicians must seek informed 
consent for its collection, storage and/or reuse. There may be exceptional situations where 
consent would be impossible or impracticable to obtain for such research. In such situations 
the research may be done only after consideration and approval of a research ethics 
committee. 


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Use of Placebo 
33. The benefits, risks, burdens and effectiveness of a new intervention must be tested 
against those of the best proven intervention(s), except in the following circumstances: 
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or 
Where for compelling and scientifically sound methodological reasons the use of any 
intervention less effective than the best proven one, the use of placebo, or no intervention is 
necessary to determine the efficacy or safety of an intervention and the patients who receive 
any intervention less effective than the best proven one, placebo, or no intervention will not 
be subject to additional risks of serious or irreversible harm as a result of not receiving the 
best proven intervention.  
Extreme care must be taken to avoid abuse of this option. 
Post-Trial Provisions 
34. In advance of a clinical trial, sponsors, researchers and host country governments should 
make provisions for post-trial access for all participants who still need an intervention 
identified as beneficial in the trial. This information must also be disclosed to participants 
during the informed consent process. 
Research Registration and Publication and Dissemination of Results 
35. Every research study involving human subjects must be registered in a publicly accessible 
database before recruitment of the first subject. 
36. Researchers, authors, sponsors, editors and publishers all have ethical obligations with 
regard to the publication and dissemination of the results of research. Researchers have a 
duty to make publicly available the results of their research on human subjects and are 
accountable for the completeness and accuracy of their reports. All parties should adhere to 
accepted guidelines for ethical reporting. Negative and inconclusive as well as positive results 
must be published or otherwise made publicly available. Sources of funding, institutional 
affiliations and conflicts of interest must be declared in the publication. Reports of research 
not in accordance with the principles of this Declaration should not be accepted for 
publication. 
Unproven Interventions in Clinical Practice 
37. In the treatment of an individual patient, where proven interventions do not exist or other 
known interventions have been ineffective, the physician, after seeking expert advice, with 
informed consent from the patient or a legally authorized representative, may use an 
unproven intervention if in the physician's judgement it offers hope of saving life, re-
establishing health or alleviating suffering. This intervention should subsequently be made 


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the object of research, designed to evaluate its safety and efficacy. In all cases, new 
information must be recorded and, where appropriate, made publicly available. 
 
 
 
 
 

SAP_001.pdf: 
 
 
Cerenis THERAPEUTICS 
256 rue de la Découverte 
BAT. A 
31670 Labège 
FRANCE 
ICTA PM 
11 rue du Bocage 
21121 Fontaine-lès-Dijon 
FRANCE 
 
STAT I ST I CAL  ANALYSI S P L AN 
TA N G O  
Prepared and drafted by the biostatistics department of ICTA PM 
Stéphanie PEROT 
 
Protocol No. 
: 
CER-001-CLIN-009 
Title 
: 
Phase III, multi-center, randomized, 48 weeks, double-blind, 
parallel-group, placebo-controlled study to evaluate efficacy and 
safety of CER-001 on vessel wall area in patients with genetically 
defined familial primary hypoalphalipoproteinemia and receiving 
background optimized lipid therapy 
Phase 
: 
III 
Study treatment 
: 
CER-001 
Date 
: 
25OCT2018 
Version 
: 
2.0 
 
This study is conducted in adherence with the Good Clinical Practices (GCPs) 
 
 
 
 
 
Confidential – This Statistical Analysis Plan is the ownership of the Sponsor and cannot be given, reproduced, published or used, even 
partially, by any authorities or organism without the authorisation of the sponsor. 
 


Cerenis THERAPEUTICS 
TANGO 
CER-001-CLIN-009 
 
CER-001 
 
Statistical Analysis Plan – Version 2.0 dated on 25OCT2018 
2 / 31 
History of versions: 
Version No. 
Date of version 
Comments / Main modifications 
1.0 
26JUL2018 
First approved version 
2.0 
25OCT2018 
Modifications following DR meeting 


Cerenis THERAPEUTICS 
TANGO 
CER-001-CLIN-009 
 
CER-001 
 
Statistical Analysis Plan – Version 2.0 dated on 25OCT2018 
3 / 31 
Contents: 
1.1 Primary objectives .......................................................................................................................................... 5 
1.2 Secondary objectives ...................................................................................................................................... 5 
1.3 Exploratory objectives .................................................................................................................................... 5 
6.1 Analysis populations of patients .................................................................................................................... 7 
6.2 Protocol deviations ........................................................................................................................................ 8 
6.3 Disposition of patients ................................................................................................................................... 8 
7.1 General principles .......................................................................................................................................... 9 
7.1.1 Software ................................................................................................................................................... 9 
7.1.2 Descriptive statistics ................................................................................................................................. 9 
7.1.3 General statistical tests ............................................................................................................................ 9 
7.1.4 Management of missing or incomplete data ........................................................................................... 9 
7.1.5 Handling of dropouts .............................................................................................................................. 10 
7.1.6 Handling of study centre effects ............................................................................................................. 10 
7.1.7 Presentation of results ............................................................................................................................ 10 
7.1.8 Examination of subgroups ...................................................................................................................... 10 
7.1.9 Validation levels ..................................................................................................................................... 10 
7.2 Demographic and other baseline characteristics ......................................................................................... 10 
7.2.1 Demography ........................................................................................................................................... 10 
7.2.2 Medical history and concomitant diseases ............................................................................................. 11 
7.2.3 Risk factors ............................................................................................................................................. 11 
7.2.4 Patient profile ......................................................................................................................................... 11 
7.3 Treatment exposure and compliance .......................................................................................................... 12 
7.3.1 Treatment exposure ............................................................................................................................... 12 
7.3.2 Treatment compliance ............................................................................................................................ 12 
7.4 Efficacy data ................................................................................................................................................. 13 
7.4.1 Primary endpoint .................................................................................................................................... 13 
7.4.2 Secondary endpoints .............................................................................................................................. 16 
7.4.3 Exploratory endpoints............................................................................................................................. 18 
7.5 Safety data.................................................................................................................................................... 19 
7.5.1 Adverse events (AE) ................................................................................................................................ 19 
7.5.2 Vital signs, physical examination, ECG ................................................................................................... 21 
7.5.3 Laboratory parameters ........................................................................................................................... 21 
7.6 Previous and concomitant medications ....................................................................................................... 23 
7.7 Listings of individual data ............................................................................................................................. 23 
12.1 Tables and graphs templates ..................................................................................................................... 25 
12.2 List of Tables, Graphs and Listings .............................................................................................................. 31 
 


Cerenis THERAPEUTICS 
TANGO 
CER-001-CLIN-009 
 
CER-001 
 
Statistical Analysis Plan – Version 2.0 dated on 25OCT2018 
4 / 31 
List of abbreviations and specialized terms: 
AE 
Adverse Event 
ANCOVA 
ANalysis of COVAriance 
ATC 
Anatomic Therapeutic Class 
BMI 
Body Mass Index 
CI 
Confidence Interval 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
DSMB 
Data and Safety Monitoring Board 
FPFV 
First Patient First Visit 
HLGT 
Highest Level Group Terms 
HLT 
Highest Level Terms 
ICH 
International Conference on Harmonisation 
LOCF 
Last Observation Carried Forward 
LPFV 
Last Patient First Visit 
LPLV 
Last Patient Last Visit 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
mITT 
modified Intention-To-Treat 
MRI 
Magnetic Resonance Imaging 
MVWA 
Mean Vessel Wall Area 
MVWV 
Mean Vessel Wall Volume 
PP 
Per Protocol 
PT 
Preferred Term 
Q1 
1st quartile 
Q3 
3rd quartile 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
TBR 
Target to Background Ratio 
TFL 
Tables Figures Listings 
WHO-DD 
World Health Organisation Drug Dictionary 


