E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Coronary heart disease patients With perceived statin Associated muscle symptoms or statin discontinuaton due to muscle symptoms |
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E.1.1.1 | Medical condition in easily understood language |
Coronary heart disease patients who report muscle symptoms during treatment with atorvastatin or who have stopped taking their atorvastatin pill due to muscle symptoms |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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. |
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E.2.2 | Secondary objectives of the trial |
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.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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) |
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E.4 | Principal 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 |
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E.5 End points |
E.5.1 | 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 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
At study start, during the 7x2 weeks treatment period and at study end |
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E.5.2 | 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.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
After each 7 weeks treatment period |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Yes |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | No |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | Yes |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
open prospecitve non randomized intervention study |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |