<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/NCT04504851</url>
  </required_header>
  <id_info>
    <org_study_id>ROSETTA</org_study_id>
    <nct_id>NCT04504851</nct_id>
  </id_info>
  <brief_title>Rosuvastatin Evaluation as a Tuberculosis Treatment Adjunct</brief_title>
  <acronym>ROSETTA</acronym>
  <official_title>Rosuvastatin Evaluation as a Tuberculosis Treatment Adjunct</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National University Hospital, Singapore</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National University Hospital, Singapore</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This trial aims to determine whether the addition of rosuvastatin to standard TB therapy in&#xD;
      pulmonary tuberculosis results in accelerated of sputum culture conversion. The trial will&#xD;
      also investigate potential new biomarkers of sterilising activity and immune-modulatory&#xD;
      activity.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Rosuvastatin is an HMG Co-A reductase inhibitor which may be of value as possible adjunctive&#xD;
      agents to standard TB therapy. Cell culture assays and animal models demonstrate that statins&#xD;
      are bactericidal against Mtb with effects that are additive to that of anti-tuberculous&#xD;
      therapy.&#xD;
&#xD;
      This is a Phase IIb randomised, controlled, open-label, early bactericidal activity trial. We&#xD;
      will recruit patients between the ages of 18 and 75 with newly-diagnosed smear or Xpert&#xD;
      positive pulmonary TB, who have had no more than 7 days of TB therapy.&#xD;
&#xD;
      Patients will be randomised to take either standard TB therapy or standard TB therapy plus&#xD;
      rosuvastatin for the first 8 weeks of their therapy. After the first 8 weeks, patients will&#xD;
      continue standard combination TB therapy and remain in trial follow-up until week 24. The&#xD;
      trial will collect sputum for culture on a weekly basis for the first 8 weeks of the trial,&#xD;
      and less frequently leading up to week 24.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">August 12, 2020</start_date>
  <completion_date type="Anticipated">March 31, 2021</completion_date>
  <primary_completion_date type="Anticipated">March 31, 2021</primary_completion_date>
  <phase>Phase 2</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>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Time to culture conversion in Liquid Media</measure>
    <time_frame>within 8 weeks after randomisation</time_frame>
    <description>Time to culture conversion is defined is time from randomisation to the first of two consecutive negative sputum cultures</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Time to culture conversion in Solid media</measure>
    <time_frame>within 8 weeks after randomisation</time_frame>
    <description>Time to culture conversion is defined is time from randomisation to the first of two consecutive negative sputum cultures</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to culture conversion in Liquid media</measure>
    <time_frame>within 12 weeks after randomisation</time_frame>
    <description>Time to culture conversion is defined is time from randomisation to the first of two consecutive negative sputum cultures</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Sputum culture negative in Liquid media</measure>
    <time_frame>at 8 weeks from randomisation</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Sputum culture negative in Solid media</measure>
    <time_frame>at 8 weeks from randomisation</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in time to positivity (TTP)</measure>
    <time_frame>from baseline to week 8</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in proportion of lung affected on CXR</measure>
    <time_frame>from baseline to week 8</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in the aggregate cavity size on CXR</measure>
    <time_frame>from baseline to week 8</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in score on St George's Respiratory Questionnaire (SGRQ)</measure>
    <time_frame>from baseline to week 8</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in FEV1/FVC</measure>
    <time_frame>from baseline to week 8</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>One or more Grade 3 or Grade 4 adverse events</measure>
    <time_frame>by week 24</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>One of more Serious Adverse Events (SAEs)</measure>
    <time_frame>by week 24</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">154</enrollment>
  <condition>Pulmonary Tuberculosis</condition>
  <arm_group>
    <arm_group_label>Arm A (Standard of Care)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Standard combination treatment for pulmonary TB of 8 weeks rifampicin, isoniazid, pyrazinamide, ethambutol, then 16 weeks rifampicin, isoniazid</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm B (Standard of Care plus Rosuvastatin)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Standard combination treatment for pulmonary TB of 8 weeks rifampicin, isoniazid, pyrazinamide, ethambutol PLUS rosuvastatin, then 16 weeks rifampicin, isoniazid</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Rosuvastatin 10mg</intervention_name>