Cerenis THERAPEUTICS 
TANGO 
CER-001-CLIN-009 
 
CER-001 
 
Statistical Analysis Plan – Version 2.0 dated on 25OCT2018 
5 / 31 
Introduction 
The Statistical Analysis Plan (SAP) was developed from the following documents: 
• 
Protocol (version 3.0 dated 13DEC2016) 
• 
Case Report Form (CRF, version 18.2 on 30MAY2017) 
• 
The International Conference on Harmonization (ICH) topics E3 (July 1996) [1] and E9 
(September 1998) [2]. 
Analyses described throughout this document were planned before database lock. All analysis 
decisions were made prior to unblinding as well.  
This SAP supersedes the protocol. Changes to the protocol (if any) will be reported in section 10 
Modifications with respect to the protocol. Finally, additional analyses not planned in this document 
should be clearly mentioned in the appropriate section of the clinical study report. 
1. Study objectives 
1.1 Primary objectives 
The primary objectives of the study are: 
• 
To evaluate the effect of 24 week treatment with CER-001 on carotid Mean Vessel Wall Area 
(MVWA) as compared to placebo using 3T Magnetic Resonance Imaging (3T-MRI); 
• 
To evaluate the safety and tolerability of CER-001 administered for 24 weeks. 
1.2 Secondary objectives 
The secondary objectives of the study are: 
• 
To evaluate the effect of 8 week and 48 week treatment with CER-001 on carotid artery 
MVWA as compared to placebo using 3T-MRI;  
• 
To evaluate the effect of 8 week, 24 week and 48 week treatment with CER-001 on femoral 
artery MVWA as compared to placebo using 3T-MRI;  
• 
To evaluate the effect of 24 week treatment with CER-001 in the target (plaque) to 
background (blood) ratio (TBR) from an index vessel (either right carotid or left carotid) based 
on the standardized 18FDG uptake measured with PET/CT. 
• 
To evaluate safety and tolerability of 48 week treatment with CER-001. 
1.3 Exploratory objectives 
The exploratory objectives of the study are: 
• 
To evaluate the effect of treatment with CER-001 with respect to other efficacy measurements 
including carotid artery and carotid normalized wall index using 3T-MRI;  
• 
To evaluate the effect of treatment with CER-001 with respect to potential surrogate markers 
on vessel wall biology including laboratory variables; 
• 
To evaluate the effect of treatment with CER-001 with respect to inflammation; 
• 
To evaluate plasma-mediated cellular Cholesterol efflux capacity; 
• 
To measure ApoA-1 levels (pharmacokinetic parameters); 
• 
To measure Cholesterols, triglycerides, lipids, apolipoprotein and lipoprotein levels 
(pharmacodynamics parameters). 


Cerenis THERAPEUTICS 
TANGO 
CER-001-CLIN-009 
 
CER-001 
 
Statistical Analysis Plan – Version 2.0 dated on 25OCT2018 
6 / 31 
2. Study summary 
This is a phase III, multi-centre, randomized, 48 weeks, double-blind, parallel-group, placebo-
controlled study to evaluate efficacy and safety of CER-001 on ApoA-1 and vessel wall area in patients 
with genetically defined familial primary hypoalphalipoproteinemia and receiving background 
optimized lipid therapy. 
The study design is illustrated in the following figure: 
 
 
3. Sample size 
The assumptions upon which the power calculations are based are data from the 7 patients completing 
the CER-001-CLIN-007 SAMBA study, given the similarity of the genetic mutations. Those patients 
presented with a median value for MVWA of 25.0 mm2 and had a follow-up median value at 6 months 
of 21.8 mm2. The mean percent reduction is reported as 6.7%, standard deviation = 4.5%. These 
observed values would provide a conservative estimate of the effect of CER-001 in the more severe 
population for this FPHA study. 
Using these results from SAMBA (i.e. an assumed standard deviation of 4.5%) and a 2:1 randomization 
scheme to maximize exposure to active drug, 16 completing patients in the CER-001 group and 8 in 
the placebo group (24 total completers for mITT) would yield 90% power to detect a difference from 
baseline versus placebo of 6.7%, using two-tailed testing with α=0.05. A total of 30 patients are 
planned to be randomized that would provide a buffer such that a 20% discontinuation rate would still 
allow the study to retain sufficient power for a supporting per protocol efficacy analysis (MVWA). 
 
 


Cerenis THERAPEUTICS 
TANGO 
CER-001-CLIN-009 
 
CER-001 
 
Statistical Analysis Plan – Version 2.0 dated on 25OCT2018 
7 / 31 
4. Randomization 
After obtaining written informed consent, completing screening procedures, and ensuring the patient 
meets all of the inclusion criteria and none of the exclusion, the patient will be randomized. 
Stratification according to the genetic mutation (ABCA-1/ApoA-1) will be done to ensure appropriate 
balanced distribution of the mutations across treatment groups. The patient will be randomized to 
receive 29 infusions of either active drug or placebo using a 2:1 randomization scheme. 
5. Unblinding 
Unblinding will be performed by the ICTA PM statistician in charge of the study once database is locked, 
at the end of the study, with sponsor’s agreement. 
The unblinding process will be conducted according to ICTA SOP46 (“Randomization and unblinding”). 
ICTA Quality Assurance department will give the CD-Rom containing the randomization number and 
the corresponding randomization treatment to the statistician. The database will then be imported in 
the statistical database of the study. A 100% review of the imported data will be performed by the 
statistician, compared to initial data provided in the CD-Rom. 
6. Populations to be analysed 
6.1 Analysis populations of patients 
The statistical analysis will be based on the three populations defined below. To be part of a 
population, patients should have signed informed consent and fullfill all inclusion / exclusion criteria. 
Some criteria have been added after the start of the study. Hence patients included before will be 
considered as compliant to these criteria via a Not Applicable (NA) status. 
Safety population 
The safety population will comprise all randomized patients who received at least one dose of study 
medication. 
Safety analysis will be performed on the safety population according to the actual treatment received. 
Modified Intent-To-Treat (mITT) population 
The mITT population will comprise all randomized patients for whom at least one of the following 
conditions is satisfied: 
• 
3T-MRI assessment available at baseline (W0) and at least one post-baseline 3T-MRI 
assessment available 
• 
18FDG-PET/CT assessment available at baseline (W0) and at least one post-baseline 18FDG-
PET/CT assessment available 
Per Protocol (PP) population 
The PP population will comprise all patients of the mITT population without any major protocol 
deviations (Cf. section 6.3). 
Defining study populations and excluding patients from the analysis will be a joint decision taken by 
Sponsor and ICTA PM' representatives (Statistician and Project Leader). Patients to be excluded and 


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reasons for their exclusion will be discussed during data review meetings, before database lock and 
unblinding. 
6.2 Protocol deviations 
A list of protocol deviations has been written by ICTA PM and sent to the sponsor for approval. The list 
contains possible protocol deviations (according to inclusion/exclusion criteria, disallowed treatments, 
minimum treatment exposure, and calendar of visits...), and significant deviations which require 
immediate information to the Sponsor. This list may be updated in the course of the data management 
process, and will be finalized during the data review meetings before database lock and unblinding. 
 
