Coronary heart disease patients With perceived statin Associated muscle symptoms or statin discontinuaton due to muscle symptoms
Conditions
Interventions
Trade Name: atorvastatin
Product Name: atorvastatin
Pharmaceutical Form: Tablet
Sponsors
Vestre Viken Trust
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: -First or recurrent diagnosis (myocardial infarction) or treatments (PCI or CABG) for a CHD event 6-36 months prior to study start and prescribed atorvastatin. -Self-reported muscle complaints (i.e. pain, weakness, tenderness, stiffness or cramp to the body of any intensity) that they attribute to atorvastatin therapy at study inclusion • Self-reported muscle complaints that has led to atorvastatin discontinuation at study inclusion -previous participation in the MUSE trial (eudract no 2018-004261-14) Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 15 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 15
Exclusion criteria
Exclusion criteria: • First or recurrent diagnosis (myocardial infarction) or treatments (PCI or CABG) for a CHD event the past 12 months prior to study start in high risk patients (i.e. at least one of following comorbid conditions: systolic heart failure, >1 previous myocardial infarction, kidney failure, diabetes, and smokers) • First or recurrent diagnosis (myocardial infarction) or treatments (PCI or CABG) for a CHD event the past 6 months prior to study start in low risk patients without any of the co-morbid conditions mentioned above and in patients who are not taking a statin at all • Patients with residual stenosis on the major coronary arteries that were not revascularized at the time of the index event, patents with symptomatic peripheral artery disease and patients with familial hypercholesterolemia • Patient has any contraindications for atorvastatin listed in the Summary of Product Characteristics (i.e. known hypersensitivity to the ingredients, acute liver failure/ ALT > 3 times upper limit of the normal range in blood at study start, pregnancy and breastfeeding ) • History of previous rhabdomyolysis, myopathy or liver failure due to statin treatment with CK > 10 times upper limit of the normal range or ALT > 3 times upper limit of the normal range. • Any condition (e.g. psychiatric illness, dementia) or situation, that in the investigator’s opinion could put the subject at significant risk, confound the study results, interfere significantly with the subject participation in the study, or rendering informed consent unfeasible • Short life expectancy due to other medical conditions • Not being able to understand Norwegian. • Women of childbearing potential defined as a premenopausal female capable of becoming pregnant. • Participation in another randomized clinical trial
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective is to develop an accurate diagnostic test that can be used in clinical practice to differentiate true statin associated muscle symptoms (SAMS) and non-SAMS (i.e. muscle symptoms not related to the atorvastatin treatment) among coronary heart disease patients with self-perceived SAMS, thereby allowing efficient diagnostics and actions to prevent future cardiovascular events. ;Secondary Objective: The key secondary objectives are: - To determine the relationship between SAMS and atorvastatin lactone metabolites in skeletal muscle, and to evaluate the metabolite concentrations in muscle as a diagnostic tool for true SAMS. - To determine the relationship between SAMS and inhibition of the mevalonate pathway in skeletal muscle, and to evaluate the concentration of mevalonate pathway intermediates in muscle as a diagnostic tool for true SAMS. -To determine the relationship between SAMS and inhibition of mitochondrial function in skeletal muscle, and to evaluate the use of mitochondrial respiratory enzymes in muscle as a diagnostic tool for true SAMS. ;Primary end point(s): The primary end-point will be assessed by the individual mean difference in muscular symptom intensity between treatment periods with statin and placebo, reported by the patients over the last three weeks (i.e. week 4-7) measured with aggregated Visual Analogue Scale (VAS) scores ;Timepoint(s) of evaluation of this end point: At study start, during the 7x2 weeks treatment period and at study end | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Assessment of the secondary study end-points will be ascertained through the self-reported diary and blood samples collected at baseline, during the treatment periods, and at study-end : - Levels of atorvastatin and its metabolites in muscle tissure, blood plasma and white blood cells. - Levels of the following mevalonate pathway intermediates in muscle, blood plasma and PBMC: Mevalonate, farnesyl-PP and geranylgeranyl-PP (calculated as the atorvastatin-mediated reduction [i.e. relative difference between on and off statin], and as the absolute Levels - Levels of the following Target protein in muscle and PBMC: The HMGCR protein expression, the ratio HMGCR protein / atorvastatin total sum, the HMGCR protein / atorvastatin lactone metabolites, the HMGCR protein / atorvastatin acid metabolites (calculated as the absolute levels) - Levels of the following enzymes in the mitochondrial respiratory chain in muscle and PBMC: The enzyme activity and protein expression of Complex I, II, III, IV and IV (calculated as the atorvastatin-mediated reduction [i.e. relative difference between on and off statin], and as the absolute levels) - Levels of the following combined target protein expression and drug: the ratio Complex III protein / atorvastatin total sum, the Complex III protein / atorvastatin lactone metabolites, the Complex III protein / atorvastatin acid metabolites (calculated as the absolute levels) - Levels of apoptosis biomarkers in muscle: Caspase-3, Bad, Bak, Bax, Bax/Bcl-2 dimer, Bcl-xL, Bcl-xL/Bak dimer, Smac, calpain activity (calculated as the atorvastatin-mediated alteration [i.e. relative difference between on and off statin], and as the absolute levels) - Statin adherence measured with indirect (self-reported questionnaires and pill counts of returned packages) and direct (liquid chromatography-tandem mass spectrometry) methods. ;Timepoint(s) of evaluation of this end point: After each 7 weeks treatment period | — |
Countries
Norway
Contacts
Public Contactjohn Munkhaugen
Vestre Viken Trust
Outcome results
None listed