<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01702987</url>
  </required_header>
  <id_info>
    <org_study_id>2012P000219</org_study_id>
    <nct_id>NCT01702987</nct_id>
  </id_info>
  <brief_title>Evaluation of Ubiquinol on Mitochondrial Oxidative Capacity in Statin Patients Using 31PMRS</brief_title>
  <official_title>Evaluation of Ubiquinol on the Association of Statins and Mitochondrial Oxidative Capacity Using 31P Magnetic Resonance Imaging</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Beth Israel Deaconess Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Beth Israel Deaconess Medical Center</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      It is our primary hypothesis that statin drugs impair skeletal muscle mitochondrial function&#xD;
      and that ubiquinol (the reduced active form of CoQ10) supplementation will block impairment&#xD;
      of PCr recovery kinetics in patients using statins. The investigators propose a pilot study&#xD;
      to extend our research to examine PCr recovery kinetics in 20 statin users randomized in a&#xD;
      parallel arm study to either ubiquinol or placebo over 4 weeks.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Synopsis: There are important gaps in our understanding of the pathogenesis and management of&#xD;
      statin-associated myalgia. Data suggest that statins block the production of CoQ10, an&#xD;
      essential component in electron transport during oxidative phosphorylation leading to&#xD;
      mitochondrial dysfunction. Preliminary data suggest that CoQ10 dietary supplements may&#xD;
      improve statin-associated muscle symptoms; however, correlation with plasma CoQ10 and&#xD;
      objective tests to assess statin-associated myalgia and response to treatment are lacking.&#xD;
&#xD;
      Phosphorus-31 magnetic resonance spectroscopy (31P-MRS) is unique in its ability to study,&#xD;
      continuously and non-invasively, the biochemical pathways for the supply and utilization of&#xD;
      energy in muscle. The post-exercise recovery rate of skeletal muscle phosphocreatine (PCr) is&#xD;
      a validated index of mitochondrial oxidative capacity in vivo. In a preliminary study, we&#xD;
      measured PCr recovery kinetics following exercise, using 31P-MRS before and after initiating&#xD;
      statin therapy and found that the return to metabolic equilibrium was longer after 4 weeks of&#xD;
      statin therapy, suggesting mitochondrial impairment. i&#xD;
&#xD;
      It is our primary hypothesis that statin drugs impair skeletal muscle mitochondrial function&#xD;
      and that ubiquinol supplementation will block impairment of PCr recovery kinetics in patients&#xD;
      using statins. We propose a pilot study to extend our research to examine PCr recovery&#xD;
      kinetics in 20 statin users randomized in a parallel arm study to either ubiquinol or placebo&#xD;
      over 4 weeks.&#xD;
&#xD;
      This study will include 10 individuals with statin myalgia on confirmed statin rechallenge (5&#xD;
      assigned to each arm), to be recruited from an ongoing clinical trial in which statin users&#xD;
      with suspected statin myalgia (based on clinical history) undergo an observed statin&#xD;
      re-challenge to confirm statin myalgia. Confirmation by re-challenge is important, as only&#xD;
      about one-third to one-half of those who report a clinical history of statin myalgia&#xD;
      demonstrate statin myalgia, confirmed by improvement of symptoms when statin is discontinued&#xD;
      and return of symptoms when undergoing an observed statin re-challenge. ii&#xD;
&#xD;
      Our team is unique in 1) having demonstrated the feasibility to perform 31P-MRS studies in&#xD;
      patients with hypercholesterolemia and 2) having access to individuals that have proven&#xD;
      statin myalgia on standardized observed statin-rechallenge. We believe that the data obtained&#xD;
      from this study will provide the critical data needed to support application to the NIH for a&#xD;
      full-scale clinical trial exploring the relationship between statin use, PCr recovery rate,&#xD;
      and ubiquinol therapy.&#xD;
&#xD;
      Aims:&#xD;
&#xD;
        1. o Aim: To compare the effects of ubiqunol on post exercise PCr recovery kinetics.&#xD;
&#xD;
           We hypothesize that statin users randomized to 300 mg of ubiquinol twice daily will&#xD;
           demonstrate shorter PCr recovery kinetics following exercise compared to statin users&#xD;
           randomized to placebo.&#xD;
&#xD;
        2. o Aims: To assess the association between plasma CoQ10 and 1) post exercise PCr recovery&#xD;
           kinetics and 2) inflammatory and vascular biomarkers We hypothesize that lower plasma&#xD;
           CoQ10 concentrations will be associated with longer PCr recovery kinetics and lower&#xD;
