<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/NCT04507373</url>
  </required_header>
  <id_info>
    <org_study_id>STU 072016-015</org_study_id>
    <nct_id>NCT04507373</nct_id>
  </id_info>
  <brief_title>7T Magnetic Resonance Spectroscopy and Skeletal Muscle Biopsy Findings in Statin Associated Adverse Muscle Events</brief_title>
  <official_title>7T Magnetic Resonance Spectroscopy and Skeletal Muscle Biopsy Findings in Statin</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Texas Southwestern Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Texas Southwestern Medical Center</source>
  <oversight_info>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Over 40 million Americans take statins to reduce their risk of atherosclerotic cardiovascular&#xD;
      disease (ASCVD). Unfortunately, 10 to 20% stop taking them due to statin-associated muscle&#xD;
      symptoms (e.g. pain, aches, weakness, cramps, or stiffness) (1, 2). The pathophysiology of&#xD;
      these statin-associated muscle symptoms (SAMS) has remained elusive. Consequently, no&#xD;
      objective diagnostic method exists, causing confusion for patient and providers since muscle&#xD;
      symptoms can often be multifactorial.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The overall objectives of this project are to identify the underlying cause of SAMS and&#xD;
      establish an in-vivo imaging technique to detect SAMS. The central hypothesis of this&#xD;
      pro-posal is that statins directly inhibit mitochondrial function in SAMS patients. Our&#xD;
      rationale is based on our own preliminary data indicating that simvastatin - the most common&#xD;
      statin to cause SAMS - can directly inhibit oxidative phosphorylation (OXPHOS) in mice. Since&#xD;
      such changes can be detected in vivo in humans utilizing 31P magnetic resonance spectroscopy&#xD;
      (MRS) techniques, the investigators will use a state-of-the art 7 Tesla (7T) MRS instrument&#xD;
      to study the so-leus muscles of SAMS patients. Additionally, the investigators will validate&#xD;
      the MRS findings by doing func-tional studies in muscle biopsy specimens.&#xD;
&#xD;
      The investigators propose double-blind randomized, placebo-controlled pilot study in 15 SAMS&#xD;
      pa-tients and 15 controls. Study participants will be treated with simvastatin 40 mg daily or&#xD;
      place-bo for 10 weeks. The investigators will perform 7T MRS of soleus muscles at&#xD;
      randomization and either at first complaint of muscle symptoms or at the end of 10 weeks if&#xD;
      no muscle symptoms occur, whichever occurs first. Quadriceps muscle biopsies will also be&#xD;
      done immediately following the second MRS scan.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    No grant obtained. Enrolled participants were not assigned to the intervention and was study&#xD;
    terminated&#xD;
  </why_stopped>
  <start_date type="Actual">August 17, 2018</start_date>
  <completion_date type="Actual">December 20, 2021</completion_date>
  <primary_completion_date type="Actual">December 20, 2021</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
    <masking_description>Double Blind</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>The Mitochondrial Changes In Muscles During Statin Use</measure>
    <time_frame>10 weeks</time_frame>
    <description>Study participants being treated with Simvastatin 40mg daily, or placebo for 10 weeks. Investigators will isolate mitochondrial from muscle biopsy sample and compare mitochondrial oxygen consumption rates, ultrastructural changes, and gene expression</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">3</enrollment>
  <condition>Muscle Cramp</condition>
  <condition>Ache</condition>
  <condition>Weakness, Muscle</condition>
  <condition>Statin Adverse Reaction</condition>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Following the baseline period, subject will be randomized to receive either simvastatin or an identical placebo at a dose of 40 mg/day for a period of 10 weeks.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Simvastatin 40mg</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Following the baseline period, subject will be randomized to receive either simvastatin or an identical placebo at a dose of 40 mg/day for a period of 10 weeks.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Simvastatin 40mg</intervention_name>
    <description>40mg oral daily for 10 weeks</description>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_label>Simvastatin 40mg</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion&#xD;
&#xD;
        • Adults, age &gt; 18 ys or &lt; 80 yrs. Patients reporting complaints of statin-associated&#xD;
