<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/NCT04453735</url>
  </required_header>
  <id_info>
    <org_study_id>REK 54041</org_study_id>
    <nct_id>NCT04453735</nct_id>
  </id_info>
  <brief_title>MUscle Side-Effects of Atorvastatin in Coronary Patients (MUSE) -Follow-up Study</brief_title>
  <official_title>MUscle Side-Effects of Atorvastatin in Coronary Patients (MUSE) -Follow-up Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Vestre Viken Hospital Trust</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>The Hospital of Vestfold</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Oslo University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Vestre Viken Hospital Trust</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Statins are cornerstone treatment in secondary cardiovascular disease (CVD) prevention.&#xD;
      Today, statin non-adherence (patients not taking their prescribed drug) remains a major&#xD;
      public health concern, leading to adverse outcomes in terms of morbidity, mortality and&#xD;
      healthcare costs. The principal reason for statin non-adherence and discontinuation is&#xD;
      statin-associated muscle symptoms (SAMS). Objective SAMS diagnostics do not exist. We aim to&#xD;
      unravel the pathophysiology of SAMS and develop diagnostic tools to differentiate real SAMS&#xD;
      from muscle symptoms not related to the statin, among coronary patients with self-perceived&#xD;
      SAMS. In this follow-up study we aims to determine the effect of 7 weeks open treatment with&#xD;
      atorvastatin 40 mg/day, followed by 7 weeks open treatment with no lipid lowering treatment,&#xD;
      on muscle symptom intensity in patients classified with confirmed statin-associated muscle&#xD;
      symptoms (SAMS) (i.e. statin-dependent muscle side-effects) and non-SAMS in the MUscle&#xD;
      Side-Effects of atorvastatin in coronary patients (MUSE) randomized double blinded cross-over&#xD;
      trial.&#xD;
&#xD;
      We have developed novel methods that will be used to measure atorvastatin metabolites and&#xD;
      drug effect biomarkers directly in skeletal muscle and blood . The diagnostic accuracy of&#xD;
      these biomarkers to differentiate real SAMS from non-SAMS will be evaluated. A new diagnostic&#xD;
      tool may potentially be implemented to assess SAMS in the individual patient and enable&#xD;
      personalized follow-up. It may also represent an important tool in the communication with&#xD;
      patients misattributing their muscle symptoms to statins. The long-term results may be better&#xD;
      quality of life and reduced morbidity, mortality and healthcare costs.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">August 19, 2020</start_date>
  <completion_date type="Actual">December 18, 2020</completion_date>
  <primary_completion_date type="Actual">December 18, 2020</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <intervention_model_description>Prospective, open, intervention study</intervention_model_description>
    <primary_purpose>Diagnostic</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Individual mean difference in muscular symptom intensity measured with a 0 (no symptoms) to 10 (worst imaginable symptoms) Visual Analogue Scale (VAS) score between treatment periods with statin and &quot;no statin treatment&quot;</measure>
    <time_frame>16 weeks following study start</time_frame>
    <description>Individual mean difference in muscular symptom (i.e. pain, aching, tenderness, stiffness, cramp and/or weakness) intensity between treatment periods with statin and no statin, reported by the patients over the last three weeks (i.e. week 4-7) measured with a 0 (no symptoms) to 10 (worst imaginable symptoms) Visual Analogue Scale (VAS) score with aggregated data from each subscale</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>The proportion of patients who report muscle symptoms on atorvastatin treatment and not on statin (dichotomous Statin Associated Muscle Symptom classification)</measure>
    <time_frame>16 weeks following study start</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Correlation between atorvastatin-related variables in muscle and the primary study endpoint. The ability of atorvastatin-related variables in muscle to differentiate confirmed SAMS and non-SAMS</measure>
    <time_frame>16 weeks following study start</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Correlation between atorvastatin-related variables in plasma vs. muscle and PBMC vs. muscle. Correlation between atorvastatin-related variables in blood and the primary study endpoint.</measure>
    <time_frame>16 weeks following study start</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Correlation between atorvastatin: HMGCR in muscle and the primary study endpoint. The ability of atorvastatin:HMGCR in muscle to differentiate confirmed SAMS and non-SAMS.</measure>
    <time_frame>16 weeks following study start</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Correlation between atorvastatin:HMGCR in PBMC vs. muscle. Correlation between atorvastatin:HMGCR in PBMC and the primary study endpoint.</measure>
    <time_frame>16 weeks following study start</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Correlation between mevalonate pathway intermediates in muscle and the primary study endpoint. The ability of mevalonate pathway intermediates in muscle to differentiate confirmed SAMS and non-SAMS.</measure>
    <time_frame>16 weeks following study start</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Correlation between mevalonate pathway intermediates in plasma vs. muscle and PBMC vs. muscle. Correlation between mevalonate pathway intermediates in blood and the primary study endpoint.</measure>
    <time_frame>16 weeks following study start</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Correlation between mitochondrial respiratory enzymes in muscle and the primary study endpoint. The ability of mitochondrial respiratory enzymes in muscle to differentiate confirmed SAMS and non-SAMS.</measure>
    <time_frame>16 weeks following study start</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Correlation between mitochondrial respiratory enzymes in PBMC vs. muscle. Correlation between mitochondrial respiratory enzymes in PMBC and the primary study endpoint.</measure>
    <time_frame>16 weeks following study start</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Correlation between the FKBP1A:RyR1 ratio in muscle and the primary study endpoint. The ability of the FKBP1A:RyR1 ratio in muscle to differentiate confirmed SAMS and non-SAMS.</measure>
    <time_frame>16 weeks following study start</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Correlation between the FKBP1A:RyR1 ratio in PBMC vs. muscle. Correlation between the FKBP1A:RyR1 ratio in PBMC and the primary study endpoint.</measure>
    <time_frame>16 weeks following study start</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Correlation between caspase 3 signalling in muscle and the primary study endpoint. The ability of caspase 3 signalling in muscle to differentiate confirmed SAMS and non-SAMS.</measure>
    <time_frame>16 weeks following study start</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Correlation between caspase 3 signalling in PBMC vs. muscle. Correlation between caspase 3 signalling in blood and the primary study endpoint.</measure>
    <time_frame>16 weeks following study start</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Difference in muscle response variables between atorvastatin period and non-statin period.</measure>
    <time_frame>16 weeks following study start</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Correlation of molecular effects in blood vs. muscle. Difference in blood response variables between atorvastatin period and non-statin period. Correlation between atorvastatin-related variables and response variables in blood.</measure>
    <time_frame>16 weeks following study start</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Statin adherence measured with indirect methods and by parent drug and metabolite concentrations in blood</measure>
    <time_frame>16 weeks following study start</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>New-onset CHD symptoms. Intolerable muscle symptoms leading to discontinuation from the treatment arm. Creatine kinase (CK) &gt; 10 times upper limit of the normal range or alaninaminotransferase (ALT) &gt; 3 times upper normal limit</measure>
    <time_frame>16 weeks following study start</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">27</enrollment>
  <condition>Statin Adverse Reaction</condition>
  <arm_group>
    <arm_group_label>Intervention</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Atorvastatin mylan 40 mg once daily</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>No statin therapy</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Atorvastatin mylan 40 Mg Oral Tablet</intervention_name>
    <description>Oral tablet on regular prescription</description>
    <arm_group_label>Intervention</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Participation in the MUSE trial (Eudract nr. 2018-004261-14) and still fulfilling the&#xD;
             study entry criteria: First or recurrent diagnosis (myocardial infarction) or&#xD;
             treatments (PCI or CABG) for a CHD event 12-42 months prior to study start.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  First or recurrent diagnosis (myocardial infarction) or treatments (PCI or CABG) for a&#xD;
             CHD event the a) past 12 months prior to study start in high risk patients (i.e. at&#xD;
             least one of following comorbid conditions: systolic heart failure, &gt;1 previous&#xD;
             myocardial infarction, kidney failure, diabetes, and smokers) and b) the past 6 months&#xD;
             prior to study start in low risk patients without any of the co-morbid conditions&#xD;
             mentioned above and in patients who are not taking a statin at all.&#xD;
&#xD;
          -  Patients with symptomatic peripheral artery disease and patients with familial&#xD;
             hypercholesterolemia&#xD;
&#xD;
          -  Patient has any contraindications for atorvastatin listed in the Summary of Product&#xD;
             Characteristics (i.e. known hypersensitivity to the ingredients, acute liver failure/&#xD;
             ALT &gt; 3 times upper limit of the normal range in blood at study start, pregnancy and&#xD;
             breastfeeding )&#xD;
&#xD;
          -  History of previous rhabdomyolysis, myopathy or liver failure due to statin treatment&#xD;
             with CK &gt; 10 times upper limit of the normal range or ALT &gt; 3 times upper limit of the&#xD;
             normal range.&#xD;
&#xD;
          -  Any condition (e.g. psychiatric illness, dementia) or situation, that in the&#xD;
             investigator's opinion could put the subject at significant risk, confound the study&#xD;
             results, interfere significantly with the subject participation in the study, or&#xD;
             rendering informed consent unfeasible&#xD;
&#xD;
          -  Short life expectancy (&lt;12 months) due to other medical conditions&#xD;
&#xD;
          -  Not being able to understand Norwegian.&#xD;
&#xD;
          -  Women of childbearing potential defined as all premenopausal female.&#xD;
&#xD;
          -  Participation in another randomized clinical trial&#xD;
&#xD;
          -  Classified with significantly more muscle symptoms on placebo than on atorvastatin in&#xD;
             the MUSE trial&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Vestre Viken HF, Drammen Hospital</name>
      <address>
        <city>Drammen</city>
        <state>Buskerud</state>
        <zip>3004</zip>
        <country>Norway</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital of Vestfold</name>
      <address>
        <city>Tønsberg</city>
        <state>Vestfold</state>
        <zip>3103</zip>
        <country>Norway</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Norway</country>
  </location_countries>
  <verification_date>June 2020</verification_date>
  <study_first_submitted>June 28, 2020</study_first_submitted>
  <study_first_submitted_qc>June 28, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 1, 2020</study_first_posted>
  <last_update_submitted>February 25, 2021</last_update_submitted>
  <last_update_submitted_qc>February 25, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">February 26, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Atorvastatin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>De-identified individual participant data will be made available for other researchers</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_time_frame>Data will be available within 5 years of study completion</ipd_time_frame>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</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/NCT04453735
org study id: REK 54041
nct id: NCT04453735
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Statins are cornerstone treatment in secondary cardiovascular disease (CVD) prevention.
      Today, statin non-adherence (patients not taking their prescribed drug) remains a major
      public health concern, leading to adverse outcomes in terms of morbidity, mortality and
      healthcare costs. The principal reason for statin non-adherence and discontinuation is
      statin-associated muscle symptoms (SAMS). Objective SAMS diagnostics do not exist. We aim to
      unravel the pathophysiology of SAMS and develop diagnostic tools to differentiate real SAMS
      from muscle symptoms not related to the statin, among coronary patients with self-perceived
      SAMS. In this follow-up study we aims to determine the effect of 7 weeks open treatment with
      atorvastatin 40 mg/day, followed by 7 weeks open treatment with no lipid lowering treatment,
      on muscle symptom intensity in patients classified with confirmed statin-associated muscle
      symptoms (SAMS) (i.e. statin-dependent muscle side-effects) and non-SAMS in the MUscle
      Side-Effects of atorvastatin in coronary patients (MUSE) randomized double blinded cross-over
      trial.

      We have developed novel methods that will be used to measure atorvastatin metabolites and
      drug effect biomarkers directly in skeletal muscle and blood . The diagnostic accuracy of
      these biomarkers to differentiate real SAMS from non-SAMS will be evaluated. A new diagnostic
      tool may potentially be implemented to assess SAMS in the individual patient and enable
      personalized follow-up. It may also represent an important tool in the communication with
      patients misattributing their muscle symptoms to statins. The long-term results may be better
      quality of life and reduced morbidity, mortality and healthcare costs.