           inflammatory/vascular biomarkers.&#xD;
&#xD;
      Exploratory Aims: In each arm we aim to include 5 individuals with previously confirmed&#xD;
      statin myalgia on statin rechallenge and to explore differences among statin users with and&#xD;
      without statin myalgia. We will evaluate for trends to assess whether statin users with&#xD;
      previously confirmed statin myalgia show longer PCr recovery kinetics compared to statin&#xD;
      users without statin myalgia.&#xD;
&#xD;
      Study Design: A pilot randomized placebo-controlled double-blinded study (pre-post statin&#xD;
      use) comparing the effects of ubiquinol on post exercise PCr recovery kinetics over 4 weeks.&#xD;
&#xD;
      Background and Rationale Statins, HMG-CoA reductase inhibitors are generally safe; however,&#xD;
      myalgia (e.g., pain, cramping, muscle soreness and/or weakness) occurs in about 5% of users&#xD;
      iii,iv and can seriously impact quality of life and adherence to statin medications.&#xD;
      Furthermore, there are no objective, non-invasive method for assessing and tracking&#xD;
      mild-moderate muscle symptoms, which are most common and often occur without significant&#xD;
      muscle enzyme &quot;CK&quot; elevation. Muscle biopsy is used to assess severe myopathy and has been&#xD;
      used to evaluate statin myalgia without CK elevation, but is invasive, painful, and provides&#xD;
      only a single time point measurement.&#xD;
&#xD;
      In contrast to invasive muscle biopsy, 31P-MRS is a non-invasive and validated technique that&#xD;
      has been applied to study the metabolic processes in skeletal muscle in many muscle&#xD;
      applications and diseases.v,vi The rate of PCr recovery following exercise is an accepted&#xD;
      gold standard for measuring mitochondrial function.&#xD;
&#xD;
      We propose to apply 31P-MRS to the important problem of statin-associated myalgia to measure&#xD;
      the rate of PCr recovery following exercise in statin users before and after statin therapy&#xD;
      (with concurrent randomization to ubiquinol or placebo). Ultimately, we believe this work&#xD;
      could have an important impact on the care and management of those with statin myalgia by 1)&#xD;
      elucidating the relationship between muscle symptoms and mitochondrial function through a&#xD;
      quantifiable, validated and non-invasive biochemical index and 2) by determining the effects&#xD;
      of supplemental ubiquinol on mitochondrial function and muscle side effects in statin users.&#xD;
&#xD;
      Methods We will measure the rate of PCr resynthesis (the time constant of PCr recovery)&#xD;
      following a controlled exercise protocol that will recruit muscles in the lower leg. We will&#xD;
      evaluate muscle symptoms using a standardized questionnaire and measure muscle strength using&#xD;
      an ergometer that was designed to apply a controlled variable pressure to a foot pedal&#xD;
      through a pneumatic cylinder. We will perform baseline measurements after participants have&#xD;
      been taken off statin medications and CoQ10 supplements (if applicable) for at least 2 weeks.&#xD;
      Additionally, those with statin myalgia will have improvement of symptoms before baseline&#xD;
      measures are taken. Following baseline testing, statin therapy+ubiquinol or statin&#xD;
      therapy+placebo will be given to participants for 4 weeks. Repeat measurements will be&#xD;
      performed at 4 weeks to compare the effects of statins+placebo versus statin+ubiquinol on PCr&#xD;
      resynthesis. The primary outcome of this study will be the PCr recovery time constant. The&#xD;
      post-exercise PCr recovery measurements will be performed in our MRI research facility using&#xD;
      our dedicated 3T research MR scanner. Assessment of safety outcomes (CK, AST, ALT), and&#xD;
      physiological parameters (BP, HR, height and weight measured), and blood measures of lipids&#xD;
      and biomarkers (CRP, IL-6, TNF- α, E-selectin, VCAM-1, ICAM-1) will be collected on site and&#xD;
      analyzed at the Harvard Catalyst Clinical Research Center (CRC) Core laboratory. Analysis of&#xD;
      reduced and oxidized plasma CoQ10 will be performed at a qualified outside lab with a strong&#xD;
      track record of using validated methods.&#xD;
&#xD;
      Data Analysis Statistical Analysis: Each subject will have PCr concentration collected at the&#xD;
      following 2 time points: pre-statin (t1), and after 4-weeks of statin therapy (with ubiquinol&#xD;
      or placebo) (t2). At each of these time points, a series of measurements of PCr concentration&#xD;
      are collected. For each subject, we will estimate this parameter using maximum likelihood&#xD;
      estimation method. Thus we will obtain the point estimate and standard error for the time&#xD;
      constant parameter for each subject at each of the time points. We will compute the relative&#xD;
      percent change from baseline to post-statin (ubiquinol vs. placebo) time points and a linear&#xD;
      mixed effects model to obtain the estimate of the relative change from baseline and the&#xD;
      relative change between the post-statin time point. The linear mixed effects model, with the&#xD;
      compound symmetry structure for the variance-covariance matrix of the within-subject PCr&#xD;
      relative changes from baseline takes into account the within-subject correlation. The&#xD;
      estimation of the linear mixed-effects model will be done via restricted maximum likelihood&#xD;
      method. The PCr recovery time constant will be calculated using a monoexponential fit of PCr&#xD;
      versus time, beginning at exercise completion and will be compared between the groups.&#xD;
&#xD;
      Additional analyses will be performed to assess associations between plasma CoQ10 (adjusted&#xD;
      for LDL) and PCr data, inflammatory and vascular biomarkers, measured muscle strength (in&#xD;
      all), and reported symptoms (among those with statin myalgia).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>October 2012</start_date>
  <completion_date type="Actual">October 2013</completion_date>
  <primary_completion_date type="Actual">October 2013</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Diagnostic</primary_purpose>
    <masking>Triple (Participant, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Phosphocreatine Recovery</measure>
    <time_frame>1 month</time_frame>
    <description>Percentage change in phosphocreatine recovery from baseline to month as measured by 31PMRS is the primary outcome measure is a representative of mitochondrial oxidative capacity</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">22</enrollment>
  <condition>Myopathy</condition>
  <condition>HMG COA Reductase Inhibitor Adverse Reaction</condition>
  <condition>Hypercholesterolemia</condition>
  <arm_group>
    <arm_group_label>Statin + placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>9 patients taking statin medications and placebo.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Statin + ubiquinol</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>12 patients on statins and ubiquinol</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>ubiquinol</intervention_name>
    <description>ubiquinol supplementation was given for 1 month to 12 patients</description>
    <arm_group_label>Statin + ubiquinol</arm_group_label>
    <other_name>coenzyme Q10</other_name>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>placebo</intervention_name>
    <description>placebo (identical in appearance to ubiquinol) was given for 1 month to 9 patients</description>
    <arm_group_label>Statin + placebo</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>statin</intervention_name>
    <description>statin was given for 1 month to 21 patients</description>
    <arm_group_label>Statin + placebo</arm_group_label>
    <arm_group_label>Statin + ubiquinol</arm_group_label>
    <other_name>Simvastatin</other_name>
    <other_name>Atorvastatin</other_name>
    <other_name>Rosuvastatin</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Persons age 18 years and older who have been advised to use a statin medication by&#xD;
             their physician.&#xD;
&#xD;
          2. Up to ten individuals will have a history of statin myalgia on observed statin&#xD;
             rechallenge. All others will have a history (&gt;6 months) of tolerating a statin at a&#xD;
             standard starting dose or higher.&#xD;
&#xD;
          3. All persons will be able to cooperate for a period of 1-2 hours, able to provided&#xD;
             informed consent and have no known adverse effects or contraindications to an MRI&#xD;
             study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Having diabetes or known lower extremity peripheral vascular disease, as these&#xD;
             conditions may interfere with interpretation of the MRI spectroscopy of the lower&#xD;
             extremity (the only site we are examining in this study).&#xD;
&#xD;
          2. Current users of a statin with a recent heart attack, stroke, or revascularization&#xD;
             procedure (within the last 1 year) who could be at higher risk of stopping a statin.&#xD;
&#xD;
          3. Creatine kinase (CK) &gt; 5 x ULN. If CK levels are greater than 3 x ULN, the participant&#xD;
             will be given the option of returning for a repeat blood draw at their earliest&#xD;
             convenience. Any elevation in CK will be treated per the safety guidelines outlined in&#xD;
