E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Asymp and symp statin users will undergo baseline measurements of skeletal muscle mitochondrial function and muscle function after which they will be switched to a single-blind placebo intervention for 12 weeks. Then the same measurements will be repeated. Hereafter, only the symptomatic statin users will continue with the intervention en will be randomely allocated to: atorvastatin, atorvastin+exercise or placebo+exercise for another 12 weeks. Then the same measurements will be repeated again. |
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E.1.1.1 | Medical condition in easily understood language |
skeletal muscle side effects of statin use |
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E.1.1.2 | Therapeutic area | Body processes [G] - Metabolic Phenomena [G03] |
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 |
•Do statins accumulate in muscle and cause inhibition of complex III activity of the mitochondrial respiratory chain ?
•Is the severity of the muscle function decline determined by the total statin concentration in muscle, as well as by the pharmacokinetic properties of the statin?
•Could aerobic exercise training on top of statin treatment offer protection against statin-associated muscle symptoms by positively influencing muscle metabolism?
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E.2.2 | Secondary objectives of the trial |
• Can we identify clinically relevant predictive parameters that could facilitate the diagnosis of Statin-associated muscle symptoms in clinical practice (e.g. plasma markers, muscle function, muscle gene expression, whole body energy metabolism)? |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
age: 18-70 years old
current statin users
mentally able/allowed to give informed consent |
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E.4 | Principal exclusion criteria |
familial hypercholesterolemia
impaired liver function
hereditary muscle defect
kidney insufficiency
unwillingness to abstain from grapefruit juice during the intervention |
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E.5 End points |
E.5.1 | Primary end point(s) |
o Energy generating capacity of muscle mitochondria (in muscle biopsy)
(see ex vivo measurement in 8.3 study procedures for the detailed biochemical assays that will be carried out in the fresh muscle tissue).
o Muscle function (= muscle force, contractile speed, relaxation and
fatigability)
o Cardiorespiratory fitness (incremental cycling test)
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
baseline (in both symptomatic and asymptomatic statin users);
at12 weeks: after a 12-week single-blind placebo intervention (in both symptomatic and asymptomatic statin users);
after 24 weeks: after a subsequent 12 weeks of double-blind randomized intervention with atorvastatin, atorvastatin+exercise or placebo+exercise in symptomatic statin users only |
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E.5.2 | Secondary end point(s) |
o Mitochondrial number (in muscle biopsy)
o Blood parameters: lipid profile (total cholesterol, HDL-, LDL-cholesterol,
triglycerides), liver enzymes (ASAT, ALAT, gamma-GT), kidney function (creatinin), creatine kinase, WBC count, pyruvate and lactate
o Statin concentrations in the muscle and blood
o Questionnaires on muscle complaints (Short-form McGill pain questionnaire
and Short-form Brief Pain Inventory)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Mitochondrial number: baseline, 12 weeks, 24 weeks
blood parameters, statin concentrations, questionnaires: every three weeks |
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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 | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
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 | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
combination of single blind and double blind intervention |
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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 | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 4 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
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 | No |
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 | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |