Conditions: Hyperlipidemias
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 263
Healthy volunteers: no

Brief summary:
The objective of this study is to evaluate the effects of adding beta-glucan (1.5 g, 3 g or 6 g daily) administered three times a day (TID) in divided doses, to atorvastatin (10 mg - 20 mg) once a day or an equivalent dose of another statin on heart disease lipid risk factors.

Detailed description:
Male and female subjects ≥ 18 years of age with an elevated LDL-C \> 3.37 mmol/L (130 mg/dL) treated with a stable dose of statin for at least 6 weeks (atorvastatin (10-20mg daily) or equivalent dose of another statin), including subject with previous cardiovascular (CV) events, with partial statin intolerance defined as an inability to tolerate statin therapy in the form and dosages required to achieve treatment goals.

Following signature of informed consent, approximately 264 subjects (66 subjects per beta-glucan treatment group and 22 subjects per matching placebo group) meeting all inclusion criteria and no exclusion criteria will be randomized to receive one of the three doses of beta-glucan (1.5 g, 3 g or 6 g daily) administered TID in divided doses or a matching placebo as an add-on therapy to atorvastatin (10- 20 mg administered once daily) or an equivalent dose of another statin.

The subjects will be assigned to the 3 different doses of beta-glucan or placebo in a tiered fashion as follows:

* The first set of 88 subjects randomized will receive either 1.5 g beta-glucan daily (1 tablet of 500 mg TID) or a matching placebo in a 3:1 ratio,
* The next set of 88 subjects randomized will receive either 3 g of beta-glucan daily (2 tablets of 500 mg TID) or a matching placebo in a 3:1 ratio,
* The last set of 88 subjects randomized will receive either 6 g of beta-glucan daily (4 tablets of 500 mg TID) or a matching placebo in a 3:1 ratio.

During the treatment period, subjects will return to the study site at Visit 3 (Week 6) and at the End of Treatment Visit (Week 12) for laboratory tests and clinical assessments, including Adverse Events (AEs), dietary guidance and study product compliance. At the Safety Follow-up Visit (Week 14), subjects will be contacted via telephone for an assessment of AEs.

Arms:
arm 1: matching placebo for 12 weeks. arm 2: CP105F (Oat beta-glucan) 1.5g (1 tablet of 0.5g TID) for 12 weeks. arm 3: CP105F (Oat beta-glucan) 3g (2 tablets of 0.5g TID) for 12 weeks. arm 4: CP105F (Oat beta-glucan) 6g (4 tablets of 0.5g TID) for 12 weeks.

Interventions: intervention 1: CP105F intervention 2: Placebo
Intervention descriptions: intervention 1: Natural Health Product intervention 2: tablet manufactured to mimic the CP105F beta-glucan

Protocol document:
Prot_000.pdf: 
 
    Protocol Name/No: BetAvena/PROJ1601 
          Version: 2.1 
Final: 23-Jan-2020  
 
Page 1 of 47 
 
 
 
 
A MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PARALLEL 
GROUP, PLACEBO-CONTROLLED STUDY TO COMPARE THE 
EFFICACY AND SAFETY OF HIGH-MEDIUM MOLECULAR WEIGHT 
BETA-GLUCAN IN SUBJECTS WITH HYPERLIPIDEMIA WITH OR 
WITHOUT STATIN THERAPY.  
 
 
  
 
 
 
Protocol Number ∕ Protocol Name:  PROJ1601 / BetAvena 
Product Code: CP105F 
Sponsor name: CEAPRO Inc. 
 
 
 
 
 
 
Version number:  Version 2.1 
23-Jan-2020 
 
 
 
Confidential Statement 
The information contained in this document, is the property of CEAPRO Inc., and it is provided to you 
in confidence as an investigator, potential investigator, consultant, service provider for review by you, 
your staff and an applicable Independent Ethics Committee ∕ Institutional Review Board.  Accordingly, 
please do not copy, use, distribute, or disclose to others without the written prior approval of CEAPRO 
Inc. or their designated representatives. 


 
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          Version: 2.1 
Final: 23-Jan-2020  
 
Page 2 of 47 
 
 
Signature Approval Page 
 
 
By signing below, I indicate that I have reviewed the Clinical Protocol in its entirety and approve 
its contents. 
 
 
 
Signature:   
 
Date:   
 
 
Ourida Mehenni Hadjeres, MD 
 
Lead, Medical and Safety 
 
MHICC 
 
 
 
Signature:   
 
Date:   
 
 
Marie-Claude Guertin, PhD 
 
Lead Biostatistics 
 
MHICC 
 
 
 
Signature:   
 
Date:   
 
Andreas Orfanos, MBBCh, FFPM, MBA 
Director 
MHICC 
 
 
 
Signature:   
 
Date:   
 
 
Jean-Claude Tardif, MD 
 
Principal Investigator 
Director, MHI Research Center 
 
 
 
Signature:   
 
Date:   
 
 
Gilles Gagnon, MSc, MBA 
 
President & CEO 
 
CEAPRO Inc.  
 
 
 


 
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Page 3 of 47 
 
 
 
 
 
 
INVESTIGATOR’S STATEMENT AND SIGNATURE 
 
A Multicenter, Randomized, Double-Blind, Parallel Group, Placebo-Controlled Study to Compare 
the Efficacy and Safety of High-medium Molecular Weight Beta-Glucan in Subjects with 
Hyperlipidemia with or without Statin Therapy.  
 
 
Protocol Number ∕ Protocol Name: PROJ1601/BetAvena 
Product Code: CP105F 
 
Version Date: 23-Jan-2020 
 
I have read the protocol described herein and I agree to comply with all applicable laws and 
regulations in accordance with Good Clinical Practice, and in accordance with the ethics 
principles outlined in the Declaration of Helsinki, and conduct this clinical study as described in 
this protocol. 
By signing below, I hereby declare that I am not debarred, disqualified, or otherwise restricted by 
any agency from conducting research studies. 
 
 
 
Principal Investigator:  
 
Print/Type Name: ________________________ 
 
Signature: ___________________________ 
   Date: _____________ 
 
 
 
 
 


 
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SYNOPSIS OF PROTOCOL NUMBER ∕ NAME: PROJ1601 
Sponsor: CEAPRO Inc.  
Name of Study Product: CP105F (Oat beta-glucan) 
Date: 23-Jan-2020 
Title of Study:  A Multicenter, Randomized, Double-Blind, Parallel Group, Placebo-Controlled Study to 
Compare the Efficacy and Safety of High-medium Molecular Weight Beta-Glucan in Subjects with 
Hyperlipidemia with or without Statin Therapy.  
Principal Investigator: Jean-Claude Tardif, MD 
Study Sites: Up to twelve (12) study sites in Canada  
Treatment duration: 12 weeks 
Phase of Development:  2  
Objective: The objective of this study is to evaluate the effects of beta-glucan (1.5 g, 3 g or 6 g daily) 
administered three times a day (TID) in divided doses on heart disease lipid risk factors.  
Methodology:  
Male and female subjects ≥ 18 years of age with an elevated LDL–C > 3.37 mmol/L (130 mg/dL) treated 
with a stable dose of statin for at least 6 weeks or not treated with a statin.  
Following signature of informed consent, approximately 264 subjects (66 subjects per beta-glucan 
treatment group and 22 subjects per matching placebo group) meeting all inclusion criteria and no 
exclusion criteria will be randomized to receive one of the three doses of beta-glucan (1.5 g, 3 g or 6 g 
daily) administered TID in divided doses or a matching placebo.  
The subjects will be assigned to the 3 different doses of beta-glucan or placebo in a tiered fashion as 
follows: 
• 
The first set of 88 subjects randomized will receive either 1.5 g beta-glucan daily (1 tablet of 500 
mg TID) or a matching placebo in a 3:1 ratio, 
• 
The next set of 88 subjects randomized will receive either 3 g of beta-glucan daily (2 tablets of 
500 mg TID) or a matching placebo in a 3:1 ratio, 
• 
The last set of 88 subjects randomized will receive either 6 g of beta-glucan daily (4 tablets of 500 
mg TID) or a matching placebo in a 3:1 ratio.  
During the treatment period, subjects will return to the study site at Visit 3 (Week 6) and at the End of 
Treatment Visit (Week 12) for laboratory tests and clinical assessments, including Adverse Events (AEs), 
dietary guidance and study product compliance. At the Safety Follow-up Visit (Week 14), subjects will be 
contacted via telephone for an assessment of AEs. 
Number of Subjects:  
Planned: Approximately 310 subjects screened to randomize approximately 264 subjects (66 per 
treatment group and 22 per matching placebo group).   
Diagnosis and Main Criteria for Inclusion:  
Male and female subjects ≥ 18 years of age with an elevated LDL–C > 3.37 mmol/L (130 mg/dL) treated 
with a stable dose of statin for at least 6 weeks or not treated with a statin. 
Test Product, Dose/Strength/Concentration, Mode of Administration:    
Test product: Oat beta-glucan tablet is a natural health product of high-medium molecular weight produced 
through CEAPRO’s proprietary and patented Pressurized Gas eXpanded technology. 
Dose:  1.5 g or 3 g or 6 g daily 
Mode of administration:  oral 


 
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Duration of Treatment:    
Twelve weeks of treatment with beta-glucan 1.5 g, beta-glucan 3 g, beta-glucan 6 g (total daily dose) or 
a matching placebo.  
Each subject is expected to participate for about 15 weeks (up to 1 week of screening, 12-weeks of 
treatment and follow-up call 2 weeks after last dose taken). 
Criteria for Evaluation:  
Efficacy:    
The primary efficacy endpoint will be the change from Week 0 to Week 12 in direct-measured LDL-C.   
The secondary efficacy endpoints will be changes from Week 0 to Week 12 in total cholesterol (TC), non-
High-density lipoprotein cholesterol (non-HDL-C), small low-density lipoprotein (LDL) subclass particle 
concentration, high sensitivity C-reactive protein (hsCRP), very low-density lipoprotein cholesterol (VLDL-
C), and apo B.  
Exploratory endpoints will include changes in HDL-C, triglycerides, Lipoprotein (a) (Lp(a)) and glycated 
hemoglobin (HbA1c). 
Safety:    
Safety will be assessed by adverse events, physical examination, vital signs, ECG, and laboratory 
analyses (hematology, biochemistry).  
Statistical Methods:  
Sample Size:  
Sample size computation is based on the change in LDL-C. Based on previous literature, we are 
expecting a mean decrease from baseline to follow-up in LDL-C of 0.30 mmol/L (11.6 mg/dL) in the control 
group and we are aiming to show that the addition of beta-glucan, either at 1.5 g, 3 g or 6 g, will further 
reduce LDL-C by 0.30 mmol/L, leading to an expected difference in change in LDL-C of 0.30 mmol/L 
between the control group and at least one of the active groups. The expected standard deviation of the 
change in LDL-C is 0.50 mmol/L (19.3 mg/dL). To reach a power of 80% in detecting this 0.30 mmol/L 
difference with a two-tailed significance level of 0.0167 (to account for the three main comparisons: 
placebo vs. beta-glucan 1.5 g, placebo vs. beta-glucan 3 g and placebo vs. beta-glucan 6 g), 60 subjects 
per group are required for a total of 240 subjects. To account for approximately 9% lost to follow-up, 264 
subjects (66 subjects per treatment group) will be randomized.  
Efficacy:    
The primary dataset for efficacy analyses will be the set of all randomized subjects (ITT Population).  
For the primary, secondary and exploratory endpoints, the values at each study visit and the changes 
from Week 0 to follow-up visits (week 6 and week 12) will be summarized for each treatment group using 
descriptive statistics. The changes will be compared between treatment groups using repeated measures 
analysis of covariance (ANCOVA) models adjusting for the Week 0 value. Contrasts under these models 
will allow for the three main comparisons: placebo vs. beta-glucan 1.5 g, placebo vs. beta-glucan 3 g and 
placebo vs. beta-glucan 6 g. For the primary endpoint, these comparisons will be done at the 0.0167 
significance level. The significance level will be set to 0.05 for all other analyses.  
Safety: 
The primary dataset for safety analyses will be the set of all randomized subjects who received at least 
one dose of investigational product (IP) (Safety Population).  
Adverse events will be coded using the Medical Dictionary for Regulatory Affairs (MedDRA) coding 
dictionary. Treatment-emergent adverse events will be summarized for each treatment group.  


 
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Treatment-emergent adverse events will be defined as adverse events with a start date on or after the 
first dose of study product.      
For all study visits as well as for the changes from Week 0 to follow-up visits (week 6 and week 12) when 
applicable, safety laboratory parameter and other safety assessments, including physical examination, 
vital signs and ECG, will be summarized for each treatment group using descriptive statistics.   
 
 
 
 
 
 
 
 
 
 
Contents 
SYNOPSIS OF PROTOCOL NUMBER ∕ NAME: PROJ1601 .......................................4 
GLOSSARY OF ABBREVIATIONS ..............................................................................9 
 BACKGROUND AND RATIONALE .....................................................................12 
 OBJECTIVES ...........................................................................................................14 
 
Primary Objective ............................................................................................ 14 
 
Secondary Objectives ...................................................................................... 14 
 
Exploratory Objectives ..................................................................................... 14 
 STUDY DESIGN AND ENDPOINTS ....................................................................14 
 
Study Design and Dosing Regimen ................................................................. 14 
 
 Study endpoints .............................................................................................. 17 
3.2.1 Primary Endpoint ................................................................................................. 17 
3.2.2 Secondary Endpoints ........................................................................................... 17 
3.2.3 Exploratory Endpoints ......................................................................................... 17 
3.2.4 Safety ................................................................................................................... 17 
 SELECTION AND WITHDRAWAL OF SUBJECTS ............................................17 
 
Inclusion Criteria .............................................................................................. 17 
 
Exclusion Criteria ............................................................................................. 18 
 
Subject Withdrawal or Termination .................................................................. 20 
 
Screen Failure ................................................................................................. 20 
 STUDY PRODUCT .................................................................................................20 
 
Study Product and Control Description ............................................................ 20 
5.1.1 Acquisition ........................................................................................................... 20 


 
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5.1.2 Formulation, Appearance, Packaging, and Labeling ........................................... 20 
5.1.3 Investigational Product Storage and Stability ...................................................... 21 
5.1.4 Preparation ........................................................................................................... 21 
5.1.5 Dosing and Administration .................................................................................. 21 
5.1.6 Route of Administration ...................................................................................... 22 
5.1.7 Duration of Treatment ......................................................................................... 22 
5.1.8 Tracking of Dose ................................................................................................. 22 
 
Blinding and Unblinding ................................................................................... 23 
 
Assessment of Compliance .............................................................................. 23 
 
Investigational Product Accountability .............................................................. 23 
 
Interruption or Discontinuation of Investigational Product ................................. 24 
 
Destruction of the Investigational Product ........................................................ 24 
 STUDY ASSESSMENTS AND PROCEDURES ....................................................24 
 
Screening Assessments .................................................................................. 24 
 
Randomization and Treatment Procedures ...................................................... 25 
 
Medical History: ............................................................................................... 25 
 
Physical Examination ....................................................................................... 26 
 
Vital Signs ........................................................................................................ 26 
 
Electrocardiogram ............................................................................................ 26 
 
Laboratory Analyses ........................................................................................ 26 
 
Concomitant and Prohibited Medications ......................................................... 27 
 
Adverse Events ................................................................................................ 27 
 Unscheduled Visit ............................................................................................ 27 
 Early Termination Visit ..................................................................................... 28 
 Efficacy Assessments ...................................................................................... 28 
6.12.1 Primary Efficacy Assessment .............................................................................. 28 
6.12.2 Secondary Efficacy Assessment .......................................................................... 28 
 Exploratory Assessments................................................................................. 28 
 Safety Assessments ........................................................................................ 28 
 End of Study .................................................................................................... 28 
 Dietary and Concomitant Medications Restrictions .......................................... 28 
 ADVERSE EVENTS (AE) AND SERIOUS ADVERSE EVENTS (SAE) ∕ SAFETY 
INSTRUCTIONS AND GUIDANCE ......................................................................28 
 
Definition of Adverse Event (AE) ...................................................................... 29 
 
Definition of Serious Adverse Event ................................................................. 29 
7.2.1 Follow-up of AEs/SAEs ...................................................................................... 29 
 
Laboratory Test Abnormalities and other abnormal assessments as AEs or SAEs
 
29 
7.3.1 Follow-up of Abnormal Laboratory Test Values ................................................. 30 


 
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Time Period, Frequency, and Method of Detecting AEs and SAEs .................. 30 
 
Recording of AEs and SAEs ............................................................................ 30 
 
Prompt Reporting of SAEs ............................................................................... 31 
 
Expeditable Events (SUSAR’s) ........................................................................ 31 
 
Evaluating AEs and SAEs ................................................................................ 32 
7.8.1 Assessment of Severity ........................................................................................ 32 
7.8.2 Assessment of Causality ...................................................................................... 32 
7.8.3 Assessment of Expectedness ............................................................................... 33 
 
Pregnancy ....................................................................................................... 33 
 CLINICAL MONITORING .....................................................................................33 
 STUDY COMMITTEES ..........................................................................................34 
 
Steering Committee: Not applicable ................................................................. 34 
 
Data and Safety Monitoring Board (DSMB): Not applicable ................................... 34 
 STATISTICAL CONSIDERATIONS .....................................................................34 
 Analysis Datasets ............................................................................................ 34 
10.1.1 Intent-to-Treat Population ................................................................................... 34 
10.1.2 Per-Protocol Population ...................................................................................... 34 
10.1.3 Safety Population ................................................................................................ 34 
 General Statistical Approach ............................................................................ 34 
 Efficacy Analyses ............................................................................................. 35 
10.3.1 Analysis of the Primary Efficacy Endpoint ......................................................... 35 
10.3.2 Analysis of the Secondary Endpoints .................................................................. 36 
10.3.3 Analysis of the Exploratory Endpoints ................................................................ 36 
10.3.4 Subgroup Analyses .............................................................................................. 36 
 Safety Analyses ............................................................................................... 36 
10.4.1 Adverse Events .................................................................................................... 36 
10.4.2 Laboratory Data ................................................................................................... 37 
10.4.3 Other safety assessments ..................................................................................... 37 
 Planned Interim Analyses ................................................................................ 37 
 Sample Size Calculation .................................................................................. 37 
11. ETHICAL AND REGULATORY CONSIDERATIONS ........................................37 
11.1. Good Clinical Practice Statement ..................................................................... 37 
11.2. Ethical Review ................................................................................................. 37 
11.3. Informed Consent ............................................................................................ 38 
11.4. Ethics Review Committee ................................................................................ 38 
11.5. Confidentiality .................................................................................................. 38 
12. FINANCIAL DISCLOSURE ...................................................................................39 


 
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13. INVESTIGATOR RESPONSIBILITY ....................................................................39 
14. PROTOCOL COMPLIANCE ..................................................................................39 
15. PROTOCOL AMENDMENT ..................................................................................39 
16. PUBLICATIONS......................................................................................................40 
17. RETENTION OF RECORDS AND ARCHIVING .................................................40 
18. REFERENCES .........................................................................................................41 
19. APPENDICES ..........................................................................................................43 
19.1. Appendix 1: Standard Cholesterol Lowering Diet ............................................. 43 
19.2. Appendix 2. Schedule of visits ......................................................................... 44 
19.3. Appendix 3. Clinical Laboratory Parameters .................................................... 45 
 
 
 
 
 
 
GLOSSARY OF ABBREVIATIONS 
• ACC 
• American College of Cardiology 
• AE 
• Adverse Event 
• AHA 
• American Heart Association 
• ALT 
• Alanine aminotransferase 
• ANCOVA 
• Analysis of Covariance 
• apo B 
• apolipoprotein B 
• AST 
• Aspartate aminotransferase 
• BMI 
• Body mass index 
• β-glucan  
• beta-glucan 
• CABG 
• Coronary artery bypass graft 
• CAD 
• Coronary artery disease 
• CHD  
• Coronary Heart Disease  
• CI 
• Confidence interval 
• COR 
• Class of Recommendation 
• CPK 
• Creatine phosphokinase 
• CRA 
• Clinical Research Associate 
• CRF 
• Case Report Form(s) 
• CQ 
• Critical Question 
• CVD 
• Cardiovascular Disease 
• DASH 
• Dietary Approaches to Stop Hypertension 
• dL 
• deciliter 


 
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GLOSSARY OF ABBREVIATIONS 
• DSMC 
• Data Safety Monitoring Committee 
• EAS 
• European Atherosclerosis Society 
• ECG 
• Electrocardiogram 
• EENT 
• Ears, eyes, nose, throat 
• EFSA 
• European Food Safety Authority 
• eCRF 
• Electronic case report form(s) 
• ES 
• Evidence Statement 
• ESC 
• European Society of Cardiology 
• EtOH 
• Ethyl alcohol or alcohol  
• FDA 
• Food and Drug Administration 
• G 
• Gram 
• GCP 
• Good Clinical Practice 
• GFR 
• Glomerular filtration rate 
• HbA1c 
• Hemoglobin A1C, glycated hemoglobin or glycosylated hemoglobin 
• Hb 
• Hemoglobin 
• HDL-C 
• High-density lipoprotein cholesterol 
• HMG-CoA 
• 3-hydroxy-3-methyl-glutaryl-co-enzyme A 
• hsCRP 
• High sensitivity C-reactive protein 
• ICF 
• Information and Consent Form 
• ICH 
• International Council for Harmonisation 
• IEC 
• Independent Ethics Committee 
• IDL-C 
• Intermediate-density lipoprotein cholesterol 
• IP 
• Investigational Product 
• IRB 
• Institutional Review Board 
• ITT 
• Intention to Treat 
• Kg 
• Kilogram 
• LDL-C 
• Low density lipoprotein-cholesterol 
• LOE 
• Level of Evidence 
• LP(a) 
• Lipoprotein (a) 
• MedDRA 
• Medical Dictionary for Regulatory Activity 
• Mg 
• Milligram 
• MHI 
• Montreal Heart Institute 
• MHICC 
• Montreal Health Innovations Coordinating Center 
• NCEP 
• National Cholesterol Education Program 
• NHLBI 
• National Heart, Lung and Blood Institute 
• Non-HDL-C 
• Non-High-density lipoprotein cholesterol 
• NYHA 
• New York Heart Association 
• PGX 
• Pressurized Gas Expanded 


 
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GLOSSARY OF ABBREVIATIONS 
• PCI 
• Percutaneous coronary intervention 
• SAE 
• Serious Adverse Event 
• SAP 
• Statistical analysis plan 
• SC 
• Steering committee 
• SUSAR 
• Suspected unexpected serious adverse reaction 
• TC 
• Total cholesterol 
• TDD 
• Total daily dose 
• TIA 
• Transient ischemic attack 
• TID 
• Three times a day 
• TLC 
• Therapeutic Lifestyle Changes 
• TG 
• Triglycerides 
• ULN 
• Upper limit of normal 
• USDA 
• US Department of Agriculture 
• VLDL-C 
• Very low-density lipoprotein cholesterol 
• WBC 
• White blood cell 


 
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BACKGROUND AND RATIONALE 
Hyperlipidemia is a potent risk factor for atherosclerosis and, implicitly for Cardiovascular 
Disease (CVD). CVD is one of the leading causes of death and disability in Canada and 
worldwide. Atherosclerotic coronary artery disease (CAD), the most common form of CVD, is 
characterised by plaque build-up inside the arteries. The plaque, or atheroma, is formed of 
fatty deposits, calcium and cells. The fatty deposits thicken the arteries and promote the 
accumulation of calcium and cells, leading to the formation of plaques. The plaque can then 
rupture diminishing the downstream blood flow by the formation of superimposed luminal 
thrombosis, which leads to either a heart attack or stroke depending on the artery affected. (1, 
2, 3) 
 
Lipid-related risk factors for atherosclerotic CAD include elevated levels of total cholesterol 
(TC), non-HDL cholesterol, very low-density lipoprotein cholesterol (VLDL-C), low-density 
lipoprotein cholesterol (LDL-C), apolipoprotein B (apo B or B-100), intermediate-density 
lipoprotein cholesterol (IDL-C), lipoprotein(a) and reduced concentrations of high-density 
lipoprotein cholesterol (HDL-C).(4,5,6) 
 
LDL-Cholesterol makes up to 60-70% of the total serum cholesterol and the LDL particle has 
been identified as being the major atherosclerotic lipoprotein. The studies across different 
populations have shown that there is a positive relationship between serum LDL-C levels and 
the development of the first or subsequent attacks of Coronary Heart Diseases (CHD). (4)  
 
LDL-Cholesterol is the primary target of treatment in clinical lipid management. The 
therapeutic goal is achieved in many persons by using therapeutic lifestyle changes (TLC), 
including LDL-lowering dietary options (plant stanols/sterols and increased viscous fibre). 
Lifestyle changes include smoking cessation, an overall healthy eating pattern, with 
maintenance of appropriate body weight, and controlled blood pressure and diabetes. 
Nonetheless, the LDL-C goal currently often requires LDL-lowering drugs in patients at risk 
for CHD.(4) Clinical lipid management consists predominantly of HMG-CoA reductase 
inhibitors (statins), but also includes non-statin therapies such as bile acid sequestrants, 
ezetimibe and soluble/viscous fibre.(4, 7) 
 
Non-HDL-Cholesterol and apo B are considered alternate therapeutic targets. Ho et al. have 
shown in a systematic review that there is a high correlation between CVD risk and both Non-
HDL-C and apo B. (8) 
 
The regulatory agencies US Food and Drug Administration (FDA), Health Canada and 
European Food Safety Authority (EFSA) Panel on Dietetic Products, Nutrition and Allergies, 
approved claims for soluble fibre, as part of a diet low in saturated fat and cholesterol. (5, 9, 10) 
 
Soluble/viscous fibre is found in whole oat food (oat bran, rolled oats, whole oat flour) and in 
barley foods. The National Cholesterol Education Program (NCEP) Expert Panel 
recommends, as part of the TLC, that the diet be enriched by foods containing at least 5–10 
grams of viscous fiber daily.  Intakes of 10–25 grams per day can be beneficial, being one of 
the therapeutic options for lowering LDL-C.(4) According to an ACC Expert Consensus, the 
mean TC and LDL-C levels were decreased relative to control by 9.7 and 11.6 mg/dL 
respectively with an intake of 3.0-12.4 g/day.(7) European guidelines for the management of 


 
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dyslipidemia notes that a consumption of 5-15 g/day of soluble fibre from oat product may be 
beneficial in reducing the CVD risk.(11) Health Authorities’ approvals are based on a diet 
containing at least 3 g oat beta-glucan per day.(12)   
 
Health Canada approval recognizes the relation between the increased oats (Avena sativa)-
soluble fibre consumption and the reduction in total serum cholesterol level, and the reduction 
of the risk of CAD. The main active food component responsible for the hypocholesterolaemic 
property of oats is beta-glucan. (9, 12) 
 
Beta-glucan is a highly viscous soluble fibre composed of D-glucose monomers linked by a 
combination of β -(1 to 4) and β -(1 to 3) glycosidic bonds. It is thought that beta-glucan 
reduces TC and LDL-C by forming a viscous mass in the small intestine, thus limiting intestinal 
absorption of dietary cholesterol as well as the re-absorption of bile acids.(9) In a randomized, 
single-blinded, controlled crossover study, it has been shown that gut microbiota were 
modulated in response to beta-glucan consumption on a molecular weight-dependent manner. 
The shift in gut microbiota might be one of the underlying mechanisms responsible for the 
physiological benefits of beta-glucan and this was correlated with reduced CVD risk factors. 
(13) 
 
The EFSA Panel assumes that the target population is the general population and that the 
claimed effects refer to the maintenance of normal blood LDL-C concentrations, increasing in 
satiety which leads to a reduction in energy intake, reduction of post-prandial glycaemic 
response and improvement of the digestive function. (10) 
 
A systematic review of 16 studies conducted by Q. Hou et al. has shown that oat intake 
reduced the concentrations of TC and LDL-C.  It is thought that the cholesterol-lowering effect 
might be due to beta-glucan binding with bile acids which leads to decreased cholesterol 
absorption, increased expression of hepatic LDL-C receptor, and increased faecal bile acid 
excretion. The effect of beta-glucan on HDL-C has varied in those studies.  
 
Hou et al. have also demonstrated that oat intake has a moderately beneficial effect on 
glycaemic control and lipid profile in patients with type 2 diabetes. The beneficial effect on 
blood lipids and glycaemia have been  found to be linked to the increased viscosity of the food 
bolus, delayed gastric emptying, lengthened intestinal transit time, slowed absorption of 
nutrients especially carbohydrates, and enhanced satiety. The authors have also shown that 
the effects on health depend on the dosage, chemical structure, molecular weight, solubility 
and viscosity of the oat. No evidence has been found linking oat consumption and allergic 
reactions or disease; however, the authors recommend using pure oats without wheat 
contamination in wheat hypersensitive patients. (14) 
 
CEAPRO’s beta-glucan is a high-medium molecular weight soluble fibre obtained by a 
Pressurized Gas eXpanded® (PGX) method, which is a novel drying technique for processing 
water-soluble biopolymers. The use of high-medium molecular weight beta-glucan, obtained 
by the PGX method, for 12 weeks may significantly reduce the level of LDL-C and contribute 
to reducing the cardiovascular disease risk.  
 


 
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This phase II trial is indicated in the context of substantial scientific evidence on the 
cholesterol lowering effect of beta-glucan, the existence of a beta-glucan monograph 
published by Health Canada and the need to better delineate the effective dosage of the new 
formulation of CEAPRO’s beta-glucan (15), (16).   
 
OBJECTIVES 
The overall aim of this study is to evaluate the effects of  beta-glucan (1.5 g, 3 g or 6 g daily) 
administered three times a day (TID) in divided doses compared to placebo on heart disease 
lipid risk factors. 
 
Primary Objective 
The primary objective is to evaluate the effects of beta-glucan on the direct-measured Low-
Density Lipoprotein Cholesterol (LDL-C) level compared to placebo after 12 weeks of 
treatment in subjects with LDL-C > 3.37 mmol/L (130 mg/dL). 
 
Secondary Objectives 
The secondary objectives are to evaluate: 
- 
The effects of beta-glucan on Total Cholesterol (TC), small LDL-C subclass particle 
concentration, high sensitivity C-reactive protein (hsCRP), non-High Density Lipoprotein 
Cholesterol (HDL-C), Apolipoprotein B (apo B) and Very Low Density Lipoprotein 
Cholesterol (VLDL-C) levels compared to placebo  after 12 weeks of treatment. 
- 
The safety profile of beta-glucan  
 
Exploratory Objectives 
The exploratory objectives are to evaluate the effects of beta-glucan on HDL-C, Triglyceride 
(TG), Lipoprotein a (Lp(a)) and glycated hemoglobin (HbA1c) levels compared to placebo  
after 12 weeks of treatment.  
 
 
STUDY DESIGN AND ENDPOINTS 
 
Study Design and Dosing Regimen  
This is a Phase 2, double-blind, randomized, multicenter, 12-week comparative study of 
beta-glucan versus placebo, in subjects with an elevated LDL–C >3.37mmol/L (130 mg/dL) 
treated with a stable dose of statin for at least 6 weeks or not treated with a statin.   
Following signature of informed consent, approximately 264 subjects (66 subjects per beta-
glucan treatment group and 22 subjects per matching placebo group) meeting all inclusion 
criteria and no exclusion criteria will be randomized to receive one of the three doses of beta-
glucan (1.5 g, 3 g or 6 g daily) TID or a matching placebo.  
The subjects will be assigned to the three different doses of beta-glucan or placebo in a 
tiered fashion as follows: 
• The first set of 88 subjects randomized will receive either 1.5 g beta-glucan (1 tablet of 
500 mg TID) or a matching placebo in a 3:1 ratio, 
• The next set of 88 subjects randomized will receive either 3 g of beta-glucan (2 tablets 
of 500 mg TID) or a matching placebo in a 3:1 ratio, 


 
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• The last set of 88 subjects randomized will receive either 6 g of beta-glucan (4 tablets 
of 500 mg TID) or a matching placebo in a 3:1 ratio. (Figure 1) 
 
At baseline Visit (Week 0), the subjects should be already on a standard cholesterol lowering 
diet (American Heart Association Guidelines) (Appendix 1) and they should maintain it 
throughout the study. Subjects are encouraged to pursue a healthy lifestyle. The subjects 
must abstain from/minimize alcohol (EtOH) intake and keep stable any other variables that 
may alter serum lipid levels (e.g., strenuous exercise, weight loss programs, drugs including 
over the counter preparations that may alter serum lipid levels). 
During the treatment period, subjects will return to the study site at Visit 3 (Week 6) and at 
the End of Treatment Visit (Week 12) for laboratory tests and clinical assessments, including 
for Adverse Events (AEs), dietary guidance and IP compliance. At the Safety Follow-up Visit 
(Week 14), subjects will be contacted via telephone for an assessment of Adverse Events 
(AEs). Time window for the Visit 3 (week 6), Final Visit (week 12) and Safety Follow-up Visit 
is ± 5 days. 
Laboratory tests and clinical assessments will be performed as noted in the schedule of visits 
(Appendix 2) and section 3.1   
Safety and tolerability assessment will include that of AEs, hematology, biochemistry, 
physical examination, vital signs and electrocardiogram (ECG). 
 
The study design is presented in Figure 1 below.  


 
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 Study endpoints  
3.2.1 Primary Endpoint 
The primary efficacy endpoint will be the change from Week 0 to Week 12 in direct-measured 
LDL-C.   
3.2.2 Secondary Endpoints 
The secondary efficacy endpoints will be the changes from Week 0 to Week 12 in:  
• 
TC  
• 
non-HDL-C  
• 
small LDL subclass particle concentration  
• 
hsCRP  
• 
VLDL-C  
• 
Apo B 
3.2.3 Exploratory Endpoints 
Exploratory endpoints will include changes in HDL-C, TG, Lp(a) and HbA1c from Week 0 to Week 
12. 
3.2.4 Safety 
Safety will be assessed by adverse events, physical examination, vital signs, ECG and laboratory 
analyses (hematology, biochemistry). 
 
 
SELECTION AND WITHDRAWAL OF SUBJECTS 
The target population will consist of subjects who are diagnosed with hyperlipidemia. In order 
to be included into the trial, subjects must fulfill all the inclusion and not meet any of the exclusion 
criteria listed below. 
 