             section B5.&#xD;
&#xD;
          4. Alanine transferase (ALT) or aspartate transferase (AST) &gt; 3 x ULN. If ALT and/or AST&#xD;
             levels are greater than 3 x ULN, the participant will return for a repeat blood draw&#xD;
             at their earliest convenience. If the participant's ALT and/or AST is found elevated&#xD;
             at this repeat analysis, they will be withdrawn from the study. Any elevation in ALT&#xD;
             and/or AST will be treated per the safety guidelines outlined in section B5.&#xD;
&#xD;
          5. Severe uncontrolled medical problems or medications that may influence measurements or&#xD;
             impair ability to participate in the study exams (e.g. poorly controlled hypertension;&#xD;
             (&gt;170/&gt;100); known creatinine &gt; 2.5 md/dl or GFR &lt; 30; anemia with Hgb &lt; 10, etc.).&#xD;
&#xD;
          6. Pregnancy or breastfeeding (a contraindication for statin use)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jim S Wu, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Beth Israel Deaconess</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Beth Israel Deaconess Medical Center</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02215</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Wu JS, Buettner C, Smithline H, Ngo LH, Greenman RL. Evaluation of skeletal muscle during calf exercise by 31-phosphorus magnetic resonance spectroscopy in patients on statin medications. Muscle Nerve. 2011 Jan;43(1):76-81. doi: 10.1002/mus.21847.</citation>
    <PMID>21171098</PMID>
  </reference>
  <verification_date>February 2017</verification_date>
  <study_first_submitted>October 5, 2012</study_first_submitted>
  <study_first_submitted_qc>October 9, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 10, 2012</study_first_posted>
  <results_first_submitted>January 4, 2016</results_first_submitted>
  <results_first_submitted_qc>March 6, 2017</results_first_submitted_qc>
  <results_first_posted type="Actual">April 17, 2017</results_first_posted>
  <last_update_submitted>March 6, 2017</last_update_submitted>
  <last_update_submitted_qc>March 6, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">April 17, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Beth Israel Deaconess Medical Center</investigator_affiliation>
    <investigator_full_name>Jim S Wu</investigator_full_name>
    <investigator_title>Assistant Professor Department of Radiology</investigator_title>
  </responsible_party>
  <keyword>ubiquinol (coenzyme Q10)</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hypercholesterolemia</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Coenzyme Q10</mesh_term>
    <mesh_term>Atorvastatin</mesh_term>
    <mesh_term>Rosuvastatin Calcium</mesh_term>
    <mesh_term>Simvastatin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Statin + Placebo</title>
          <description>9 patients taking statin medications and placebo.&#xD;
placebo: placebo (identical in appearance to ubiquinol) was given for 1 month to 9 patients&#xD;
statin: statin was given for 1 month to 21 patients</description>
        </group>
        <group group_id="P2">
          <title>Statin + Ubiquinol</title>
          <description>12 patients on statins and ubiquinol&#xD;
ubiquinol: ubiquinol supplementation was given for 1 month to 12 patients&#xD;
statin: statin was given for 1 month to 21 patients</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="10"/>
                <participants group_id="P2" count="12"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="9"/>
                <participants group_id="P2" count="12"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Statin + Placebo</title>
          <description>9 patients taking statin medications and placebo.&#xD;
placebo: placebo (identical in appearance to ubiquinol) was given for 1 month to 9 patients&#xD;
statin: statin was given for 1 month to 21 patients</description>
        </group>
        <group group_id="B2">
          <title>Statin + Ubiquinol</title>
          <description>12 patients on statins and ubiquinol&#xD;
ubiquinol: ubiquinol supplementation was given for 1 month to 12 patients&#xD;
statin: statin was given for 1 month to 21 patients</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="10"/>
            <count group_id="B2" value="12"/>
            <count group_id="B3" value="22"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="22"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="51" spread="12"/>
                    <measurement group_id="B2" value="53" spread="7"/>
                    <measurement group_id="B3" value="52" spread="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="10"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="12"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="22"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Phosphocreatine Recovery</title>
