The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial registered on ANZCTR


Registration number
ACTRN12618000660280
Ethics application status
Approved
Date submitted
19/04/2018
Date registered
24/04/2018
Date last updated
12/03/2020
Date data sharing statement initially provided
28/03/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Natural products to lower cholesterol
Scientific title
Nutraceuticals in the management of statin associated muscle symptoms (SAMS) in statin-intolerant participants.
Secondary ID [1] 294652 0
VG101861
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
cardiovascular disease 307494 0
statin intolerance 307495 0
hyperlipidemia 307496 0
Condition category
Condition code
Cardiovascular 306581 306581 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Randomsied, double-blind, placebo controlled trial. Three interventional arms and 1 placebo/comparator arm. Participants are randomised to one treatment arm only and study is parallel in design.
Arm 1: Ezetrol 10mg taken once daily for 8 weeks via oral tablet + Nutraceutical Placebo once daily for 8 weeks via oral tablets.
Arm 2: Nutraceutical containing: 500mg Berberine (berberine hydrochloride) + 200mg Red Yeast Rice (equivalent to 3mg Monacolin K) + 2g Plant Sterols taken once daily for 8 weeks via oral tablets + Ezetrol Placebo taken once daily for 8 weeks via oral tablet
Arm 3: Ezetrol 10mg taken once daily for 8 weeks via oral tablet + Nutraceutical containing: 500mg Berberine (berberine hydrochloride) + 200mg Red Yeast Rice (equivalent to 3mg Monacolin K) + 2g Plant Sterols taken once daily for 8 weeks via oral tablets
Arm 4: Ezetrol Placebo taken once daily for 8 weeks via oral tablet + Nutraceutical Placebo taken once daily for 8 weeks via oral tablets
For additional notes on placebo tablets, please see section below.

Compliance will be monitored via drug tablet return.
Intervention code [1] 300949 0
Treatment: Drugs
Comparator / control treatment
Ezetrol is usual care for this population, so this also acts as a comparator treatment, however we are also investigating the effect of the Ezetrol/Nutraceutical combination. The fourth arm will be a control placebo group with no active comparator or interventional treatment. There will be matching placebos for the Ezetrol and Nutraceutracals. The placebo tablets will be identical in appearance to their active counterparts and contain Avicel (microcrystalline cellulose).
Control group
Placebo

Outcomes
Primary outcome [1] 305577 0
Change in lipid profile (total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglycerides) as assessed via fasting blood sample following a 12 hour fast.
Timepoint [1] 305577 0
Baseline, 4 weeks and 8 weeks (primary timepoint) after intervention commencement.
Secondary outcome [1] 345810 0
Development of side effects as assessed by plasma creatinine kinase measures as an indication of myopathy.
Timepoint [1] 345810 0
Baseline, 4 weeks and 8 weeks after intervention commencement.
Secondary outcome [2] 345811 0
Perceived quality of life as assessed by the validated EQUAL quality of life questionnaire.
Timepoint [2] 345811 0
Baseline and 8 weeks after intervention commencement.