 
Inclusion Criteria 
Subjects must meet ALL of the following inclusion criteria in order to be eligible for this study: 
1. Male or female  ≥18 years of age   
 
2. Subjects with hyperlipidemia with LDL-C level >3.37 mmol/L (130 mg/dL) in fasting 
conditions at screening, treated with a stable dose of statin for at least 6 weeks or not 
treated with a statin at the time of informed consent.  
 
3. Subjects willing to maintain stable standard cholesterol lowering diet (Appendix 1) and 
physical activity level throughout the study 
 
4. Female of childbearing potential must have a negative urine pregnancy test at screening 
and randomization baseline Visit 2   


 
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Women are considered not of childbearing potential if they: 
a. Have had a hysterectomy, a bilateral oophorectomy or tubal ligation prior to Baseline 
Visit. 
b. Are postmenopausal defined as no menses for at least 1 year and have a serum FSH 
level of 40 IU/L. 
Women of childbearing potential must agree to use an effective method of birth control 
throughout the study. Acceptable means of birth control include: implantable 
contraceptives, 
injectable 
contraceptives, 
oral 
contraceptives, 
transdermal 
contraceptives, intrauterine devices, male or female condoms with spermicide, 
abstinence, or a sterile sexual partner 
 
5. Ability and willingness to give written informed consent and to comply with the 
requirements of the study 
 
 
Exclusion Criteria 
A subject who meets any of the following criteria will NOT be eligible to the study: 
 
1. Use of any other lipid modifying drugs including but not limited to:  
a. Niacin (nicotinic acid) or niacinamide (nicotinamide) 
b. Bile acid sequestrants including cholestyramine, colesevelam, colestipol  
c. Ezetimibe 
d. PCSK9 inhibitors 
e. Systemic corticosteroids 
 
2. Use of any other lipid modifying supplements within the last 30 days, including 
       but not limited to (a 30-day wash out period is permitted): 
a. Beta-glucan supplements other than the investigational product 
b. Omega-3 fatty acids 
c. Supplements containing flaxseed, fish oil, or algal oil 
d. Sterol/stanol products 
e. Red yeast rice supplements or soy isoflavone supplements 
f. Dietary fiber supplements including > 2 teaspoonful of Metamucil® or psyllium 
containing supplements per day 
g. Supplements containing oats, oatmeal and oat bran. 
 
3. Use of nonsteroidal anti-inflammatory drugs (NSAIDs) with the exception of 
acetylsalicylic acid (ASA) at a concentration of up to 325 mg twice a day and 
occasional/intermittent use for the symptomatic control of minor acute ailments (e.g. 
headaches).  
 
4. BMI ≥ 40 kg/m2 
 
5. Female who is pregnant, planning to become pregnant during the study, or breast 
feeding 


 
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6. Subject who is not willing to keep stable the exercise level during the study 
 
7. History of poorly controlled diabetes within the last 3 months (HbA1C >10%) 
 
8. Subjects with poorly controlled blood pressure defined as a sustained mean systolic 
blood pressure 160 or <100 mmHg and/or diastolic blood pressure 100 or <60 
mmHg at screening 
 
9. History of unstable angina, myocardial infarction, coronary artery bypass graft surgery 
(CABG), percutaneous coronary intervention (PCI), carotid surgery or stenting, 
cerebrovascular accident, or transient ischemic attack (TIA) within 6 months prior to 
screening 
 
10. History of heart failure NYHA III-IV within 12 months prior to screening  
 
11. Subjects with clinically significant electrocardiographic abnormalities 
 
12. Subjects with history of clinically significant endocrine disease known to influence 
serum lipids  
 
13. Subjects with evidence of hepatic disease (ALT and/or AST greater than 2X ULN,  total 
bilirubin greater than 1.5X ULN, or cirrhosis) at screening  
 
14. Renal dysfunction defined as glomerular filtration rate (GFR) ≤45 mL/min/1.73 m2 
at screening 
 
15. Subjects who suffer from inflammatory bowel disease or irritable bowel syndrome 
 
16. Known allergies or intolerance to oats 
 
17. History of malignancy, except subjects who have been disease-free for > 3 yrs or 
resected basal or squamous cell skin carcinoma or cervical carcinoma in situ 
 
18. Consumption of > 14 alcoholic drinks per week (1 drink = 12 oz beer, 5 oz wine, or 1.5 
oz hard liquor at screening). Counseling should be given to encourage the subject to 
maintain consumption at or below this level throughout the study 
 
19. History of drug abuse  
 
20. Participation in another clinical trial within 30 days of signing the Information and 
Consent Form (ICF) 
 
21. Any condition or therapy that the investigator believes might pose a risk to the subject 
or makes participation in the study not in the subject’s best interest  
 


 
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Subject Withdrawal or Termination 
A subject has the right to withdraw from the study at any time, for any reason, and without 
repercussion. 
The investigator and sponsor have the right to discontinue temporarily or permanently the 
IP for a subject in the event of an intercurrent illness, adverse event (AE), or other reasons.   
An excessive rate of study withdrawal would diminish the informative value of the study 
data; therefore, unnecessary withdrawal of subjects should be avoided.  
The reason for the subject’s premature discontinuation from the study must be fully documented 
in the source documents and electronic Case Report Form (eCRF). 
Subjects who discontinue IP but who consent to remain in the study will continue to comply with 
study visits and assessments. See section 6.6. 
Subjects prematurely discontinued from the study will not be replaced.  
 
 
Screen Failure 
Subjects who sign the ICF and who are discontinued or withdraw from the study before they 
are randomized are defined as screen failures. Date of the visit, date of consent, 
demographic information as well as the reason for screen failure will be collected in the eCRF 
for screen failure subjects.  
 
 
STUDY PRODUCT  
 
Study Product and Control Description 
5.1.1 Acquisition 
The  investigational product (IP) beta-glucan and placebo are shipped to the investigator’s 
pharmacy or suitable storage area by the sponsor’s packaging contractor. The IP is prepared 
according to the randomization algorithm provided by the MHICC and is supplied in a double-
blind fashion. Each subject kit contains a 6-week (± 5 days for visit window) supply of therapy, 
i.e. either beta-glucan or placebo for dispensing of one kit at the randomization baseline Visit 
2 and one kit at Week 6 (Visit 3).  
The IP is to be dispensed only to subjects included in the study and per the Investigator’s 
instructions. The Investigator is the person responsible for the distribution of the IP, and 
he/she or his/her delegate will record the distribution of the IP. Instructions will be given to 
Investigators regarding the return or destruction of remaining IP and any other clinical trial 
supplies after the end of the study. 
5.1.2 Formulation, Appearance, Packaging, and Labeling  
 
CEAPRO’s CP105F is supplied as enteric coated 500 mg oral tablets or matching placebo. 
The batch number is filed at CEAPRO Inc. (7824 – 51 Avenue, Edmonton, AB T6E 6W2). 


 
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Each CP105F tablet contains oat beta-glucan concentrate, other oat dietary fibers, oat 
proteins, food grade salts, and oat lipids. Each placebo tablet resembling CP105F contains 
Mannitol 100SD, Prosolv SMCC HD90, Copovidone S-630, Crospovidone XL-10, Sodium 
starch glycolate, Mg St MF-2-V, Opadry II White85F18422. 
 
IP label is designed to comply with the Regulations of the country where the clinical trial will 
be conducted: in Canada this is the Natural Health Products Regulations, Part 4, Sponsor’s 
Obligations, Labelling Sections 75-76 and the following information shall be included on 
labels in both official languages: 
a) a statement indicating that the natural health product is an investigational 
natural health product to be used only by a qualified investigator; 
b) the brand name or code of the natural health product; 
c) the expiry date of the natural health product; 
d) the recommended storage conditions for the natural health product, if any; 
e) the lot number of the natural health product; 
f) 
the name and address of the manufacturer; 
g) the name and address of the sponsor; and 
h) the protocol code or identification. 
Additional components of the label may include:  
• 
A space to complete the subject number  
• 
A space to complete the dispensing date of the kit 
• 
Identification of the group: 1.5 g, 3 g, or 6 g TDD CP105F or placebo, 
whether by text or colour-code or other means of identification   
 
5.1.3 Investigational Product Storage and Stability  
 
Product stability data on file at the sponsor indicate exposure to temperatures between -15 
and 40 °C (5 to 104  °F) does not affect the active ingredient. 
Investigational Product (IP) should be stored at room temperature in a dry environment.  
 
5.1.4 Preparation  
 
No special preparation is required. The IP kit label (subject number and dispensing date, as 
applicable) and log(s) are to be completed by the investigator’s delegate at the time of 
dispensing to subjects. 
 
5.1.5 Dosing and Administration  
 


 
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CEAPRO’s CP105F (oat beta-glucan) 1.5 g, 3 g, or 6 g daily or matching placebo are to be 
given as 500 mg tablets taken 3 times daily in the morning before breakfast, at mid-day before 
lunch and before supper time. The product should not be taken at the same time as statins 
(for subjects who are taking statins) which should be taken in the evening or at least 2 hours 
after the last dose of IP.  
 
Subject should be instructed on administration of the IP: 
 
IP tablets should be taken whole (not cut or crushed) with plenty of liquid (>350 ml or 1½ c.), 
preferably with warm or hot water before the meal. It is best not to consume alcohol 
immediately after ingesting the tablet, as beta-glucan is not soluble in alcohol.  If a dose is 
missed, the next regularly scheduled dose should be taken. Unused tablets and empty 
containers (bottles and kit box) returned to the site at the next study visit. 
 
5.1.6 Route of Administration  
IP is to be administered orally per dosing and administration instructions in section 5.1.5.   
 
5.1.7 Duration of Treatment  
The duration of treatment is twelve weeks with beta-glucan 1.5 g, beta-glucan 3 g, beta-
glucan 6 g (total daily dose) or matching placebo.  
Each subject is expected to participate for about 15 weeks (up to 1 week of screening, 12-
weeks of treatment and follow-up call 2 weeks after last dose taken). 
 
5.1.8 Tracking of Dose  
A dosing schedule will be provided to each subject. A product intake card will be maintained 
by the subject to help with compliance and will be returned to the site along with remaining 
IP tablets and containers.  


 
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Blinding and Unblinding 
This is a double-blind study. With the exception of the study unblinded statistician who 
generates and provides the randomization algorithm for the Interactive Web Response 
System (IWRS) all site staff and study subjects will remain blinded until study completion and 
database closure. 
 
Unblinding of the treatment assignment for a subject may be necessary due to a medical 
emergency, a Serious Adverse Event (SAE) that is unexpected and for which a causal 
relationship to the IP cannot be ruled out or any other significant medical event.  
 
Details for unblinding will be provided under a separate cover. 
 
If unblinding is required: 
- 
Only the investigator will make the decision to unblind the treatment assignment 
- 
Only the treatment assignment for the affected subject will be unblinded 
- 
Treatment assignment will be provided to the investigator 
- 
The investigator will notify Sponsor and /or designee immediately that the subject has 
been unblinded 
 
 
Assessment of Compliance 
At each visit, all unused tablets and empty containers (bottles and kit box) should be returned 
by the subjects to the investigator or designee as a measure of compliance.  Compliance is 
defined as consumption of at least 80% of the required dosage. 
Accountability will be assessed by maintaining adequate IP dispensing records. The 
investigator is responsible for ensuring that dosing is administered in compliance with the 
protocol. Delegation of this task must be clearly documented and approved by the 
investigator.  
If for any reason the IP is not administered or partially administered it should be reported in 
the eCRF and the reason for this must also be clearly reported in the eCRF. If this is due 
to occurrence of an AE the details of the event must be collected in the eCRF. 
 
 
Investigational Product Accountability 
The investigator is responsible for the control of products/drugs under investigation. 
Adequate records of the receipt (e.g., IP Receipt Record(s) and Master IP Log or equivalent) 
and disposition (e.g., IP Dispensing Log or equivalent) of the IP must be maintained. The IP 
Dispensing Log must be kept current and should contain the following information: 
• 
Documentation of IP shipments received from the sponsor (date received and 
quantity) 
• 
Disposition of unused IP not dispensed to study participants 
• 
The identification of the study participant to whom the IP was dispensed (for example, 
a unique subject number of other study participant identifier) 
• 
The date(s), quantity of the IP dispensed to the study participant 
• 
The identification of the person who dispensed the IP 


 
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All records and IP supplies must be available for inspection by the Clinical Research 
Associate (CRA) and any other sponsor representatives. When the study is completed, the 
investigator will return any unused IP and containers (i.e., empty, partially used, and unused 
containers) to CEAPRO Inc. or designee unless alternate destruction has been authorized 
by CEAPRO Inc. or designee, or required by local or institutional requirements. The 
investigator's copy of the IP Return Record(s) or equivalent must accurately document the 
return of all IP supplies to CEAPRO Inc.  
 
 
Interruption or Discontinuation of Investigational Product 
Study participants may be interrupted or discontinued from the IP if any of the following 
occur: 
1. A IP-related adverse event or other reason which, in the investigator’s opinion, will 
jeopardize the subject’s participation in the study or the interpretation of study data 
(e.g., severe intercurrent illness requiring additional care measures or preventing 
further dosing) 
2. Significant tolerability issues 
3. Participant’s decision 
At the time of IP interruption, the study site will document in the eCRF the reason for IP 
discontinuation. The study participant should continue to be followed for all other study related 
procedures and visits, and clinical study outcomes and evaluation.   
 
 
Destruction of the Investigational Product  
IP must be returned or destroyed locally following CRA authorization.  
Written authorization of local IP destruction must be obtained from the sponsor or delegate 
before destruction occurs. 
Written documentation of destruction must contain the following: 
• 
Identity [batch numbers or subject numbers] of IP [and placebo] destroyed 
• 
Quantity of IP destroyed 
• 
Date of destruction 
• 
Method of destruction 
• 
Name and signature of responsible person [or company] who destroyed IP. 
 
 
STUDY ASSESSMENTS AND PROCEDURES 
The schedule of visits for this study is outlined in Appendix 2, however, a subject may be 
seen at any time for safety reasons. 
 
Screening Assessments 
All subjects must provide written informed consent before any study-specific assessments or 
procedures are performed including 10-hour fasting for labs.   


 
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Screening procedures (Visit 1, up to 7 days prior to Baseline Visit 2) to assess eligibility 
include medical history, height, weight, physical examination, vital signs, ECG, concomitant 
medications, and lab blood draw per Appendix 3.  
Urine pregnancy test is performed in females of childbearing potential. 
Subjects who fail to meet inclusion/exclusion criteria may not be re-screened for study entry.  
Subjects taking supplements defined in the exclusion criterion #2 and who accept to stop 
taking these supplements, may be randomized after a 30-day wash out period. If during the 
screening period it is determined that a subject is taking an excluded supplement, it is 
permissible to extend the 7-day screening period to allow for a 30-day washout in these 
exceptional circumstances. 
Any clinically significant AE occurring prior to subject randomization is to be reported in the 
Medical History, and if serious, should be recorded as a SAE.  
 
Randomization and Treatment Procedures 
Urine pregnancy test is repeated in females of childbearing potential at the randomization 
Visit 2.  
Subjects considered by the investigator to meet all entry criteria are scheduled for 
randomization at Week 0 (Visit 2) where subject receives either CP105F (1.5 g, 3 g or 6 g) or 
matching placebo in a double-blinded fashion.  Dietary counselling per Appendix 1, and IP 
and statin (for subjects who are taking statins) administration instructions are reviewed with 
the subject at each dispensing visit (Visits 2 and 3), and IP and statin (for subjects who are 
taking statins) compliance is assessed at subsequent visits (Visits 3 and 4): 
• 
IP administration: 1, 2 or 4 tablets (based on the dosing arm currently recruiting) 
taken TID in the morning before breakfast, at mid-day before lunch and before 
supper time preferably at the same times every day. Subjects should be clearly 
instructed that if a dose is missed, the next regularly scheduled dose should be 
taken and unused tablets returned at the next study visit. 
• 
Statin administration (for subjects who are taking statins):  in the evening or least 2 
hours after the last dose of IP. 
During the 12-week treatment period, visits will take place at Weeks 6 and 12 (Visit 3 and 4 
respectively, ± 5 days), followed by a Safety Follow up (Visit 5, ± 5 days) at Week 14.   
Subjects will continue to receive dietary counselling throughout the course of the treatment 
period and have labs measured as outlined in Appendices 2 and 3. Subjects will be assessed 
for compliance to IP through pill counts (see section 5.3).  At each visit, subjects will be 
questioned in a non-specific manner for the occurrence of Adverse Events.      
Safety assessments may be done at any time during the subject’s participation in the study. 
Follow-up phone call will be performed 2 weeks after last dose taken for capturing any AEs. 
 
 
Medical History: 
Medical History will consist of detailed information, with particular attention to identify factors 
that would exclude a patient, including: age, race, sex, current medications, drug sensitivities 
or any adverse reactions to medications, history of hepatic, renal, or cardiovascular disease, 


 
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smoking history, alcohol intake, drug abuse, prior hospitalizations, surgeries, interventions, 
and serious illnesses 
 
 
Physical Examination  
Physical examinations will include examination of the following body systems: general 
appearance, skin (including hair and nails), EENT (ears, eyes, nose, throat), neck/thyroid, 
chest/lungs, 
cardiovascular, 
gastrointestinal, 
genito-urinary (optional), 
neurological, 
lymphatic and musculoskeletal systems. Height and body weight will also be measured and 
recorded at Screening Visit (V1), and weight at the End of Treatment Visit (V4). 
Any new clinically significant finding identified upon physical examination that meets the 
definition of an AE or SAE must be documented as such. 
 
