The Patient Autonomy and Statin Therapy Adherence (PASTA) Trial: A Randomized Controlled Trial Comparing Adherence to Atorvastatin Therapy in Primary Prevention Patients Who Decline Statin Therapy, When Given a Choice Between Atorvastatin and Red Yeast Rice Extract as Their Initial Therapy
Phase: NA
Conditions: Drug Adherence
Sponsor: Lithuanian University of Health Sciences

 
 
STUDY PROTOCOL  
May 2022  
 
 
 
 
Main sponsor:  
 
 
Lithuanian University of Health Sciences 
Funders:  
 
Study coordination centre:  
Lithuanian University of Health Sciences 
NRES reference:   
 
 
Principal Investigators:   
Ayman Haq MD, Ali Aldujeli MD, PhD 
 
 
 
 
 
 

 
Study management group 
 
 
Chief investigators: Ayman Haq MD, Ali Aldujeli MD, PhD 
 
 
Co-investigator(s):  
 
Statistician: Dimitrios Strepkos MD 
Advisor: Michael Miedema MD MPH 
Advisor: Emmanouil Brilakis MD PhD 
 
 
 
 
Head of Trial monitoring oversight:  Lithuanian University of Health Sciences Clinical Trials 
Unit 
 
Study coordination centre:  Lithuanian University of Health Sciences 
 
 
For general queries, supply of study documentation, and collection of data, please contact: 
 
Study coordinator:  Ali Aldujeli MD 
 
 
 
 
 
 
 
Email:   
 
Ali.Aldujeli@kaunoklinikos.lt 
Clinical Queries:  
Clinical queries should be directed to Ali Aldujeli or Ayman Haq who will direct the query to the 
appropriate person. 
 
Sponsor:  
Lithuanian University of Health Sciences is the main research sponsor for this study.  For further 
information regarding the sponsorship conditions, please contact the Head of Regulatory 
Compliance at:  
 
Joint Research Compliance Office  
5L10C, 5th Floor Lab Block  
Charing Cross Hospital, Fulham Palace Road London W6 8RF  
Tel: 0203 311 0204  
Fax: 0203 311 0203  
 
Funder: NA 
This protocol describes the Red Yeast Extract study and provides information about procedures 
for entering participants. Every care was taken in its drafting, but corrections or 
amendments may be necessary. These will be circulated to investigators in the study.   

Problems relating to this study should be referred, in the first instance, to the Chief 
Investigator.  
 
This study will adhere to the principles outlined in the Lithuanian ministry of health Research 
Governance Framework for Health and Social Care (2nd edition). It will be conducted in 
compliance with the protocol, the Data Protection Act and other regulatory requirements as 
appropriate. 
 
 
This protocol is strictly confidential and not for public distribution.  

Table of Contents  
 
1. Study overview 
 Page 6 
1.1. Study summary .................................................................... Page 6 
1.2. Glossary of abbreviations .................................................... Page 7 
1.3. Keywords ............................................................................. Page 7 
 
2. Introduction ...................................................................................... Page 8 
2.1. Background ........................................................................ Page 8 
 
3. Study objectives ................................................................................ Page 9 
 
4. Study design ...................................................................................... Page 10 
4.1. Study review diagram ........................................................ Page 10 
4.2. Study protocol .................................................................... Page 11 
4.3. Study outcome measures............................................ ...... Page 12 
4.4. Relevance and implications of the trial results ..............  Page 12 
4.5. Sample size/Power calculation  .....................................  Page 12 
5. Participant Entry ............................................................................... Page 13 
5.1. Pre-registration evaluation ............................................... Page 13 
5.2. Inclusion criteria  ............................................................  Page 13 
5.3. Exclusion criteria  ...........................................................  Page 13 
5.4. Withdrawal criteria  ........................................................  Page 13 
5.5. Screening record ............................................................ Page 13 
6.  Clinical events ................................................................................... Page 14 
6.1. Definitions .......................................................................... Page 14 
6.2. Reporting procedures ........................................................ Page 14 
 
7. Assessment and follow-up ............................................................... Page 15 
 
8. Statistics and data analysis .........................................................  Page 15 
 
9. Regulatory issues .............................................................................. Page 15 
9.1. Ethics approval ...............................................................  Page 15 
9.2. Consent ..........................................................................  Page 15 
9.3. Risks of procedure .............................................................. Page 15 
9.4. Confidentiality ................................................................  Page 16 
9.5. Indemnity .......................................................................  Page 16 
9.6. Sponsor...........................................................................  Page 16 
9.7. Funding ...........................................................................  Page 16 
9.8. Audits and inspections ...................................................... Page 16 

 
 
10.  Study management ........................................................................ Page 16 
 
10.1. Study reporting .............................................................  Page 16 
10.2. Study sites and enrolment ............................................  Page 16 
10.3. Documentation .............................................................  Page 16 
 
11. Publication policy ............................................................................ Page 17 
 
12. References ....................................................................................... Page 18 
 
13. Appendices  ..................................................................................... Page 19 
 
Appendix A: 
 
Final Follow-up questionnaire …………………………………………… Page 19 
 
Appendix B: 
 
Clinical Encounter Conversation Guidelines……..………………… Page 19 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 

1. Study overview 
 
 
1.1. Study summary  
 
Design 
Patients will be randomized to receive either 30mg of atorvastatin or be presented with a choice 
of receiving either a “natural” statin (red yeast rice extract) or 30mg of atorvastatin. 
In the intervention arm, a goal of either LDL-C reduction of at least 50% or an LDL-C < 100 mg/dl 
will be discussed on the initial visit. Goals will be re-assessed at 2 months, if goals are not met, 
patients will be given 30mg of atorvastatin. 
 
Aims 
To assess if introducing greater patient autonomy increases patient compliance with statin 
therapy.  
 
Outcome measures 
The primary endpoint will be 6-month compliance of statin therapy, after the initiation of 
atorvastatin. 
 
Secondary endpoints will be rates of perceived side effects from statin use, including myalgias, 
fatigue, mental fog and GI upset. 
 
Population 
This will be a multi-center study of 300 pts, 150 in each arm. 
 
Eligibility 
Primary prevention (no history of CAD, MI, or stroke) patients with a moderate 10-year ASCVD risk 
who decline statin therapy. 
 
Duration 
Anticipated recruitment is 6 months. Follow-up will be performed at 6 months in the control arm 
and 2 and 8 months in the intervention arm, for a total study duration of 14 months.  
 
 
 
 

1.2.  Glossary of abbreviations 
ALT 
Alanine aminotransferase 
ASCVD 
Atherosclerotic cardiovascular disease 
AST 
Aspartate aminotransferase 
BMI 
Body mass index 
CAD  
Coronary artery disease 
CVD 
Cardiovascular disease 
EAS 
European atherosclerosis society 
ESC 
European society of cardiology 
HDL 
high-density lipoprotein 
LDL 
low-density lipoprotein 
MI 
Myocardial infarction 
PCE 
Pooled cohorts equation 
 
1.3. Keywords 
 
Statin Intolerance 
Autonomy 
Therapeutic Relationship 

2. Introduction 
2.1. Background 
 
Statin therapy is an integral tool in the primary and secondary prevention of ASCVD. Higher 
compliance with their statin therapy is associated with a lower risk of mortality in a step-wise 
manner (1). Despite this, rates of statin compliance are abysmally low. Prior studies suggest 
that less than 40% of primary prevention patients are compliant with their prescribed statin 
therapy. Individuals who have suffered a prior MI have an incremental improvement in 
compliance to around 60%. Younger individuals and women appear to have exceptionally low 
rates of compliance to statin therapy (2). Low rates of compliance remains a significant barrier 
to reducing the burden of ASCVD, with some suggesting efforts to increase compliance can 
have an oversized impact on reducing rates of ASCVD (3).  
 
On the other hand, patients often prefer “natural” therapies over conventional medicine for a 
variety of reasons (6). Monacolin-K is a naturally occurring molecule in red yeast-rice extract, a 
commonly used health supplement. It is structurally identical to lovastatin and has been shown 
to reduce LDL-C levels and ASCVD events in randomized placebo controlled trials (7, 8). 
 
Patient autonomy is a core bioethical principle affirming the right of the patient to determine 
the trajectory of their health care at times. This bioethical principle has been referred to as 
“first among equals”, implying that it is the most important bioethical principle (4). The role of 
autonomy in patient compliance is not entirely clear, but there is evidence that suggests that 
increased patient autonomy in the decision-making process can result in higher rates of long 
term compliance (5). 
 

3. Study objectives 
 
 
Primary Objective 
 
The objective of this study is to determine if introducing autonomy in the decision-making 
process will increase statin compliance and reduce the rate of perceived side effects from statin 
use. 
 
Rationale for the study 
1) Statin use has been repeatedly shown to reduce the risk of ASCVD events 
2) Patient compliance is a significant and often insurmountable barrier to statin therapy 
3) Increased patient autonomy may be associated with greater rates of long-term 
compliance and warrants further investigation 
 
 
Study hypotheses 
Patients who perceive a higher degree of autonomy in the decision-making process are more 
likely to be compliant with statin therapy and less likely to perceive side effects from statin 
therapy. 
 

4. Study design 
 
1.1. Study overview diagram 
 
 
 
 
 
 
 
 
 

4.2 Study protocol: 
 
Patients meeting the study criteria will be enrolled at outpatient cardiology clinics at four 
centers: Lithuanian University of Health Sciences, Northway Medical Centre, Prienu Hospital, 
and Unomeda Medical Centre. The enrolment period will last six months, with an estimated 50 
patients per month enrolled into the study, for a total of 300 patients. 
 
Patients will be randomized to either the control group or the intervention group. Baseline 
variables will include demographic variables (age, gender, BMI, blood pressure, heart rate), 
medical history (hypertension, hyperlipidaemia, type 2 diabetes mellitus, tobacco use), 
laboratory variables (total cholesterol, HDL, LDL, triglycerides, AST, ALT, creatine kinase, and, 
vitamin D levels) and socioeconomic variables (education level, income level, rural or urban, 
and marriage status). 
 
The control group will be provided reassurance through a short, semi-structured discussion on 
the excellent safety profile of statins, similar to a typical interaction between a clinician and 
patient. They will then be prescribed 30mg atorvastatin daily as a 30 tablets supply with five 
patient-initiated re-fills for 30 tablets each. Final follow-up in this group will occur at 6 months.  
 
The intervention group will be offered a red yeast rice extract 20mg nightly to achieve a goal 
LDL-cholesterol of <2.6 mmol/L (100 mg/dL) in accordance with the 2019 ESC/EAS guidelines 
(9). Initial follow-up will take place in 2 months to assess the efficacy of their treatment. 
Patients who are not at the goal LDL-cholesterol will be prescribed 30mg atorvastatin nightly as 
a 30 tablets supply with five patient-initiated re-fills for 30 tablets each, with final follow-up 
after 6 additional months. Patients who are at goal on the red yeast rice extract will be 
recommended to switch to lovastatin 20mg nightly as a bio-identical substitute, but they will be 
excluded from further analysis. 
 
In both groups, statin adherence will be assessed by pharmacy refill records at the final follow-
up. A short, four question questionnaire (Appendix A) will be administered at this point as well. 
Final follow-up laboratory variables collected will include total cholesterol, HDL, LDL, 
triglycerides, AST, ALT, creatine kinase, and vitamin D levels. 
 
Conversation guidelines for each clinical encounter in the intervention group are included in 
Appendix B. 
 
Randomisation 
Patients will be randomized by block randomization. On the first week of enrollment, the 
clinician will only enroll patients into the control arm. On the subsequent week, the clinician 
will only enroll patients into the intervention arm. 
 

4.3. Study outcome measures 
Primary Endpoint 
Rate of statin compliance, based on pharmacy refill records. Values per patient can range from 
0-6 according to the number of refills. 
 
Secondary Endpoints: 
Rate of perceived side-effects from statin use, including muscle aches, fatigue, mental fog, and 
gastrointestinal upset. 
 
4.4. Relevance and implications of the trial results 
1. 
Low compliance with statin therapy is widely observed and limits the preventative 
potential of the therapy and results in increased ASCVD events 
2. 
Empowering patients by allowing autonomy in clinical decision making may be an 
effective tool to increase long term compliance. 
 