Eligibility
Key inclusion criteria
Patients who are intolerant to statins and not currently achieving lipid targets (fasting LDL-c >1.8 mmol/L and <7 mmol/L). Statin intolerance will be defined as an inability to tolerate 2 or more statins, one at a low dose, due to an adverse safety effect that started or increased during statin therapy and resolved or improved when statin therapy was discontinued. Low dose statin therapy is defined as an average daily dose of rosuvastatin 5mg, atorvastatin 10mg, simvastatin 10mg, lovastatin 20mg, pravastatin 40mg, fluvastatin 40mg or pitavastatin 2mg. Patients tolerating very low dose statin therapy (rosuvastatin <5mg, atorvastatin <10mg, simvastatin <10mg, lovastatin <20mg, pravastatin <40mg, fluvastatin <40mg or pitavastatin <2mg) are considered to be intolerant to that low dose statin.
Minimum age
30 Years
Maximum age
70 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Participants with pre-existing coronary artery disease (calcium score >0, previous coronary event) who are currently taking Ezetimibe or other cholesterol-lowering medication
- No documented statin intolerance
- Abnormal biochemistry at screening suggestive of an additional underlying cause of statin intolerance
- Pregnant or lactating women
- Inability to provide informed written consent.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation via numbered containers.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomization using a randomization table generated by computer software.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Efficacy
Statistical methods / analysis
The primary outcome is a reduction in LDL cholesterol. This will be assessed using a maximum-likelihood random effect mixed regression model for main effects and intergroup comparison by mixed models with Bonferroni adjustment. All analysis will be performed at the completion of the trial on an intention to treat basis. Participants who withdraw from the study will be replaced. Sample size calculations are based on assumptions made on the primary outcome, reduction in LDL cholesterol levels. With 80 participants, this 2-by-2 factorial study is powered for a 0.8 mmol/L reduction in LDL cholesterol with either the nutraceutical or ezetimibe (ezetrol) intervention. It is expected that the combination nutraceutical and ezetimibe (ezetrol) treatments will be additive in their effects on LDL cholesterol. The level of significance is p<0.05.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 10751 0
Royal Perth Hospital - Perth
Recruitment postcode(s) [1] 22477 0
6000 - Perth

Funding & Sponsors
Funding source category [1] 299266 0
Charities/Societies/Foundations
Name [1] 299266 0
National Heart Foundation of Australia
Address [1] 299266 0
Heart Foundation WA Division
PO Box 1133, Subiaco WA 6904
Country [1] 299266 0
Australia
Primary sponsor type
University
Name
Curtin University
Address
Kent Street, Bentley WA 6102
Country
Australia
Secondary sponsor category [1] 298537 0
None
Name [1] 298537 0
N/A
Address [1] 298537 0
N/A
Country [1] 298537 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300181 0
Royal Perth Hospital Human Research Ethics Comittee
Ethics committee address [1] 300181 0
Ground Floor, Kirkman House Royal Perth Hospital Wellington Street, PERTH WA 6000,
Ethics committee country [1] 300181 0
Australia
Date submitted for ethics approval [1] 300181 0
Approval date [1] 300181 0
17/04/2018
Ethics approval number [1] 300181 0
RGS0000000891

Summary
Brief summary
This project will investigate the role of natural plant and food-derived compounds (nutraceuticals) and their ability to lower cholesterol levels in high-risk patients who are unable to take standard statin therapy due to side effects. It is expected that a combination of natural compounds with known cholesterol lowering ability will reduce cholesterol levels in this high-risk population. When taken in conjunction with non-statin pharmacotherapy, these natural compounds will offer additional benefits, including additive reduction in cholesterol levels. In addition to helping these patients achieve cholesterol targets, these natural compounds will prevent the development of side effects associated with statin use, leading to greater adherence to their medication regime and an overall reduction in the risk of heart disease. Given the prevelance of heart disease within the Australian population and the need to identify alternative treatment options to lower cholesterol, the findings of this study will have enormous significance and translation potential for clinical practice.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 82818 0
Dr Natalie Ward
Address 82818 0
School of Public Health
Curtin University
Kent Street
Bentley WA 6102
Country 82818 0
Australia
Phone 82818 0
+61 8 92664188
Fax 82818 0
Email 82818 0
natalie.ward@curtin.edu.au
Contact person for public queries
Name 82819 0
Dr Natalie Ward
Address 82819 0
School of Public Health
Curtin University
Kent Street
Bentley WA 6102
Country 82819 0
Australia
Phone 82819 0
+61 8 92664188
Fax 82819 0
Email 82819 0
natalie.ward@curtin.edu.au
Contact person for scientific queries
Name 82820 0
Dr Natalie Ward
Address 82820 0
School of Public Health
Curtin University
Kent Street
Bentley WA 6102
Country 82820 0
Australia
Phone 82820 0
+61 8 92664188
Fax 82820 0
Email 82820 0
natalie.ward@curtin.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
No other documents available
Summary results
No Results