 
Vital Signs 
Blood pressure and pulse will be recorded after at least 5-minute rest in the sitting position. 
Two measurements should be made for each blood pressure measurement and the average 
recorded. Vital sign checks will be performed according to the schedule summarized in 
Appendix 3.  
 
 
Electrocardiogram 
All ECGs will be obtained in the decubitus position following a 10-minute rest time. 
All ECG recordings must be performed using a standard high-quality, high-fidelity 
electrocardiograph machine equipped with computer-based interval measurements. Digital 
ECG recording is recommended. 
For safety monitoring purposes, the investigator or physician delegate must review, sign 
and date all ECG tracings. Paper copies will be kept at the study center with the subject's 
clinical file as part of the permanent record. The ECG intervals and interpretation will be 
recorded on the eCRF  
The following parameters PQ (PR), QRS, QT and QTcB (calculated according to Bazett’s 
formula) and the heart rate will be measured automatically and recorded in the eCRF. In 
addition, any observed abnormality will be reported and documented.  
 
 
Laboratory Analyses 
A full clinical laboratory profile including hematology, biochemistry, lipids and other analyses 
will be performed during the study as outlined in Appendix 3. 
All lab tests are performed in the 10-hour fasting state (water allowed). If a subject has not 
adhered to the 10-hour fast, the visit can be rescheduled within approximately 1-3 days 
(maximum visit window is +/- 5-days).  Urine samples will be analysed and destroyed.  Blood 
samples will be retained during the study and for up to 6 months following completion of the 
trial to facilitate complete analysis and for the potential analysis of additional lipid, or 
lipoprotein or biomarker analyses. 


 
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Concomitant and Prohibited Medications 
The investigator or designee will review the concomitant medications being taken by the 
subject.  Any AE that leads to the administration of any new concomitant medications will be 
reported as an AE. 
The use of medications or supplements which may have a possibility of altering lipid levels 
(see Exclusion #1 and #2) should be avoided until after end of treatment or ideally, study 
completion at Week 14. Oral or parenteral hormonal contraceptive agents should be 
stabilized prior to study entry and maintained stable throughout the course of the trial. Use of 
NSAIDs is prohibited with the exception of acetylsalicylic acid (ASA) at a concentration of up 
to 325 mg twice a day and occasional/intermittent use for the symptomatic control of minor 
acute ailments (e.g. headaches).  
 
In the course of the study, patients will be receiving standard medical care at the discretion 
of the treating physician. During the treatment period, the investigators will carefully monitor 
and consider adjusting the dose in patients who are taking concomitant medications known 
to have hypotensive properties such as immunosuppressants, antihypertensive drugs or 
natural health products (e.g. andrographis, casein peptides, cat’s claw, coenzyme Q-10, fish 
oil, L-arginine, lyceum, stinging nettle, theanine). 
 
 
Adverse Events 
Adverse events (serious and non-serious) will be collected throughout the study from 
randomization to last dose of IP taken. SAEs will be collected from the time of consent through 
to 2 weeks after the last dose of study product. At each visit, the investigator or designated 
qualified study site staff will ask the subject if any untoward medical event occurred since the 
last visit. For each event, the date of onset and end, severity, relationship to IP, outcome and 
treatments administered for the event will be recorded in the eCRF. 
 
 Unscheduled Visit 
All attempts should be made to keep subjects on the study schedule. Unscheduled visits may 
be necessary to repeat testing following abnormal laboratory results, for follow-up of AEs, or 
for any other reason, as warranted.  
The following information will be collected at any unscheduled visit: 
• 
New/change in concomitant medications 
• 
AEs 
Details of these visits will be recorded as appropriate. 
 


 
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 Early Termination Visit 
Any subject terminating from the study early during the treatment period will, at the time of 
withdrawal, be encouraged to complete all Visit 4 (Week 12) procedures if possible. 
 
 
Efficacy Assessments   
6.12.1 
Primary Efficacy Assessment 
The primary efficacy assessment is direct-measured of LDL-cholesterol.   
6.12.2 Secondary Efficacy Assessment 
The secondary efficacy assessments include TC, non-HDL-C, small LDL subclass particle 
concentration, hsCRP, apo B, and VLDL-C.   
 
 
Exploratory Assessments  
Exploratory assessments include HDL-C, TG, Lp(a) and HbA1c. 
 
 
Safety Assessments 
Safety will be assessed by adverse events, physical examination, ECG, vital signs, and 
laboratory analyses (hematology and biochemistry). 
 
 End of Study 
The end of the study is defined as the date of the last visit of the last subject. Last visit of the 
last subject is either the date of the last visit of the last participant to complete the study, or 
the date at which the last data point from the last subject, which was required for statistical 
analysis (i.e. key safety and efficacy results for decision making), was received, whichever is 
the later date. 
 
 
Dietary and Concomitant Medications Restrictions 
At the screening visit subjects should be already on a standard cholesterol lowering diet and 
they should maintain it throughout the study. Subjects are encouraged to pursue a healthy 
lifestyle. The subjects must abstain from/minimize alcohol (EtOH) intake and control any other 
variables that may alter serum lipid levels (e.g., strenuous exercise, weight loss programs, 
drugs including over the counter preparations that may alter serum lipid levels).  
 
 
ADVERSE EVENTS (AE) AND SERIOUS ADVERSE EVENTS (SAE) ∕ SAFETY 
INSTRUCTIONS AND GUIDANCE 
The investigator is responsible for the detection and documentation of events meeting the 
criteria and definition of an adverse event (AE) or a serious adverse event (SAE) as provided 


 
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in this protocol. During the study, when there is a safety evaluation, the investigator or site 
staff will be responsible for detecting AEs and SAEs, as detailed in this section of the protocol. 
 
Definition of Adverse Event (AE) 
As per Natural Health Products Regulations SOR/2003-196, an AE is any adverse 
occurrence in the health of a clinical trial subject who is administered a natural health product 
that may or may not be caused by the administration of the natural health product, and 
includes an adverse reaction, a serious adverse reaction and a serious unexpected adverse 
reaction. 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition is to be reported as AE. Signs, symptoms, or the 
clinical sequelae of a suspected overdose of either IP or a concurrent medication are to be 
reported as AEs.  
Medical or surgical procedures (e.g. endoscopy, appendectomy) are not to be reported as 
AEs; the medical condition that leads to the procedure is an AE. 
 
 
Definition of Serious Adverse Event  
A serious adverse event is a noxious and unintended response to a natural health product 
that occurs at any dose and that requires in-patient hospitalization or prolongation of existing 
hospitalization that causes congenital malformation, results in persistent or significant 
disability or incapacity, is life-threatening or results in death. 
 
7.2.1 Follow-up of AEs/SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each study 
participant and provide further information on the study participant’s condition.   
All AEs/SAEs documented at a previous visit or contact and designated as ongoing, will be 
reviewed at subsequent visit or contacts. All AEs/SAEs will be followed until resolution, until 
the condition stabilises, until the event is otherwise explained, or until the study participant is 
lost to follow-up.  
The appropriate AE/SAE eCRF page(s) will be completed and updated with follow-up 
information. Follow-up will include any supplemental investigations carried out to elucidate 
the nature and /or causality of the AE or SAE. This may include additional laboratory tests or 
investigations, histopathological investigations, or consultation with other health care 
physicians. 
 
 
Laboratory Test Abnormalities and other abnormal assessments as AEs or 
SAEs 
Abnormal laboratory findings (e.g. clinical biochemistry, hematology) or other abnormal 
assessments (e.g. ECG, vital signs) that are judged by the investigator as clinically significant 
will be recorded as AEs or SAEs if they meet the definition of an AE, as defined in Section 
7.1, or SAE as defined in Section 7.2.  


 
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Clinically significant abnormal laboratory findings or other abnormal assessments that are 
detected during the study or are present at baseline and significantly worsen following the 
start of the study will be reported as AEs or SAEs. However, clinically significant abnormal 
laboratory findings or other abnormal assessments that are associated with a disease 
reported in the medical history, unless judged by the investigator as more severe than 
expected for the participant’s condition, or that are present or detected at the start of the study 
and do not worsen, will not be reported as AEs or SAEs.  
 
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 page in the eCRF: 
• 
Accompanied by clinical symptoms 
• 
Leading to a change in IP (permanent or temporary 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 IP, 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 (which will be 
analysed and reported as laboratory abnormalities) or those which are a result of an AE 
which has already been reported. 
 
7.3.1 Follow-up of Abnormal Laboratory Test Values 
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. 
 
 
Time Period, Frequency, and Method of Detecting AEs and SAEs 
All serious adverse events (SAEs) will be captured from the time of consent through to week 
14 safety Follow up phone call. All AEs will be captured between the time of randomization 
up to the last dose IP taken. Each study participant will be monitored by the investigator and 
study staff for AEs/SAEs occurring throughout the study. The investigator or designee will 
enquire about AEs/SAEs in a non-specific manner through the study at all visits. 
 
 
Recording of AEs and SAEs 
When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation 
(e.g. hospital progress notes, laboratory, and diagnostic reports) relative to the event. The 
investigator will then record all relevant information regarding an AE/SAE into the eCRF. It is 


 
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not acceptable for the investigator to send photocopies of the study participant’s medical 
records to the MHICC in lieu of completion of the appropriate AE/SAE eCRF pages. However, 
there may be instances when copies of medical records for certain cases will be requested 
by the MHICC Medical Reviewer. In this instance, all study participant identifiers (subject 
number is acceptable) will be blinded on the copies of the medical records prior to submission 
to MHICC Medical Reviewer. 
For each adverse event, start and stop dates, action taken, outcome, intensity and 
relationship to IP (causality) must be documented. If an AE changes in frequency or intensity 
during a study, an update of the event must be made on the eCRF. 
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. In the absence of a diagnosis, the individual signs/symptoms 
should be documented. 
All details of any treatments initiated due to the AE should be recorded in the study 
participant’s clinic notes and the eCRF. 
 
 
Prompt Reporting of SAEs   
This study adheres to the definition and reporting requirements of Natural Health Products 
Regulations SOR/2003-196. 
Once an investigator becomes aware that an SAE has occurred in a study participant, he/she 
will immediately notify the MHICC Medical Reviewer by completing the study-specific eCRF 
SAE form. The SAE form must be completed as thoroughly as possible with all available 
details of the event, within 24 hours of first becoming aware of the event. 
If the investigator does not have all information regarding an SAE, he/she will not wait to 
receive additional information before completing the eCRF SAE form. The form will be 
updated when additional information is received.  
The investigator will always provide an assessment of causality at the time of the initial report. 
If data obtained after the initial report, indicate that the assessment of causality is incorrect, 
the SAE form may be appropriately amended by the investigator, and resubmitted to sponsor 
or delegate. 
The investigator must also notify their ethics committee, whether local or central.  
 
 
Expeditable Events (SUSAR’s) 
During the course of a clinical trial, the sponsor / or delegate shall notify the regulatory 
authorities of any serious unexpected adverse reaction to the natural health product that has 
occurred inside or outside Canada as follows: 
a) if it is neither fatal nor life threatening, the regulatory authorities should be notified 
immediately if possible, and no later 15 days after the sponsor becomes aware of the 
information; and  
b) if it is fatal or life threatening, the regulatory authorities should be notified immediately if 
possible and no later than seven days after the sponsor becomes aware of the information.  


 
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c) Within eight days after having informed the regulatory authorities of a serious unexpected 
adverse reaction to the natural health product, the sponsor must submit a report as complete 
as possible that includes an assessment of the importance and implication of any 
findings. The final report should include relevant previous experience with the same or similar 
health products. 
A serious adverse reaction is a serious adverse event that is CAUSALLY related to the 
investigational product. 
Serious expected adverse reactions could qualify for an expedited reporting if there is a 
clinically significant increase in the rate of its occurrence within the study population. 
Appropriate scientific and medical judgment should be applied. 
 
 
Evaluating AEs and SAEs 
7.8.1 Assessment of Severity 
The investigator will make an assessment of severity for each AE and SAE reported during 
the study. The assessment will be based on the investigator’s clinical judgment. The severity 
of each AE and SAE recorded in the eCRF should be assigned to one of the following 
categories: 
Mild: An event that is easily tolerated by the participant, causing minimal discomfort, requiring 
minimal or no treatment and not interfering with everyday activities. 
Moderate: An event that results in a low level of inconvenience or concern with the 
therapeutic measures. Moderate event may cause some interference with the normal 
everyday activities. 
Severe: An event which interrupts a participant’s everyday activities and may require 
systemic drug therapy or other treatment. Severe event is usually potentially life-threatening 
or incapacitating. 
An AE that is assessed as severe should not be confused with an SAE. Severity is a category 
utilised for rating the intensity of an event; and both AEs and SAEs can be assessed as 
severe. An event is defined as “serious” when it meets one of the pre-defined outcomes as 
described in Section 7.2 “Definition of Serious Adverse Events”. 
7.8.2 Assessment of Causality 
The investigator is obligated to assess the relationship between IP and the occurrence of 
each AE/SAE. The investigator will use clinical judgment to determine the relationship. 
Alternative causes, such as natural history of the underlying diseases, concomitant therapy, 
other risk factors, and the temporal relationship of the event to the IP will be considered and 
investigated.  
The causal relationship to the study product assessed by the Investigator (or medically 
qualified delegate) should be assessed using the following classifications: 
Not Related: The adverse event is completely independent of IP administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an 
alternative, a definitive etiology documented by the clinician. 


 
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Related: There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The adverse event occurs in a plausible time relationship 
to IP administration and cannot be explained by concurrent disease or other drugs or 
chemicals. The response on dechallenge of the IP should be clinically plausible. The event 
must be pharmacologically or phenomenologically definitive, with use of a satisfactory 
rechallenge procedure if necessary. 
7.8.3 Assessment of Expectedness 
The sponsor (or delegate) will be responsible for determining whether an adverse event is 
expected or unexpected. An adverse event will be considered unexpected if the nature, 
severity, or frequency of the event is not consistent with the risk information previously 
described for the IP. 
 
Pregnancy 
A female subject must be instructed to immediately inform the investigator if she becomes 
pregnant during the study. The investigator should report all pregnancies within 24 hours to 
the sponsor. The investigator should counsel the subject; discuss the risks of continuing with 
the pregnancy and the possible effects on the foetus. Monitoring of the subject should 
continue until conclusion of the pregnancy. 
 
 
CLINICAL MONITORING 
The Investigator(s) and delegated Investigator staff undertake(s) to perform the clinical trial in 
accordance with this the protocol, ICH guidelines for Good Clinical Practice (16) and the 
applicable regulatory requirements. The Investigator agrees to provide reliable data and all 
information requested by the protocol in an accurate and legible manner according to the 
instructions provided and to ensure direct access to source documents by sponsor and its 
delegates. 
The sponsor of this clinical trial is responsible to Health Authorities for taking all reasonable 
steps to ensure the proper conduct of the clinical trial protocol as regards ethics, clinical trial 
protocol compliance, and integrity and validity of the data recorded on the eCRFs. Thus, the 
main duty of the Monitoring Team (CRA and MHICC Medical Reviewer) is to help the 
Investigator and the sponsor maintain a high level of ethical, scientific, technical and regulatory 
quality in all aspects of the Clinical Trial. 
According to the ICH guidelines for Good Clinical Practice, the Monitoring Team must check 
the eCRF entries against the source documents, except for the pre-identified source data 
directly recorded in the eCRF. The Informed Consent Form will include a statement by which 
the subject allows the Sponsor’s duly authorized personnel, the Ethics Committee (IRB/IEC), 
and the regulatory authorities to have direct access to original medical records which support 
the data on the eCRFs (e.g., subject's medical file, appointment books, original laboratory 
records, etc.). These personnel, bound by professional secrecy, must maintain the 
confidentiality of all personal identity or personal medical information (according to 
confidentiality and personal data protection rules). 
A separate Monitoring Plan will describe in detail who will conduct the monitoring, at what 
frequency monitoring will be done, at what level of detail monitoring will be performed, and 
the distribution of monitoring reports. 


 
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STUDY COMMITTEES 
 Not Applicable  
 
Steering Committee: Not applicable 
 
 
Data and Safety Monitoring Board (DSMB): Not applicable 
 
 
STATISTICAL CONSIDERATIONS 
 
Analysis Datasets 
10.1.1 Intent-to-Treat Population 
The intent-to treat (ITT) population will include all randomized subjects. Subjects will be 
assigned to treatment groups as randomized for analysis purposes.   
10.1.2 Per-Protocol Population 
The per-protocol (PP) population will include all randomized subjects who were compliant to 
IP and who were not subject to major protocol deviation. Subjects will be assigned to treatment 
groups as randomized for analysis purposes. 
10.1.3 Safety Population 
The safety population will include all randomized subjects who received at least one dose of 
IP. Subjects will be assigned to treatment groups as per actual treatment received for analysis 
purposes. 
 