allocation: Non-Randomized
intervention model: Sequential Assignment
intervention model description: Prospective, open, intervention study
primary purpose: Diagnostic
masking: None (Open Label)
measure: Individual mean difference in muscular symptom intensity measured with a 0 (no symptoms) to 10 (worst imaginable symptoms) Visual Analogue Scale (VAS) score between treatment periods with statin and "no statin treatment"
time frame: 16 weeks following study start
description: Individual mean difference in muscular symptom (i.e. pain, aching, tenderness, stiffness, cramp and/or weakness) intensity between treatment periods with statin and no statin, reported by the patients over the last three weeks (i.e. week 4-7) measured with a 0 (no symptoms) to 10 (worst imaginable symptoms) Visual Analogue Scale (VAS) score with aggregated data from each subscale
measure: The proportion of patients who report muscle symptoms on atorvastatin treatment and not on statin (dichotomous Statin Associated Muscle Symptom classification)
time frame: 16 weeks following study start
measure: Correlation between atorvastatin-related variables in muscle and the primary study endpoint. The ability of atorvastatin-related variables in muscle to differentiate confirmed SAMS and non-SAMS
time frame: 16 weeks following study start
measure: Correlation between atorvastatin-related variables in plasma vs. muscle and PBMC vs. muscle. Correlation between atorvastatin-related variables in blood and the primary study endpoint.
time frame: 16 weeks following study start
measure: Correlation between atorvastatin: HMGCR in muscle and the primary study endpoint. The ability of atorvastatin:HMGCR in muscle to differentiate confirmed SAMS and non-SAMS.
time frame: 16 weeks following study start
measure: Correlation between atorvastatin:HMGCR in PBMC vs. muscle. Correlation between atorvastatin:HMGCR in PBMC and the primary study endpoint.
time frame: 16 weeks following study start
measure: Correlation between mevalonate pathway intermediates in muscle and the primary study endpoint. The ability of mevalonate pathway intermediates in muscle to differentiate confirmed SAMS and non-SAMS.
time frame: 16 weeks following study start
measure: Correlation between mevalonate pathway intermediates in plasma vs. muscle and PBMC vs. muscle. Correlation between mevalonate pathway intermediates in blood and the primary study endpoint.
time frame: 16 weeks following study start
measure: Correlation between mitochondrial respiratory enzymes in muscle and the primary study endpoint. The ability of mitochondrial respiratory enzymes in muscle to differentiate confirmed SAMS and non-SAMS.
time frame: 16 weeks following study start
measure: Correlation between mitochondrial respiratory enzymes in PBMC vs. muscle. Correlation between mitochondrial respiratory enzymes in PMBC and the primary study endpoint.
time frame: 16 weeks following study start
measure: Correlation between the FKBP1A:RyR1 ratio in muscle and the primary study endpoint. The ability of the FKBP1A:RyR1 ratio in muscle to differentiate confirmed SAMS and non-SAMS.
time frame: 16 weeks following study start
measure: Correlation between the FKBP1A:RyR1 ratio in PBMC vs. muscle. Correlation between the FKBP1A:RyR1 ratio in PBMC and the primary study endpoint.
time frame: 16 weeks following study start
measure: Correlation between caspase 3 signalling in muscle and the primary study endpoint. The ability of caspase 3 signalling in muscle to differentiate confirmed SAMS and non-SAMS.
time frame: 16 weeks following study start
measure: Correlation between caspase 3 signalling in PBMC vs. muscle. Correlation between caspase 3 signalling in blood and the primary study endpoint.
time frame: 16 weeks following study start
measure: Difference in muscle response variables between atorvastatin period and non-statin period.
time frame: 16 weeks following study start
measure: Correlation of molecular effects in blood vs. muscle. Difference in blood response variables between atorvastatin period and non-statin period. Correlation between atorvastatin-related variables and response variables in blood.
time frame: 16 weeks following study start
measure: Statin adherence measured with indirect methods and by parent drug and metabolite concentrations in blood
time frame: 16 weeks following study start
measure: New-onset CHD symptoms. Intolerable muscle symptoms leading to discontinuation from the treatment arm. Creatine kinase (CK) > 10 times upper limit of the normal range or alaninaminotransferase (ALT) > 3 times upper normal limit
time frame: 16 weeks following study start
arm group label: Intervention
arm group type: Active Comparator
description: Atorvastatin mylan 40 mg once daily
arm group label: Control
arm group type: No Intervention
description: No statin therapy
intervention type: Drug
intervention name: Atorvastatin mylan 40 Mg Oral Tablet
description: Oral tablet on regular prescription
arm group label: Intervention
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
facility: 
country: Norway
responsible party type: Sponsor
mesh term: Atorvastatin
sharing ipd: Yes
ipd description: De-identified individual participant data will be made available for other researchers
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd time frame: Data will be available within 5 years of study completion