During the data review, the impact of each deviation (minor/major) on the primary endpoint will be 
discussed and thus, the list of patients to be excluded from the PP population will be defined. 
Number and percentage of patients with at least one deviation, at least one major deviation, at least 
one deviation by type (Entry criteria / Study procedures / Investigational medicinal product) will be 
described. Each deviation will also be summarized by the number and percentage of patients who 
experienced it. 
6.3 Disposition of patients 
The following data will be described: 
• 
Number of screened patients [a] 
• 
Number of screening failures and reasons for screening failures 
• 
Number of randomized patients grouped by treatment 
• 
Number of patients for whom the blind was broken 
• 
Number of patients with ABCA-1, ApoA-1 or both mutations 
• 
Number of patients who did not receive any medication and reason for non-treatment 
• 
Number of patients who received double-blind medication 
• 
Treatment actually received (CER-001/Placebo) 
• 
Number of patients who completed the study 
• 
Number of premature discontinuations of the study treatment and reason for premature 
discontinuation (at each visit, and overall) 
• 
Number of premature withdrawals and reason for premature withdrawal (at each visit, and 
overall) 
• 
Number of patients who completed the induction period grouped by treatment (visit at W8 
performed) 
• 
Number of patients who completed the maintenance period grouped by treatment (visit at 
W24 performed) 
• 
Number of patients who completed the extension period grouped by treatment (visit at W48 
performed) 
• 
Patient’s follow-up duration 
• 
Inclusion date of the first patient (FPFV: First Patient First Visit), date of first visit of the last 
patient (LPFV) and last visit date of the last patient (LPLV: Last Patient Last Visit) 
• 
Number of patients in each analysis set and reasons for exclusion from the analysis sets 
• 
Number of visits performed 
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Flow chart for analysis populations 
• 
Flow chart for disposition of patients 
• 
Flow chart for visits 
[a] A screened patient is a patient who completed a screening visit 
7. Statistical methodology 
7.1 General principles 
7.1.1 Software 
All statistical analyses will be performed using Statistical Analysis System (SAS®) release 9.4. All 
computer programs will be developed and validated according to ICTA PM (CRO) standard operating 
procedures (SOP). 
7.1.2 Descriptive statistics 
Quantitative data will be summarized by the following descriptive statistics: number of data available, 
number of missing data, mean, standard deviation, first quartile (Q1), median, third quartile (Q3), 
minimum and maximum. If relevant, a 95% t-based mean confidence interval (CI) will also be 
presented. 
Qualitative data will be summarized by the following descriptive statistics: number of data available, 
number of missing data, frequency and percentage for each modality. 
Percentages will be calculated without taking into account missing data. 
7.1.3 General statistical tests 
No general statistical tests are planned. Statistical tests will be performed when running analysis of 
covariance (ANCOVA) and are detailed in section 7.5. 
7.1.4 Management of missing or incomplete data 
Previous and concomitant medications 
For the purposes of determining whether a medication was taken during the conduct of the study, any 
missing or partial start or stop dates for which a definitive determination cannot be made will result in 
that medication will be assumed to be concomitant, to be conservative. 
Linear Mixed Model 
Missing data handling for assessing efficacy endpoints using linear mixed model will be described in 
section 7.4.1. 
Adverse Events (AE) 
If part of the date/time of an AE is missing, but the existing parts allow determination of timing of AE 
onset/end relative to start and stop date of the study drug, then the AE will be classified (treatment-
emergent or not treatment-emergent) per review of the existing parts of the date/time field. If timing 
of the AE onset/end relative to start and stop date of the study medication cannot be made, then the 
AE will be assumed to be a Treatment-Emergent Adverse Event (TEAE). 
Vital signs, physical examination, ECG and laboratory values 
For absolute, relative changes and shifts from baseline (W0), in case of missing data for the baseline 
value, the latter will be replaced by the value obtained at screening visit. 


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7.1.5 Handling of dropouts 
Dropouts will be handled for the primary endpoint as described in section 7.1.4. 
The reasons of study termination will be assessed among treatment groups as well as the proportion 
of dropouts at each visit performed (Cf. section 6.4). 
7.1.6 Handling of study centre effects 
No centre effect will be assessed. 
7.1.7 Presentation of results 
Statistical Tables, Figures and Listing (TFL) will be produced in English, and templates are shown in 
appendix 12.2. 
For summary statistics, mean, standard deviation and median will be presented with 1 more decimal 
place than the raw data; min and max with the same number of decimal places as the raw data. P-
values will be presented with three decimal places. 
7.1.8 Examination of subgroups 
Individual genetic mutation will compose the three following subgroups: 
• 
ABCA-1 
• 
ApoA-1 
• 
ABCA-1 & ApoA-1 
These subgroups will be used as independent variable for each primary and secondary ANCOVA. 
Description of each exploratory outcome will also be performed on these subgroups. 
7.1.9 Validation levels 
Internal review by the statistician in charge of the project will be performed, including SAS® codes and 
programming, SAS® logs and outputs and edition of the TFL. Then, an external review of the TFL will 
be performed by the ICTA PM project manager and by the sponsor. 
A double-programming of the primary endpoint analysis will be performed. 
7.2 Demographic and other baseline characteristics 
Demographic and other baseline characteristics will be described according to randomization group 
for all randomized patients. Description will also be performed for each subgroup of interest (based 
on genetic mutation). Baseline is defined as the last observation for any given parameter observed 
prior to the first infusion of study drug. 
The following characteristics will be summarized using standard descriptive statistics (Cf. 7.1.2): 
7.2.1 Demography 
• 
Age at inclusion (years) 
Patient’s age will be a derived variable, defined in years according to the formula:  
Age = (date of signature of written informed consent– date of birth) / 365.25. 
• 
Sex (Male/Female) 
o If Female, Childbearing potential assessed (Yes / Not done / NA) 
 
If Not done, reason 


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 
If Yes, Childbearing potential (Childbearing potential with contraceptive 
protection / Uncertain childbearing potential or post-menopausal status / 
Surgically sterilized / Post-menopausal) 
• 
If Childbearing potential with contraceptive protection, method(s) of 
contraception 
 
If Yes, FSH value (IU/L) 
 
If Yes, Pregnancy test result (Negative/Positive/NA) 
• 
Race (Caucasian / Asian / Black or African American / American Indian or Alaska native / Native 
Hawaiian / Other pacific island / Other / NA) 
o If Other, specification 
• 
Ethnicity (Hispanic/Non-Hispanic/NA) 
7.2.2 Medical history and concomitant diseases 
Medical history and concomitant diseases will be assigned to the Lowest Level Term (LLT), and a 
Preferred Term (PT) will be classified by a High Level Term (HLT), a High Level Group Term (HLGT) and 
a System Organ Class (SOC) according to the Medical Dictionary for Regulatory Activities (MedDRA) 
thesaurus, version 19.1. 
Concomitant diseases will be defined as all diseases/conditions which are ongoing at screening visit. 
All others will be considered as medical history. 
Concomitant diseases and medical history will be summarized according to the Table 2 template (Cf. 
Section 12.2) as follows: 
• 
Number and percentage of patients presenting at least one event (medical history / 
concomitant disease) 
• 
Number and percentage of patients presenting at least one event (medical history / 
concomitant disease) tabulated by SOC and PT 
7.2.3 Risk factors 
• 
Smoking status (Smoker / Former smoker / Non-smoker) 
o If Smoker, Current daily consumption (cigarettes/day) 
o If Former smoker, time since smoking cessation (< 1 year / Between 1-5 years / > 5 
years) 
7.2.4 Patient profile 
• 
Cardiovascular disease background (Symptomatic/Asymptomatic) 
If Symptomatic: 
o History of cardio or cerebrovascular events (Yes/No) 
o Diagnosed coronary artery disease (Yes/No) 
o Diagnosed carotid or peripheral stenosis (Yes/No) 
o Previous myocardial revascularisation - percutaneous coronary intervention, or 
coronary artery bypass graft (Yes/No) 
If Asymptomatic, imaging methods used for diagnosis: 
o Doppler ultrasound (Yes/No) 
o B-mode ultrasonography (Yes/No) 
o Intravascular ultrasonography (Yes/No) 
o Computed Tomography (Yes/No) 
o Magnetic Resonance Imaging (Yes/No) 
 
 