4.5. Sample size/Power calculation 
This study is designed as a superiority trial. Based on prior literature, we estimate a 50% statin 
compliance rate with a standard deviation of 10% (2). We will set the minimal detectable effect 
at a 5% increase in statin compliance, with an α < 0.05 and power of 0.9. Based on case-to-
control ratio of 1:1, our total minimum sample size for the primary endpoint is 138. However, 
we will plan on a total sample size of 300 patients, to account for patients who drop out of the 
study as well as patients who will be excluded due to attaining an LDL-cholesterol of <2.6 
mmol/L (100 mg/dL) on red yeast rice extract. 
 
 

5. Participant entry 
 
5.1. Pre-registration evaluation 
Recruitment 
Primary prevention patients with a moderate ASCVD risk. 
 
5.2. Inclusion criteria 
1. Over 40 
2. Moderate ASCVD risk 
3. Decline statin therapy 
 
5.3. Exclusion criteria 
 
1. Dementia 
2. Severe Mental Illness 
3. History of statin intolerance 
4. High-risk for ASCVD 
5. Currently on lipid lowering therapy 
6. Currently taking red yeast rice extract 
7. Pregnant or breast feeding 
8. Concomitant use of the following drugs: anti-retroviral therapy, niacin, calcineurin 
inhibitors, mTOR inhibitors, amiodarone, and fibrates 
5.4. Withdrawal criteria 
Patients will be able to withdraw from the study at any time at their request. 
 
Patient who develop statin intolerance will be withdrawn from the study. 
 
5.5. Screening record 
Any patient initially considered suitable, but then found inappropriate due to study exclusion 
criteria will be recorded into the screening record.  
 

6. Clinical events 
 
6.1. Definitions 
The following definitions will be employed in this study. 
 
Statin intolerance 
Development of an increase in creatine kinase OR AST/ALT elevation> 3x upper limit of normal 
OR rhabdomyolysis with statin initiation during the study period. 
History of statin intolerance 
History of an increase in creatine kinase OR AST/ALT elevation> 3x upper limit of normal OR 
rhabdomyolysis with statin initiation, prior to enrollment in this study 
 
Moderate risk for ASCVD 
7.5%-20% 10-year ASCVD risk by the Pooled Cohorts Equation 
 
Severe Mental Illness 
History of schizophrenia or another mental illness with psychotic features 
 
6.2 Reporting procedures 
Clinical Events Committee  
The CEC is made up of cardiologists who are not participants in the trial. The CEC is charged 
with the development of specific criteria used for the adjudication of clinical events and clinical 
endpoints in the trial which are based on protocol. 
 
The Clinical Events Committee will establish explicit rules outlining the minimum amount of 
data required, and the algorithm followed in order to classify a clinical event. All members of 
the Clinical Events Committee will be blinded to the treatment arm and the primary results of 
the trial. 
 
The Clinical Events Committee will meet regularly to review and adjudicate all clinical events in 
which the required minimum data is available. The Committee will also review and rule on all 
deaths that occur throughout the trial. 
Reports of clinical events should be submitted within 15 days of the Chief Investigator 
becoming aware of the event.    
Local investigators should report any clinical events as required by their Local Research Ethics 
Committee, Sponsor and/or Research & Development Office.  
 
Contact for reporting clinical events: Ramunas Unikas 
Email: ramunas.unikas@kaunoklinikos.lt 
 

Case report form  
An online CRF form will be used throughout the study. This will be secure, and compatible with 
currently guidelines to ensure security of patient data. It will be managed via the Lithuanian 
University of Health Sciences Clinical Trials Unit , and data achieved securely. 
 
7. Assessment and follow-up 
Routine follow-up will be performed with a clinic visit at 6 months in the control group and at 2 
months and 8 months in the intervention group.  The CRF should be completed. 
 
 
8. Statistics and data analysis 
Data will be summarised as mean (SD) or median (interquartile range) for skewed data. 
Statistical comparisons will be undertaken using a paired Student’s t-test (after log 
transformation if necessary) or nonparametric alternative if data are not normalised by log 
transformation.  Kaplan-Meier survival analysis curves will be used to assess clinical event 
timelines.  
 
9. Regulatory issues 
 
9.1. Ethics approval 
The Chief Investigator will obtain approval from the TBC Research Ethics Committee. The study 
must be submitted for Site Specific Assessment (SSA) at each participating NHS Trust.  The Chief 
Investigator will require a copy of the Trust R&D approval letter before accepting participants 
into the study. The study will be conducted in accordance with the recommendations for 
physicians involved in research on human subjects adopted by the 18th World Medical 
Assembly, Helsinki 1964 and later revisions.  
 
9.2. Consent 
Consent to enter the study must be sought from each participant only after a full explanation 
has been given, an information leaflet offered and time allowed for consideration. Signed 
participant consent should be obtained. The right of the participant to refuse to participate 
without giving reasons must be respected. After the participant has entered the study the 
clinician remains free to give alternative treatment to that specified in the protocol at any stage 
if he/she feels it is in the participant’s best interest, but the reasons for doing so should be 
recorded. In these cases the participants remain within the study for the purposes of 
follow-up and data analysis. All participants are free to withdraw at any time from the 
protocol treatment without giving reasons and without prejudicing further treatment.  
 
9.3. Risks of procedure 
No procedures are involved in this study 
 
 

9.4. Confidentiality 
The Chief Investigator will preserve the confidentiality of participants taking part in the study and 
is registered under the Data Protection Act.  
 
9.5. Indemnity 
Lithuanian University of Health Sciences holds negligent harm and non-negligent harm 
insurance policies which apply to this study.  
 
9.6. Sponsor 
Lithuanian University of Health Sciences will act as the main Sponsor for this study. Delegated 
responsibilities will be assigned to the NHS trusts taking part in this study.  
 
9.7. Funding 
This study is not funded 
 
9.8. Audits 
The study may be subject to inspection and audit by Lithuanian University of Health Sciences 
under their remit as sponsor and other regulatory bodies to ensure adherence to GCP and the 
NHS Research Governance Framework for Health and Social Care (2nd edition).   
 
10. Study management 
 
The day-to-day management of the study will be co-ordinated through Lithuanian University of 
Health Sciences. 
 
10.1. Study reporting 
We anticipate that it will take 6 months to complete patient recruitment and another 8 months 
to complete follow-up. We will aim to begin recruitment after Ethics review approval with first 
results available for presentation in late 2023 
 
10.2. Study sites and enrolment  
We anticipate the study enrolling patients through up to 10 large high volume CABG centres 
with interventional experience in all of the physiological techniques proposed in this study. We 
envisage enrolment would take place within 12 months. 
 
10.3. Documentation 
All documentation will be collected electronically using ICTU. The ICTU has a track record for 
running large multi-centre international (e.g. ASCOT study). Clinical, and physiological records 
will be saved to DVD and then to a central server within ICTU in accordance with GCP 
guidelines.   
 
 
 

 
11. Publication policy 
 
Publication and future studies committee 
A publication committee, consisting of member of the steering committee and study principal 
investigators will meet to formulate a publication plan to disseminate the principal findings of 
the study, and the primary and secondary endpoints.   
 
Future studies, and sub-studies will be actively encouraged, by investigators and other 
interested parties. These will be assessed via the formal application process, and the committee 
will decide on the applicability and suitability of the study request. Sub-study proposals which 
aim to look at subset analyses of the primary and secondary endpoints will be underpowered 
and in general discouraged.   
 
 
 
 
 
 
 

