<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/NCT02968927</url>
  </required_header>
  <id_info>
    <org_study_id>TBHDT-AUR1-8-178</org_study_id>
    <nct_id>NCT02968927</nct_id>
  </id_info>
  <brief_title>TB Host Directed Therapy</brief_title>
  <acronym>TBHDT</acronym>
  <official_title>A Ph2 Randomized Trial to Evaluate the Safety Preliminary Efficacy and Biomarker Response of Host Directed Therapies Added to Rifabutin-modified Standard Therapy in Adults With Drug-Sensitive Smear-Positive Pulmonary TB</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>The Aurum Institute NPC</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>The Aurum Institute NPC</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      To examine the safety and preliminary efficacy of multiple adjunctive host directed TB&#xD;
      therapies (TB HDT), to assess their potential to shorten TB treatment and/or prevent&#xD;
      permanent lung damage.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      OBJECTIVES:&#xD;
&#xD;
      To determine the safety and preliminary efficacy of 4 TB HDT candidates:&#xD;
&#xD;
        1. Safety (treatment emergent serious adverse events and SUSARs)&#xD;
&#xD;
        2. Microbiologic effects in sputum (culture conversion, change in MGIT TTP) and blood (WBA)&#xD;
&#xD;
        3. PET/CT imaging&#xD;
&#xD;
        4. Serum markers of inflammation&#xD;
&#xD;
        5. Effects on Mtb-specific and general immune function&#xD;
&#xD;
        6. Pulmonary effects (spirometry, 6MWT, O2 saturation, and St. George Respiratory Symptom&#xD;
           Questionnaire) In each case, TB HDT effects will be determined by comparison to patients&#xD;
           treated with standard TB therapy alone with regard to a common set of primary and&#xD;
           secondary endpoints.&#xD;
&#xD;
      PRIMARY ENDPOINTS&#xD;
&#xD;
        1. For auranofin, everolimus, and vitamin D: the proportions of patients experiencing&#xD;
           suspected unexpected serious adverse reactions (SUSARs).&#xD;
&#xD;
        2. For CC-11050: the proportion of patients experiencing treatment emergent serious adverse&#xD;
           events (SAEs).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Active, not recruiting</last_known_status>
  <start_date type="Actual">November 2016</start_date>
  <completion_date type="Anticipated">December 2020</completion_date>
  <primary_completion_date type="Actual">September 2018</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>SAEs and SUSARs</measure>
    <time_frame>through day 180</time_frame>
    <description>For auranofin, everolimus, and vitamin D: the proportions of patients experiencing suspected unexpected serious adverse reactions (SUSARs).&#xD;
For CC-11050: the proportion of patients experiencing treatment emergent serious adverse events (SAEs).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>TEAEs other than SAEs and SUSARs</measure>
    <time_frame>through day 180</time_frame>
    <description>TEAEs other than SAEs, categorized according to severity, drug relatedness, and leading to early withdrawal.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Sputum culture status on day 56</measure>
    <time_frame>day 56</time_frame>
    <description>Proportion of patients with positive sputum cultures on solid culture medium after 8 weeks of treatment</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Change in FEV1 from baseline to 2 and 6 months</measure>
    <time_frame>days 56 and 180</time_frame>
    <description>FEV1 (% of expected value)</description>
  </other_outcome>
  <other_outcome>
    <measure>18F-FDG PET/CT imaging (change from baseline to 2 months):</measure>
    <time_frame>day 56</time_frame>
    <description>Maximum and mean standardized uptake values (SUV)</description>
  </other_outcome>
  <other_outcome>
    <measure>Serum neopterin</measure>
    <time_frame>day 56</time_frame>
    <description>change from baseline b. CRP</description>
  </other_outcome>
  <other_outcome>
    <measure>Quantiferon gold in tube</measure>
    <time_frame>day 56</time_frame>
    <description>change from baseline</description>
  </other_outcome>
  <other_outcome>
    <measure>Gene expression profiles (exploratory)</measure>
    <time_frame>days 56 and 180</time_frame>
    <description>Change from baseline to 2 and 6 months in gene expression profiles</description>
  </other_outcome>
  <other_outcome>
    <measure>PD-1 expression (exploratory)</measure>
    <time_frame>days 56 and 180</time_frame>
    <description>PD-1 expression on CD4 and CD8 lymphocytes</description>
  </other_outcome>
  <number_of_arms>5</number_of_arms>
  <enrollment type="Actual">200</enrollment>
  <condition>Tuberculosis</condition>
  <arm_group>
    <arm_group_label>2HRbEZ/4HRb</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>2HRbZE</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Everolimus</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Everolimus 0.5 MG</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Auranofin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Auranofin 6 MG</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Vitamin D</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Vitamin D3</description>
  </arm_group>
  <arm_group>
    <arm_group_label>CC-11050</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>CC-11050</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Everolimus 0.5 MG</intervention_name>
    <arm_group_label>Everolimus</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Auranofin 6 MG</intervention_name>
    <arm_group_label>Auranofin</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Vitamin D3</intervention_name>
    <arm_group_label>Vitamin D</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>CC-11050</intervention_name>