    <description>10mg of Rosuvastatin in the Intensive Phase of Therapy (8 weeks)</description>
    <arm_group_label>Arm B (Standard of Care plus Rosuvastatin)</arm_group_label>
    <other_name>Crestor</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Rifampicin</intervention_name>
    <description>Rifampicin 10mg/kg</description>
    <arm_group_label>Arm A (Standard of Care)</arm_group_label>
    <arm_group_label>Arm B (Standard of Care plus Rosuvastatin)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Isoniazid</intervention_name>
    <description>Isoniazid 5mg/kg</description>
    <arm_group_label>Arm A (Standard of Care)</arm_group_label>
    <arm_group_label>Arm B (Standard of Care plus Rosuvastatin)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pyrazinamide</intervention_name>
    <description>Pyrazinamide 25mg/kg</description>
    <arm_group_label>Arm A (Standard of Care)</arm_group_label>
    <arm_group_label>Arm B (Standard of Care plus Rosuvastatin)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ethambutol</intervention_name>
    <description>Ethambutol 15mg/kg</description>
    <arm_group_label>Arm A (Standard of Care)</arm_group_label>
    <arm_group_label>Arm B (Standard of Care plus Rosuvastatin)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Aged 18 - 75 years of age&#xD;
&#xD;
          2. Abnormalities on CXR compatible with pulmonary TB&#xD;
&#xD;
          3. At least one sputum specimen, produced at or prior to screening during the current&#xD;
             illness episode, that is:&#xD;
&#xD;
             (i) positive for acid-fast bacilli on smear microscopy (with at least 1+ on the&#xD;
             IUATLD/WHO scale) and/or (ii) positive on testing by Xpert MTB/RIF or Xpert Ultra&#xD;
             (with semi-quantitative cycle threshold (CT) result of 'medium' or 'high')&#xD;
&#xD;
          4. Able to produce at least 5ml of sputum per day at the time of screening&#xD;
&#xD;
          5. Current or planned treatment with a regimen containing rifampicin, isoniazid and&#xD;
             pyrazinamide (with or without ethambutol) only&#xD;
&#xD;
          6. Resident at a fixed address within feasible travelling distance to the site and likely&#xD;
             to remain a local resident for the duration of trial follow-up&#xD;
&#xD;
          7. Willing to have directly observed therapy (DOT)&#xD;
&#xD;
          8. Willing to comply with the study visits and procedures&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. More than 7 days of standard TB treatment by the time of the baseline visit&#xD;
&#xD;
          2. Known rifampicin resistance or isoniazid resistance at the time of randomization&#xD;
             (results by conventional DST or molecular tests are not required to be available prior&#xD;
             to randomization)&#xD;
&#xD;
          3. Previous treatment for active TB disease, unless rifampicin susceptibility has been&#xD;
             demonstrated on a molecular test performed during this episode.&#xD;
&#xD;
          4. Extrapulmonary TB that, in the opinion of the treating clinician, is likely to require&#xD;
             concurrent use of steroids, or require surgical management.&#xD;
&#xD;
          5. Known hypersensitivity to rosuvastatin&#xD;
&#xD;
          6. History of myopathy or family history of hereditary muscular disorders&#xD;
&#xD;
          7. Acute liver failure or decompensated chronic liver disease&#xD;
&#xD;
          8. Current alcohol abuse&#xD;
&#xD;
          9. Known hypothyroidism&#xD;
&#xD;
         10. Any of the following laboratory parameters at screening:&#xD;
&#xD;
               1. ALT &gt;3 times upper limit of normal (ULN)&#xD;
&#xD;
               2. Estimated glomerular filtration rate (eGFR) &lt; 60ml/min/1.73m2 (calculated using&#xD;
                  the CKD-EPI equation) (81)&#xD;
&#xD;
               3. Creatine Kinase &gt;5 times ULN&#xD;
&#xD;
               4. Potassium &lt;2.5 mmol/L&#xD;
&#xD;
         11. Active malignancy on chemotherapy or radiotherapy&#xD;
&#xD;
         12. Current use of immunosuppressive medication (≤ 5mg/ day of prednisolone or equivalent&#xD;
             is acceptable).&#xD;
&#xD;
         13. HIV infection (unless patient has been stable on continuous antiretroviral therapy for&#xD;
             at least 6 months, with CD4 count &gt;/= 250 cells/mm3 and viral load &lt;/= 200 copies/ml,&#xD;
             on a test performed at screening or during the last 12 months prior to screening, in&#xD;
             which case they may be enrolled)&#xD;
&#xD;
         14. Use of any statin drug at screening or during the 3 months prior to screening&#xD;
&#xD;
         15. History of Atherosclerotic Cardiovascular Disease (ASCVD; defined as myocardial&#xD;
