Conditions: Hypercholesterolemia
Keywords: LDL & HDL Cholesterol, Statin, Dietary Supplements
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 203
Healthy volunteers: no

Brief summary:
A research study that is evaluating a low dose of an FDA approved statin medication in comparison to several commercially available over the counter dietary supplements which are marketed for cholesterol health. The study is comparing their effect on LDL cholesterol. LDL-cholesterol is low-density cholesterol and is sometimes referred to as "bad" cholesterol. Participants must live in Ohio and have a documented elevated LDL cholesterol level between 70-189mg/dL, must not currently be taking a statin or one of the dietary supplements included in the trial. Participants willing to discontinue a prohibited supplement for 4 weeks prior to enrollment will be allowed to participate. Trial participation is 4 weeks. Study medication will be provided at no charge. There will be 2 visits which include a lab draw at any Cleveland Clinic laboratory. Participants will be randomized (like a coin flip) to be in one of 8 possible groups: Rosuvastatin, Fish oil, Cinnamon, Garlic, Turmeric, Plant sterol, Red yeast rice, or placebo. The study will enroll 200 participants.

Detailed description:
Few well-controlled trials have studied the LDL-lowering effects of dozens of marketed "cholesterol health" dietary supplements. Prior research suggests most U.S. consumers believe cholesterol health supplements are safer than statins, and a majority of the public also believe supplements are as effective, or more effective, than prescription statins. Approximately one third of US adults who have been told they have elevated cholesterol are using a supplement to provide heart health protection rather than a statin. This represents a significant public health concern.

The purpose of this study is to evaluate the effect of select dietary supplements on cholesterol health compared with a low dose of a statin.

The study is comparing their effect on LDL and HDL cholesterol and inflammatory markers.

A randomized, single blind study design will be used to evaluate rosuvastatin 5 mg. vs. placebo and 6 commercially available over the counter supplements in a hierarchical testing order. Each participant will take study medication/supplement for a total of 4 weeks.

The study will randomize primary prevention patients who are considered borderline and intermediate risk for ASCVD based upon the 2018 Cholesterol Treatment Guidelines7 and are not taking any of the studied medication/supplements at the time of randomization.

Participants must have a documented elevated LDL cholesterol level between 70-189mg/dL, must not currently be taking a statin or one of the dietary supplements included in the trial. Participants willing to discontinue a prohibited supplement for 4 weeks prior to enrollment will be allowed to participate. Study medication will be provided at no charge. There will be 2 visits which include a lab draw at any Cleveland Clinic laboratory. Participants will be randomized (like a coin flip) to be in one of 8 possible groups: Rosuvastatin, Fish oil, Cinnamon, Garlic, Turmeric, Plant sterol, Red yeast rice, or placebo. The study will enroll 200 participants.

Arms:
arm 1: 5 mg once per day arm 2: comparable to rosuvastatin 5 mg once per day arm 3: Nature Made 2 soft gels per day arm 4: 1200mg, 2 capsules per day arm 5: Manufactured by Focus Consumer Health Marketgate,1 tablet per day arm 6: Bio Schwartz Turmeric Curcumin 1500 mg, 3 capsules per day arm 7: Nature Made CholestOff Plus, 2 soft gels twice a day arm 8: Arazo Nutrition 1200 mg, 2 capsules per day

Interventions: intervention 1: Fish Oil, Cinnamon, Garlique,Turmeric, Plant Sterol, Red Yeast Rice intervention 2: Rosuvastatin intervention 3: Placebo
Intervention descriptions: intervention 1: Subjects will be randomized to a Statin (Rosuvastatin 5 mg), a placebo, or a dietary supplement (Fish oil, Cinnamon, Garlic, Turmeric, Plant sterol, Red yeast rice). intervention 2: Subjects will be randomized to a Statin (Rosuvastatin 5 mg), a placebo, or a dietary supplement (Fish oil, Cinnamon, Garlic, Turmeric, Plant sterol, Red yeast rice). intervention 3: Subjects will be randomized to a Statin (Rosuvastatin 5 mg), a placebo, or a dietary supplement (Fish oil, Cinnamon, Garlic, Turmeric, Plant sterol, Red yeast rice).

Protocol document:
Prot_000.pdf: 
Cleveland Clinic 
CONFIDENTIAL 
Page 1 
 
 
 
 
 Supplements, Placebo, or RosuvastaTin Study 
 
SPORT Trial Protocol Version 1.0 
 
23February 2021 
 
 
 
 
 
IND Number: 154728 
 
Study Chair: Steven E. Nissen, MD, MACC 
 
Principal Investigator: Luke Laffin, MD,  
 
Co-Investigator: Dennis Bruemmer, MD, PhD 
 
Sponsor: Cleveland Clinic Investigator Initiated Trial 
 
Funded by: Astra Zeneca 
 
 
 
 


Cleveland Clinic 
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Page 2 
 
 
 
 
Study Chairman Protocol Approval Page 
 
 
 
Study Title: 
Supplements, Placebo, or RosuvastaTin Study 
 
 
SPORT Trial Protocol Version 1.0 
 
 
23February 2021 
 
Study Sponsor: Cleveland Clinic Investigator Initiated Trial 
 
 
I, the undersigned, have read and approve this protocol and agree on its content. It is confirmed that the 
information and guidance given in this protocol complies with scientific principles, the guidelines of 
Good Clinical Practice. 
 
 
Study Chairman Signature:    _
 
 
 
23Feb2021 
 
 
 
 
     
Steven Nissen, MD, MACC  
 
(Date) 
 
 
 
 
     
Cleveland Clinic  
 
 
 
                      
 
 
 
 
 
 
 
 


Cleveland Clinic 
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Table of Contents 
List of abbreviations/definitions .......................................................................................... 5 
1 
Introduction ......................................................................................................................... 6 
1.1 
Background .............................................................................................................. 6 
1.2 
Purpose .................................................................................................................... 6 
2 
Objectives and endpoints ..................................................................................................... 6 
3 
Study design ........................................................................................................................ 7 
3.1 
Rationale for duration of administration ................................................................. 7 
3.2 
Risks and benefits .................................................................................................... 7 
4 
Population ............................................................................................................................ 7 
4.1 
Inclusion criteria ...................................................................................................... 7 
4.2 
Exclusion criteria ..................................................................................................... 8 
4.3 
Study medication/supplements ................................................................................ 8 
4.3.1 
Study medication/supplement groups ..................................................... 8 
4.3.2 
Medication/supplement study groups ..................................................... 9 
4.3.3 
Concomitant therapy ............................................................................... 9 
4.3.4 
Prohibited medication/supplement and therapies ................................... 9 
4.3.5 
Study group assignment, randomization ................................................. 9 
4.4 
Study group blinding ............................................................................................. 10 
5 
Informed consent procedures ............................................................................................ 10 
6 
Visit schedule and assessments ......................................................................................... 10 
6.1 
Subject demographics/other baseline characteristics ............................................ 13 
6.1.1 
Pregnancy assessments ......................................................................... 13 
7 
Study discontinuation and completion .............................................................................. 13 
7.1 
Discontinuation ...................................................................................................... 13 
7.1.1 
Discontinuation of study medication/supplement ................................. 13 
7.1.2 
Withdrawal of informed consent ........................................................... 14 
7.1.3 
Lost to follow-up ................................................................................... 14 
7.1.4 
Early study termination by the sponsor ................................................. 14 
7.2 
Study completion ................................................................................................... 15 
8 
Safety monitoring and reporting ........................................................................................ 15 
8.1 
Definition of adverse events and reporting requirements ...................................... 15 


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8.1.1 
Adverse events ...................................................................................... 15 
8.1.2 
Pregnancy reporting .............................................................................. 16 
8.1.3 
Executive Committee ............................................................................ 16 
9 
Data collection and database management ........................................................................ 16 
9.1 
Data collection ....................................................................................................... 16 
9.2 
Safety monitoring .................................................................................................. 17 
10 Data analysis and statistical methods ................................................................................ 17 
10.1 
Analysis sets .......................................................................................................... 17 
10.2 
Subject disposition ................................................................................................. 17 
10.3 
Subject demographics and baseline characteristics ............................................... 17 
10.4 
Study evaluations ................................................................................................... 17 
10.5 
Analysis of the primary endpoint .......................................................................... 18 
10.6 
Analysis of secondary endpoints ........................................................................... 18 
10.6.1 
Adverse events ...................................................................................... 19 
11 Ethical considerations and administrative procedures ...................................................... 19 
11.1 
Regulatory and ethical compliance........................................................................ 19 
11.2 
Responsibilities of the investigator and IRB ......................................................... 19 
12 References ......................................................................................................................... 20 
 
 


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List of abbreviations/definitions 
AE 
Adverse Event 
ASCVD 
Atherosclerotic Cardiovascular Disease 
eCRF 
Electronic Case Report Form  
dL 
Deciliter 
GCP 
Good Clinical Practice 
mg 
milligram(s) 
OTC 
Over the Counter 
SAE 
Serious adverse event 
Study 
Medication 
Study medication refers to FDA approved rosuvastatin 
Supplement 
Refers to over the counter fish oil, cinnamon, garlic, turmeric, plant sterol 
Sponsor 
Cleveland Clinic 


Cleveland Clinic 
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1 
Introduction 
1.1 
Background 
Few well-controlled trials have studied the LDL-lowering effects of dozens of marketed “cholesterol 
health” dietary supplements. These products combine for sales of billions of dollars annually, primarily 
via online marketing.  The business model for the dietary supplement industry often relies on efforts to 
undermine FDA-approved cholesterol lowering medications in favor of “all natural” alternatives for 
“heart protection” and “cholesterol management.” Marketing of dietary supplements (without evidence 
of benefit) is protected by the Dietary Supplement Health and Education Act of 1994, which assigns 
oversight of this industry primarily to the Federal Trade Commission, rather than the Food and Drug 
Administration. The supplement industry markets against prescription statins on eCommerce platforms, 
but rarely, if ever, perform comparative studies. Furthermore, prior research suggests most U.S. 
consumers believe cholesterol health supplements are safer than statins, and a majority of the public also 
believe supplements are as effective, or more effective, than prescription statins.   Approximately one 
third of US adults who have been told they have elevated cholesterol are using a supplement to provide 
heart health protection rather than a statin.  This represents a significant public health concern. 1-6 
1.2 
Purpose 
The purpose of this study is to evaluate the effect of select dietary supplements on cholesterol health 
compared with a low dose of a statin. 
2 
Objectives and endpoints 
Primary Objective 
The primary objective of this study is to compare the LDL lowering of rosuvastatin with the effect of 
six commonly used dietary supplements on cholesterol health  
Secondary Objective 
Assess the effect of each supplement on inflammatory markers compared with rosuvastatin 5 mg. 
Primary Endpoint 
The percent change in LDL-C for rosuvastatin 5 mg compared with dietary supplements after 4 weeks. 
Secondary Endpoints 
 The percent change in high sensitivity C reactive protein (hsCRP) for rosuvastatin 5 mg and 
dietary supplements compared with placebo after 4 weeks. 
 The percent change in HDL-C, total cholesterol, and triglycerides for each supplement compared 
with rosuvastatin. 
 The percent change in HDL-C, total cholesterol, and triglycerides for each supplement compared 
with placebo. 


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3 
Study design 
A randomized, single blind study design will be used to evaluate rosuvastatin 5 mg. vs. placebo and 6 
commercially available over the counter supplements in a hierarchical testing order. Each participant 
will take study medication/supplement for a total of 4 weeks.  
3.1 
Rationale for duration of administration 
The duration of 4 weeks is sufficient as steady-state LDL-C levels are reached for rosuvastatin 5mg 
within two weeks.  
3.2 
Risks and benefits 
The risks may include a lack of effect on cholesterol health with supplements over a short duration, or 
an adverse effect of one of the study medication/supplements. Undeclared ingredients are a possibility 
with over-the-counter supplements. 
The benefits may include the potential to have an effect on cholesterol health with one or more of the 
study medication/supplements. 
4 
 Population 
The study will randomize primary prevention patients who are considered borderline and intermediate 
risk for ASCVD based upon the 2018 Cholesterol Treatment Guidelines7 and are not taking any of the 
studied medication/supplements at the time of randomization. 
4.1 
Inclusion criteria 
Subjects eligible for inclusion in this study must meet all of the following criteria: 
1. Written informed consent must be obtained before any assessment is performed. 
2. U.S. adults with primary hypercholesterolemia, 40-75 years of age. 
3. Not currently taking statins or one of the dietary supplements included in the trial. Patients 
willing to discontinue a prohibited supplement for 4 weeks prior to enrollment will be allowed to 
participate. 
4. LDL-cholesterol between 70 and 189 mg/dL. 
5. Patients without diabetes mellitus and a 10-year risk of ASCVD between 5 and <20% using the 
pooled cohort risk equation. * 
Or 
Patients with diabetes mellitus in females 50-60 years of age or males 40-50 years of age with an 
LDL-C between 70-189 mg/dL and with an ASCVD risk below 20%. 
 
 
 
*http://tools.acc.org/ASCVD-Risk-Estimator-Plus/#!/calculate/estimate/ 


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4.2 
Exclusion criteria 
Subjects meeting any of the following criteria are not eligible for inclusion in this study: 
1. Age < 40  or >75 years of age 
2. Women who are pregnant, plan to become pregnant within the next 6 months, or are 
breastfeeding. 
3. Documented liver dysfunction or history of elevated LFTs indicating active liver disease 
4. Documented chronic renal dysfunction within the past two years defined as an 
eGFR<30mL/min/m2. 
5. Known hypersensitivity to rosuvastatin or any supplement under investigation (i.e. shellfish 
allergy, etc.). 
6. Currently taking any prescription statin, or other prescription medication/supplements to treat 
elevated cholesterol or triglycerides.  
7. Currently taking a medication/supplement that has known interaction with rosuvastatin, including 
fenofibrate, gemfibrozil, HIV medications, colchicine, cyclosporine, warfarin, anti-viral 
medications to treat Hepatitis C, regorafenib, and darolutamide. 
8. Are unwilling to discontinue prohibited dietary supplement(s) for 4 weeks prior to participation 
or during the course of the trial. Other non-prohibited supplements will be permitted if doses 
have been stable for at least 4 weeks. 
9. Known cardiovascular disease including a history of prior MI, stroke/TIA, PAD or prior 
revascularization procedures of the heart or vasculature (e.g. CABG, stenting, PCI etc.). 
10. Fasting Triglycerides >200mg/dl.  
11.  In the opinion of the investigator, any other condition that will preclude participation in the 
study. 
 
4.3 
Study medication/supplements 
4.3.1 
 Study medication/supplement groups 
Eight groups will be studied, Rosuvastatin 5 mg compared with the following: 
1. Placebo (comparable to rosuvastatin 5mg) 
2. Fish oil (Nature Made™ 2 soft gels / day) 
3. Cinnamon (1200mg,  2 capsules / day) 
4. Garlique™ (1 tablet / day) 
5. Turmeric (Bio Schwartz Turmeric Curcumin, 1500mg, 3 capsules / day)  
6. Plant sterol (Nature Made CholestOff™ Plus, 2 soft gels 2x / day)  
7. Red yeast rice (Arazo Nutrition, Red Yeast Rice, 1200mg, 2 capsules / day) 
 


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4.3.2 
Medication/supplement study groups 
Eligible subjects will be randomized 1:1:1:1:1:1:1:1 to the study groups in a blinded fashion. There will 
be 25 subjects per study group. The total sample size will be 200 patients. 
Sample Size and Power 
Assuming a common standard deviation of 15 and an alpha of 0.05, enrolling a total of 25 in each group 
will have 90% power to detect an average difference in percent change in LDL of 15 between 
rosuvastatin and each study group. 
4.3.3 
Concomitant therapy 
Medication/supplement classification used by the subject prior to randomization will be recorded in the 
eCRF pages. 
4.3.4 
Prohibited medication/supplement and therapies 
New use of prescription medication/supplements for elevated cholesterol or triglycerides during 
participation in the trial. 
New use of over the counter dietary supplements marketed for cholesterol health or triglyceride health 
for 4 weeks prior to or during participation in this study are prohibited. Chronic use of supplement types 
other than those being assessed in the trial will be permitted if doses have been stable for 4 weeks or 
longer.   
Patients will be encouraged to maintain lifestyle habits present at the time of trial enrollment during the 
course of the trial. Significant dietary and physical activity modifications will be discouraged over the 4 
weeks of participation. Participants are not to enroll in weight loss programs during the trial. 
4.3.5 
Study group assignment, randomization 
Randomization 
will 
occur 
using 
REDCap 
Cloud 
electronic 
database 
platform. 
Study 
medication/supplement will be dispensed by the investigational pharmacy in a blinded fashion for in 
person visits to study personnel or shipped to the subjects by the investigational pharmacy following 
randomization. Day 1 of the study is the first day that subjects start study medication/supplement. In the 
event that study medication/supplement is shipped to subjects, study personnel will verify the start of 
study medication/supplement (Day1) for medication/supplement accountability.  
 
The study medication/supplement will be supplied from commercially available products and 
administered according to the package insert. The rosuvastatin 5mg and placebo will be provided by 
Astra Zeneca.  The over the counter supplements will be purchased and due to documented history of 
supplement tainting, supplements may be tested for unlabeled enhancing impurities retrospectively if 
deemed necessary per data findings. If we observe > 15% lowering in LDL cholesterol, we will test for 
impurities. 
 
 


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4.4 
Study group blinding 
Subjects, investigator staff, persons performing the assessments, and the clinical trial team will be 
blinded to assigned study group. Baseline laboratory values will not be blinded to the subjects, 
investigator staff, and the clinical team. Additional lipid labs will be prohibited for the 4 week 
participation period. The Day 28 labs will not be blinded.  
 
It is expected that the need for unblinding of a patient’s study group will be extremely rare.  Every 
effort should be made to preserve the blind unless there is a compelling reason that knowledge of the 
specific treatment would alter the medical care of the patient. 
5 
Informed consent procedures 
Eligible subjects may only be included in the study after providing IRB approved informed consent. 
Informed consent must be obtained before conducting any study-specific procedures.  Subjects will be 
prescreened using historical laboratory values within 13 months of screening prior to consenting.  
Subjects that screen fail will not be eligible for rescreening.  
6 
Visit schedule and assessments 
Subjects should be seen for all visits/assessments as outlined in the assessment schedule.  The baseline 
and final visits will be completed in-person or remotely. 
The fasting lipid draw and complete metabolic panel (CMP) at Day 0 and Day 28 must be obtained from 
a Cleveland Clinic lab. Recently acquired lipid labs and complete metabolic panel may be used in place 
of a Day 0 lab draw if acquired within 4 weeks of screening at a Cleveland Clinic lab and performed in 
the fasting state. Subjects are to remain on study medication/supplement until Day 28 labs are drawn.  
 
Study personnel will use the following historical information to input into the ASCVD risk calculator to 
determine eligibility:  
 Age 
 Gender 
 Race 
 Systolic blood pressure 
 Diastolic blood pressure 
 Treatment for high blood pressure and diabetes 
 Current smoking status 
If a historical blood pressure is not found within 1 year of screening, patient reported is acceptable. 


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Lipid panel, hs-CRP will be collected at the initial visit and Day 28.   
 
 Lipids: Indirect LDL-C (Total Cholesterol, HDL-C, and Triglycerides)  
 Inflammatory markers:  hs-CRP    


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Table 7-1 
Assessment Schedule 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a  Females of child-bearing potential only, urine or serum at investigator’s discretion.  
b The baseline (0) and 28 Day visit may be completed remotely. Consent will be obtained 
prior to completion of the baseline visit and may be completed remotely in accordance with 
Cleveland Clinic guidelines 
c Fasting lipid panel and complete metabolic panel should be drawn a Cleveland Clinic lab 
facility. Patients should fast for approximately 8 hours. 
d Recently acquired lipid and complete metabolic panel labs may be used in place of a Day 0 
lab draw if acquired within 4 weeks of screening at a Cleveland Clinic lab. 
e  Study medication/supplement adherence will be assessed with a pill count.  The bottle will 
be returned to the study site to retain until the end of study. 
f  If enrolled for over 14 days and the patient discontinues study medication/supplement 
perform Day 28 lab work (ITT principle). 
g Historical documented height and weight may be used.  Weight to be within the last 3 
months.  Subject reported is acceptable. 
h Randomization and eligibility confirmation may occur on different days from baseline 
pending lab results 
i Study medication/supplement will be dispensed by the investigational pharmacy for in 
person visits to study personnel or shipped to the subjects by the investigational pharmacy 
following randomization. 
  
Study Day 
Activity 
Day 0 b 
Day 28b,f +4/-4 days 
Informed consent obtainedb 
X 
 
Demographics 
X 
 
Medical history 
X 
 
Eligibility confirmed & subject randomizedh 
X 
 
Body weightg 
X 
 
Heightg 
X 
 
Concomitant Medication/supplements 
X 
X 
Hs-CRP  
X 
X 
CMP, LDL-C,  TC, HDL-C, and TGsc, d 
X 
X 
Pregnancy test a 
X 
 
Study medication/supplement dispensedi 
X 
 
Adverse events 
 
X 
Study medication/supplement adherencee 
 
X 


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6.1 
Subject demographics/other baseline characteristics 
Patient demographic and baseline characteristic data will be collected on all subjects. 
6.1.1 
Pregnancy assessments  
All pre-menopausal women who are not surgically sterile will have a urine or serum 
pregnancy test performed at the Day 0 visit. Pregnancy testing is not required for post-
menopausal women.  
7 
Study discontinuation and completion 
7.1 
Discontinuation 
7.1.1 
Discontinuation of study medication/supplement 
Discontinuation of study medication/supplement for a subject occurs when the study 
medication/supplement is stopped earlier than the protocol planned duration, and can be 
initiated by either the subject or the investigator. 
The investigator must discontinue study medication/supplement for a given subject if, he/she 
believes that continuation would negatively impact the subject's well-being. After study 
medication/supplement discontinuation, the patient should remain in the study, unless he/she 
withdraws consent, preferably in writing. 
Study medication/supplement must be discontinued under the following circumstances: 
 Subject decision 
 Pregnancy 
 Any situation in which study participation might result in a safety risk to the subject 
 Any laboratory abnormalities that in the judgment of the investigator prevents the 
subject from continuing study medication/supplement administration 
If discontinuation of study medication/supplement occurs, the investigator should make a 
reasonable effort to understand the primary reason for the subject’s premature discontinuation 
of study medication/supplement and record this information.  
Subjects who discontinue study medication/supplement or who decide they do not wish to 
participate in the study further should NOT be considered withdrawn from the study UNLESS 
they withdraw their consent. If discontinuation occurs after Day 14, study personnel should 
attempt to obtain Day 28 labs as close as possible to last dose of study medication/supplement 
taken. 
Where possible, they should return for the Day 28 assessments indicated in the assessment 
schedule. If they fail to return for these assessments for unknown reasons, every effort (e.g. 
telephone, e-mail, and letter) should be made to contact the subject/pre-designated contact per 
institutional guidelines to collect as much data as possible according to the visit schedule. 


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Patient’s vital status can also be verified by the study site upon contact with patient’s primary 
care physician or other sources according to local rules and regulations. 
After study medication/supplement discontinuation, at a minimum, in the abbreviated visit, the 
following data should be collected either during an in person visit or via telephone/email 
contact: 
 new / concomitant treatments 
 adverse events/Serious Adverse Events 
7.1.1.1 
Replacement policy 
Subjects will not be replaced on study.  
7.1.2 
Withdrawal of informed consent 
Subjects may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a subject: 
 Does not want to participate in the study anymore 
And 
 Does not allow  further collection of personal data 
It is encouraged that patient provides withdrawal of consent in writing. 
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information. Patient’s vital status can be verified upon contact with patient’s primary 
care physician or other sources according to local rules and regulations. 
Study medication/supplement must be discontinued and no further assessments conducted, and 
the data that would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up. 
The study will continue to keep and use collected study information (including any data 
resulting from the analysis of a subject’s samples until the time of withdrawal) according to 
applicable regulations. 
7.1.3 
Lost to follow-up 
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must continue to attempt to contact the 
subject until the end of the study per institutional guidelines. A subject should not be considered 
as lost to follow-up until the end of the study. Vital status can be determined using publically 
available information in accordance with institutional guidelines. 
7.1.4 
Early study termination by the sponsor 
The study can be terminated by the sponsor at any time. Reasons for early termination: 


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 Unexpected, significant, or unacceptable safety risk to subjects enrolled in the study 
 Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data 
In making the decision to terminate, the sponsor will always consider the subject welfare and 
safety. Should early termination be necessary, subjects must be seen as soon as possible and 
treated as a prematurely withdrawn subject. The investigator may be informed of additional 
procedures to be followed in order to ensure that adequate consideration is given to the 
protection of the subject’s interests. The sponsor will be responsible for informing IRB of the 
early termination of the trial. 
7.2 
Study completion  
Study completion is defined as when the last subject finishes their Day 28 visit, and any repeat 
assessments associated with this visit have been documented and followed-up appropriately by 
the Investigator, or in the event of an early study termination decision, the date of that decision.  
8 
Safety monitoring and reporting 
8.1 
Definition of adverse events and reporting requirements 
8.1.1 
Adverse events 
An adverse event is an untoward event that affects the patient’s health or safety. When reporting 
an adverse event, the investigator will complete the AE report form. Adverse events that require 
reporting include any clinical changes in condition that could possibly be attributed to: 
 Any of the study medication/supplements 
 Any study required procedures (lab draws) 
Each adverse event will be evaluated by the investigator for relatedness and seriousness.  
i) Relatedness  
The relatedness of an adverse event to the study medication/supplement will be assessed by the 
Investigator for each submitted adverse event form.  
 Possibly Related: An adverse event that is noted in the package insert. 
 Unknown: An adverse event that cannot be determined to have a causal relationship with 
either the study medication/supplement or study procedure will be classified as unknown.  
 Not Related: An adverse event that is determined to not have a causal relationship with 
either the study medication/supplement or study procedure.  
ii) Seriousness  
Adverse events as described above will be evaluated for serious injury. Adverse events resulting 
in death or serious injury are to be reported to the sponsor within 24 hours of learning of the 
event. An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the 
view of either the investigator or sponsor, it results in any of the following outcomes: death, a 


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life-threatening adverse event, inpatient hospitalization or prolongation of existing 
hospitalization, a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions, or a congenital anomaly/birth defect. Important medical events 
that may not result in death, be life-threatening, or require hospitalization may be considered 
serious when, based upon appropriate medical judgment, they may jeopardize the participant 
and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. 
iii) SUSARS 
All Suspected Unexpected Serious Adverse Reactions (SUSARS) related to Rosuvastatin or 
supplements (if required per regulatory guidelines) are to be reported to the sponsor within 24 
hours of learning of the event.  
8.1.2 
Pregnancy reporting 
Pregnancies 
To ensure subject safety, each pregnancy occurring after signing the informed consent must be 
reported by the investigator to the sponsor. The pregnancy should be followed up to determine 
outcome, including spontaneous or voluntary termination, details of the birth, and the presence 
or absence of any birth defects, congenital abnormalities, or maternal and/or newborn 
complications. Pregnancy follow-up should include an assessment of the possible relationship 
to the study medication/supplement of any pregnancy outcome. Any SAE experienced during 
pregnancy must be reported. 
8.1.3 
Executive Committee 
The Executive Committee (EC) will play an active role in providing scientific guidance and 
advice to the sponsor related to the design, conduct, results analysis, and publication strategy 
for the SPORT study. The EC will be composed of members who are experts in preventive 
cardiology with relevant clinical trial methodological expertise. Meeting frequency, 
membership, and specific responsibilities will be further described in the EC Charter. 
9 
Data collection and database management 
9.1 
Data collection 
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF) within the REDCap Cloud database. The eCRFs have been built 
using fully validated secure web-enabled software that conforms to 21 CFR Part 11 
requirements.  
The investigator/designee is responsible for assuring that the data entered into eCRF is 
complete, accurate, and that entry and updates are performed in a timely manner. The 
Investigator must certify that the data entered are complete and accurate. 
After final database lock, the investigator will receive copies of the subject data for archiving 
at the investigational site. 


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All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification. 
9.2 
Safety monitoring 
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) which may include demographic and 
medical information, laboratory data, and the results of any other tests or assessments. All 
information on eCRFs must be traceable to these source documents in the subject’s file. The 
investigator must also keep the original informed consent form signed by the subject (a signed 
copy is given to the subject). 
A Medical Monitor will review safety data for the study as specified in the Medical Monitor 
Charter. 
10 
Data analysis and statistical methods 
10.1 
Analysis sets 
The following analysis populations will be defined for statistical analysis: 
The full analysis set (FAS) consists of all enrolled patients.  Efficacy variables will be analyzed 
based on the FAS as the primary population. 
The safety analysis set (SAS) consists of all patients who received at least one dose of study 
medication/supplement. The safety population will be used for the analyses of safety variables. 
10.2 
Subject disposition  
The number of patients screened will be presented by study group and overall for the screened 
set. In addition, the reasons of screen failures will be provided for screened set as well. The 
number and percentage of patients who completed the study, who discontinued the study and 
the reason for discontinuation will be presented for each study group and all patients. The 
frequency (%) of patients with major protocol deviations will be presented in separate tables.  
10.3 
Subject demographics and baseline characteristics 
 
All demographic and baseline characteristics summaries will be based on the FAS. They will 
be presented in summary tables by study group. Continuous data will be summarized by 
descriptive statistics, and categorical data will be summarized by frequency distributions. 
Finally, the number of enrolled patients by site will be presented descriptively. 
10.4 
Study evaluations 
10.4.1     Study medication/supplement 
The duration of the study medication/supplement use will be computed as the time from the 
first dose to the patient’s study completion visit during the study close-out period. 


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The duration of the study medication/supplement use will be summarized for the full analysis 
set and safety set by study group descriptively including by duration categories.  
The safety set will be used for the above analyses unless otherwise specified. 
10.4.2     Prior and concomitant therapies 
Prior or concomitant medication/supplements will be summarized for the safety set in separate 
tabulations based on a predetermined list of medication/supplements.  Prior 
medication/supplement are defined as any medication/supplement a subject was taking prior 
to randomization in the study.  Concomitant medication/supplements will include any 
medication/supplements taken during the study period. 
10.5 
Analysis of the primary endpoint 
To control the overall alpha of the study, the primary endpoint will be evaluated hierarchically. 
Each comparison to rosuvastatin will use an alpha of 0.05.  Once a comparison is not met (2-
sided p-value ≥ 0.05) all subsequent comparisons will be considered exploratory with nominal 
p-values. The change in LDL-C for rosuvastatin will be compared with the other 7 study groups 
using ANCOVA in a hierarchical fashion in the following order: 
 Rosuvastatin 5 mg compared with the following: 
1. Placebo (identical to rosuvastatin 5mg) 
2. Fish oil (Nature Made™ 2 soft gels / day) 
3. Cinnamon (1200mg,  2 capsules / day) 
4. Garlique™ (1 tablet / day) 
5. Turmeric (Bio Schwartz Turmeric Curcumin, 1500mg, 3 capsules / day)  
6. Plant sterol (Nature Made CholestOff™ Plus, 2 soft gels 2x / day)  
7. Red yeast rice (Arazo Nutrition, Red Yeast Rice, 1200mg, 2 capsules / day) 
 
If the percent change in LDL has a non-normal distribution (graphically assessed), median 
values will be used to summarize the endpoints and compared with a non-parametric test. At a 
minimum, adjustments for baseline LDL and age will be used in summarizing the endpoints.  
Other adjustments may be warranted if differences in factors across study groups are 
statistically significant. The primary endpoint will be analyzed in the FAS. 
10.6 
Analysis of secondary endpoints 
The following secondary endpoints will be analyzed in the FAS: 
 Percent change in high sensitivity C reactive protein (hsCRP) for each study group 
compared with rosuvastatin 5 mg  
 The percent changes in HDL-C, total cholesterol, and triglycerides for each study group 
compared with rosuvastatin 5 mg 


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 The percent changes in HDL-C, total cholesterol, and triglycerides for each study group 
compared with placebo  
 
The comparisons of each study group to placebo will utilize placebo-subtracted changes from 
baseline.  Percent change from baseline for each study group and placebo will first be 
calculated.  The difference found in the placebo arm will then be subtracted from each study 
group. The mean and 95% confidence intervals will be used to summarize the effect of each 
study group. 
 
No hierarchical testing of the secondary endpoints will be conducted.  Since the study was not 
powered to test secondary endpoints, all testing and p-values will be considered exploratory.  
No adjustments will be made for multiplicity. 
10.6.1 
Adverse events 
All information obtained on adverse events will be summarized by study group.  A subject with 
multiple adverse events of the same type is only counted once towards the total of that event.  
Serious adverse event and deaths resulting from an adverse events will be tabulated.   All 
adverse events, deaths and serious adverse events will be provided in patient listings. 
11 
Ethical considerations and administrative procedures 
11.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations US CFR 21), and with the ethical principles laid down in the Declaration of 
Helsinki. 
11.2 
Responsibilities of the investigator and IRB 
Before initiating a trial, the investigator will obtain approval/favorable opinion from the 
Institutional Review Board (IRB) for the trial protocol, written informed consent form, consent 
form updates, subject recruitment procedures and any other written information to be provided 
to subjects.  
The protocol will be registered in a publicly accessible database clinicaltrials.gov. In addition, 
after study completion and finalization of the study report the results of this trial will be 
submitted for publication and posted in a publicly accessible database of clinical trial results in 
clinicaltrials.gov. 


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12 
References 
 
1. Grant, SJ, Bin, YS, Kiat, H, Chang, DHT. The use of complementary and alternative 
medicine by people with cardiovascular disease: a systematic review. BMC Public Health 
2012, 12: 299. 
2. Bailey, RL, Gahche, JJ, Lentino, CV et al. Dietary Supplement Use in the United States, 
2003-2006. J Nutr 2011,141: 261-266. 
3. Bailey, RL, Gahche, JJ, Miller, PE, Thomas, PR, Swyer, JT. Why US Adults Use Dietary 
Supplements. JAMA Intern Med 2013;173(5):355-361. 
4. Geller, AI, Shehab, N, Weidle, NJ, et al. Emergency Department Visits for Adverse Events 
Related to Dietary Supplements. 2015; N Engl J Med 373;16. 
5.  Becker, DJ, Gordon RY, Morris PB, et al. Simvastatin vs. Therapeutic Lifestyle Changes 
and Supplements: Randomized Primary Prevention Trial. Mayo Clin Proc 2008; 83(7):758-
764. 
6.  Ford, ES, Li, C, Pearson, WS, Zhao, G, Mokdad, AH. Int J Cardiol 2010;140(2):226-35. 
7. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun LT, de 
Ferranti S, Faiella-Tommasino J, Forman DE, Goldberg R, Heidenreich PA, Hlatky MA, 
Jones DW, Lloyd-Jones D, LopezPajares N, Ndumele CE, Orringer CE, Peralta CA, Saseen 
JJ,SmithSCJr,SperlingL,ViraniSS,YeboahJ.2018AHA/ACC/AACVPR/AAPA/ABC/ACP
M/ADA/AGS/APhA/ASPC/NLA/PCNAguidelineon the management of blood cholesterol: 
a report of the American College of Cardiology/American Heart Association Task Force on 
Clinical Practice Guidelines. J Am Coll Cardiol 2019;73:e285–350. 
8.   Code of Federal Regulations Title 21, Volume 3 Revised as of April 1, 2020, 21CFR182.20; 
Subchapter B-Food for Human Consumption Part 182 Substances Generally Recognized as 
Safe. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=182.209.  
https://www.cfsanappsexternal.fda.gov/scripts/fdcc/?set=GRASNotices. Fish Oil. 
 
 

SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
Statistical Analysis Plan 
IND Number: 154728 
 
 
Supplements, Placebo, or RosuvastaTin Study 
 
SPORT Study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Final version 1.0 
12 January 2022 
 
 
 


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Approval of Statistical Analysis Plan 
 
Protocol: IND Number: 154728, 23 February 2021 
 
Supplements, Placebo, or RosuvastaTin Study 
SPORT Study 
 
Date Effective: 
12 January 2022 
 
Author: 
 
Danielle Brennan, MS, Lead Biostatistician 
 
 
Signature: 
 
 
 
 
The Statistical Analysis Plan for the SPORT study has been reviewed and approved by: 
 
 
Steven E. Nissen, MD, MACC, Study Chairman 
 
Signature:  
 
 
 
____________________________________________ Date: ______________________ 
 
 
Luke Laffin, MD, Principal Investigator 
 
Signature:  
 
 
 
____________________________________________ Date: ______________________ 
 
 
Dennis Bruemmer, MD, PhD. Co-Investigator 
 
Signature:  
 
 
 
____________________________________________ Date: ______________________ 
 
 


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Table of Contents 
 
1. 
Introduction .......................................................................................................... 5 
2. 
Objectives and Endpoints ...................................................................................... 5 
2.1. 
Primary Objective ........................................................................................... 5 
2.2. 
Secondary Objective ....................................................................................... 5 
2.3. 
Primary Endpoint ............................................................................................ 5 
2.4. 
Secondary Endpoints....................................................................................... 5 
3. 
Study Design......................................................................................................... 5 
3.1. 
Randomization................................................................................................ 6 
3.2. 
Blinding ......................................................................................................... 6 
3.3. 
Sample Size and Power ................................................................................... 6 
4. 
Study Analysis Sets ............................................................................................... 7 
4.1. 
Full Analysis Set ............................................................................................. 7 
4.2. 
Safety Analysis Set ......................................................................................... 7 
4.3. 
Per-protocol Analysis Set ................................................................................ 7 
5. 
General Data Considerations.................................................................................. 7 
6. 
Data Handling ....................................................................................................... 7 
6.1. 
Missing data ................................................................................................... 7 
6.2. 
Incomplete dates ............................................................................................. 8 
6.3. 
Data Definitions.............................................................................................. 8 
6.3.1. 
Study Day................................................................................................ 8 
6.3.2. 
Baseline laboratory values ........................................................................ 8 
6.3.3. 
Change from baseline............................................................................... 8 
6.4. 
Study medication/supplement adherence .......................................................... 9 
7. 
Study Population ................................................................................................... 9 
7.1. 
Subject Disposition ......................................................................................... 9 
7.2. 
Demographic Characteristics ........................................................................... 9 
7.3. 
Baseline Characteristics and Vital Signs ........................................................ 10 
7.4. 
Medical History ............................................................................................ 10 
7.5. 
Study medications/supplements ..................................................................... 10 
7.6. 
Prior and Concomitant Medications ............................................................... 10 
7.7. 
Laboratory Parameters .................................................................................. 11 
8. 
Analysis of Endpoints.......................................................................................... 11 
8.1. 
Primary Endpoint .......................................................................................... 11 


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8.2. 
Secondary Endpoints..................................................................................... 12 
9. 
Analysis of Safety Data ....................................................................................... 13 
9.1. 
Adverse Events ............................................................................................. 13 
9.2. 
Serious Adverse Events ................................................................................. 13 
9.3. 
All-Cause Mortality ...................................................................................... 13 
10. 
Safety Monitoring Review ................................................................................ 14 
11. 
Appendix A...................................................................................................... 15 
 
 
 


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1. Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to provide a description of the 
statistical methods to be implemented for the analysis of data from the study with 
IND Number: 154728. The SAP will be finalized prior to database lock.  Any 
deviations from the SAP after database lock will be documented in the final Clinical 
Study Report (CSR). 
2. Objectives and Endpoints 
2.1. Primary Objective  
The primary objective of this study is to compare the low density lipoprotein 
cholesterol (LDL-C) lowering of rosuvastatin with the effect of six commonly-
used nonprescription dietary supplements promoted for cholesterol health. 
2.2. Secondary Objective 
The secondary objective of this study is to assess the effect of each supplement on 
inflammatory markers compared with rosuvastatin 5 mg. 
2.3. Primary Endpoint 
The percent change in LDL-C for rosuvastatin 5 mg compared with each dietary 
supplement after 4 weeks of treatment  
2.4. Secondary Endpoints 
The secondary endpoints of this study are: 
 
 The percent change in LDL-C for rosuvastatin 5 mg and each dietary 
supplement compared with placebo after 4 weeks. 
 The percent change in high sensitivity C reactive protein (hsCRP) for 
rosuvastatin 5 mg and each dietary supplement compared with placebo 
after 4 weeks. 
 The percent change in HDL-C, total cholesterol, and triglycerides for each 
supplement compared with rosuvastatin. 
 The percent change in HDL-C, total cholesterol, and triglycerides for each 
supplement compared with placebo. 
 
3. Study Design 
SPORT is a randomized, single blind study design used to evaluate rosuvastatin 5 mg. 
vs. placebo and 6 commercially available over the counter supplements in a hierarchical 
testing order. Each participant will take study medication/supplement for a total of 4 
weeks. Eight groups will be studied, rosuvastatin 5 mg compared with each of the 
following: 
1. Placebo (visually similar to rosuvastatin 5mg) 
2. Fish oil (Nature Made™ 2 soft gels / day) 


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3. Cinnamon (1200mg,  2 capsules / day) 
4. Garlique™ (1 tablet / day) 
5. Turmeric (Bio Schwartz Turmeric Curcumin, 1500mg, 3 capsules / day)  
6. Plant sterol (Nature Made CholestOff™ Plus, 2 soft gels 2x / day)  
7. Red yeast rice (Arazo Nutrition, Red Yeast Rice, 1200mg, 2 capsules / day) 
 
3.1. Randomization  
Randomization will occur using REDCap Cloud electronic database platform. 
Study medication/supplement will be dispensed by the investigational pharmacy 
in a blinded fashion for in person visits to study personnel or shipped to the 
subjects by the investigational pharmacy following randomization. Day 1 of the 
study is the first day that subjects start study medication/supplement. In the event 
that study medication/supplement is shipped to subjects, study personnel will 
verify the start of study medication/supplement (Day1) for medication/supplement 
accountability.  
 
The study medication/supplement will be supplied from commercially available 
products and administered according to the package insert. The rosuvastatin 5mg 
and placebo will be provided by Astra Zeneca.  The over the counter supplements 
will be purchased and due to documented history of supplement tainting, 
supplements may be tested for unlabeled enhancing impurities retrospectively if 
deemed necessary per data findings. If we observe > 15% lowering in LDL 
cholesterol, we will test for impurities. 
 
3.2. Blinding 
Subjects, investigator staff, persons performing the assessments, and the clinical 
trial team will be blinded to assigned study group. Baseline laboratory values will 
not be blinded to the subjects, investigator staff, and the clinical team. Additional 
lipid labs will be prohibited for the 4 week participation period. The Day 28 labs 
will not be blinded.  
 
It is expected that the need for unblinding of a patient’s study group will be 
extremely rare.  Every effort should be made to preserve the blind unless there is a 
compelling reason that knowledge of the specific treatment would alter the 
medical care of the patient. 
 
3.3. Sample Size and Power 
Eligible subjects will be randomized 1:1:1:1:1:1:1:1 to the study groups in a 
blinded fashion. There will be 25 subjects per study group. The total sample size 
will be 200 patients.  Assuming a common standard deviation of 15 and an alpha 
of 0.05, enrolling a total of 25 in each group will have 90% power to detect an 


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average difference in percent change in LDL-C of 15 between rosuvastatin and 
each supplement. 
 
4. Study Analysis Sets 
4.1. Full Analysis Set 
The full analysis set (FAS) consists of all enrolled patients.  Efficacy variables 
will be analyzed based on the FAS as the primary population. 
 
4.2. Safety Analysis Set 
The safety analysis set (SAS) consists of all patients who received at least one dose 
of study medication/supplement. The safety population will be used for the analyses 
of safety variables. 
 
4.3. Per-protocol Analysis Set 
The per-protocol analysis set (PPAS) consists of all patients who received at least 
80% of the prescribed study medication/supplement.  Patients will be categorized 
by they study medication/supplement taken. 
 
5. General Data Considerations 
Continuous variables will be summarized in terms of the number of observations (n), 
mean, standard deviation (SD), median, Q1 (25th percentile), Q3 (75th percentile), 
minimum and maximum. Other descriptive statistics (e.g. geometric mean) may be 
reported when appropriate.  
 
Categorical variables will be summarized using frequency counts and percentages. 
Analyses that use other descriptive statistics will be identified with the analysis in the 
applicable SAP section.  
 
SAS version 9.4 or higher will be used to perform all analyses and to generate output. 
 
6. Data Handling 
All data will be exported from the REDCap Cloud database.  Randomization data will 
also be exported from the REDCap Cloud database. Assigned study medication will 
be blinded to study personnel.  A general description of how the data will be handled 
is outlined below however, it may not encompass all that is found at the time of the 
analysis. 
6.1. Missing data 
Missing data will not be imputed unless otherwise specified. Only observed data 
will be used in the summaries and analyses.  


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6.2. Incomplete dates 
If a day or month is recorded as missing, it will be replaced by the first day of the 
month or January, respectively, provided this does not contradict any other dates 
recorded. 
6.3. Data Definitions 
The following sections provide a general description of the derived variables for 
data analyses.  
6.3.1. Study Day 
6.3.1.1. 
Fasting lipid panel 
The fasting lipid draw and complete metabolic panel (CMP) at Day 
0 and Day 28 must be obtained from a Cleveland Clinic lab. 
Recently acquired lipid labs and complete metabolic panel may be 
used in place of a Day 0 lab draw if acquired within 4 weeks of 
screening at a Cleveland Clinic lab and performed in the fasting state.  
6.3.1.2. 
Study Medication 
Day 1 of the study is the first day that subjects start study 
medication/supplement. 
6.3.1.3. 
Body Weight 
Historical documented height and weight may be used.  Weight to 
be within the last 3 months.  Subject reported is acceptable. 
6.3.2. Baseline laboratory values 
Baseline is defined as the Day 0 lab draw. Recently acquired lipid labs and 
CMP may be used in place of a Day 0 lab draw if acquired within 4 weeks 
of screening at a Cleveland Clinic lab and performed in the fasting state 
6.3.3. Change from baseline 
Change from baseline will only be calculated for measures that have post-
baseline records. Change from baseline is calculated as:  
 
(Day 28 value) – Baseline value.  
 
Percentage change from baseline is calculated as:  
 
((change from baseline) / baseline value) * 100  
 
If either the baseline or visit value is missing, the change from baseline 
and percentage change from baseline is set to missing as well. 
 


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6.4. Study medication/supplement adherence 
Study medication/supplement adherence will be determined by the pill count 
returned, the pill count dispensed, and the amount of pills that are expected to be 
taken: 
 
(Number of pills dispensed – number of pills returned) /  
(number of pills indicated per day per study 
medication/supplement*number of days of follow-up†) 
 
The number of pills expected to be taken through day 28 days will vary for each 
medication/supplement (Appendix A).  The expected amount per day will be 
multiplied by the number of days of follow-up to get the total number of pill 
expected by the end of the study period.   
 
Study medication/supplement adherence is defined as patients consuming at least 
80% of the expected amount. 
 
†The range of follow-up is 24-32 days.  Only patients with at least 24 days of 
follow-up will be included in the study medication/supplement adherence 
calculation. 
7. Study Population 
A limited amount of baseline patient and laboratory data will be collected from 
historical records.  Patient reported data may be used as noted. 
7.1. Subject Disposition 
The number of patients screened will be presented by study group and overall for 
the screened set. In addition, the reasons of screen failures will be provided for 
screened set as well. The number and percentage of patients who completed the 
study, who discontinued the study and the reason for discontinuation will be 
presented for each study group and all patients. The frequency (%) of patients with 
major protocol deviations will be presented in separate tables.  
7.2. Demographic Characteristics 
All demographic summaries will be based on the FAS.  The following summaries 
of patient demographic characteristics will be provided by treatment group: 
 
 Age 
 Gender 
 Race 
 Ethnicity 


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7.3. Baseline Characteristics and Vital Signs 
All baseline characteristics summaries will be based on the FAS. They will be 
presented in summary tables by study group. Continuous data will be summarized 
by descriptive statistics.  
 