        muscle symptoms, aches, weakness, cramps, or stiffness in the legs.&#xD;
&#xD;
        Exclusion Criteria&#xD;
&#xD;
          -  Patient who drink large quantities of grapefruit juice (&gt; 1 quart daily).&#xD;
&#xD;
          -  Patients on the following drugs for which the FDA has issued restrictions for using&#xD;
             simvastatin 40 mg daily do to an increased risk of severe muscle injury such as&#xD;
             itraconazole, posaconazole, ketoconazole, erythromycin, clarithromycin, telithromycin,&#xD;
             HIV-1 protease inhibitors, nefazodone, gemfibrozil, cyclosporine, danazol, amiodarone,&#xD;
             amlodipine, ranolazine, and verapamil.&#xD;
&#xD;
          -  Patients with muscle-related pain that is not related to statin-use (e.g. muscle aches&#xD;
             from strain or trauma) or remains unexplained.&#xD;
&#xD;
          -  Any patients with underlying non-statin related muscle disorders.&#xD;
&#xD;
          -  Presence of any clinically significant uncontrolled endocrine disease known to&#xD;
             influence serum lipids or lipoproteins.&#xD;
&#xD;
          -  Conditions of severe acute vascular stress (acute coronary syndrome, ischemic stroke,&#xD;
             or major vascular surgery) within prior 3 months.&#xD;
&#xD;
          -  Any patients with a history of severe or life-threatening reactions to statins&#xD;
             including rhabdomyolysis (defined as evidence of organ damage with CK &gt;10,000 IU/L),&#xD;
             CK elevation &gt; 10 times the upper limit of normal, cognitive decline, transaminitis,&#xD;
             or allergic reactions.&#xD;
&#xD;
          -  History of fibromyalgia or rheumatologic disease with symptoms that may be confounded&#xD;
             with statin-related muscle complaints.&#xD;
&#xD;
          -  Patients unable to maintain their current activity level or planning to increase their&#xD;
             activity level (e.g. new exercise regimen). Such changes may have acute effects on&#xD;
             muscle metabolism.&#xD;
&#xD;
          -  Pregnant or breast-feeding women. Statins are teratogenic, and the effects of high&#xD;
             magnetic fields on a fetus are unknown.&#xD;
&#xD;
          -  Women of reproductive age not on effective contraception. Adequate contraceptive&#xD;
             measures include intrauterine device (IUD); bilateral tubal ligation; condom or&#xD;
             diaphragm plus either contraceptive sponge, foam or jelly.&#xD;
&#xD;
          -  Any person with implanted metal, because of MRS safety.&#xD;
&#xD;
          -  Use of any active investigational drugs within 1 month or 5 half-lives, whichever is&#xD;
             longer.&#xD;
&#xD;
          -  History of antibodies to HMGCoA.&#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>Zahid Ahmad, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Texas Southwestern Medical Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>UT Southwestern Medical Center</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75390</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>January 2023</verification_date>
  <study_first_submitted>January 31, 2019</study_first_submitted>
  <study_first_submitted_qc>August 7, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">August 11, 2020</study_first_posted>
  <results_first_submitted>January 23, 2023</results_first_submitted>
  <results_first_submitted_qc>January 23, 2023</results_first_submitted_qc>
  <results_first_posted type="Actual">February 14, 2023</results_first_posted>
  <last_update_submitted>January 23, 2023</last_update_submitted>
  <last_update_submitted_qc>January 23, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 14, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Texas Southwestern Medical Center</investigator_affiliation>
    <investigator_full_name>Zahid Ahmad</investigator_full_name>
    <investigator_title>Associate Professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Muscle Cramp</mesh_term>
    <mesh_term>Muscle Weakness</mesh_term>
    <mesh_term>Spasm</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Simvastatin</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>April 25, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/73/NCT04507373/Prot_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>July 7, 2016</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/73/NCT04507373/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <pre_assignment_details>The 3 participants who were consented/ enrolled were not assigned/ randomized to the interventions because no grant was obtained for the study to continue further and the study was terminated.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Placebo</title>