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7.3 Treatment exposure and compliance 
7.3.1 Treatment exposure 
Duration of treatment exposure (weeks) will be described on the safety population according to the 
actual treatment received. It will be calculated as follows: 
Duration of treatment exposure (weeks) = (Date of last infusion – Date of first infusion + 1) / 7 
7.3.2 Treatment compliance 
Treatment compliance will be assessed on the mITT population according to randomized treatment 
group. Compliance (%) with the study treatment will be summarized on each study period (Induction 
/ Maintenance / Extension) and at W24, W48 as follows: 
• 
Compliance during induction phase (%) = Number of infusions totally administered between 
W0 and W8 / 9 * 100 
• 
Compliance during maintenance phase (%) = Number of infusions totally administered between 
W10 and W24 / 8* 100 
• 
Compliance during extension phase(%) = Number of infusions totally administered between 
W26 and W48 / 12 * 100 
• 
Compliance at W24 (%) = Number of infusions totally administered between W0 and W24 / 17 
* 100 
• 
Compliance at W48 (%) = Number of infusions totally administered between W0 and W48 / 
29* 100 
Average dose, total dose of CER-001 as well as administered dose vs expected dose will be summarized 
at W8, W24, W48, and are defined as follows: 
• 
Total dose at Wi (mg) = ∑
𝐶𝐶𝐶𝐶𝐶𝐶001 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑓𝑓𝑓𝑓𝑓𝑓 𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖 𝑣𝑣 ቀ
𝑚𝑚𝑚𝑚
𝑘𝑘𝑘𝑘ቁ∗
𝑛𝑛𝑛𝑛
𝑣𝑣=1
 𝑊𝑊𝑊𝑊𝑊𝑊𝑊𝑊ℎ𝑡𝑡 𝑎𝑎𝑎𝑎 𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖 𝑣𝑣 (𝑘𝑘𝑘𝑘) ∗ 𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑎𝑎𝑎𝑎 𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖 𝑣𝑣 (𝑚𝑚𝑚𝑚) / 250, 
when ni = number of infusions received between W0 and Wi 
• 
Average dose at Wi (mg) = Total dose at Wi (mg) / number of infusions received between W0 
and Wi 
• 
Administered dose vs expected dose at Wi (%) = Total dose at Wi (mg) / (8 * 
∑
𝑊𝑊𝑊𝑊𝑊𝑊𝑊𝑊ℎ𝑡𝑡 𝑎𝑎𝑎𝑎 
𝑚𝑚𝑚𝑚
𝑣𝑣=1
𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖 𝑣𝑣) * 100, when mi = number of infusions planned between W0 and 
Wi 
In addition, a by-patient listing will be produced for each patient who verified for at least one visit: 
• 
Dose prescription different from 8 mg/kg 
• 
Time elapsed between study medication infusion preparation and study medication 
administration > 72h (48h for Canadian sites) 
• 
Start infusion time – stop infusion time > 65 min or < 55 min 
• 
Total volume administered = No 
For these patients, the listing will include, for all available visits: 
• 
Patient ID, visit, treatment arm 
• 
Dose prescription (mg/kg) 
• 
Date and time of study medication infusion preparation 
• 
Date of infusion, start and stop infusion time 
• 
If not administered, reason 
• 
If infusion duration different from 60 min, reason 


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• 
Total volume administered (Yes/No) 
• 
If No, volume administered (mL) 
 
7.4 Efficacy data 
7.4.1 Primary endpoint 
The primary efficacy endpoint is defined as the difference in the change from baseline in carotid artery 
MVWA at 24 weeks in patients treated with CER-001 compared to patients treated with placebo. 
Analysis of the primary endpoint will consist of a main analysis, a supportive analysis and several 
sensitivity analyses. 
7.4.1.1 
Main analysis 
A linear mixed model with repeated measures (MMRM) will be fitted to observed data for the mITT 
population without any imputation. An unstructured covariance matrix will be used to model random 
effects. The model will include the following variables: 
• 
Change from baseline in carotid artery MVWA (mm², dependent variable) 
• 
Randomized treatment group (CER-001 vs Placebo, independent variable) 
• 
Genetic mutation (ABCA-1/ApoA-1/ABCA-1 and ApoA-1), independent variable) 
• 
Carotid artery MVWA at W0 (mm², covariate) 
• 
Visit (W8/W24/W48, independent variable) 
• 
Treatment-by-Visit interaction (independent variable) 
• 
Carotid artery MVWA at W0 by Visit interaction (independent variable) 
• 
Treatment-by-carotid artery MVWA at W0 (independent variable) 
• 
Subject (random factor) 
Sample SAS Code 
proc mixed data=DATASET method=reml covtest asycov alpha=0.05; 
 
class USUBJID TRTGRP (ref=”Placebo”) VISIT (ref=LAST) GENETIC_MUT (ref=”REF”); 
 
model CHANGE = BASELINE GENETIC_MUT BASELINE*VISIT TRTGRP VISIT  
VISIT*TRTGRP BASELINE*TRTGRP / s ddfm=kr; 
 
repeated visit / subject=USUBJID type=UN r rcorr; 
 
lsmeans VISIT*TRTGRP / diff cl om e; 
 
estimate “Treatment Effect” TRTGRP 1 -1 VISIT*TRTGRP 0 1 0 0 -1 0 / cl; 
run; 
 
Adjusted means in change from baseline for each treatment group (with 95%CI) as well as treatment 
effect (with 95%CI) at W24 will be provided. Treatment effect will be calculated as the difference in 
adjusted mean values for the two treatment groups at W24. 
Adjusted means in change from baseline and treatment effect will also be estimated at W24 within 
each genetic mutation subgroup. 


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A scatter plot will also be drawn representing the evolution of the carotid artery MVWA (mm²) 
according to the carotid artery MVWA at week 0 (mm2) grouped by treatment group.  
Adjusted means (with 95%CI) of each randomized treatment group will also be plotted. 
Results will be displayed according to table 5 of section 12.1. 
7.4.1.2 
Supportive analysis 
As a supportive analysis, the linear mixed model described in the previous section (7.4.1.1) will also be 
fitted to observed and imputed data for the mITT population. Thus, a multiple imputation procedure 
will be set up and is described below. 
First, in case of non-monotone missing data pattern, a MI procedure will be applied using a MCMC 
algorithm to create 20 imputed datasets with a monotone missing data pattern. The number of burn-
in iterations before each imputation will be set to 200. Sample SAS code is displayed below. 
Sample SAS Code 
proc mi data=DATWIDE nimpute=20 seed=111 out=MONODAT; 
 
var TRTGRP GENETIC_MUT BASELINE CHANGE8 CHANGE24 CHANGE48; 
 
mcmc chain=MULTIPLE impute=MONOTONE nbiter=200; 
run; 
 
Second, the 20 datasets with a monotone missing data pattern will be fully imputed based on a 
monotone method. Corresponding sample SAS code is provided below. 
Sample SAS Code 
proc mi data= MONODAT nimpute=1 seed=222 out=MONODAT; 
 
by _IMPUTATION_; 
 
class TRTGRP GENETIC_MUT; 
 
var TRTGRP GENETIC_MUT BASELINE CHANGE8 CHANGE24 CHANGE48; 
 
monotone regression (CHANGE8 CHANGE24 CHANGE48); 
run; 
 
Finally, the linear mixed model described in section 7.4.1.1 will be applied for each complete data sets 
producing 20 analysis results. The final treatment effect estimate will be obtained combining these 20 
estimates as follows: 


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Sample SAS Code 
proc mianalyze data=MRESULTS_; 
 
modeleffects ESTIMATE; 
 
stderr STDERR; 
 
ods output parameterestimates=RESULTS_; 
run; 
 
7.4.1.3 
Sensitivity analyses 
7.4.1.3.1 Missing Not At Random data mechanism 
These sensitivity analyses require partitioning the analysis mITT population into groups, based on 
treatment group and available information about the reasons for missing values, before multiple 
imputation.  
Control-based I: all dropouts grouped with placebo 
In the first control-based sensitivity analysis, all monotone missing values will be imputed such as all 
dropouts and the placebo group form a subset with similar trajectories. A dataset, MONOREF_all, 
containing all the placebo group subjects and the treatment group subjects with missing data, will be 
imputed as shown in sample SAS code below. The complement of MONOREF_all will be the complete 
observation treated group data, so this could be concatenated with the 20 imputed datasets in 
DATIMP1. 
Sample SAS Code 
proc mi data= MONOREF_all nimpute=1 seed=333 out=DATIMP1; 
 
by _IMPUTATION_; 
 
class GENETIC_MUT; 
 
var GENETIC_MUT BASE CHANGE8 CHANGE24 CHANGE48; 
 
monotone regression (CHANGE8 CHANGE24 CHANGE48); 
run; 
Control-based II (informative-dropout): poor-outcome dropouts grouped with placebo 
In the informative-dropout sensitivity analysis, some subjects are characterized as likely to have poor 
unobserved outcomes, for example if study withdrawal is due to clinical worsening. In this case, the 
datasets in MONODAT (monotone dataset) will be first split by treatment groups, either randomized 
to the experimental (TRTGRP) or reference/placebo (REF) condition, and then the poor-outcome 
dropouts will be shifted to the REF group, resulting in the datasets MONOTRT_minus and 
MONOREF_plus. The multiple imputation will be conducted separately for each subset as shown in the 
following sample code. The output datasets, DATIMP2T and DATIMP2R, will simply be concatenated 
before the analysis step. 


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proc MI data= MONOTRT_minus nimpute=1 seed=444 out=DATIMP2T; 
 
by _IMPUTATION_; 
 
class GENETIC_MUT; 
 
var GENETIC_MUT BASE CHANGE8 CHANGE24 CHANGE48; 
 
monotone regression (CHANGE8 CHANGE24 CHANGE48); 
run; 
 
proc MI data= MONOREF_plus nimpute=1 seed=555 out=DATIMP2R; 
 
by _IMPUTATION_; 
 
class GENETIC_MUT; 
 
var GENETIC_MUT BASE CHANGE8 CHANGE24 CHANGE48; 
 
monotone regression (CHANGE8 CHANGE24 CHANGE48); 
run; 
Control-based III: poor-outcome dropouts act like reference 
In the third control-based sensitivity analysis, the MNAR statement will be used to allow poor-outcome 
subjects to follow the expected trajectory of a subject in the reference group (see sample code below). 
Since the treated subjects from MONOTRT_minus are treated similarly as in the informative-dropout 
scenario, the results here in DATIMP3R could be contatenated with DATAIMP2T for analysis. 
proc MI data= MONOREF_plus nimpute=1 seed=666 out=DATIMP3R; 
 
by _IMPUTATION_; 
 
class GENETIC_MUT; 
 
var GENETIC_MUT BASE CHANGE8 CHANGE24 CHANGE48; 
 
monotone regression; 
 
mnar model (CHANGE8 CHANGE24 CHANGE48) / modelobs=(TRTGRP=”REF”); 
run; 
For each scenario, every 20 analysis estimates will be combined in one final estimate. 
7.4.1.3.2 Analysis on the PP population 
Primary efficacy analysis described for ITT population will also be performed on PP population in the 
same way (see sections 7.4.1.1 & 7.4.1.2). 
 
7.4.2 Secondary endpoints 
All secondary endpoints will be analysed on the mITT population. 


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7.4.2.1 
Change from baseline in carotid artery MVWA 
Estimators of the secondary endpoints listed below will be obtained using the mixed model already 
fitted in section 7.4.1.1: 
• 
Difference in change (Experimental treatment vs placebo) from baseline (W0) in carotid artery 
MVWA at 8 weeks 
• 
Difference in change (Experimental treatment vs placebo) from baseline (W0) in carotid artery 
MVWA at 48 weeks 
7.4.2.2 
Change from baseline in femoral artery MVWA 
A linear mixed model with repeated measures (MMRM) will be fitted to observed data for the mITT 
population without any imputation. An unstructured covariance matrix will be used to model random 
effects. The model will include the following variables: 
• 
Change from baseline in femoral artery MVWA (mm², dependent variable) 
• 
Randomized treatment group (CER-001 vs Placebo, independent variable) 
• 
Genetic mutation (ABCA-1/ApoA-1/ABCA-1 and ApoA-1), independent variable) 
• 
Femoral artery MVWA at W0 (mm², covariate) 
• 
Visit (W8/W24/W48, independent variable) 
• 
Treatment-by-Visit interaction (independent variable) 
• 
Femoral artery MVWA at W0 by Visit interaction (independent variable) 
• 
Treatment-by-femoral artery MVWA at W0 (independent variable) 
• 
Subject (random factor) 
Analysis will be based on that described for the main analysis of the primary endpoint (section 7.4.1.1). 
No multiple imputation will be performed. 
The following differences between placebo and the experimental treatment will be estimated: 
• 
Change from baseline (W0) in femoral artery MVWA at 8 weeks 
• 
Change from baseline (W0) in femoral artery MVWA at 24 weeks 
• 
Change from baseline (W0) in femoral artery MVWA at 48 weeks. 
These estimators will also be calculated within each genetic mutation. 
7.4.2.3 
Change from baseline in target (plaque) to background (blood) ratio 
An analysis of covariance (ANCOVA) will be fitted to observed data for the mITT population without 
any imputation. The model will include the following variables: 
• 
Change from baseline (W0) in TBR based on standardized 18FDG uptake measured with 
18FDG-PET/CT MVWA at 24 weeks (dependent variable) 
• 
Randomized treatment group (CER-001 vs Placebo, independent variable) 
• 
Genetic mutation (ABCA-1/ApoA-1/ABCA-1 and ApoA-1), independent variable) 
• 
TBR at W0 (covariate) 
• 
Interaction Treatment by TBR at W0 (independent variable) 
Adjusted means for the change in TBR and the associated 95%CI will be provided for each randomized 
treatment group. Adjusted mean difference and the associated 95%CI will also be displayed. 


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Sample SAS Code 
proc glm data=DATWIDE alpha=0.05; 
 
class TRTGRP GENETIC_MUT; 
 
model CHANGE24 = BASELINE GENETIC_MUT BASELINE*TRTGRP TRTGRP / s; 
 
lsmeans TRTGRP / cl pdiff=control(“REF”); 
run; 
 
The previous statistics will also be estimated within each genetic mutation. 
A scatter plot will be drawn representing the evolution of the TBR at week 24 according to the baseline 
TBR grouped by treatment group. Adjusted means (with 95%CI) for the change from baseline in each 
randomized treatment group will also be plotted. 
 
7.4.3 Exploratory endpoints 
The following exploratory endpoints will be summarized on the mITT population overall according to 
randomized study treatment and for each genetic subgroup within the randomized group using 
descriptive statistics: 
• 
Percent change from baseline in femoral artery MVWA at 8, 24, 48, 72 weeks 
• 
Percent change from baseline in maximum vessel wall thickness (MaxVWT) at 8, 24, 48, 72 
weeks 
• 
Percent change from baseline in mean vessel wall thickness at 8, 24, 48, 72 weeks 
• 
Absolute and percent change in carotid mean vessel wall volume (MVWV) at 8, 24, 48, 72 
weeks 
• 
Percent change from baseline in the mean of the carotid normalized wall index at 8, 2448, 72 
weeks 
• 
Absolute and percent change from baseline in femoral artery MVWV at 8, 24, 48, 72 weeks 
Percent change from baseline at Wi is defined as follows: 
(Value at Wi – Value at baseline (W0)) / Value at baseline (W0)*100 
Vessel wall biology (C-reactive protein (mg/L), PON-1 (IU/L), MMP-9, TNFα, IL-6, soluble VCAM-1, 
sMCP1, oxysterols, ABCA-1 mRNA and protein levels) will be summarized at screening, W0 (baseline), 
W4, W8, W24, W48. Absolute and relative changes from W0 (baseline) at W8, W24 and W48 will also 
be summarized. For changes calculation, if value at W0 is missing then value observed at screening will 
be used. 
Cholesterol efflux capacity will be summarized at screening, W0, W8, W24 and W48. Absolute and 
relative changes from W0 (baseline) at W8, W24 and W48 will also be summarized. For changes 
calculation, if value at W0 is missing then value observed at screening will be used. 
Lipid profile will be summarized at screening, W0, W8, W24 and W48. Absolute and relative changes 
from screening at W8, W24 and W48 will also be summarized (LABTYPE = Lipids): 
• 
Total Cholesterol (mmol/L) 
• 
Free Cholesterol (mmol/L) 


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• 
Esterified Cholesterol (mmol/L) 
• 
LDL Cholesterol (mmol/L) 
• 
HDL Cholesterol (mmol/L) 
• 
Triglycerides (mmol/L) 
• 
Apolipoprotein A-1 (g/L) 
• 
Apolipoprotein A-2 (g/L) 
• 
Apolipoprotein B (g/L) 
• 
Apolipoprotein C-3 (g/L) 
• 
Apolipoprotein E (g/L) 
For changes calculation, if value at W0 is missing then value observed at screening will be used. 
HDL-C Particle Size (2D-gel/NMR) will be summarized at screening, W0, W8, W24 and W48. NMR 
laboratory tests are the following (LABTYPE = Liposcience): 
HDL particles (µmol/L), Large HDL particles (µmol/L), Medium HDL particles (µmol/L), Small HDL 
particles (µmol/L), HDL size (nm), IDL particles (nmol/L), LDL particles (nmol/L), Large LDL particles 
(nmol/L), Small LDL particles (nmol/L), LDL size (nm), HDL cholesterol (mg/dL), Triglyceride (total) 
(mg/dL), VLDL & Chylomicron Triglyceride (total) (mg/dL), Large VLDL & Chylomicron Particles 
(nmol/L), VLDL & Chylomicron Particles (total) (nmol/L), Medium VLDL Particles (nmol/L), Small VLDL 
Particles (nmol/L), VLDL Size (nm). 
7.5 Safety data 
All safety analyses will be performed on the safety population according to the actual treatment 
received. 
7.5.1 Adverse events (AE) 
AE term (Investigator term) will be assigned to the lowest level term (LLT), and a preferred term (PT) 
will be classified by a high level term (HLT), a high level group term (HLGT) and a system organ class 
(SOC) according to the Medical Dictionary for Regulatory Activities (MedDRA) thesaurus, version 19.1 
or higher. 
An adverse event will be considered as treatment-emergent (TEAE) if AE onset date is between first 
infusion of CER-001 and last infusion of CER-001 + 28 days, or if AE occurred before the first infusion 
of CER-001 but gets worse on study treatment. In case of incomplete date(s), see section 7.1.4. 
An overview of the number of patients with at least one AE and the corresponding number of AEs will 
be presented including: 
• 
Any AE 
• 
Any TEAE 
• 
Any serious TEAE 
• 
Any severe TEAE 
• 
Any TEAE leading to dose reduction of the study medication 
• 
Any TEAE leading to temporary discontinuation of the study medication 
• 
Any TEAE leading to permanent discontinuation of the study medication 
• 
Any TEAE related to the study medication (Related = definite, probable or possible) 
• 
Fatal AE 
• 
Fatal TEAE 
• 
Any coronary event (Coronary event = event for which HLGT = Coronary artery disorders) 
All PT with HLGT = Coronary artery disorders will be described in the same way in a separate table. 


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Note: recurring AEs (i.e. AEs classified with the same Preferred Term (PT)) for a given patient will be 
only counted once and only their most severe intensity or most severe relationship to the study 
medication will be described. 
TEAEs will also be tabulated by System Organ Class (SOC) and PT. They will be presented according to 
seriousness (Serious / Not serious), severity (Mild/Moderate/Severe) and relationship with the study 
medication (Related / Not related). They will finally be tabulated by SOC and PT according to 
relationship with the study medication within severity. 
The different analyses described above will be summarized overall, on the induction period and on the 
post-induction period (AEs that occurred during maintenance or extension phase). Assignment of AEs 
to periods will be performed as follows: 
Period 
Assignment 
Induction 
Start date of TEAE < date of infusion at W10 
(if day of AE is missing then impute to first of the month) 
Post-induction 
Start date of TEAE ≥ date of infusion at W10 
(if day of AE is missing then impute to first of the month) 
 
TEAE leading to death, other SAE (AE leading to death excluded) and other significant AE (any events 
leading to dose reduction, leading to temporary/permanent discontinuation of the study medication) 
will also be described on an individual basis. These listings will include the following information: 
• 
Randomization group 
• 
Patient identifier 
• 
Age, race, ethnicity, sex, weight at inclusion 
• 
Investigator's reported term, preferred term 
• 
Duration of the adverse event 
• 
Severity 
• 
Seriousness 
• 
Action taken 
• 
Outcome 
• 
Relationship with the study medication 
• 
Timing of onset of the adverse event in relation to last dose of study medication 
• 
Study treatment at time of event or most recent study treatment taken 
• 
Study drug dose in absolute amount 
• 
Total number of infusions received 
 
 


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7.5.2 Vital signs, physical examination, ECG 
Clinical examination and vital signs will be summarized at each time point (screening, W0 (baseline), 
W4, W8, W16, W24, W32, W40, W48, 4 weeks after last dose). In addition, absolute changes from W0 
(baseline) will be calculated at each post-baseline time point. Absolute change at Wi is defined as 
follows: Value at Wi - Value at W0. 
• 
Respiratory rate (breaths/min) 
• 
Systolic blood pressure (mmHg) 
• 
Diastolic blood pressure (mmHg) 
• 
Heart rate (beats/min) 
• 
Body temperature (°C) 
• 
Body weight (kg) 
• 
Body mass index (kg/m²) 
ECG diagnosis (Normal / Abnormal, not clinically significant (NCS) / Abnormal and clinically significant 
(CS)) will be summarized at screening and presented through shift tables from W0 (baseline) for the 
following time points: W4, W8, W16, W24, W32, W40, W48, 4 weeks after last dose). 
In case of abnormal result regarding ECG (clinically significant or not) for a given patient, a listing will 
be produced including patient’s identification, visit, date of assessment, ECG diagnosis, specification 
for the result and remarks, whatever the visit. 
Assessment of physical examination (Normal / Abnormal non-clinically significant / Abnormal clinically 
significant) will be described at screening and presented through shift tables from W0 (baseline) for 
the following time points: W4, W8, W16, W24, W32, W40, W48, 4 weeks after last dose). 
In case of missing value at W0 for a variable, imputation will be performed using the value obtained at 
screening. This imputation will be performed for shift tables only and absolute changes. 
Shift tables will be: 
- 
No change (from normal to normal / from abnormal NCS to abnormal NCS / from abnormal CS 
to abnormal CS) 
- 
Improvement (from abnormal NCS to normal / from abnormal CS to abnormal NCS / from 
abnormal CS to normal) 
- 
Deterioration (from normal to abnormal CS / from normal to abnormal NCS / from abnormal 
NCS to abnormal CS) 
7.5.3 Laboratory parameters 
All laboratory parameters will be summarized using descriptive statistics. Then, shift tables and 
absolute changes for each laboratory parameter will be displayed summarizing individual patient 
changes from baseline to each post-baseline time point. In case of missing value at W0 (baseline) for 
a variable, imputation will be performed using the value obtained at screening. This imputation 
method will only be applied for generation of shift tables. Unreportable values will be replaced by 0. 
Haematology results will be assessed at screening, W0 (baseline), W4, W8, W16, W24, W32, W40, 
W48): 
• 
Red blood cell count (109/L) 
• 
Haemoglobin (g/L) 
• 
Haematocrit (%) 
• 
White blood cell count (109/L) 
• 
Platelet count (109/L) 


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• 
Neutrophils (109/L) 
• 
Lymphocytes (109/L) 
• 
Monocytes (109/L) 
• 
Eosinophils (109/L) 
• 
Basophils (109/L) 
Biochemistry results will be assessed at screening, W0 (baseline), W4, W8, W16, W24, W32, W40, 
W48: 
• 
Glucose (mmol/L) 
• 
Blood urea nitrogen (mmol/L) 
• 
Creatinine (µmol/L) 
• 
Creatinine clearance (mL/min) 
• 
Uric acid (µmol/L) 
• 
Albumin (g/L) 
• 
Total protein (g/L) 
• 
Total bilirubin (µmol/L) 
• 
Indirect bilirubin (µmol/L) 
• 
Creatine Kinase (IU/L) 
• 
Alkaline phosphatase (IU/L) 
• 
AST (SGOT) (IU/L) 
• 
ALT (SGPT) (IU/L) 
• 
Lactate dehydrogenase (IU/L) 
• 
Calcium (mmol/L) 
• 
Potassium (mmol/L) 
• 
Sodium (mmol/L) 
• 
Phosphorous (mmol/L) 
• 
Chloride (mmol/L) 
• 
Total CO2 (mmol/L) 
Urinalysis will be assessed at screening, W0 (baseline), W4, W8, W16, W24, W32, W40, W48: 
• 
White Blood Cell (WBC) (per HPF) 
• 
Red Blood Cell (RBC) (per HPF) 
• 
Total protein (positive/negative) 
• 
Glucose (positive/negative) 
• 
Total bilirubin (positive/negative) 
• 
Ketones (positive/negative) 
• 
pH 
• 
Microalbuminuria (mg/L) 
• 
Casts (per LPF) 
• 
Specific gravity 
Fasting blood glucose will be summarized at screening, W0, W4, W8, W16, W24, W32, W40 and W48. 
In case of abnormal and clinically significant result for a parameter, a by-patient listing of all laboratory 
values for the parameter during the study will be produced. 
Shift tables will be: 
- 
No change (from positive to positive / from negative to negative) 
- 
Improvement (from negative to positive) 


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- 
Deterioration (from positive to negative) 
7.6 Previous and concomitant medications 
All medications for which end date is prior to the first study drug infusion will be considered as previous 
medication. Otherwise they will be concomitant. 
Previous and concomitant medications will be described by randomization groups by their therapeutic 
class (ATC) level 2 and ATC level 4 (WHO Drug Dictionary, version of March 2016 or later) according to 
the Table 3 template (Cf. Section 12.2): 
• 
Number and percentage of patients presenting at least one previous/concomitant medication 
will be described in each treatment group.  
• 
Previous/concomitant medication will also be presented per ATC and PT in a frequency table, 
for each treatment group. 
7.7 Listings of individual data 
All collected data and derived variables used for the statistical analysis will also be presented in 
individual patient listings, in accordance with ICH appendix 16.2. Each patient will be identified in these 
listings by his/her unique patient number. 
8. Interim analyses 
No interim analysis is planned. 
9. Data and Safety Monitoring Board 
The Data and Safety Monitoring Board (DSMB) will formally review unblinded study safety data to 
ensure there is no avoidable increased risk for harm to patients. Analyses for the DSMB meetings will 
be performed by an independent statistician (different from the one who will perform the final 
analysis). A specific SAP displays the safety data generated needed for the DSMB review. 
10. Modifications with respect to the protocol 
Analysis of efficacy endpoints 
Statistical analysis of the primary and secondary outcomes (changes from baseline) were modified with 
respect to the protocol. In order to gain in terms of power, model will be fitted using all observations 
available for each patient during the study. Hence, linear mixed model with repeated measures will be 
used instead of analysis of covariance, Changes from baseline for a specified outcome could therefore 
be estimated at different time points based on the same model. 


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11. Approval of the Statistical Analysis Plan 
ICTA PM 
SPONSOR 
Project Manager: 
Banu DEMIRCI-GUILLERMET 
Date:  
Signature: 
 
 
Sr VP Clinical Development & Operations: 
Constance KEYSERLING 
Date: 
Signature: 
 
Biostatistician: 
Stéphanie PEROT 
Date: 
Signature: 
 
 
 
Head of Medical and Scientific Development: 
Jérémy SJRZYPSKI 
Date: 
Signature: 
 
 
 
 


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12. Appendices 
12.1 Tables and graphs templates 
Table 1 Disposition of patients 
 
 
CER-001 
Placebo 
Total 
Patients screened 
 
 
 
xx 
Screening failures 
 
 
 
xx 
Reason for screening failures xxxxx 
 
 
xx 
 
xxxxx 
 
 
xx 
 
 
 
 
 
Patients randomized 
 
xx 
xx 
xx 
Patients with ABCA-1 mutation 
 
xx 
xx 
xx 
Patients with homozygous ABCA-1 mutation  
xx 
xx 
xx 
Patients with ApoA-1 mutation 
 
xx 
xx 
xx 
Patients with homozygous ApoA-1 mutation  
xx 
xx 
xx 
Patients with both ABCA-1 and ApoA-1 mutation  
xx 
xx 
xx 
 
 
 
 
 
Patients who did not receive any medication 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Reasons xxxxx 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xxxxx 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
Patients who received double-blind medication 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
Treatment actually received 
CER-001 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Placebo 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
Study completed 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Study prematurely withdrawn 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Reason for premature withdrawal xxxxx 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xxxxx 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
Study treatment prematurely discontinued 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Reason for premature discontinuation xxxxx 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xxxxx 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
Induction period completed 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Maintenance period completed 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Extension period completed 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 


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CER-001 
Placebo 
Total 
 
 
 
 
 
Patient’s follow-up duration 
N 
xx 
xx 
xx 
 
Missing values 
xx 
xx 
xx 
 
Mean ± SD 
xx ± xx 
xx ± xx 
xx ± xx 
 
Median 
xx 
xx 
xx 
 
Q1 ; Q3 
xx ; xx 
xx ; xx 
xx ; xx 
 
Min ; Max 
xx ; xx 
xx ; xx 
xx ; xx 
 
 
 
 
 
First Patient First Visit (FPFV)  
 
 
 
DD/MM/YYYY 
Last Patient First Visit (LPFV)  
 
 
 
DD/MM/YYYY 
Last Patient Last Visit (LPLV) 
 
 
 
DD/MM/YYYY 
 
Table 2 Descriptive statistics of quantitative and qualitative variables 
 
 
 
CER-001 
N=xx 
Placebo 
N=xx 
Total 
N=xx 
 
 
 
 
 
Quantitative variable 
N 
xx 
xx 
xx 
 
Missing values 
xx 
xx 
xx 
 
Mean ± SD 
xx ± xx 
xx ± xx 
xx ± xx 
 
Median 
xx 
xx 
xx 
 
Q1 ; Q3 
xx ; xx 
xx ; xx 
xx ; xx 
 
Min ; Max 
xx ; xx 
xx ; xx 
xx ; xx 
 
 
 
 
 
Qualitative variable 
N 
xx 
xx 
xx 
 
Missing values 
xx 
xx 
xx 
 
Modality 1 
xx (xx. x %) 
xx (xx. x %) 
xx (xx. x %) 
 
Modality 2 
xx (xx. x %) 
xx (xx. x %) 
xx (xx. x %) 
 
… 
… 
… 
… 
 
 
 


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Table 3 Medical History by System Organ Class and Preferred Term 
 
System Organ Class 
 
Preferred term 
CER-001 
N=xx 
Placebo 
N=xx 
Total 
N=xx 
At least one medical History 
xx ( xx.x%) 
xx ( xx.x%) 
xx ( xx.x%) 
 
 
 
 
System organ class 1 
xx   (xx.x%) 
xx   (xx.x%) 
xx   (xx.x%) 
 
Preferred term 1 
x   (x.x%) 
x   (x.x%) 
x   (x.x%) 
 
… 
x   (x.x%) 
x   (x.x%) 
x   (x.x%) 
 
Preferred term X 
x   (x.x%) 
x   (x.x%) 
x   (x.x%) 
 
 
 
 
System organ class 2 
xx   (xx.x%) 
xx   (xx.x%) 
xx   (xx.x%) 
 
… 
x   (x.x%) 
x   (x.x%) 
x   (x.x%) 
 
Table 4 Concomitant treatments by Therapeutic Class and Preferred Term 
 
Therapeutic class 
 
Preferred term 
CER-001 
N=xx 
Placebo 
N=xx 
Total 
N=xx 
At least one concomitant medication 
xx ( xx.x%) 
xx ( xx.x%) 
xx ( xx.x%) 
 
 
 
 
Therapeutic class 1 
xx   (xx.x%) 
xx   (xx.x%) 
xx   (xx.x%) 
 
Preferred term 1 
x   (x.x%) 
x   (x.x%) 
x   (x.x%) 
 
… 
x   (x.x%) 
x   (x.x%) 
x   (x.x%) 
 
Preferred term X 
x   (x.x%) 
x   (x.x%) 
x   (x.x%) 
 
 
 
 
Therapeutic class 2 
xx   (xx.x%) 
xx   (xx.x%) 
xx   (xx.x%) 
 
… 
x   (x.x%) 
x   (x.x%) 
x   (x.x%) 
 
Table 5 Adverse events by System Organ Class and Preferred Term 
 
System Organ Class 
 
Preferred term 
CER-001 
N=xx 
Placebo 
N=xx 
Total 
N=xx 
At least one AE 
xx ( xx.x%) 
xx ( xx.x%) 
xx ( xx.x%) 
 
 
 
 
System organ class 1 
xx   (xx.x%) 
xx   (xx.x%) 
xx   (xx.x%) 
 
Preferred term 1 
x   (x.x%) 
x   (x.x%) 
x   (x.x%) 
 
… 
x   (x.x%) 
x   (x.x%) 
x   (x.x%) 
 
Preferred term X 
x   (x.x%) 
x   (x.x%) 
x   (x.x%) 
 
 
 
 
System organ class 2 
xx   (xx.x%) 
xx   (xx.x%) 
xx   (xx.x%) 
 
… 
x   (x.x%) 
x   (x.x%) 
x   (x.x%) 
 
 


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Table 6 Primary and secondary endpoints: linear mixed model with repeated measures for change in 
outcome xx from baseline to W8, W24 and W48 
Independent variable 
Covariate 
Parameter estimate 
P-value 
 
 
 
Intercept 
xx.x 
x.xxx 
 
 
 
Genetic mutation 
 
 
 
ABCA-1 
xx.x 
x.xxx 
 
ApoA-1 
xx.x 
x.xxx 
 
ABCA-1 and ApoA-1 
xx.x 
x.xxx 
 
 
 
Baseline outcome xx 
xx.x 
x.xxx 
 
 
 
Interaction Baseline outcome * Visit 
 
 
 
W8 
xx.x 
x.xxx 
 
W24 
xx.x 
x.xxx 
 
W48 
0.0 
-- 
 
 
 
Interaction Baseline outcome * Treatment 
 
 
 
CER-001 
xx.x 
x.xxx 
 
Placebo 
0.0 
-- 
 
 
 
Visit 
 
 
 
W8 
xx.x 
x.xxx 
 
W24 
xx.x 
x.xxx 
 
W48 
0.0 
-- 
 
 
 
Randomized treatment 
 
 
 
CER-001 
xx.x 
x.xxx 
 
Placebo 
0.0 
-- 
 
 
 
Interaction Visit by Treatment 
 
 
 
W8 * CER-001 
xx.x 
x.xxx 
 
W24 * CER-001 
xx.x 
x.xxx 
 
W48 * CER-001 
0.0 
-- 
 
W8 * Placebo 
0.0 
-- 
 
W24 * Placebo 
0.0 
-- 
 
W48 * Placebo 
0.0 
-- 
 
 
 


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Table 7 Primary and secondary endpoints: linear mixed model with repeated measures for change in 
outcome xx from baseline to W8, W24 and W48 – Changes adjusted for the model and treatment 
effect 
 
CER-001 
LS-mean [95% CI] (p-value) 
Placebo  
LS-mean [95% CI] (p-value) 
Treatment effect 
Difference in LS-means [95% 
CI] (p-value) 
 
 
 
 
Overall change in outcome x from 
baseline to: 
 
 
 
 
W8 
xx.x [xx.x ; xx.x] (x.xxx) 
xx.x [xx.x ; xx.x] (x.xxx) 
xx.x [xx.x ; xx.x] (x.xxx) 
 
W24 
xx.x [xx.x ; xx.x] (x.xxx) 
xx.x [xx.x ; xx.x] (x.xxx) 
xx.x [xx.x ; xx.x] (x.xxx) 
 
W48 
xx.x [xx.x ; xx.x] (x.xxx) 
xx.x [xx.x ; xx.x] (x.xxx) 
xx.x [xx.x ; xx.x] (x.xxx) 
 
 
 
 
(ABCA-1 genetic mutation subgroup)  
Change in outcome x from baseline to 
 
 
 
 
W8 
xx.x [xx.x ; xx.x] (x.xxx) 
xx.x [xx.x ; xx.x] (x.xxx) 
xx.x [xx.x ; xx.x] (x.xxx) 
 
W24 
xx.x [xx.x ; xx.x] (x.xxx) 
xx.x [xx.x ; xx.x] (x.xxx) 
xx.x [xx.x ; xx.x] (x.xxx) 
 
W48 
xx.x [xx.x ; xx.x] (x.xxx) 
xx.x [xx.x ; xx.x] (x.xxx) 
xx.x [xx.x ; xx.x] (x.xxx) 
 
 
 
 
(ApoA-1 genetic mutation subgroup)  
Change in outcome x from baseline to 
 
 
 
 
W8 
xx.x [xx.x ; xx.x] (x.xxx) 
xx.x [xx.x ; xx.x] (x.xxx) 
xx.x [xx.x ; xx.x] (x.xxx) 
 
W24 
xx.x [xx.x ; xx.x] (x.xxx) 
xx.x [xx.x ; xx.x] (x.xxx) 
xx.x [xx.x ; xx.x] (x.xxx) 
 
W48 
xx.x [xx.x ; xx.x] (x.xxx) 
xx.x [xx.x ; xx.x] (x.xxx) 
xx.x [xx.x ; xx.x] (x.xxx) 
 
 
 
 
(ABCA-1 & ApoA-1 genetic mutations 
subgroup)  
Change in outcome x from baseline to 
 
 
 
 
W8 
xx.x [xx.x ; xx.x] (x.xxx) 
xx.x [xx.x ; xx.x] (x.xxx) 
xx.x [xx.x ; xx.x] (x.xxx) 
 
W24 
xx.x [xx.x ; xx.x] (x.xxx) 
xx.x [xx.x ; xx.x] (x.xxx) 
xx.x [xx.x ; xx.x] (x.xxx) 
 
W48 
xx.x [xx.x ; xx.x] (x.xxx) 
xx.x [xx.x ; xx.x] (x.xxx) 
xx.x [xx.x ; xx.x] (x.xxx) 
 
 
 


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Table 8 Secondary endpoint: analysis of covariance for change from baseline in TBR: 
Independent variable 
Covariate 
Parameter estimate 
P-value 
 
 
 
Model 
 
x.xxx 
 
 
 
Intercept 
xx.x 
x.xxx 
 
 
 
CER-001 
xx.x 
x.xxx 
Placebo 
0.00 
-- 
 
 
 
 
 
 
ABCA-1 genetic mutation 
xx.x 
x.xxx 
ApoA-1 genetic mutation 
xx.x 
x.xxx 
ABCA-1 and ApoA-1 genetic mutations 
0.00 
-- 
 
 
 
Baseline outcome 
xx.x 
x.xxx 
 
Table 9 Secondary endpoint: analysis of covariance for change from baseline in TBR - Changes adjusted 
for the model and treatment effect 
 
 
See Table 7 
 
Table 10 Shifts from baseline: 
 
CER-001 
N=xx 
Placebo 
N=xx 
Total 
N=xx 
 
 
 
 
 
Variable available at visit 
N 
xx 
xx 
xx 
 
No 
x   (x.x%) 
x   (x.x%) 
x   (x.x%) 
 
Yes 
x   (x.x%) 
x   (x.x%) 
x   (x.x%) 
 
 
 
 
 
If yes, exam result at visit 
N 
xx 
xx 
xx 
 
Normal 
x   (x.x%) 
x   (x.x%) 
x   (x.x%) 
 
Abnormal and not clinically significant x   (x.x%) 
x   (x.x%) 
x   (x.x%) 
 
Abnormal and clinically significant 
x   (x.x%) 
x   (x.x%) 
x   (x.x%) 
 
 
 
 
 
If yes, shift table at visit (from W0) 
N 
xx 
xx 
xx 
 
No change 
x   (x.x%) 
x   (x.x%) 
x   (x.x%) 
 
Improvement 
x   (x.x%) 
x   (x.x%) 
x   (x.x%) 
 
Deterioration 
x   (x.x%) 
x   (x.x%) 
x   (x.x%) 
 
 
 


Cerenis THERAPEUTICS 
TANGO 
CER-001-CLIN-009 
 
CER-001 
 
Statistical Analysis Plan – Version 2.0 dated on 25OCT2018 
31 / 31 
12.2 List of Tables, Graphs and Listings 
Dry-runs for statistical outputs will be provided and approved by the Sponsor before database lock.