Evaluation of Ubiquinol on Mitochondrial Oxidative Capacity in Statin Patients Using 31PMRS
Condition: Myopathy; HMG COA Reductase Inhibitor Adverse Reaction; Hypercholesterolemia
MeSH terms: Hypercholesterolemia
Study type: Interventional

Summary: 
      It is our primary hypothesis that statin drugs impair skeletal muscle mitochondrial function
      and that ubiquinol (the reduced active form of CoQ10) supplementation will block impairment
      of PCr recovery kinetics in patients using statins. The investigators propose a pilot study
      to extend our research to examine PCr recovery kinetics in 20 statin users randomized in a
      parallel arm study to either ubiquinol or placebo over 4 weeks.
    

Detailed description: 
      Synopsis: There are important gaps in our understanding of the pathogenesis and management of
      statin-associated myalgia. Data suggest that statins block the production of CoQ10, an
      essential component in electron transport during oxidative phosphorylation leading to
      mitochondrial dysfunction. Preliminary data suggest that CoQ10 dietary supplements may
      improve statin-associated muscle symptoms; however, correlation with plasma CoQ10 and
      objective tests to assess statin-associated myalgia and response to treatment are lacking.

      Phosphorus-31 magnetic resonance spectroscopy (31P-MRS) is unique in its ability to study,
      continuously and non-invasively, the biochemical pathways for the supply and utilization of
      energy in muscle. The post-exercise recovery rate of skeletal muscle phosphocreatine (PCr) is
      a validated index of mitochondrial oxidative capacity in vivo. In a preliminary study, we
      measured PCr recovery kinetics following exercise, using 31P-MRS before and after initiating
      statin therapy and found that the return to metabolic equilibrium was longer after 4 weeks of
      statin therapy, suggesting mitochondrial impairment. i

      It is our primary hypothesis that statin drugs impair skeletal muscle mitochondrial function
      and that ubiquinol supplementation will block impairment of PCr recovery kinetics in patients
      using statins. We propose a pilot study to extend our research to examine PCr recovery
      kinetics in 20 statin users randomized in a parallel arm study to either ubiquinol or placebo
      over 4 weeks.

      This study will include 10 individuals with statin myalgia on confirmed statin rechallenge (5
      assigned to each arm), to be recruited from an ongoing clinical trial in which statin users
      with suspected statin myalgia (based on clinical history) undergo an observed statin
      re-challenge to confirm statin myalgia. Confirmation by re-challenge is important, as only
      about one-third to one-half of those who report a clinical history of statin myalgia
      demonstrate statin myalgia, confirmed by improvement of symptoms when statin is discontinued
      and return of symptoms when undergoing an observed statin re-challenge. ii

      Our team is unique in 1) having demonstrated the feasibility to perform 31P-MRS studies in
      patients with hypercholesterolemia and 2) having access to individuals that have proven
      statin myalgia on standardized observed statin-rechallenge. We believe that the data obtained
      from this study will provide the critical data needed to support application to the NIH for a
      full-scale clinical trial exploring the relationship between statin use, PCr recovery rate,
      and ubiquinol therapy.

      Aims:

        1. o Aim: To compare the effects of ubiqunol on post exercise PCr recovery kinetics.

           We hypothesize that statin users randomized to 300 mg of ubiquinol twice daily will
           demonstrate shorter PCr recovery kinetics following exercise compared to statin users
           randomized to placebo.

        2. o Aims: To assess the association between plasma CoQ10 and 1) post exercise PCr recovery
           kinetics and 2) inflammatory and vascular biomarkers We hypothesize that lower plasma
           CoQ10 concentrations will be associated with longer PCr recovery kinetics and lower
           inflammatory/vascular biomarkers.

      Exploratory Aims: In each arm we aim to include 5 individuals with previously confirmed
      statin myalgia on statin rechallenge and to explore differences among statin users with and
      without statin myalgia. We will evaluate for trends to assess whether statin users with
      previously confirmed statin myalgia show longer PCr recovery kinetics compared to statin
      users without statin myalgia.

      Study Design: A pilot randomized placebo-controlled double-blinded study (pre-post statin
      use) comparing the effects of ubiquinol on post exercise PCr recovery kinetics over 4 weeks.

      Background and Rationale Statins, HMG-CoA reductase inhibitors are generally safe; however,
      myalgia (e.g., pain, cramping, muscle soreness and/or weakness) occurs in about 5% of users
      iii,iv and can seriously impact quality of life and adherence to statin medications.
      Furthermore, there are no objective, non-invasive method for assessing and tracking
      mild-moderate muscle symptoms, which are most common and often occur without significant
      muscle enzyme "CK" elevation. Muscle biopsy is used to assess severe myopathy and has been
      used to evaluate statin myalgia without CK elevation, but is invasive, painful, and provides
      only a single time point measurement.

      In contrast to invasive muscle biopsy, 31P-MRS is a non-invasive and validated technique that
      has been applied to study the metabolic processes in skeletal muscle in many muscle
      applications and diseases.v,vi The rate of PCr recovery following exercise is an accepted
      gold standard for measuring mitochondrial function.

      We propose to apply 31P-MRS to the important problem of statin-associated myalgia to measure
      the rate of PCr recovery following exercise in statin users before and after statin therapy
      (with concurrent randomization to ubiquinol or placebo). Ultimately, we believe this work
      could have an important impact on the care and management of those with statin myalgia by 1)
      elucidating the relationship between muscle symptoms and mitochondrial function through a
      quantifiable, validated and non-invasive biochemical index and 2) by determining the effects
      of supplemental ubiquinol on mitochondrial function and muscle side effects in statin users.

      Methods We will measure the rate of PCr resynthesis (the time constant of PCr recovery)
      following a controlled exercise protocol that will recruit muscles in the lower leg. We will
      evaluate muscle symptoms using a standardized questionnaire and measure muscle strength using
      an ergometer that was designed to apply a controlled variable pressure to a foot pedal
      through a pneumatic cylinder. We will perform baseline measurements after participants have
      been taken off statin medications and CoQ10 supplements (if applicable) for at least 2 weeks.
      Additionally, those with statin myalgia will have improvement of symptoms before baseline
      measures are taken. Following baseline testing, statin therapy+ubiquinol or statin
      therapy+placebo will be given to participants for 4 weeks. Repeat measurements will be
      performed at 4 weeks to compare the effects of statins+placebo versus statin+ubiquinol on PCr
      resynthesis. The primary outcome of this study will be the PCr recovery time constant. The
      post-exercise PCr recovery measurements will be performed in our MRI research facility using
      our dedicated 3T research MR scanner. Assessment of safety outcomes (CK, AST, ALT), and
      physiological parameters (BP, HR, height and weight measured), and blood measures of lipids
      and biomarkers (CRP, IL-6, TNF- α, E-selectin, VCAM-1, ICAM-1) will be collected on site and
      analyzed at the Harvard Catalyst Clinical Research Center (CRC) Core laboratory. Analysis of
      reduced and oxidized plasma CoQ10 will be performed at a qualified outside lab with a strong
      track record of using validated methods.

      Data Analysis Statistical Analysis: Each subject will have PCr concentration collected at the
      following 2 time points: pre-statin (t1), and after 4-weeks of statin therapy (with ubiquinol
      or placebo) (t2). At each of these time points, a series of measurements of PCr concentration
      are collected. For each subject, we will estimate this parameter using maximum likelihood
      estimation method. Thus we will obtain the point estimate and standard error for the time
      constant parameter for each subject at each of the time points. We will compute the relative
      percent change from baseline to post-statin (ubiquinol vs. placebo) time points and a linear
      mixed effects model to obtain the estimate of the relative change from baseline and the
      relative change between the post-statin time point. The linear mixed effects model, with the
      compound symmetry structure for the variance-covariance matrix of the within-subject PCr
      relative changes from baseline takes into account the within-subject correlation. The
      estimation of the linear mixed-effects model will be done via restricted maximum likelihood
      method. The PCr recovery time constant will be calculated using a monoexponential fit of PCr
      versus time, beginning at exercise completion and will be compared between the groups.

      Additional analyses will be performed to assess associations between plasma CoQ10 (adjusted
      for LDL) and PCr data, inflammatory and vascular biomarkers, measured muscle strength (in
      all), and reported symptoms (among those with statin myalgia).
    

Intervention name(s): ubiquinol; placebo; statin
Intervention type(s): Dietary Supplement; Dietary Supplement; Drug
Intervention description(s): ubiquinol supplementation was given for 1 month to 12 patients; placebo (identical in appearance to ubiquinol) was given for 1 month to 9 patients; statin was given for 1 month to 21 patients
Other intervention name(s): coenzyme Q10; Simvastatin; Atorvastatin; Rosuvastatin
Intervention MeSH terms: Coenzyme Q10; Atorvastatin; Rosuvastatin Calcium; Simvastatin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Diagnostic
Keywords: ubiquinol (coenzyme Q10)