          <description>Following the baseline period, subject will be randomized to receive either simvastatin or an identical placebo at a dose of 40 mg/day for a period of 10 weeks.&#xD;
Simvastatin 40mg: 40mg oral daily for 10 weeks</description>
        </group>
        <group group_id="P2">
          <title>Simvastatin 40mg</title>
          <description>Following the baseline period, subject will be randomized to receive either simvastatin or an identical placebo at a dose of 40 mg/day for a period of 10 weeks.&#xD;
Simvastatin 40mg: 40mg oral daily for 10 weeks</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>The 3 participants who were consented/ enrolled were not assigned/ randomized to the interventions because no grant was obtained for the study to continue further and the study was terminated.</population>
      <group_list>
        <group group_id="B1">
          <title>Placebo</title>
          <description>Following the baseline period, subject will be randomized to receive either simvastatin or an identical placebo at a dose of 40 mg/day for a period of 10 weeks.&#xD;
Simvastatin 40mg: 40mg oral daily for 10 weeks</description>
        </group>
        <group group_id="B2">
          <title>Simvastatin 40mg</title>
          <description>Following the baseline period, subject will be randomized to receive either simvastatin or an identical placebo at a dose of 40 mg/day for a period of 10 weeks.&#xD;
Simvastatin 40mg: 40mg oral daily for 10 weeks</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="0"/>
            <count group_id="B2" value="0"/>
            <count group_id="B3" value="0"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                </category>
                <category>
                  <title>Male</title>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                </category>
                <category>
                  <title>Asian</title>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                </category>
                <category>
                  <title>Black or African American</title>
                </category>
                <category>
                  <title>White</title>
                </category>
                <category>
                  <title>More than one race</title>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>The Mitochondrial Changes In Muscles During Statin Use</title>
        <description>Study participants being treated with Simvastatin 40mg daily, or placebo for 10 weeks. Investigators will isolate mitochondrial from muscle biopsy sample and compare mitochondrial oxygen consumption rates, ultrastructural changes, and gene expression</description>
        <time_frame>10 weeks</time_frame>
        <population>The participants who were consented/ enrolled were not assigned/ randomized to the interventions because no grant was obtained for the study to continue further and the study was terminated.</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Following the baseline period, subject will be randomized to receive either simvastatin or an identical placebo at a dose of 40 mg/day for a period of 10 weeks.&#xD;
Simvastatin 40mg: 40mg oral daily for 10 weeks</description>
          </group>
          <group group_id="O2">
            <title>Simvastatin 40mg</title>
            <description>Following the baseline period, subject will be randomized to receive either simvastatin or an identical placebo at a dose of 40 mg/day for a period of 10 weeks.&#xD;
Simvastatin 40mg: 40mg oral daily for 10 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>The Mitochondrial Changes In Muscles During Statin Use</title>
          <description>Study participants being treated with Simvastatin 40mg daily, or placebo for 10 weeks. Investigators will isolate mitochondrial from muscle biopsy sample and compare mitochondrial oxygen consumption rates, ultrastructural changes, and gene expression</description>
          <population>The participants who were consented/ enrolled were not assigned/ randomized to the interventions because no grant was obtained for the study to continue further and the study was terminated.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Data was never collected</time_frame>
      <desc>Data was never collected</desc>
      <group_list>
        <group group_id="E1">
          <title>Placebo</title>
          <description>Following the baseline period, subject will be randomized to receive either simvastatin or an identical placebo at a dose of 40 mg/day for a period of 10 weeks.&#xD;
Simvastatin 40mg: 40mg oral daily for 10 weeks</description>