             infarction, stable or unstable angina, coronary artery disease or coronary or other&#xD;
             arterial revascularization, stroke, transient ischemic attack, or peripheral artery&#xD;
             disease including aortic aneurysm, all of atherosclerotic origin)&#xD;
&#xD;
         16. Known Familial Hypercholesterolaemia&#xD;
&#xD;
         17. Other reasons, in the opinion of the investigator (and taking into consideration&#xD;
             current local and international guidelines for primary prevention of cardiovascular&#xD;
             disease), why the patient should commence statin treatment during the 6-month period&#xD;
             following randomization&#xD;
&#xD;
         18. Current use of drugs contraindicated for use with rosuvastatin or standard TB drugs&#xD;
             including fusidic acid, gemfibrozil, feno-fibrate, nicotinic acid (&gt;1 gram/day),&#xD;
             cyclosporine, directly acting antivirals for chronic Hepatitis C, protease inhibitors&#xD;
             for HIV and praziquantel.&#xD;
&#xD;
         19. Women who are pregnant or breastfeeding&#xD;
&#xD;
         20. Women of childbearing potential unwilling or unable to use appropriate effective&#xD;
             contraception for the first 12 weeks of the trial.&#xD;
&#xD;
         21. Any serious condition suggestive of myopathy or predisposing to the development of&#xD;
             renal failure secondary to rhabdomyolysis (such as extensive surgery, significant&#xD;
             trauma, uncontrolled seizures)&#xD;
&#xD;
         22. Any other severe underlying condition that would, in the opinion of the investigator,&#xD;
             compromise the patient's safety or outcome in the trial.&#xD;
&#xD;
         23. Participation in other clinical intervention trial or research protocol (participation&#xD;
             in other studies that do not involve an intervention may be allowed, but this must be&#xD;
             discussed and approved by the Chief Investigator).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Nicholas Paton</last_name>
    <role>Principal Investigator</role>
    <affiliation>National University Hospital, Singapore</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Gail Cross</last_name>
    <phone>+65 83280377</phone>
    <email>mdcgbc@nus.edu.sg</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Nicholas Paton</last_name>
    <phone>+65 6601 5371</phone>
    <email>mdcnijp@nus.edu.sg</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Tropical Disease Foundation</name>
      <address>
        <city>Makati City</city>
        <country>Philippines</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>De La Salle Health Sciences Institute</name>
      <address>
        <city>Manila</city>
        <country>Philippines</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Lung Center Philippines</name>
      <address>
        <city>Quezon City</city>
        <country>Philippines</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>National University Hospital, Singapore</name>
      <address>
        <city>Singapore</city>
        <country>Singapore</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Joint Clinical Research Centre</name>
      <address>
        <city>Kampala</city>
        <country>Uganda</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Vietnam Military Medical University</name>
      <address>
        <city>Hanoi</city>
        <country>Vietnam</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Philippines</country>
    <country>Singapore</country>
    <country>Uganda</country>
    <country>Vietnam</country>
  </location_countries>
  <verification_date>August 2020</verification_date>
  <study_first_submitted>August 5, 2020</study_first_submitted>
  <study_first_submitted_qc>August 5, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">August 7, 2020</study_first_posted>
  <last_update_submitted>August 5, 2020</last_update_submitted>
  <last_update_submitted_qc>August 5, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">August 7, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Statin</keyword>
  <keyword>Rosuvastatin</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tuberculosis</mesh_term>
    <mesh_term>Tuberculosis, Pulmonary</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Rifampin</mesh_term>
    <mesh_term>Isoniazid</mesh_term>
    <mesh_term>Pyrazinamide</mesh_term>
    <mesh_term>Ethambutol</mesh_term>
    <mesh_term>Rosuvastatin Calcium</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </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/NCT04504851
org study id: ROSETTA
nct id: NCT04504851
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
This trial aims to determine whether the addition of rosuvastatin to standard TB therapy in
      pulmonary tuberculosis results in accelerated of sputum culture conversion. The trial will
      also investigate potential new biomarkers of sterilising activity and immune-modulatory
      activity.
Rosuvastatin is an HMG Co-A reductase inhibitor which may be of value as possible adjunctive
      agents to standard TB therapy. Cell culture assays and animal models demonstrate that statins
      are bactericidal against Mtb with effects that are additive to that of anti-tuberculous
      therapy.

      This is a Phase IIb randomised, controlled, open-label, early bactericidal activity trial. We
      will recruit patients between the ages of 18 and 75 with newly-diagnosed smear or Xpert
      positive pulmonary TB, who have had no more than 7 days of TB therapy.

      Patients will be randomised to take either standard TB therapy or standard TB therapy plus
      rosuvastatin for the first 8 weeks of their therapy. After the first 8 weeks, patients will
      continue standard combination TB therapy and remain in trial follow-up until week 24. The
      trial will collect sputum for culture on a weekly basis for the first 8 weeks of the trial,
      and less frequently leading up to week 24.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Time to culture conversion in Liquid Media
time frame: within 8 weeks after randomisation
description: Time to culture conversion is defined is time from randomisation to the first of two consecutive negative sputum cultures
measure: Time to culture conversion in Solid media
time frame: within 8 weeks after randomisation
description: Time to culture conversion is defined is time from randomisation to the first of two consecutive negative sputum cultures
measure: Time to culture conversion in Liquid media
time frame: within 12 weeks after randomisation
description: Time to culture conversion is defined is time from randomisation to the first of two consecutive negative sputum cultures
measure: Sputum culture negative in Liquid media
time frame: at 8 weeks from randomisation
measure: Sputum culture negative in Solid media
time frame: at 8 weeks from randomisation
measure: Change in time to positivity (TTP)
time frame: from baseline to week 8
measure: Change in proportion of lung affected on CXR
time frame: from baseline to week 8
measure: Change in the aggregate cavity size on CXR
time frame: from baseline to week 8
measure: Change in score on St George's Respiratory Questionnaire (SGRQ)
time frame: from baseline to week 8
measure: Change in FEV1/FVC
time frame: from baseline to week 8
measure: One or more Grade 3 or Grade 4 adverse events
time frame: by week 24
measure: One of more Serious Adverse Events (SAEs)
time frame: by week 24
arm group label: Arm A (Standard of Care)
arm group type: Active Comparator
description: Standard combination treatment for pulmonary TB of 8 weeks rifampicin, isoniazid, pyrazinamide, ethambutol, then 16 weeks rifampicin, isoniazid
arm group label: Arm B (Standard of Care plus Rosuvastatin)
arm group type: Experimental
description: Standard combination treatment for pulmonary TB of 8 weeks rifampicin, isoniazid, pyrazinamide, ethambutol PLUS rosuvastatin, then 16 weeks rifampicin, isoniazid
intervention type: Drug
intervention name: Rosuvastatin 10mg
description: 10mg of Rosuvastatin in the Intensive Phase of Therapy (8 weeks)
arm group label: Arm B (Standard of Care plus Rosuvastatin)
other name: Crestor
intervention type: Drug
intervention name: Rifampicin
description: Rifampicin 10mg/kg
arm group label: Arm A (Standard of Care)
arm group label: Arm B (Standard of Care plus Rosuvastatin)
intervention type: Drug
intervention name: Isoniazid
description: Isoniazid 5mg/kg
arm group label: Arm A (Standard of Care)
arm group label: Arm B (Standard of Care plus Rosuvastatin)
intervention type: Drug
intervention name: Pyrazinamide
description: Pyrazinamide 25mg/kg
arm group label: Arm A (Standard of Care)
arm group label: Arm B (Standard of Care plus Rosuvastatin)
intervention type: Drug
intervention name: Ethambutol
description: Ethambutol 15mg/kg
arm group label: Arm A (Standard of Care)
arm group label: Arm B (Standard of Care plus Rosuvastatin)
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Nicholas Paton
role: Principal Investigator
affiliation: National University Hospital, Singapore
last name: Gail Cross
phone: +65 83280377
email: mdcgbc@nus.edu.sg
last name: Nicholas Paton
phone: +65 6601 5371
email: mdcnijp@nus.edu.sg
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Philippines
country: Singapore
country: Uganda
country: Vietnam
responsible party type: Sponsor
mesh term: Tuberculosis
mesh term: Tuberculosis, Pulmonary
mesh term: Rifampin
mesh term: Isoniazid
mesh term: Pyrazinamide
mesh term: Ethambutol
mesh term: Rosuvastatin Calcium
sharing ipd: No