 
General Statistical Approach 
This is a randomized, parallel study with four treatment groups (placebo, beta-glucan 1.5 g, 
beta-glucan 3 g and beta-glucan 6 g). The statistical analysis will focus on the comparisons 
of the three active groups vs. placebo.  
Descriptive statistics of all study variables will be presented overall and broken down by 
treatment group. Number of observations, mean, standard deviation, median, minimum and 
maximum will be presented for continuous variables. Count and proportion will be displayed 
for categorical variables. 
Basic assumptions of the proposed analyses will be checked and data transformation or other 
analyses could be done if appropriate. For example, as some endpoints are likely to be 
skewed (ex. triglycerides, hsCRP), log-transformation might be used, in which case 
descriptive statistics would also include geometric means. 
All statistical tests will be two-sided. Tests involving the comparisons of the active groups vs. 
placebo for the primary endpoint will be conducted at the 0.0167 significance level. All other 
tests will be considered secondary or exploratory and will be conducted at the 0.05 
significance level.  


 
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A statistical analysis plan (SAP) will be written to fully describe the statistical analyses that 
will be done. The SAP will be finalized prior to database lock and unblinding.  
Statistical analyses will be done using SAS version 9.4 or higher. 
 
 
Efficacy Analyses 
All efficacy analyses will be conducted on the ITT population. However, as a sensitivity 
analysis, the analysis of the primary endpoint described in section 10.3.1 will be repeated 
on the PP population. 
 
10.3.1 Analysis of the Primary Efficacy Endpoint 
The primary endpoint is the change from Week 0 to Week 12 in direct-measured LDL-C. The 
changes, as well as the LDL-C values at each study visit, will be summarized with descriptive 
statistics.  
The primary endpoint will be compared between treatment groups using a repeated measures 
analysis of covariance (ANCOVA) model adjusting for the Week 0 value of LDL-C. More 
specifically, the dependent variable will be the change from Week 0 in LDL-C (change 
calculated as post Week 0 level – Week 0 level). The model will include treatment group, time 
(Week 6 and Week 12) and treatment group x time interaction as factors. Contrasts under this 
model will allow for the three main comparisons: placebo vs. beta-glucan 1.5 g, placebo vs. 
beta-glucan 3 g and placebo vs. beta-glucan 6 g. More specifically, the following hypotheses 
will be tested: 
H0: 
W12,placebo = 
W12,1.5g vs. H1: 
W12,placebo ≠ 
W12,1.5g 
H0: 
W12,placebo = 
W12,3g vs. H1: 
W12,placebo ≠ 
W12,3g 
H0: 
W12,placebo = 
W12,6g vs. H1: 
W12,placebo ≠ 
W12,6g 
where 
W12,placebo, 
W12,1.5g, 
W12,3g and 
W12,6g are respectively the mean change from Week 
0 to Week 12 in LDL-C in the placebo, beta-glucan 1.5 g, beta-glucan 3 g and beta-glucan 6 
g group. 
All sets of hypotheses will be tested at the 0.0167 significance level to maintain the overall 
type I error to 0.05 for the primary endpoint. These tests will be considered as the primary 
analysis of the study. 
For illustrative purposes, changes within groups will be tested at the 0.05 significance level. 
Estimates of the changes within groups and of the between-group differences will also be 
presented along with 95% confidence intervals.  
The same ANCOVA model will also allow for the examination of the change from Week 0 to 
Week 6 in LDL-C. In other words, the hypotheses described above will also be tested at Week 
6 at the 0.05 significance level. 
Because the SAS procedure PROC MIXED will be used, subjects with missing data at a 
given study visit will not be excluded from the analysis. 


 
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10.3.2 Analysis of the Secondary Endpoints 
Secondary endpoints are expressed as change from Week 0 to Week 12 and will be analysed 
as the primary endpoint, with the exception that tests will be conducted at the 0.05 significance 
level. 
 
10.3.3 Analysis of the Exploratory Endpoints 
Similarly, exploratory endpoints are expressed as change from Week 0 to Week 12 and will 
be analysed as the primary endpoint, with the exception that tests will be conducted at the 
0.05 significance level. 
 
10.3.4 Subgroup Analyses 
The following subgroup analyses are planned for the primary endpoint: mild vs severe 
hypercholesterolemia, male vs female, diabetic vs non-diabetic, hypertensive vs non-
hypertensive, age < 65 years old vs. age ≥ 65 years old and treated with a statin at baseline 
vs. not treated with a statin at baseline. 
 
For subgroup analyses, ANCOVA models on the change from Week 0 to Week 12 in LDL-C 
will be used. These models will include a factor for the Week 0 value of LDL-C, as well as 
factors for the treatment group, the subgroup variable and the treatment group x subgroup 
variable interaction. This interaction term will determine the impact of the subgroup on the 
treatment effect. For illustrative purposes, estimates of treatment effect will be presented within 
each subgroup. 
 
 
Safety Analyses 
Safety will be assessed by adverse events, physical examination, vital signs, ECG, and 
laboratory analyses (hematology, biochemistry). 
No formal statistical testing will be done for the safety endpoints. Statistical analysis will be 
mainly descriptive, broken down by treatment group, and conducted on the safety population. 
 
10.4.1 Adverse Events 
Adverse events will be coded by body system as defined by the latest version of the 
MedDRAs, following classification of investigator assessments into MedDRA preferred terms.  
Treatment-emergent adverse events, defined as adverse events with a start date on or after 
the first dose of IP will be tabulated by preferred term, body system, severity and treatment 
group. 
Serious adverse events will be presented in a manner similar to that described for adverse 
events. 
 


 
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10.4.2 Laboratory Data 
All laboratory parameters will be summarized using descriptive statistics and presented by 
study visit and treatment group. Changes from Week 0 to post Week 0 visits will also be 
summarized. 
 
10.4.3 Other safety assessments 
Other safety assessments, including physical examination, vital signs and ECG, will be 
summarized using descriptive statistics and presented by study visit and treatment group. 
When applicable, changes from Week 0 to post Week 0 visits will also be summarized. 
 
 
Planned Interim Analyses 
No interim analysis on efficacy endpoints is planned for this study. 
 
 
Sample Size Calculation 
Sample size computation is based on the change in LDL-cholesterol. Based on previous 
literature, we are expecting a mean decrease from baseline to follow-up in LDL-C of -0.30 
mmol/L (11.6 mg/dl) in the placebo group and we are aiming to show that the addition of beta-
glucan, either at 1.5 g, 3 g or 6 g, will further reduce LDL-C by -0.30 mmol/L, leading to an 
expected difference in change in LDL-C of 0.30 mmol/L between the placebo group and at 
least one of the active groups. The expected standard deviation of the change in LDL-C is 
0.50 mmol/L (19.3 mg/dl). To reach a power of 80% in detecting this 0.30 mmol/L difference 
with a two-tailed significance level of 0.0167 (to account for three main comparisons (placebo 
vs. beta-glucan 1.5 g, placebo vs. beta-glucan 3 g and placebo vs. beta-glucan 6 g), 60 
subjects per group are needed for a total of 240 subjects. To account for approximately 9% 
lost to follow-up, 264 subjects (66 subjects per treatment group) will be randomized. 
Sample size was calculated with nQuery + nTerim 2.0. 
 
11. 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
11.1. Good Clinical Practice Statement  
It is the responsibility of both the sponsor and the investigator (s) to ensure that this clinical 
study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki, and that are consistent with the International Council for 
Harmonisation (ICH) guidelines for Good Clinical Practice (GCP) and applicable regulatory.  
11.2. Ethical Review  
It is the understanding of the Sponsor that this protocol (and any amendment) as well as 
appropriate consent procedures, will be reviewed and approved by a Research Ethics Board 
/ an Institutional Review Board (REB/IRB). This Board must operate in accordance with the 
currently applicable regulations. For sites with local ethics committee, a letter or certification 


 
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of approval will be sent by the Investigator to the Sponsor prior to initiation of the study, and 
also whenever subsequent modifications to the protocol are made. 
11.3. Informed Consent   
It is the responsibility of the Investigator to obtain written informed consent from each 
individual participating in this study after adequate explanation of the aims, methods, 
objectives and potential hazards of the study. It must also be explained to the subjects that 
they are completely free to refuse to enter the study or to withdraw from it at any time for any 
reason. 
The ICF should be signed and dated by the subject and by the investigator or authorized 
designee who reviewed the ICF with the subject. 
The original ICF must be retained by the investigator as part of the subject's study record, 
and a copy of the signed ICF must be given to the subject. 
If new safety information results in significant changes in the risk/benefit assessment or any 
new information that may affect willingness to continue to participate, the consent form should 
if necessary be reviewed and updated by the REB/IRB. All subjects (including those already 
being treated) should be informed of the new information, given a copy of the revised form 
and asked to give their consent to continue in the study per local requirements. The original 
signed revised ICF must be maintained in the subject’s study record and a copy must be 
given to the subject. A notation that written informed consent has been obtained will be made 
on the participant’s eCRF.   
11.4. Ethics Review Committee 
The protocol will be submitted for approval to the REB/IRB, and a written approval will be 
obtained before study participants are recruited and enrolled in this study. The Investigators 
will receive from the MHICC all the documentation needed for submitting the clinical study to 
the Ethics Committee. A copy of the respective approval letters will be forwarded to the 
MHICC and to the sponsor if applicable before starting to recruit study participants in this 
study. The composition of the Ethics Committee must also be provided to the MHICC as part 
of the essential documents.  If approval is suspended or terminated by the local ethics, the 
Investigator will notify the MHICC immediately. 
It is the responsibility of the Investigator to report study progress to the local Ethics Committee 
as required or at intervals not greater than one year. 
The Principal Investigator, or his/her delegate, will be responsible for reporting any serious 
adverse events to the local Ethics Committee and as soon as possible, and in accordance 
with local regulatory requirements. 
11.5. Confidentiality 
The investigator must take all appropriate measures to ensure that the anonymity of each 
study subject will be maintained.  Subjects should only be identified by their initials (or coded 
initials if required by institutional policy) and a subject identification number on eCRFs or 
other documents submitted to the sponsor.  Documents that will not be submitted to the 
sponsor (e.g., signed ICF, subject identity log) must be kept in strict confidence. 
 


 
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The subject's and investigator's personal data, which may be included in the sponsor 
database, will be treated in compliance with all applicable laws and regulations. The sponsor 
shall take all appropriate measures to safeguard and prevent access to this data by any 
unauthorized third party. 
 
12. 
FINANCIAL DISCLOSURE 
Financial disclosure is provided as a separate agreement. 
 
13. 
INVESTIGATOR RESPONSIBILITY 
Except where the Principal Investigator’s signature is specifically required, it is understood 
that the term ‘Investigator’ as used in this study protocol and on the eCRFs refers to the 
Principal Investigator or an appropriately qualified member of the clinical staff that the 
Principal Investigator designates to perform specified duties of the study Protocol.  The 
Principal Investigator is ultimately responsible for the conduct of all aspects of the study.  
Each Investigator will comply with the local regulations regarding clinical studies and the 
Investigator responsibilities outlined in the ICH GCP guidelines.  
 
14. 
PROTOCOL COMPLIANCE 
The instructions and procedures specified in this protocol require diligent attention to their 
execution. Should there be questions or consideration of deviation from the protocol, 
clarification will be sought from the study team.  Any study participant treated in a manner 
that deviates from the protocol, or who is admitted into the study but is not qualified according 
to the protocol, may be ineligible for analysis and thereby compromise the study. 
Only when an emergency occurs that requires a departure from the protocol for an individual 
will there be such a departure.  The nature and reasons for the protocol violation/deviation 
shall be recorded in the eCRF and the investigator should notify the sponsor and the Ethics 
Committee. 
The Investigator and designees will comply with all applicable federal, provincial and local 
laws. 
 
15. 
PROTOCOL AMENDMENT 
The Investigator may recommend changes to the protocol. The sponsor will decide if an 
amendment to the original protocol is warranted. Protocol modifications that impact on study 
participant safety or the validity of the study will be reviewed and approved by the Ethics 
Committee prior to implementation. 
 
It is the responsibility of the Investigator to submit the amendment to the Ethics Committee 
for their approval; written approval must be obtained and a copy provided to the Sponsor.  
The Sponsor is responsible for determining whether or not the local regulatory authority 


 
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Do not disclose or use except as authorized in writing by the study sponsor 
 
must be notified of the protocol change.  Completed and signed protocol amendments will 
be circulated to all those who were on the circulation list for the original protocol. 
 
16. 
PUBLICATIONS 
All information and data regarding the IP obtained in connection with the conduct of this study 
are considered confidential.  Accordingly, the sponsor retains the right to review manuscripts, 
abstracts, and presentation material related to this protocol and its amendments/addenda 
prior to presentation or submission to a journal. This review will not restrict publication of facts 
or opinions formulated by the investigator. 
 
 
17. 
RETENTION OF RECORDS AND ARCHIVING 
All source documents, eCRFs and study documentation will be kept by the Investigator for 
the appropriate retention period as stipulated by local regulations and ICH-GCP. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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18. REFERENCES 
1. Ann Marie Navar-Boggan et al., Hyperlipidaemia in Early Adulthood Increases Long-Term Risk of 
Coronary Heart Disease, Circulation. 2015 February 3; 131(5): 451–458. 
doi:10.1161/CIRCULATIONAHA.114.012477. 
2. Ralph .B. D’Agostino et al., Cardiovascular Disease Risk Assessment: Insights from Framingham, 
Glob Heart. 2013 March; 8(1): 11–23. doi:10.1016/j.gheart.2013.01.001. 
3. Heart and Stroke Foundation of Canada, consulted on 24-Oct-2016 at: 
http://www.heartandstroke.com/site/c.ikIQLcMWJtE/b.3483923/k.FCD0/Heart_disease__Heart_di
sease_conditions.htm. 
4. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and 
Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the 
National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and 
Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 
2002;106:3143-421. 
5. Michelle L. O’Donoghue et al., Lipoprotein(a) for Risk Assessment in Patients With Established 
Coronary Artery Disease, Journal of the American College of Cardiology Vol. 63, No. 6, 2014, 
http://dx.doi.org/10.1016/j.jacc.2013.09.042 
6. M. Bucci et all., Lp(a) and cardiovascular risk: Investigating the hidden side of the moon, 
Nutrition, Metabolism & Cardiovascular Diseases (2016) 26, 980e986. 
7. Donald M. Lloyd-Jones et al., 2016 ACC Expert Consensus Decision Pathway on the Role of 
Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic 
Cardiovascular Disease Risk, A Report of the American College of Cardiology Task Force on 
Clinical Expert Consensus Documents, Endorsed by the National Lipid Association, Journal of 
American College of Cardiology, 2016, Vol. 68, No 1. doi: 10.1016/j.jacc.2016.03.519. 
8. Hoang V.T. Ho et al., The effect of oat β-glucan on LDL-cholesterol, non-HDL-cholesterol and 
apoB for CVD risk reduction: a systematic review and meta-analysis of randomised-controlled 
trials, British Journal of Nutrition, doi:10.1017/S000711451600341X 
9. Ifeanyi D. Nwachukwu et al., Cholesterol-lowering properties of oat β-glucan and the promotion of 
cardiovascular health: did Health Canada make the right call? Appl. Physiol. Nutr. Metab.2015, 
40: 535–542. dx.doi.org/10.1139/apnm-2014-0410. 
10. EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA),  European Food Safety Authority 
(EFSA), Parma, Italy, Scientific Opinion on the substantiation of health claims related to beta-
glucans from oats and barley and maintenance of normal blood LDL-cholesterol concentrations 
(ID 1236, 1299), increase in satiety leading to a reduction in energy intake (ID 851, 852), 
reduction of post-prandial glycaemic responses (ID 821, 824), and “digestive function” (ID 850) 
pursuant to Article 13(1) of Regulation (EC) No 1924/2006, EFSA Journal 2011;9(6):2207. 
11. The Task Force for the Management of Dyslipidaemias of the European Society of Cardiology 
(ESC) and the European Atherosclerosis Society (EAS). ESC/EAS guidelines for the 
management of dyslipidaemias, Eur Heart J 2011;32:1769–818. doi:10.1093/eurheartj/ehr169 
12. Anne Whitehead, Cholesterol-lowering effects if oar β-glucan: a meta-analysis of randomized 
controlled trials, Am J Clin Nutr 2014;100:1413–21. 
13. Yanan Wang et al., High Molecular Weight Barley β-Glucan Alters gut Microbiota Toward 
Reduced Cardiovascular Disease Risk, Original Research, Frontiers in Microbiology, published: 
10 February 2016 doi: 10.3389/fmicb.2016.00129. 
14. Qingtao Hou et al., The Metabolic Effects of Oats Intake in Patients with Type 2 Diabetes: A 
Systematic Review and Meta-Analysis, Nutrients 2015; 7, 10369–10387; doi:10.3390/nu7125 


 
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15. Health Canada Beta glucan monograph, September 27, 2013 
16. Investigator’s brochure: Beta-Glucan CP105F. Effective date 20 March 2018 
17. Robert H. Eckel et al., 2013 AHA/ACC Guidelines on Lifestyle Management to Reduce 
Cardiovascular Risk, A Report of the American College of Cardiology/American Heart Association 
Task Force on Practice Guidelines, Circulation 2014; 129 [suppl 2]: S76-S99. 
18. Stone NJ  et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce 
atherosclerotic cardiovascular risk in adults: a report of the American College of 
Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129 
(suppl 2):S1–S45. 
19. Natural Health Products Regulations (SOR/2003-196) 
20. Clinical 
Trials 
For 
Natural 
Health 
Products 
Guidance 
Document 
- 
https://www.canada.ca/en/health-canada/services/drugs-health-products/natural-non-
prescription/legislation-guidelines/guidance-documents/clinical-trials.html#a7.2 
 
 
 
 
 
 
 
 


 
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19. APPENDICES 
 
19.1. Appendix 1: Standard Cholesterol Lowering Diet 
  
DIET 
 
1. Consume a dietary pattern that emphasizes intake of vegetables, fruits, and whole 
grains; includes low-fat dairy products, poultry, fish, legumes, nontropical vegetable oils 
and nuts; and limits intake of sweets, sugar-sweetened beverages and red meats. 
a. Adapt this dietary pattern to appropriate calorie requirements, personal and 
cultural food preferences, and nutrition therapy for other medical conditions 
(including diabetes mellitus). 
b. Achieve this pattern by following plans such as the 
DASH dietary pattern, the USDA Food Pattern, or the AHA Diet. 
2. Aim for a dietary pattern that achieves 5% to 6% of calories from saturated fat. 
3. Reduce percent of calories from saturated fat. 
4. Reduce percent of calories from trans fat. 
 
*Refer to 2013 Blood Cholesterol Guideline (17, 18) 
 
 


 
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19.2. Appendix 2. Schedule of visits 
 
Procedure/Visit  
 
Screening 
Period  
(V1) 
Randomization 
Baseline Visit 
(V2) 
 
Visit 3  
(V3) 
 
End of 
Treatment Visit 
(V4) 
 
Safety Follow-up 
Visit (V5) 
(telephone) 
Week -1  
Up to 7 days  
Week 0  
 
Week 6  
( ± 5 days) 
Week 12  
( ± 5 days) 
Week 14  
(± 5 days) 
Informed consent form 
X 
 
 
 
 
Inclusion & Exclusion criteria 
X 
X 
 
 
 
Medical History 
X 
X 
 
 
 
Demographics 
X 
 
 
 
 
Physical examination 
X 
 
 
X 
 
Vital signs (blood pressure, pulse) 
X 
X 
X 
X 
 
Height  
X 
 
 
 
 
Weight  
X 
 
 
X 
 
Dietary counselling including alcohol 
consumption,  and timing of statin vs. IP 
intake 
X 
X 
X 
 
 
Check compliance on statin and IP 
 
 
         X 
          X 
 
12-Lead ECG 
X 
 
 
X 
 
Hematology  
           X 
X 
         X 
X 
 
AST, ALT, Creatinine 
X 
X 
X 
X 
 
Bilirubin 
X 
 
 
 
 
LDH, CPK 
 
X 
X 
X 
 
TG, TC, LDL-C, HDL-C 
X 
X 
X 
X 
 
LDL-C (direct-measured), VLDL-C, apo-
B, Lp(a), non-HDL-C, small low-density 
lipoprotein (LDL) subclass particle 
concentration 
 
X 
X 
X 
 
HbA1c, Insulin, Glucose and hsCRP 
 
X 
 
X 
 
Concomitant medication 
X 
X 
X 
X 
 
Pregnancy test* 
X* 
X* 
 
 
 
Randomization 
 
X 
 
 
 
IP dispensing 
 
X 
X 
 
 
Adverse Events 
X** 
X** 
X** 
X** 
X** 
*Female patients of childbearing potential will have a urine pregnancy test performed at the screening visit and at randomization (visit 2)  
**Serious Adverse Events (SAEs) are captured from the time of consent through to week 14 safety Follow up phone call. AEs are 
captured between the time of randomization up to the last dose IP taken. 
 
 
 
 
 
 


 
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19.3. Appendix 3. Clinical Laboratory Parameters 
 
Screening (Visit 1):  The following screening laboratory assessments are to be performed 
during the screening period for the determination of study eligibility and the patient’s current 
medical state at the time of study entry: 
 
Determinations 
 
Hematology 
RBC 
 
 
Hemoglobin 
 
 
Hematocrit 
 
 
WBC 
 
 
Platelet Count 
 
 
Differential 
(to be performed only 
if WBC is abnormal) 
Neutrophils 
 
Lymphocytes 
 
Monocytes 
 
 
Eosinophils 
 
 
Basophils 
Biochemistry 
AST 
 
 
ALT 
 
 
            Bilirubin 
 
 
Creatinine 
 
Lipids 
Triglycerides  
Total cholesterol 
LDL-Cholesterol 
HDL-Cholesterol 
 
Urine (only for 
females of 
childbearing 
potential) 
human chorionic 
gonadotropin (hCG) urine 
pregnancy test 
 


 
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Baseline and Treatment Period (Visits 2, 3, and 4) 
 
Determinations 
Hematology 
RBC 
 
Hemoglobin 
 
Hematocrit 
 
WBC 
 
Platelet Count 
 
Differential 
(to be performed only 
if WBC is abnormal) 
Neutrophils 
 
Lymphocytes 
 
Monocytes 
 
 
Eosinophils 
 
 
Basophils 
Biochemistry 
AST 
 
ALT 
 
LDH 
 
CPK 
 
Creatinine 
Glucose (fasting) (at visit 2 and 4 only) 
Insulin (fasting) (at visit 2 and 4 only) 
 
 
HbA1c (at visit 2 and 4 only) 
hs-CRP (at visit 2 and 4 only) 
 
            
 Lipids / Other 
 
Triglycerides  
Total cholesterol 
            LDL-Cholesterol (direct-measured) 
HDL-Cholesterol 
VLDL Cholesterol 
Apolipoprotein B (apo B) 
Lipoprotein (a) [Lp(a)] 
Non-HDL-C 
small low-density lipoprotein (LDL) subclass particle 
concentration 


 
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Urine (only for 
females of 
childbearing 
potential) 
 
human chorionic gonadotropin (hCG) urine pregnancy test 
(Visit 2 only)  
 
 
Female patients of childbearing potential will have a urine pregnancy test performed at the 
screening visit and at randomization (visit 2). 
 
 
 
 
 
 
 
 

SAP_001.pdf: 
 
BS-T1-001-05 
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Page 1 of 27 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
 
 
 
 
Protocol number: PROJ1601 
 
A MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PARALLEL GROUP, PLACEBO-
CONTROLLED STUDY TO COMPARE THE EFFICACY AND SAFETY OF HIGH-
MEDIUM MOLECULAR WEIGHT BETA-GLUCAN IN SUBJECTS WITH 
HYPERLIPIDEMIA WITH OR WITHOUT STATIN THERAPY 
 
THE BETAVENA STUDY 
 
 
 
 
Date of Final Statistical Analysis Plan:  
24-SEP-2021 
Amendment 1:  
14-OCT-2021 
 
 
Prepared by: 
Sylvie Levesque, M.Sc. 
Senior Biostatistician 
Montreal Health Innovations Coordinating Center (MHICC) 
5000 Bélanger Street 
Montréal, QC  H1T 1C8 
Phone: 514-461-1300 ext. 2890 / Fax: 514-461-1301 
 
 
 


 
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Signature Approval Page 
 
 
By signing below, I indicate that I have reviewed the Statistical Analysis Plan in its entirety and approve its 
contents. 
 
 
Signature: 
 
 
Date: 
 
 
Jean-Claude Tardif, MD 
Principal Investigator 
Director, MHI Research Center 
 
 
(DD-MMM-YYYY) 
Signature: 
 
 
Date: 
 
 
Denis Bilodeau BSc, MBA, AdmA 
Strategic Advisor 
CEAPRO INC 
 
 
(DD-MMM-YYYY) 
Signature: 
 
 
Date: 
 
 
Marie-Claude Guertin, Ph.D. 
Lead, Biostatistics 
MHICC 
 
 
(DD-MMM-YYYY) 
 
 


 
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Revision History 
 
Version 
Date 
(DD-MMM-YYYY) 
Author 
Summary of Changes 
Final 
24-SEP-2021 
Sylvie Levesque 
Initial version 
Amendment 1 
14-OCT-2021 
Sylvie Levesque 
Section 6.3.6: Modification of the formula to 
calculate compliance to account for missing 
information. 
 
Section 6.4.4.1: Addition of a sensitivity 
analysis on a modified PP population with 
compliance criteria set to 70%. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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TABLE OF CONTENTS  
 
1 
Introduction ......................................................................................................................................... 7 
2 
Study Description ................................................................................................................................. 7 
2.1 
Study Design ................................................................................................................................ 7 
2.2 
Study Objectives ........................................................................................................................ 10 
3 
Datasets Analyzed .............................................................................................................................. 10 
3.1 
Intent-To-Treat (ITT) Population ............................................................................................... 10 
3.2 
Per-Protocol Population ............................................................................................................ 10 
3.3 
Safety Population ...................................................................................................................... 11 
4 
Efficacy Endpoints .............................................................................................................................. 11 
4.1 
Primary Efficacy Endpoint.......................................................................................................... 11 
4.2 
Secondary Efficacy Endpoints .................................................................................................... 11 
4.3 
Exploratory Endpoints ............................................................................................................... 11 
5 
Safety Parameters .............................................................................................................................. 12 
5.1 
Adverse Events .......................................................................................................................... 12 
5.2 
Serious Adverse Events.............................................................................................................. 12 
5.3 
Physical Examination ................................................................................................................. 12 
5.4 
Vital Signs................................................................................................................................... 12 
5.5 
Electrocardiogram ..................................................................................................................... 13 
5.6 
Laboratory Parameters .............................................................................................................. 13 
6 
Statistical Methodology ..................................................................................................................... 14 
6.1 
Determination of Sample Size ................................................................................................... 14 
6.2 
Statistical Considerations .......................................................................................................... 15 
6.2.1 
Handling of Missing Data ...................................................................................................... 15 
6.3 
Study Subjects ........................................................................................................................... 16 
6.3.1 
Subject Disposition ................................................................................................................ 16 
6.3.2 
Protocol Deviations ............................................................................................................... 16 
6.3.3 
Datasets Analyzed ................................................................................................................. 16 
6.3.4 
Demographic and Baseline Characteristics ........................................................................... 16 
6.3.5 
Prior and Concomitant Medications ..................................................................................... 16 
6.3.6 
Treatment Compliance .......................................................................................................... 17 
6.4 
Efficacy Analysis ......................................................................................................................... 17 
6.4.1 
Primary Analysis .................................................................................................................... 17 
6.4.2 
Secondary Analysis ................................................................................................................ 18 
6.4.3 
Exploratory Analysis .............................................................................................................. 18 
6.4.4 
Sensitivity Analysis ................................................................................................................ 19 
6.4.4.1 
Per-Protocol Analysis .................................................................................................... 19 
6.4.4.2 
Dose-Response Analysis ............................................................................................... 19 
6.4.5 
Subgroup Analysis ................................................................................................................. 19 
6.5 
Safety Analysis ........................................................................................................................... 20 
6.5.1 
Treatment Exposure .............................................................................................................. 20 
6.5.2 
Adverse Events and Serious Adverse Events ......................................................................... 20 
6.5.2.1 
Adverse Events ............................................................................................................. 20 
6.5.2.2 
Serious Adverse Events ................................................................................................ 20 
6.5.3 
Physical Examination ............................................................................................................. 21 


 
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6.5.4 
Vital Signs .............................................................................................................................. 21 
6.5.5 
Electrocardiogram ................................................................................................................. 21 
6.5.6 
Laboratory Parameters ......................................................................................................... 21 
7 
Summary Tables, Figures and Listings ................................................................................................ 22 
8 
References .......................................................................................................................................... 25 
9 
Appendices ......................................................................................................................................... 26 
9.1 
Appendix 1 - Schedule of visits .................................................................................................. 26 
9.2 
Appendix 2 - Reporting windows for laboratory parameters ................................................... 27 


 
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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
apo B 
Apolipoprotein B 
AST 
Aspartate Aminotransferase 
BLQ 
Below Limit of Quantification 
CPK 
Creatine Phosphokinase 
CRF 
Case Report Form 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EENT 
Ears, Eyes, Nose, Throat 
EtOH 
Ethyl Alcohol or Alcohol 
HbA1c 
Hemoglobin A1C, Glycated Hemoglobin or Glycosylated Hemoglobin 
hCG 
Human Chorionic Gonadotropin 
HDL-C 
High-Density Lipoprotein Cholesterol 
hsCRP 
High Sensitivity C-Reactive Protein 
ITT 
Intent To Treat 
LDH 
Lactate Dehydrogenase 
LDL-C 
Low Density Lipoprotein-Cholesterol 
LP(a) 
Lipoprotein (a) 
MedDRA 
Medical Dictionary for Regulatory Activity 
MHI 
Montreal Heart Institute 
MHICC 
Montreal Health Innovations Coordinating Center 
PP 
Per Protocol 
RBC 
Red Blood Cell 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
TC 
Total Cholesterol 
TG 
Triglycerides 
TID 
Three Times a Day 
VLDL-C 
Very Low-Density Lipoprotein Cholesterol 
WBC 
White Blood Cell 
WHO 
World Health Organization 
 
 
 


 
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1 
INTRODUCTION 
 
The purpose of this statistical analysis plan (SAP) is to present the statistical methodology that will be used 
for the final analysis of CEAPRO Inc. protocol PROJ1601.  This plan also provides a description of the tables, 
figures and listings that will be included in the final statistical report. It is based on the protocol version 
2.1 dated 23JAN2020 and on the annotated case report form (CRF) version 2.0. In case of differences in 
terms of descriptions or explanations between the SAP and the clinical protocol, the SAP will supersede 
the protocol. Any deviation to this SAP would be reported in the statistical report. 
 
2 
STUDY DESCRIPTION 
 
2.1 
Study Design 
 
This is a Phase 2, double-blind, randomized, multicenter, 12-week comparative study of beta-glucan 
versus placebo, in subjects with an elevated LDL–C >3.37mmol/L (130 mg/dL) treated with a stable dose 
of statin for at least 6 weeks or not treated with a statin.   
Following signature of informed consent, approximately 264 subjects (66 subjects per beta-glucan 
treatment group and 22 subjects per matching placebo group) meeting all inclusion criteria and no 
exclusion criteria will be randomized to receive one of the three doses of beta-glucan (1.5 g, 3 g or 6 g 
daily) TID or a matching placebo.  
The subjects will be assigned to the three different doses of beta-glucan or placebo in a tiered fashion as 
follows: 
• The first set of 88 subjects randomized will receive either 1.5 g beta-glucan (1 tablet of 500 mg TID) 
or a matching placebo in a 3:1 ratio, 
• The next set of 88 subjects randomized will receive either 3 g of beta-glucan (2 tablets of 500 mg 
TID) or a matching placebo in a 3:1 ratio, 
• The last set of 88 subjects randomized will receive either 6 g of beta-glucan (4 tablets of 500 mg 
TID) or a matching placebo in a 3:1 ratio.  
 
The duration of treatment is twelve weeks with beta-glucan 1.5 g, beta-glucan 3 g, beta-glucan 6 g (total 
daily dose) or matching placebo. Each subject is expected to participate for about 15 weeks (up to 1 week 
of screening, 12-weeks of treatment and follow-up call 2 weeks after last dose taken). 
 
At baseline Visit (Week 0), the subjects should be already on a standard cholesterol lowering diet 
(American Heart Association Guidelines) and they should maintain it throughout the study. Subjects are 
encouraged to pursue a healthy lifestyle. The subjects must abstain from/minimize alcohol (EtOH) intake 
and keep stable any other variables that may alter serum lipid levels (e.g., strenuous exercise, weight loss 
programs, drugs including over the counter preparations that may alter serum lipid levels). 
During the treatment period, subjects will return to the study site at Visit 3 (Week 6) and at the End of 
Treatment Visit (Week 12) for laboratory tests and clinical assessments, including for Adverse Events 
(AEs), dietary guidance and IP compliance. At the Safety Follow-up Visit (Week 14), subjects will be 
contacted via telephone for an assessment of Adverse Events (AEs). Time window for the Visit 3 (Week 
6), Final Visit (Week 12) and Safety Follow-up Visit is ± 5 days. 


 
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Laboratory tests and clinical assessments will be performed as noted in the schedule of visits (Appendix 
1).   
Safety and tolerability assessment will include AEs, hematology, biochemistry, physical examination, 
vital signs and electrocardiogram (ECG). 
 
The study design is presented in the following figure.  


 
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2.2 
Study Objectives 
 
The overall aim of this study is to evaluate the effects of beta-glucan (1.5 g, 3 g or 6 g daily) administered 
three times a day (TID) in divided doses compared to placebo on heart disease lipid risk factors. 
 
The primary objective is to evaluate the effects of beta-glucan on the direct-measured Low-Density 
Lipoprotein Cholesterol (LDL-C) level compared to placebo after 12 weeks of treatment in subjects with 
LDL-C > 3.37 mmol/L (130 mg/dL). 
 
The secondary objectives are to evaluate: 
- 
The effects of beta-glucan on Total Cholesterol (TC), small LDL-C subclass particle concentration, 
high sensitivity C-reactive protein (hsCRP), non-High Density Lipoprotein Cholesterol (HDL-C), 
Apolipoprotein B (apo B) and Very Low Density Lipoprotein Cholesterol (VLDL-C) levels compared 
to placebo  after 12 weeks of treatment. 
- 
The safety profile of beta-glucan. 
 
The exploratory objectives are to evaluate the effects of beta-glucan on HDL-C, Triglyceride (TG), 
Lipoprotein a (Lp(a)) and glycated hemoglobin (HbA1c) levels compared to placebo after 12 weeks of 
treatment. 
 
3 
DATASETS ANALYZED 
 
Subjects who were not eligible for randomization but who have been erroneously randomized into the 
study will be excluded from all datasets analyzed, if they did not take study medication. All populations of 
analysis will be approved by the sponsor prior to unblinding. 
 
3.1 
Intent-To-Treat (ITT) Population 
 
All patients randomized will be included in the ITT population (i.e. subjects having a randomization 
number on the Randomization Form of the electronic case report form (eCRF)). In the ITT population, 
subjects allocated to a treatment group by randomization will be followed up, assessed and analyzed as 
members of that group irrespective of their compliance to the planned course of treatment.  
 
3.2 
Per-Protocol Population 
 
The per-protocol population will include all subjects randomized, excluding subjects who were not 
compliant to IP and who had major protocol deviation. Subjects will be assigned to treatment groups as 
randomized for analysis purposes. Specific requirements are: 
 
▪ Compliance of at least 80%. The compliance will be taken from the Drug Accountability Form 
of the eCRF. 
▪ Absence of any major protocol deviations that could affect the primary endpoint. Those major 
protocol deviations are defined as: 
o “Incorrect investigational product kit administrated to subject” on Protocol 
Deviation Form of the eCRF 


 
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o “Subject received another investigational product” on Protocol Deviation Form of 
the eCRF 
o Inclusion criteria “Subjects with hyperlipidemia treated with stable dose of statin 
for at least 6 weeks; either atorvastatin (10 mg to 20 mg daily) or equivalent dose 
of another statin at the time of informed consent and with LDL-C level >3.37 
mmol/L (130 mg/dL) in fasting conditions at screening.” not met on 
Inclusion/Exclusion Criteria Form of the eCRF version previous 2.1. 
o Inclusion criteria “Subjects with hyperlipidemia with LDL-C level >3.37 mmol/L 
(130 mg/dL) in fasting conditions at screening, treated with a stable dose of statin 
for at least 6 weeks or not treated with a statin at the time of informed consent.” 
not met on Inclusion/Exclusion Criteria Form of the eCRF version 2.1. 
o Any other protocol deviations considered as major as per the sponsor. 
 
3.3 
Safety Population 
 
The safety population will include all randomized subjects who received at least one dose of IP (i.e. 
subjects with at least one non missing Investigational Product treatment period start date (variable 
EXSTDAT or a comment indicating unknown date of first dose) on Investigational Product Use Form of the 
eCRF). Subjects will be assigned to treatment groups as per actual treatment received for analysis 
purposes.  
 
4 
EFFICACY ENDPOINTS 
 
4.1 
Primary Efficacy Endpoint 
 
The primary efficacy endpoint will be the change from Week 0 to Week 12 in direct-measured LDL-C.  
 
4.2 
Secondary Efficacy Endpoints 
 
The secondary efficacy endpoints will be the changes from Week 0 to Week 12 in:  
• 
TC  
• 
non-HDL-C  
• 
small LDL subclass particle concentration  
• 
hsCRP  
• 
VLDL-C  
• 
Apo B 
 
4.3 
Exploratory Endpoints 
 
Exploratory endpoints will include changes from Week 0 to Week 12 in: 
• 
HDL-C 
• 
TG 
• 
Lp(a) 
• 
HbA1c 
 


 
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5 
SAFETY PARAMETERS 
 
Safety will be assessed by adverse events (AEs) and serious adverse events (SAEs), physical examination 
results, vital signs, ECG and laboratory parameters (hematology, biochemistry). 
 
5.1 
Adverse Events 
 
As per Natural Health Products Regulations SOR/2003-196, an AE is any adverse occurrence in the health 
of a clinical trial subject who is administered a natural health product that may or may not be caused by 
the administration of the natural health product, and includes an adverse reaction, a serious adverse 
reaction and a serious unexpected adverse reaction. 
 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency 
and/or intensity of the condition is to be reported as AE. Signs, symptoms, or the clinical sequelae of a 
suspected overdose of either IP or a concurrent medication are to be reported as AEs.  
 
Medical or surgical procedures (e.g. endoscopy, appendectomy) are not to be reported as AEs; the 
medical condition that leads to the procedure is an AE. For each adverse event, start and stop dates, 
action taken, outcome, intensity and relationship to IP (causality) must be documented by the 
investigator. If an AE changes in frequency or intensity during a study, an update of the event must be 
made on the eCRF. 
 
Treatment-emergent adverse events will be defined as adverse events with a start date on or after the 
first dose of study product (which will be derived as the earliest date of variable EXSTDAT on 
Investigational Product Use Form of the eCRF). 
 
5.2 
Serious Adverse Events 
 
A serious adverse event is a noxious and unintended response to a natural health product that occurs at 
any dose and that requires in-patient hospitalization or prolongation of existing hospitalization that causes 
congenital malformation, results in persistent or significant disability or incapacity, is life-threatening or 
results in death.  
 
SAEs will be collected from the time of consent through to 2 weeks after the last dose of study product. 
 
5.3 
Physical Examination 
 
Physical examinations will include examination of the following body systems: general appearance, skin 
(including hair and nails), EENT (ears, eyes, nose, throat), neck/thyroid, chest/lungs, cardiovascular, 
gastrointestinal, genito-urinary (optional), neurological, lymphatic and musculoskeletal systems. Height 
and body weight will also be measured and recorded at Screening, and weight at the Week 12. 
Any new clinically significant finding identified upon physical examination that meets the definition of an 
AE or SAE must be documented as such. 
 
5.4 
Vital Signs 
 


 
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Blood pressure and pulse will be recorded after at least 5-minute rest in the sitting position. Two 
measurements should be made for each blood pressure measurement and the average recorded. Vital 
sign checks will be performed at Screening, Baseline, Week 6 and Week 12. 
 
5.5 
Electrocardiogram 
 
All ECGs will be obtained in the decubitus position following a 10-minute rest time. The following 
parameters PQ (PR), QRS, QT, RR, QTcB (calculated according to Bazett’s formula) and the heart rate will 
be measured automatically and recorded in the eCRF at Screening and Week 12. 
 
5.6 
Laboratory Parameters 
 
A full clinical laboratory profile including hematology, biochemistry, lipids and other analyses will be 
performed during the study. Laboratory data will be transferred electronically by the Dynacare central 
lab. Blood samples are to be collected at Screening, Baseline, Week 6, Week 12 and at some unscheduled 
visits if it is necessary to repeat testing following abnormal laboratory results. Here is the list of the 
collected laboratory assessment: 
 
Screening (Visit 1):  The following screening laboratory assessments are to be performed during the 
screening period for the determination of study eligibility and the patient’s current medical state at the 
time of study entry: 
 
Determinations 
 
Hematology 
RBC 
Hemoglobin 
Hematocrit 
WBC 
Platelet Count 
 
 
Differential 
(to be performed only 
if WBC is abnormal) 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Biochemistry 
AST 
ALT 
Bilirubin 
Creatinine 
eGFR 
 
Lipids 
Triglycerides  
Total cholesterol 
LDL-Cholesterol 
HDL-Cholesterol 
 
Urine (only for females of 
childbearing potential) 
Human chorionic gonadotropin (hCG) 
urine pregnancy  test 
 
 


 
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Baseline and Treatment Period (Visits 2, 3, and 4) 
 
Determinations 
Hematology 
RBC 
Hemoglobin 
Hematocrit 
WBC 
Platelet Count 
 
Differential 
(to be performed only 
if WBC is abnormal) 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Biochemistry 
AST 
ALT 
LDH 
CPK 
Creatinine 
eGFR 
Glucose (fasting) (at visit 2 and 4 only) 
Insulin (fasting) (at visit 2 and 4 only) 
HbA1c (at visit 2 and 4 only) 
hs-CRP (at visit 2 and 4 only) 
Lipids / Other   
 
Triglycerides  
Total cholesterol 
LDL-Cholesterol (direct-measured) 
HDL-Cholesterol 
VLDL Cholesterol 
Apolipoprotein B (apo B) 
Lipoprotein (a) [Lp(a)] 
Non-HDL-C 
small low-density lipoprotein (LDL) subclass particle concentration 
Urine (only for females 
of childbearing potential) 
 
Human chorionic gonadotropin (hCG) urine pregnancy  test (Visit 2 only)  
Female patients of childbearing potential will have a urine pregnancy test performed at the Screening visit 
and at Baseline. 
 
6 
STATISTICAL METHODOLOGY 
 
6.1 
Determination of Sample Size 
 
Sample size computation was based on the change in LDL-cholesterol. Based on previous literature, we 
are expecting a mean decrease from baseline to follow-up in LDL-C of -0.30 mmol/L (11.6 mg/dl) in the 
placebo group and we are aiming to show that the addition of beta-glucan, either at 1.5 g, 3 g or 6 g, will 
further reduce LDL-C by -0.30 mmol/L, leading to an expected difference in change in LDL-C of 0.30 


 
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mmol/L between the placebo group and at least one of the active groups. The expected standard 
deviation of the change in LDL-C is 0.50 mmol/L (19.3 mg/dl). To reach a power of 80% in detecting this 
0.30 mmol/L difference with a two-tailed significance level of 0.0167 (to account for three main 
comparisons (placebo vs. beta-glucan 1.5 g, placebo vs. beta-glucan 3 g and placebo vs. beta-glucan 6 g), 
60 subjects per group were needed for a total of 240 subjects. To account for approximately 9% lost to 
follow-up, 264 subjects (66 subjects per treatment group) were randomized. 
 
Sample size was calculated with nQuery + nTerim 2.0. 
 
6.2 
Statistical Considerations 
 
This is a randomized, parallel study with four treatment groups (placebo, beta-glucan 1.5 g, beta-glucan 3 
g and beta-glucan 6 g). The statistical analysis will focus on the comparisons of the three active groups vs. 
placebo.  
Descriptive statistics of all study variables will be presented overall and broken down by treatment group. 
Number of observations, mean, standard deviation, median, minimum and maximum will be presented 
for continuous variables. Count and proportion will be displayed for categorical variables. 
Basic assumptions of the proposed analyses will be checked and data transformation or other analyses 
could be done if appropriate. For example, as some endpoints are likely to be skewed (ex. triglycerides, 
hsCRP), log-transformation might be used, in which case descriptive statistics would also include 
geometric means. 
 
Laboratory parameters will be assigned to visits based on number of days from randomization and not 
based on scheduled visit at which the measurement was made. The time windows that will be used to 
assign measurements to visits are given in Appendix 2. 
 
Values entered as less than a specified value will be considered as the specified value divided by 2 (e.g. 
entered value <0.2 will be analyzed as 0.1). Values entered as BLQ (Below Limit of Quantification) will be 
considered as the limit of quantification divided by 2. Values entered as more than a specified value will 
be considered as the specified value. 
 
All statistical tests will be two-sided. Tests involving the comparisons of the active groups vs. placebo for 
the primary endpoint will be conducted at the 0.0167 significance level. All other tests will be considered 
secondary or exploratory and will be conducted at the 0.05 significance level.  
 
No interim analysis on efficacy endpoints is planned for this study. 
 
Statistical analyses will be done using SAS version 9.4 or higher. 
 
6.2.1 
Handling of Missing Data  
 
For efficacy laboratory endpoints, the screening value will be taken if the baseline value is missing.  
 
In addition, the proposed statistical analysis will account for all available data and will not disregard 
subjects with missing data at either Week 6 or Week 12. However, in subjects who will only have a baseline 
measurement, the last observation carried forward approach will be used. 


 
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6.3 
Study Subjects 
 
6.3.1 
Subject Disposition  
 
Number of subjects screened, number of subjects randomized, number of subjects who took at least one 
dose of study medication, number of randomized subjects who complete all study visits and reasons if 
not will be summarized overall and by treatment group.  A listing of subject disposition will be provided. 
Subject disposition will also be presented with a flow chart. 
 
6.3.2 
Protocol Deviations  
 
Protocol deviations, as collected on the Protocol Deviation Form of the eCRF, will be summarized overall 
and by treatment group for the ITT population. A listing will also be provided.  
 
6.3.3 
Datasets Analyzed 
 
The number of subjects in each datasets will be summarized overall and by treatment group. A listing, 
including reason for being excluded from a given dataset, will be provided as well. 
 
6.3.4 
Demographic and Baseline Characteristics 
 
Demographic data and baseline characteristics such as medical history will be summarized using 
descriptive statistics, overall and by treatment group for the ITT population.  A listing will be presented 
for demographic data. 
 
6.3.5 
Prior and Concomitant Medications 
 
Prior and concomitant medications will be coded with respect to indication and generic name using the 
WHO Drug dictionary (version C March 2018).   
 
Frequency of use of medications at randomization will be presented for the subjects of the ITT population 
by therapeutic class and preferred term, overall and for each treatment group.   
 
A medication will be flagged as being ongoing at the time of randomization if: 
• 
Medication start date < randomization date 
 AND 
• 
Medication end date ≥ randomization date OR Medication is ongoing 
 
In case of missing or incomplete medication start / end dates, the following rules will be applied: 
• 
If 1) the medication start date is completely missing or 2) only the year is specified and it is the 
same as the randomization year or 3) only the month/year are specified and they are the same 
as the randomization month/year, then the medication will be assumed to have started before 
randomization. 
• 
If 1) the medication end date is completely missing or 2) only the year is specified and it is the 
same as the randomization year or 3) only the month/year are specified and they are the same 


 
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as the randomization month/year, then the medication will be assumed to have ended after 
randomization. 
• 
Otherwise, partial medication start / end dates will be compared to the randomization date and 
the medication will be classified accordingly. 
 
Frequency of use of prior and concomitant medications will also be presented for the subjects of the ITT 
population by therapeutic class and preferred term, overall and for each treatment group. 
 
6.3.6 
Treatment Compliance  
 
An overall compliance calculation will be performed using primarily the study administration intake 
recorded on the Drug Accountability Form of the eCRF or on the Investigational Product Use Form of the 
eCRF if information regarding study medication returned/lost is missing. Compliance for the whole study 
is derived as follows: 
                                        
Compliance 
overall (%)  
Pill counts (%) 
[sum of caplets dispensed – sum of caplets returned – sum of caplets lost] x 100 
[# caplets to take per day x (date last scheduled visit – date rando)] 
Days on 
treatment (%) 
If # of caplets dispensed ≠ missing 
AND 
If information regarding study medication returned is missing (i.e. # of caplets returned is 
missing and/or # of caplets lost is missing) 
 
[date of last dose – date of first dose] x 100 
[date last scheduled visit – date rando] 
NA 
If # of caplets dispensed = missing 
OR 
If last scheduled visit = baseline 
 
Where  
➢ Cohort 1 (rando number 001 à 280): Number of tablets dispensed = 147 (# caplets per day = 3) 
➢ Cohort 2 (rando number 281 à 563): Number of tablets dispensed = 294 (# caplets per day = 6) 
➢ Cohort 3 (rando number 564 à 997): Number of tablets dispensed = 588 (# caplets per day = 12) 
 
Compliance will also be categorized as follow: < 80%, [80%-120%] or >120% and summarized accordingly 
using frequencies and percentages, by treatment arm, for the subjects of the ITT population. 
 
6.4 
Efficacy Analysis 
 
Unless otherwise specified, all efficacy analyses will be conducted on the ITT population.  
 
6.4.1 
Primary Analysis 
 
The primary endpoint is the change from Week 0 to Week 12 in direct-measured LDL-C. The changes, as 
well as the LDL-C values at each study visit, will be summarized with descriptive statistics. 
 
The primary endpoint will be compared between treatment groups using a repeated measures analysis of 
covariance (ANCOVA) model.. More specifically, the dependent variable will be the change from Week 0 
in LDL-C (change calculated as post Week 0 level – Week 0 level) the model will include treatment group, 
time (Week 6 and Week 12) and treatment group x time interaction as well as the covariates of Week 0 
value of LDL-C and Week 0 value of LDL-C x time interaction. An unstructured covariance structure will be 


 
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used to model the within-patient errors and the Kenward-Roger approximation will be used to estimate 
denominator degrees of freedom. Contrasts under this model will allow for the three main comparisons: 
placebo vs. beta-glucan 1.5 g, placebo vs. beta-glucan 3 g and placebo vs. beta-glucan 6 g. More 
specifically, the following hypotheses will be tested: 
 
H0: ∆W12,placebo = ∆W12,1.5g   vs.   H1: ∆W12,placebo ≠ ∆W12,1.5g 
H0: ∆W12,placebo = ∆W12,3g     vs.   H1: ∆W12,placebo ≠ ∆W12,3g 
H0: ∆W12,placebo = ∆W12,6g     vs.   H1: ∆W12,placebo ≠ ∆W12,6g 
 
where ∆W12,placebo, ∆W12,1.5g, ∆W12,3g and ∆W12,6g are respectively the mean change from Week 0 to Week 12 
in LDL-C in the placebo, beta-glucan 1.5 g, beta-glucan 3 g and beta-glucan 6 g group. 
 
All sets of hypotheses will be tested at the 0.0167 significance level to maintain the overall type I error to 
0.05 for the primary endpoint. These tests will be considered as the primary analysis of the study. 
For illustrative purposes, changes within groups will be tested at the 0.05 significance level. Estimates of 
the changes within groups and of the between-group differences will also be presented along with 95% 
confidence intervals.  
 
The same ANCOVA model will also allow for the examination of the change from Week 0 to Week 6 in 
LDL-C. In other words, the hypotheses described above will also be tested at Week 6 at the 0.05 
significance level for illustrative purposes. 
 
Because the SAS procedure PROC MIXED will be used, subjects with missing data at a given study visit will 
not be excluded from the analysis.  
 
6.4.2 
Secondary Analysis 
 
Secondary endpoints are expressed as change from Week 0 to Week 12. Those that are measured at 
baseline (Week 0), Week 6 and Week 12 will be analyzed as the primary endpoint, with the exception that 
tests will be conducted at the 0.05 significance level. Those measured at baseline (Week 0) and Week 12 
only will be analyzed with an analysis of covariance (ANCOVA) model including treatment group and 
baseline value. Because it is expected that the distribution of hsCRP will be skewed, a log-transformation 
will be applied to hsCRP data prior to analysis. Geometric mean and geometric mean percent change will 
be added to the descriptive statistics that will be presented. 
 
 
6.4.3 
Exploratory Analysis 
 
Similarly, exploratory endpoints are expressed as change from Week 0 to Week 12. Those that are 
measured at baseline (Week 0), Week 6 and Week 12 will be analyzed as the primary endpoint, with the 
exception that tests will be conducted at the 0.05 significance level. Those measured at baseline (Week 
0) and Week 12 only will be analyzed with an ANCOVA model including treatment group and baseline 
value. Because it is expected that the distribution of triglycerides will be skewed, a log-transformation will 
be applied to triglycerides data prior to analysis. Geometric mean and geometric mean percent change 
will be added to the descriptive statistics that will be presented. 


 
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6.4.4 
Sensitivity Analysis 
 
6.4.4.1 
Per-Protocol Analysis 
 
The analysis of the primary endpoint described in section 6.4.1 will be repeated on the PP population. The 
tests will be conducted at the 0.05 significance level. 
 
To better understand the impact of compliance, the same analysis will be repeated on a 
modified version of the PP population where the compliance criteria will be set to 70%. In other 
word, the analysis of the primary endpoint will be conducted in patients who had a compliance 
of at least 70% and no major protocol deviations that could affect the primary endpoint. 
6.4.4.2 
Dose-Response Analysis 
 
In order to visualize the dose-response relationship, a regression model including linear and quadratic 
terms will be used to characterize the relationship between dose level (considered as a continuous 
variable) and the change from Week 0 to Week 12 in direct-measured LDL-C.  More specifically, the model 
will be: 
 
 
Yj = β0 + β1dj + β2dj2 + εj 
 
where Yj is the change from Week 0 to Week 12 of the jth patient, β0 is the intercept, β1 is the coefficient 
of the linear dose term, β2 is the coefficient of the quadratic dose term, dj is the dose level (0g, 1.5g, 3g, 
6g) and εj is the error term.  A test of the null hypothesis H0: β2 = 0 versus the alternative hypothesis H1: 
β2 ≠ 0 will be performed at the 0.05 significance level.  Non rejection of the null hypothesis will result in 
dropping the quadratic term from the model and concluding that a linear relationship provides a better 
fit. Otherwise, the quadratic term will be kept in the model. A plot of the predicted dose-response curve 
with 95% CIs will be provided to visualize the dose response relationship, along with the estimate of the 
coefficients β1 and β2 (if applicable) with associated 95% CI and p-values. 
 
6.4.5 
Subgroup Analysis 
 
The following subgroup analyses are planned for the primary endpoint:  
• 
Hypercholesterolemia according to median of direct-measured LDL-C at baseline, 
• 
Hypercholesterolemia according to quartiles of direct-measured LDL-C at baseline,  
• 
Male vs female,  
• 
Diabetic vs non-diabetic,  
• 
Hypertensive vs non-hypertensive,  
• 
Age < 65 years old vs. age ≥ 65 years old, 
• 
Age according to quartiles, 
• 
Treated with a statin at baseline vs. not treated with a statin at baseline (based on variable 
DS_STATIN on the Randomization Form of the electronic case report form (eCRF)). 
 
For subgroup analyses, ANCOVA models on the change from Week 0 to Week 12 in LDL-C will be used. 
These models will include a factor for the Week 0 value of LDL-C, as well as factors for the treatment 


 
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group, the subgroup variable and the treatment group x subgroup variable interaction. This interaction 
term will determine the impact of the subgroup on the treatment effect. For illustrative purposes, 
estimates of treatment effect will be presented within each subgroup. The tests will be conducted at the 
0.05 level for the ITT population. 
 
6.5 
Safety Analysis 
 
The safety analyses described in this section will be conducted on the safety population.  No formal 
statistical testing is planned for the safety parameters. 
 
6.5.1 
Treatment Exposure 
 
Duration of exposure will be defined as number of days on treatment (computed as date of last dose – 
date of first dose + 1) for each subject. Date of last dose of study drug will be derived as the latest date of 
variable EXENDAT and date of first dose of study drug will be derived as the earliest date of variable 
EXSTDAT both on Investigational Product Use Form. In subjects with a comment indicating unknown date 
of first dose, randomization date will be used. In addition, if the date of last dose is missing the minimum 
of Week 12 visit date or study completion date will be used. Duration of exposure will be summarized 
overall and by treatment group. Duration of exposure will also be categorized according to 14 days 
intervals ([1-14], [15-28], [29-42], etc.) and summarized accordingly using frequencies and percentages, 
overall and by treatment group. Summary of study treatment discontinuation will also be presented 
overall and by treatment group.  
 
6.5.2 
Adverse Events and Serious Adverse Events 
 
6.5.2.1 
Adverse Events 
 
AEs will be coded by system organ class and body system according to the MedDRA dictionary (version 
22.0). 
 
The total number of TEAEs reported, the number and proportion of subjects experiencing at least one 
TEAE, at least one severe TEAE, at least one TEAE related to the study treatment, and at least one TEAE 
leading to drug withdrawal will be presented. In addition, number and proportion of subjects experiencing 
a treatment-emergent AE will be presented by system organ class and preferred term overall and for each 
treatment group.  
 
A treatment-emergent AE will be defined as an AE with onset date on or after the date of first dose. If it 
is not possible to assess the timing of the start of the AE to the date of first dose due to incomplete AE 
onset date and/or incomplete date of first dose, the event will be assumed to be treatment-emergent.  
 
All AEs will be listed but only treatment-emergent AEs will be summarized. 
 
6.5.2.2 
Serious Adverse Events 
 
Serious adverse events will be presented in a manner similar to that described for adverse events. 
 


 
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6.5.3 
Physical Examination 
 
Physical examinations will include examination of various body systems and will be summarized by visit 
(Screening, Week 12) using frequencies and percentages, overall and by treatment group. 
 
6.5.4 
Vital Signs 
 
Vital signs will be summarized by visit (Screening, Baseline, Week 6, Week 12) using descriptive statistics, 
overall and by treatment group. 
 
6.5.5 
Electrocardiogram 
 
ECGs parameters will be summarized by visit (Screening, Week 12) using descriptive statistics, overall and 
by treatment group. 
 
6.5.6 
Laboratory Parameters 
 
Laboratory parameters, more specifically hematology and biochemistry parameters, will be summarized 
using descriptive statistics and presented by study visit (Screening, Baseline, Week 6 and Week 12) and 
treatment group.  
 
All laboratory results will be listed.  


 
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7 
SUMMARY TABLES, FIGURES AND LISTINGS 
 
1 Study subject 
1.1 Subject disposition 
Table 1.1.1 
Subject disposition 
Table 1.1.2 
Datasets analyzed 
Table 1.1.3 
Protocol deviation, ITT population 
 
 
1.2 Demographic and baseline characteristics 
Table 1.2.1 
Summary of demographics, ITT population 
Table 1.2.2 
Summary of medical history, ITT population 
 
 
1.3 Prior and concomitant medication 
Table 1.3.1 
Summary of medication at randomization, ITT Population 
Table 1.3.2 
Summary of prior and concomitant medication, ITT Population 
 
 
1.4 Treatment compliance 
Table 1.4.1 
Summary of treatment compliance, ITT population 
 
2 Efficacy analysis 
2.1 Primary analysis 
Table 2.1.1 
Summary of and statistical analysis for change in direct-measured LDL-C 
(mg/dL), ITT population 
Table.2.1.2 
Summary of and statistical analysis for change in direct-measured LDL-C 
(mg/dL), PP population 
Table.2.1.3 
Summary of and statistical analysis for change in direct-measured LDL-C 
(mg/dL), Modified PP population with compliance criteria set to 70% 
 
 
2.2 Secondary analysis 
Table 2.2.1 
Summary of and statistical analysis for change in TC (mmol/L), ITT population 
Table 2.2.2 
Summary of and statistical analysis for change in non-HDL-C (mmol/L), ITT 
population 
Table 2.2.3 
Summary of and statistical analysis for change in small LDL subclass particle 
concentration (nmol/L), ITT population 
Table 2.2.4 
Summary of and statistical analysis for change in hsCRP (mg/L), ITT population 
Table 2.2.5 
Summary of and statistical analysis for change in VLDL-C (mmol/L), ITT 
population 
Table 2.2.6 
Summary of and statistical analysis for change in Apo B (g/L), ITT population 
 
 
2.3 Exploratory analysis 


 
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Table 2.3.1 
Summary of and statistical analysis for change in HDL-C (mmol/L), ITT 
population 
Table 2.3.2 
Summary of and statistical analysis for change in TG (mmol/L), ITT population 
Table 2.3.3 
Summary of and statistical analysis for change in Lp(a) (g/L), ITT population 
Table 2.3.4 
Summary of and statistical analysis for change in HbA1c (%), ITT population 
 
 
2.4 Subgroup analysis 
Table 2.4.1 
Summary of and statistical analysis for change in direct-measured LDL-C 
(mg/dL) broken down by severity of hypercholesterolemia (below median or 
greater or equal to median of direct-measured LDL-C at baseline), ITT 
population 
Table 2.4.2 
Summary of and statistical analysis for change in direct-measured LDL-C 
(mg/dL) broken down by severity of hypercholesterolemia (according to 
quartiles of direct-measured LDL-C at baseline), ITT population 
Table 2.4.3 
Summary of and statistical analysis for change in direct-measured LDL-C 
(mg/dL) broken down by sex (male or female), ITT population 
Table 2.4.4 
Summary of and statistical analysis for change in direct-measured LDL-C 
(mg/dL) broken down by diabetes (yes or no), ITT population 
Table 2.4.5 
Summary of and statistical analysis for change in direct-measured LDL-C 
(mg/dL) broken down by hypertension (yes or no), ITT population 
Table 2.4.6 
Summary of and statistical analysis for change in direct-measured LDL-C 
(mg/dL) broken down by age (<65 years or ≥ 65 years), ITT population 
Table 2.4.7 
Summary of and statistical analysis for change in direct-measured LDL-C 
(mg/dL) broken down by age (according to quartiles), ITT population 
Table 2.4.8 
Summary of and statistical analysis for change in direct-measured LDL-C 
(mg/dL) broken down by statin treatment at baseline (yes or no), ITT 
population 
 
3 Safety analysis 
3.1 Treatment exposure 
Table 3.1.1 
Summary of extent of exposure, safety population 
Table 3.1.2 
Summary of discontinuation of study treatment, safety population 
 
 
3.2 Adverse events and serious adverse events 
Table.3.2.1 
Overall summary of treatment emergent adverse events (TEAE), safety 
population 
Table 3.2.2 
Summary of treatment emergent adverse events (TEAE) by system organ class  
and preferred term, safety population 
Table 3.2.3 
Overall summary of treatment emergent serious adverse events (TESAE), 
safety population 


 
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Table 3.2.4 
Summary of treatment emergent serious adverse events (TESAE) by system 
organ class and preferred term, safety population 
 
 
3.3 Physical examination 
Table 3.3.1 
Summary of physical examination, safety population 
 
 
3.4 Vital signs 
Table 3.4.1 
Summary of vital signs, safety population 
 
 
3.5 Electrocardiogram 
Table 3.5.1 
Summary of ECG, safety population 
 
 
3.6 Laboratory parameters 
Table 3.6.1 
Summary of hematology laboratory results, safety population 
Table 3.6.2 
Summary of biochemistry laboratory results, safety population 
 
Figures 
Figure 1 
Subject disposition (flow chart) 
Figure 2 
Plot of predicted change from Week 0 to Week 12 in direct-measured LDL-C  
(mg/dL) with 95% CIs against dose level, ITT population 
 
Listings 
Listing 1 
Subject disposition 
Listing 2 
Datasets analyzed 
Listing 3 
Protocol deviations 
Listing 4 
Demographics 
Listing 5 
Adverse events 
Listing 6 
Serious adverse events 
Listing 7 
Laboratory results 
Listing 8 
Deaths 


 
SAP: 14-OCT-2021 
Protocol Number: PROJ1601 
 
BS-T1-001-05 
Confidential 
Page 25 of 27 
8 
REFERENCES 
 
Not applicable. 
 
 


 
SAP: 14-OCT-2021 
Protocol Number: PROJ1601 
 
BS-T1-001-05 
Confidential 
Page 26 of 27 
9 
APPENDICES 
 
9.1 
Appendix 1 - Schedule of visits 
 
 
Procedure/Visit  
 
Screening Period 
(V1) 
Randomization 
Baseline Visit  
(V2) 
 
Visit 3  
(V3) 
 
End of Treatment 
Visit  
(V4) 
 
Safety Follow-up 
Visit  
(V5)  
(telephone) 
Week -1  
Up to 7 days  
Week 0  
 
Week 6  
( ± 5 days) 
Week 12  
( ± 5 days) 
Week 14  
(± 5 days) 
Informed consent form 
X 
 
 
 
 
Inclusion & Exclusion criteria 
X 
X 
 
 
 
Medical History 
X 
X 
 
 
 
Demographics 
X 
 
 
 
 
Physical examination 
X 
 
 
X 
 
Vital signs (blood pressure, pulse) 
X 
X 
X 
X 
 
Height  
X 
 
 
 
 
Weight  
X 
 
 
X 
 
Dietary counselling including alcohol 
consumption,  and timing of statin vs. IP 
intake 
X 
X 
X 
 
 
Check compliance on statin and IP 
 
 
         X 
          X 
 
12-Lead ECG 
X 
 
 
X 
 
Hematology  
           X 
X 
         X 
X 
 
AST, ALT, Creatinine 
X 
X 
X 
X 
 
Bilirubin 
X 
 
 
 
 
LDH, CPK 
 
X 
X 
X 
 
TG, TC, LDL-C, HDL-C 
X 
X 
X 
X 
 
LDL-C (direct-measured), VLDL-C, apo-
B, Lp(a), non-HDL-C, small low-density 
lipoprotein (LDL) subclass particle 
concentration 
 
X 
X 
X 
 
HbA1c, Insulin, Glucose and hsCRP 
 
X 
 
X 
 
Concomitant medication 
X 
X 
X 
X 
 
Pregnancy test* 
X* 
X* 
 
 
 
Randomization 
 
X 
 
 
 
IP dispensing 
 
X 
X 
 
 
Adverse Events 
X** 
X** 
X** 
X** 
X** 
*Female patients of childbearing potential will have a urine pregnancy test performed at the screening visit and at randomization (visit 2)  
**Serious Adverse Events (SAEs) are captured from the time of consent through to week 14 safety Follow up phone call. AEs are captured between 
the time of randomization up to the last dose IP taken. 
 
 
 


 
SAP: 14-OCT-2021 
Protocol Number: PROJ1601 
 
BS-T1-001-05 
Confidential 
Page 27 of 27 
9.2 
Appendix 2 - Reporting windows for laboratory parameters 
 
Number of days between a laboratory assessment and randomization will be calculated (date of 
assessment – date of randomization + 1 day), compared to the lab reporting window below, and the 
assessment will be assigned to the corresponding visit.  
 
VISIT 
SCHEDULED VISIT 
SCHEDULED 
DAY 
SCHEDULED 
WINDOW  
(± DAYS) 
SCHEDULED 
WINDOW (DAYS) 
LAB 
 REPORTING 
WINDOW (DAYS) 
V1 
Screening 
 
Up to 7 days before 
randomization 
<1 
<1 
V2 
Baseline (randomization) 
1 
 
1 
1 to 2 
V3 
Week 6 
42 
±5 
37 to 47 
3 to 63 
V4 
Week 12 
84 
±5 
79 to 89 
≥64 
 
Notes: 
The algorithm chooses the mid-point between consecutive scheduled visits and so achieves that no gaps 
between reporting windows occur, and that reporting windows correspond to the schedule of 
assessments. 
 
In cases where more than one non missing assessment falls within the same window, the closest 
assessment will be chosen. 
 
The LAB reporting window for baseline visit include day 2 because some subjects were randomized on 
scheduled day 1 but laboratory parameters were taken only the next day, where day 2 is the day of first 
dose.