        </group>
        <group group_id="E2">
          <title>Simvastatin 40mg</title>
          <description>Following the baseline period, subject will be randomized to receive either simvastatin or an identical placebo at a dose of 40 mg/day for a period of 10 weeks.&#xD;
Simvastatin 40mg: 40mg oral daily for 10 weeks</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="0"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="0"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="0"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="0"/>
              </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="0"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="0"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE 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>Dr. Zahid Ahmad</name_or_title>
      <organization>UT Southwestern Medical Center</organization>
      <phone>214/648-2377</phone>
      <email>ZAHID.AHMAD@UTSouthwestern.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/NCT04507373
org study id: STU 072016-015
nct id: NCT04507373
lead sponsor: 
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
Over 40 million Americans take statins to reduce their risk of atherosclerotic cardiovascular
      disease (ASCVD). Unfortunately, 10 to 20% stop taking them due to statin-associated muscle
      symptoms (e.g. pain, aches, weakness, cramps, or stiffness) (1, 2). The pathophysiology of
      these statin-associated muscle symptoms (SAMS) has remained elusive. Consequently, no
      objective diagnostic method exists, causing confusion for patient and providers since muscle
      symptoms can often be multifactorial.
The overall objectives of this project are to identify the underlying cause of SAMS and
      establish an in-vivo imaging technique to detect SAMS. The central hypothesis of this
      pro-posal is that statins directly inhibit mitochondrial function in SAMS patients. Our
      rationale is based on our own preliminary data indicating that simvastatin - the most common
      statin to cause SAMS - can directly inhibit oxidative phosphorylation (OXPHOS) in mice. Since
      such changes can be detected in vivo in humans utilizing 31P magnetic resonance spectroscopy
      (MRS) techniques, the investigators will use a state-of-the art 7 Tesla (7T) MRS instrument
      to study the so-leus muscles of SAMS patients. Additionally, the investigators will validate
      the MRS findings by doing func-tional studies in muscle biopsy specimens.

      The investigators propose double-blind randomized, placebo-controlled pilot study in 15 SAMS
      pa-tients and 15 controls. Study participants will be treated with simvastatin 40 mg daily or
      place-bo for 10 weeks. The investigators will perform 7T MRS of soleus muscles at
      randomization and either at first complaint of muscle symptoms or at the end of 10 weeks if
      no muscle symptoms occur, whichever occurs first. Quadriceps muscle biopsies will also be
      done immediately following the second MRS scan.
allocation: Randomized
intervention model: Single Group Assignment
primary purpose: Basic Science
masking: Triple (Participant, Care Provider, Investigator)
masking description: Double Blind
measure: The Mitochondrial Changes In Muscles During Statin Use
time frame: 10 weeks
description: Study participants being treated with Simvastatin 40mg daily, or placebo for 10 weeks. Investigators will isolate mitochondrial from muscle biopsy sample and compare mitochondrial oxygen consumption rates, ultrastructural changes, and gene expression
arm group label: Placebo
arm group type: Placebo Comparator
description: Following the baseline period, subject will be randomized to receive either simvastatin or an identical placebo at a dose of 40 mg/day for a period of 10 weeks.
arm group label: Simvastatin 40mg
arm group type: Active Comparator
description: Following the baseline period, subject will be randomized to receive either simvastatin or an identical placebo at a dose of 40 mg/day for a period of 10 weeks.
intervention type: Drug
intervention name: Simvastatin 40mg
description: 40mg oral daily for 10 weeks
arm group label: Placebo
arm group label: Simvastatin 40mg
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: Zahid Ahmad, M.D.
role: Principal Investigator
affiliation: University of Texas Southwestern Medical Center
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: University of Texas Southwestern Medical Center
investigator full name: Zahid Ahmad
investigator title: Associate Professor
mesh term: Muscle Cramp
mesh term: Muscle Weakness
mesh term: Spasm
mesh term: Simvastatin
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 