        <description>Percentage change in phosphocreatine recovery from baseline to month as measured by 31PMRS is the primary outcome measure is a representative of mitochondrial oxidative capacity</description>
        <time_frame>1 month</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Statin + Placebo</title>
            <description>9 patients taking statin medications and placebo.&#xD;
placebo: placebo (identical in appearance to ubiquinol) was given for 1 month to 9 patients&#xD;
statin: statin was given for 1 month to 21 patients</description>
          </group>
          <group group_id="O2">
            <title>Statin + Ubiquinol</title>
            <description>12 patients on statins and ubiquinol&#xD;
ubiquinol: ubiquinol supplementation was given for 1 month to 12 patients&#xD;
statin: statin was given for 1 month to 21 patients</description>
          </group>
        </group_list>
        <measure>
          <title>Phosphocreatine Recovery</title>
          <description>Percentage change in phosphocreatine recovery from baseline to month as measured by 31PMRS is the primary outcome measure is a representative of mitochondrial oxidative capacity</description>
          <units>percentage change from baseline</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="9"/>
                <count group_id="O2" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-18.9" spread="137"/>
                    <measurement group_id="O2" value="7.7" spread="38"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>1 month</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Statin + Ubiquinol</title>
          <description>12 patients on statins and ubiquinol&#xD;
ubiquinol: ubiquinol supplementation was given for 1 month to 12 patients&#xD;
statin: statin was given for 1 month to 21 patients</description>
        </group>
        <group group_id="E2">
          <title>Statin + Placebo</title>
          <description>9 patients taking statin medications and placebo.&#xD;
placebo: placebo (identical in appearance to ubiquinol) was given for 1 month to 9 patients&#xD;
statin: statin was given for 1 month to 21 patients</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Jim Wu</name_or_title>
      <organization>Beth Israel Deaconess Medical Center</organization>
      <phone>617-754-2390</phone>
      <email>jswu@bidmc.harvard.edu</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01702987
org study id: 2012P000219
nct id: NCT01702987
lead sponsor: 
has dmc: No
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.
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).
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Diagnostic
masking: Triple (Participant, Investigator, Outcomes Assessor)
measure: Phosphocreatine Recovery
time frame: 1 month
description: Percentage change in phosphocreatine recovery from baseline to month as measured by 31PMRS is the primary outcome measure is a representative of mitochondrial oxidative capacity
arm group label: Statin + placebo
arm group type: Placebo Comparator
description: 9 patients taking statin medications and placebo.
arm group label: Statin + ubiquinol
arm group type: Active Comparator
description: 12 patients on statins and ubiquinol
intervention type: Dietary Supplement
intervention name: ubiquinol
description: ubiquinol supplementation was given for 1 month to 12 patients
arm group label: Statin + ubiquinol
other name: coenzyme Q10
intervention type: Dietary Supplement
intervention name: placebo
description: placebo (identical in appearance to ubiquinol) was given for 1 month to 9 patients
arm group label: Statin + placebo
intervention type: Drug
intervention name: statin
description: statin was given for 1 month to 21 patients
arm group label: Statin + placebo
arm group label: Statin + ubiquinol
other name: Simvastatin
other name: Atorvastatin
other name: Rosuvastatin
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: Jim S Wu, MD
role: Principal Investigator
affiliation: Beth Israel Deaconess
facility: 
country: United States
citation: Wu JS, Buettner C, Smithline H, Ngo LH, Greenman RL. Evaluation of skeletal muscle during calf exercise by 31-phosphorus magnetic resonance spectroscopy in patients on statin medications. Muscle Nerve. 2011 Jan;43(1):76-81. doi: 10.1002/mus.21847.
PMID: 21171098
responsible party type: Principal Investigator
investigator affiliation: Beth Israel Deaconess Medical Center
investigator full name: Jim S Wu
investigator title: Assistant Professor Department of Radiology
mesh term: Hypercholesterolemia
mesh term: Coenzyme Q10
mesh term: Atorvastatin
mesh term: Rosuvastatin Calcium
mesh term: Simvastatin
sharing ipd: No
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 