Baseline characteristics and vital signs will be summarized as follows overall: 
 
 Weight (kg), BMI (kg/m2) will be summarized as appropriate to 
continuous variables  
 Systolic and diastolic blood pressure -  may be patient reported if no 
historical records are found 
7.4. Medical History 
The following medical history will be summarized by treatment group to describe 
the patient population enrolled in the study:  
 
 Diabetes, if yes, insulin use  
 Hypertension 
 Hyperlipidemia 
 Arrhythmia 
o Atrial fibrillation  
o Other 
 Congestive Heart Failure 
 Smoking  - current use, previous, never 
7.5. Study medications/supplements 
Because each medication/supplement is dispensed at different amounts, adherence 
to study medication/supplement will summarized categorically: 
 < 30% 
 30-50% 
 50-70% 
 70-90% 
 ≥90% 
 
Patients taking at least 80% of their randomized medication/supplement will be 
considered adherent. 
7.6. Prior and Concomitant Medications 
A predetermined list of medications will be summarized at baseline, day 28 and 
any unscheduled visit.  Prior or concomitant medication/supplements will be 
summarized for the safety set in separate tabulations based on a predetermined list 
of medication/supplements.  Prior medication/supplement are defined as any 
medication/supplement a subject was taking prior to randomization in the study.  
Concomitant medication/supplements will include any medication/supplements 
taken during the study period.  They include the following: 


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 ACE-Inhibitors 
 Anticoagulants 
 Angiotensin II Receptor Blockers (ARBs) 
 Aspirin 
 Beta Blockers 
 Calcium Channel Blockers 
 Diuretics 
 Nitrates 
 Thyroid medications 
 Vitamin D 
 Diabetic medications  (insulin, oral meds) 
7.7. Laboratory Parameters 
The following laboratory parameters will be summarized by treatment group: 
 HDL-C (mg/dL) 
 LDL-C (mg/dL) 
 Total cholesterol (mg/dL) 
 Triglycerides (mg/dL) 
 High sensitivity C-reactive protein (mg/dL) 
8. Analysis of Endpoints 
8.1. Primary Endpoint 
The primary endpoint is defined as percent change in LDL-C for rosuvastatin 5 mg 
compared with dietary supplement after 4 weeks. 
 
To control the overall alpha of the study, the primary endpoint will be evaluated 
hierarchically. Each comparison to rosuvastatin will use an alpha of 0.05.  Once a 
comparison is not met (2-sided p-value ≥ 0.05) all subsequent comparisons will be 
considered exploratory with nominal p-values. The change in LDL-C for 
rosuvastatin will be compared with the other 7 study groups using ANCOVA in a 
hierarchical fashion in the following order: 
Rosuvastatin 5 mg compared with the following: 
1. Placebo (visually similar to rosuvastatin 5mg) 
2. Fish oil (Nature Made™ 2 soft gels / day) 
3. Cinnamon (1200mg,  2 capsules / day) 
4. Garlique™ (1 tablet / day) 
5. Turmeric (Bio Schwartz Turmeric Curcumin, 1500mg, 3 capsules / day)  
6. Plant sterol (Nature Made CholestOff™ Plus, 2 soft gels 2x / day)  
7. Red yeast rice (Arazo Nutrition, Red Yeast Rice, 1200mg, 2 capsules / day) 


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A generalized linear model will be used to compare the percent change in LDL-C 
between rosuvastatin and each of the other study groups.  Least-square means and 
standard error will be used to summarize the adjusted percent changes in LDL-C.  
The differences in the percent changes between rosuvastatin and each study 
medication/supplement will be calculated by subtracting the LS-means of each 
comparison. At a minimum, adjustments for baseline LDL-C and age will be used 
in each model.  Other adjustments may be warranted if differences in factors across 
study groups are statistically significant.   
 
If the percent change in LDL-C has a non-normal distribution (graphically 
assessed), median values will be used to summarize the endpoints and compared 
with a non-parametric test. The primary endpoint will be analyzed in the FAS.  A 
sensitivity analysis will be performed using the PPAS, to determine the differences 
in the percent change in LDL-C in patients using the prescribed about of study 
medication/supplement. 
8.2. Secondary Endpoints 
The following secondary endpoints will be analyzed in the FAS: 
 Percent change in high sensitivity C reactive protein (hsCRP) for each 
dietary supplement compared with rosuvastatin 5 mg after 4 weeks 
treatment  
 The percent changes in HDL-C, total cholesterol, and triglycerides for 
each dietary supplement compared with rosuvastatin 5 mg after 4 
weeks treatment 
 The percent changes in HDL-C, total cholesterol, and triglycerides for 
each dietary supplement compared with placebo after 4 weeks 
treatment  
A generalized linear model will be used to analyze the percent changes for 
secondary endpoints.  Percent change from baseline for each laboratory 
measurement will first be calculated.  Least-square means and standard error will 
be used to summarize the adjusted percent changes in LDL-C.  The differences in 
the percent changes for each secondary endpoint will be calculated by subtracting 
the LS-means of the percent change of each study medication/supplement to its 
comparator. The mean and 95% confidence intervals will be used to summarize the 
effect of each study group. At a minimum, adjustments for baseline laboratory 
measurement and age will be used in each model.  Other adjustments may be 
warranted if differences in factors across study groups are statistically significant.   
 
No hierarchical testing of the secondary endpoints will be conducted.  Since the 
study was not powered to test secondary endpoints, all testing and p-values will be 
considered exploratory.  No adjustments will be made for multiplicity. A sensitivity 
analysis will be performed using the PPAS, to determine the differences in the 


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percent change in each laboratory measurement in patients using the prescribed 
about of study medication/supplement. 
9. Analysis of Safety Data 
9.1. Adverse Events 
Adverse events will be summarized by study group.  A subject with multiple 
adverse events of the same type is only counted once towards the total of that 
event, however the total number of adverse events experiences will also be 
calculated.  Adverse events will be collected through the end of the study period.  
No formal statistical tests will be conducted.  All summaries and analyses of the 
safety data will be conducted on the SAS. 
 
Adverse events will be summarized in patient listings with the following 
characteristics: 
 
 Seriousness (mild, moderate, severe potentially life threatening) 
 Relatedness (possibly, unknown, not related) 
 Status (expected, unexpected) 
 Action taken (drug withdrawn, drug interrupted, not applicable, unknown) 
 Resolution (unresolved, resolved, resolved with sequelae, unknown) 
 Considered a serious adverse event 
 
Adverse events occurring at least 5% of the time in the overall population will be 
summarized in a separate table. 
9.2. Serious Adverse Events 
Adverse events classified as serious adverse events (SAEs) will separately be 
summarized by treatment group.  SAEs will also be summarized in a listing with 
the following characteristics: 
 
 Death 
 Life threatening 
 Inpatient hospitalization or prolongation of existing hospitalization 
 Persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions 
 Congenital anomaly/birth defect 
 Other important medical event 
9.3. All-Cause Mortality 
All-cause mortality through the end of the study period will be summarized by 
treatment group.  Listings may be produced with any available information that is 
collected. 


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10. Safety Monitoring Review 
Medical monitoring review will begin 3 months after enrollment of the first patient 
and then every 3 months thereafter during the enrollment phase of the study through 
completion of the final visit by the last patient. The Medical Monitor will escalate any 
findings regarding death, serious adverse events, adverse events, and safety data to 
the Principal Investigator. 
 
Elements of the report may include but are not limited to: 
 Cumulative number of subjects enrolled 
 Patient demographics 
 Protocol deviations 
 Study drug discontinuations due to adverse events 
 Adverse event tables and listings (as described in section 9.1) 
 Serious adverse event tables and listing (as described in 9.2) 
 Any MEDWATCH form related to rosuvastatin or the supplements 
 Any Suspected Unexpected Serious Adverse Reaction (SUSAR) 
 
All safety monitoring reports and listings will be unblinded to study treatment. 
 
 


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11. Appendix A 
 
Study medication/supplement expected pill count: 
 
Study medication/supplement 
Expected 28-day pill count (total) 
Rosuvastatin 
28 
Placebo 
28 
Fish Oil 
56 
Cinnamon 
56 
Garlique™ 
28 
Tumeric 
84 
Plant Sterol 
112 
Red yeast rice 
56