12. References 
1. Rodriguez F, Maron DJ, Knowles JW, Virani SS, Lin S, Heidenreich PA. Association of statin 
adherence with mortality in patients with atherosclerotic cardiovascular disease. JAMA 
Cardiol. 2019;4(3):206-213. 
2. Colantonio LD, Rosenson RS, Deng L, et al. Adherence to statin therapy among us adults 
between 2007 and 2014. Journal of the American Heart Association. 2019;8(1):e010376. 
3. Shroufi A, Powles JW. Adherence and chemoprevention in major cardiovascular disease: a 
simulation study of the benefits of additional use of statins. J Epidemiol Community Health. 
2010;64(2):109-113. 
4. Gillon R. Ethics needs principles--four can encompass the rest--and respect for autonomy 
should be “first among equals.” J Med Ethics. 2003;29(5):307-312. 
5. Wilton-Clark MS, Feasel AL, Kline GA, Billington EO. Autonomy begets adherence: decisions 
to start and persist with osteoporosis treatment after group medical consultation. Arch 
Osteoporos. 2020;15(1):138. 
6. Foley H, Steel A. Patient perceptions of clinical care in complementary medicine: A 
systematic review of the consultation experience. Patient Educ Couns. 2017;100(2):212-
223. 
7. Lu ZL, Collaborative Group for China Coronary Secondary Prevention Using Xuezhikang. 
[China coronary secondary prevention study (Ccsps)]. Zhonghua Xin Xue Guan Bing Za Zhi. 
2005;33(2):109-115. 
8. Kasliwal RR, Bansal M, Gupta R, et al. ESSENS dyslipidemia: A placebo-controlled, 
randomized study of a nutritional supplement containing red yeast rice in subjects with 
newly diagnosed dyslipidemia. Nutrition. 2016;32(7-8):767-776. 
9. Authors/Task Force Members, ESC Committee for Practice Guidelines (CPG), ESC National 
Cardiac Societies. 2019 ESC/EAS guidelines for the management of dyslipidaemias: Lipid 
modification to reduce cardiovascular risk. Atherosclerosis. 2019;290:140-205. 
 
 
 

13. Appendices 
 
Appendix A 
Final Follow-up questionnaire 
 
Have you had any of the following symptoms from atorvastatin over the past 6 months? 
Myalgias (muscle aches) 
☐ Yes 
☐ No 
☐ Not Sure 
Fatigue 
☐ Yes 
☐ No 
☐ Not Sure 
Mental fog (slow thinking or memory issues) 
☐ Yes 
☐ No 
☐ Not Sure 
Gastrointestinal upset 
☐ Yes 
☐ No 
☐ Not Sure 
 
 
Appendix B 
Clinical Encounter Conversation Guidelines 
Control Group Initial Encounter 
Point(s) to discuss 
1. Acknowledge the patient’s reluctance to start statin therapy 
2. Reassure the patient that long term data supports the safety of statins 
3. Reassure the patient that long term data supports the efficacy of statins 
Sample Conversation(s): 
“I understand that you are hesitant to start statin therapy. We over two decades 
of long-term follow-up data regarding statin use. The data clearly shows that 
statins are extremely safe and patients who stay on statins live longer and 
healthier lives.” 
Intervention Group Initial Encounter 
Point(s) to discuss 
1. Acknowledge the patient’s reluctance to start statin therapy 

2. ESC/EAS 2019 guidelines recommend an LDL-cholesterol < 2.6 mmol/L (100 
mg/dL) 
3. Present the option of a natural supplement as an open-ended question 
4. The impact of the therapy will be assessed in two months 
Sample Conversation(s): 
“I understand that you are hesitant to start statin therapy. According to European 
guidelines, your LDL-cholesterol should be less than 2.6 mmol/L (100 mg/dL)to 
reduce your risk of a cardiovascular event. What is your opinion on trying a 
natural supplement to reduce your cholesterol?” 
If the patient agrees to red yeast rice extract 
“Let's follow up in two months to see if our LDL-cholesterol goals have been met” 
Intervention Group Initial Follow-up 
If LDL-cholesterol > 2.6 mmol/L (100 mg/dL) 
Point(s) to discuss 
1. Since the natural remedy did not work, we should switch to the statin to 
reduce cardiovascular events 
Sample Conversation(s): 
“Unfortunately, we were not able to meet our goals with the natural supplement. 
Because of this, let’s try the prescription medicine instead (atorvastatin 30mg 
nightly)” 
If LDL-cholesterol < 2.6 mmol/L (100 mg/dL) 
Point(s) to discuss 
1. 
The natural remedy did reduce your LDL-cholesterol to our original 
goal 
2. 
However, the effect of the natural remedy is unreliable over time 
due to lack of regulation 

3. 
Let’s switch to a bio-identical prescription medicine for reliability  
“Congratulations, we were able to meet our goal using a natural supplement. This 
supplement contains naturally occurring lovastatin; however it is difficult to 
predict the dose that you are receiving since supplements are not regulated. Let’s 
try a medium dose of lovastatin instead (20mg lovastatin nightly)”