    <arm_group_label>CC-11050</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>2HRbZE/4HRb</intervention_name>
    <arm_group_label>2HRbEZ/4HRb</arm_group_label>
    <arm_group_label>Auranofin</arm_group_label>
    <arm_group_label>CC-11050</arm_group_label>
    <arm_group_label>Everolimus</arm_group_label>
    <arm_group_label>Vitamin D</arm_group_label>
    <other_name>rifabutin-modified TB therapy</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Willing and able to provide signed written consent or witnessed oral consent in the&#xD;
             case of illiteracy, prior to undertaking any trial-related procedures.&#xD;
&#xD;
          2. Aged 18 to 65 years, male, or if female, either not of reproductive potential&#xD;
             (post-menopause, or status-post surgical sterilization) or with an intrauterine&#xD;
             contraceptive device in place.&#xD;
&#xD;
          3. Body weight (in light clothing without shoes) between 40 and 90 kg.&#xD;
&#xD;
          4. First episode of pulmonary tuberculosis diagnosed by positive sputum AFB smear with&#xD;
             subsequent culture confirmation OR positive Xpert TB/RIF with Ct &lt;20 [4].&#xD;
&#xD;
          5. RIF susceptibility diagnosed by Xpert TB/RIF OR Hain test&#xD;
&#xD;
          6. Chest radiograph meeting criteria for moderate or far advanced pulmonary tuberculosis&#xD;
             [5]&#xD;
&#xD;
          7. HIV-1 seronegative&#xD;
&#xD;
          8. HBsAg negative&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Any condition for which participation in the trial, as judged by the investigator,&#xD;
             could compromise the well-being of the subject or prevent, limit or confound protocol&#xD;
             specified assessments&#xD;
&#xD;
          2. Current or imminent treatment for malaria.&#xD;
&#xD;
          3. Is critically ill, and in the judgment of the investigator has a diagnosis likely to&#xD;
             result in death during the trial or the follow-up period.&#xD;
&#xD;
          4. TB meningitis or other forms of severe tuberculosis with high risk of a poor outcome&#xD;
             as judged by the investigator.&#xD;
&#xD;
          5. History of allergy or hypersensitivity to any of the trial therapies or related&#xD;
             substances, including known allergy or suspected hypersensitivity to rifampin or&#xD;
             rifabutin.&#xD;
&#xD;
          6. Having participated in other clinical trials with investigational agents within 8&#xD;
             weeks prior to trial start or currently enrolled in an investigational trial.&#xD;
&#xD;
          7. Subjects with any of the following at screening:&#xD;
&#xD;
               1. Cardiac arrhythmia requiring medication;&#xD;
&#xD;
               2. Prolongation of QT/QTc interval with QTcF (Fridericia correction) &gt;450 ms;&#xD;
&#xD;
               3. History of additional risk factors for Torsade de Pointes, (e.g., heart failure,&#xD;
                  hypokalemia, family history of Long QT Syndrome);&#xD;
&#xD;
               4. Any clinically significant ECG abnormality, in the opinion of the investigator.&#xD;
&#xD;
               5. Patients requiring concomitant medications that prolong the QT inter-val.&#xD;
&#xD;
          8. Random blood glucose &gt;140 mg/dL, or history of unstable Diabetes Mellitus which&#xD;
             required hospitalization for hyper- or hypoglycaemia within the past year prior to&#xD;
             start of screening.&#xD;
&#xD;
          9. Use of systemic corticosteroids within the past 28 days.&#xD;
&#xD;
         10. Subjects with any of the following abnormal laboratory values:&#xD;
&#xD;
               1. creatinine &gt;2 mg/dL&#xD;
&#xD;
               2. haemoglobin &lt;8 g/dL&#xD;
&#xD;
               3. platelets &lt;100x109 cells/L&#xD;
&#xD;
               4. serum potassium &lt;3.5&#xD;
&#xD;
               5. aspartate aminotransferase (AST) ≥2.0 x ULN&#xD;
&#xD;
               6. alkaline phosphatase (AP) &gt;5.0 x ULN&#xD;
&#xD;
               7. total bilirubin &gt;1.5 mg/dL&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Robert S Wallis, MD,FIDSA</last_name>
    <role>Principal Investigator</role>
    <affiliation>The Aurum Institute NPC</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>The Aurum Institute: Tembisa Clinical Research Centre</name>
      <address>
        <city>Tembisa</city>
        <state>Gauteng</state>
        <zip>1736</zip>
        <country>South Africa</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>South Africa</country>
  </location_countries>
  <verification_date>January 2019</verification_date>
  <study_first_submitted>September 8, 2016</study_first_submitted>
  <study_first_submitted_qc>November 17, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 21, 2016</study_first_posted>
  <last_update_submitted>January 9, 2019</last_update_submitted>
  <last_update_submitted_qc>January 9, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">January 10, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tuberculosis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Vitamin D</mesh_term>
    <mesh_term>Cholecalciferol</mesh_term>
    <mesh_term>Rifabutin</mesh_term>
    <mesh_term>Everolimus</mesh_term>
    <mesh_term>Auranofin</mesh_term>
    <mesh_term>CC-11050</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</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/NCT02968927
org study id: TBHDT-AUR1-8-178
nct id: NCT02968927
lead sponsor: 
has dmc: Yes
To examine the safety and preliminary efficacy of multiple adjunctive host directed TB
      therapies (TB HDT), to assess their potential to shorten TB treatment and/or prevent
      permanent lung damage.
OBJECTIVES:

      To determine the safety and preliminary efficacy of 4 TB HDT candidates:

        1. Safety (treatment emergent serious adverse events and SUSARs)

        2. Microbiologic effects in sputum (culture conversion, change in MGIT TTP) and blood (WBA)

        3. PET/CT imaging

        4. Serum markers of inflammation

        5. Effects on Mtb-specific and general immune function

        6. Pulmonary effects (spirometry, 6MWT, O2 saturation, and St. George Respiratory Symptom
           Questionnaire) In each case, TB HDT effects will be determined by comparison to patients
           treated with standard TB therapy alone with regard to a common set of primary and
           secondary endpoints.

      PRIMARY ENDPOINTS

        1. For auranofin, everolimus, and vitamin D: the proportions of patients experiencing
           suspected unexpected serious adverse reactions (SUSARs).

        2. For CC-11050: the proportion of patients experiencing treatment emergent serious adverse
           events (SAEs).
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: SAEs and SUSARs
time frame: through day 180
description: For auranofin, everolimus, and vitamin D: the proportions of patients experiencing suspected unexpected serious adverse reactions (SUSARs).
For CC-11050: the proportion of patients experiencing treatment emergent serious adverse events (SAEs).
measure: TEAEs other than SAEs and SUSARs
time frame: through day 180
description: TEAEs other than SAEs, categorized according to severity, drug relatedness, and leading to early withdrawal.
measure: Sputum culture status on day 56
time frame: day 56
description: Proportion of patients with positive sputum cultures on solid culture medium after 8 weeks of treatment
measure: Change in FEV1 from baseline to 2 and 6 months
time frame: days 56 and 180
description: FEV1 (% of expected value)
measure: 18F-FDG PET/CT imaging (change from baseline to 2 months):
time frame: day 56
description: Maximum and mean standardized uptake values (SUV)
measure: Serum neopterin
time frame: day 56
description: change from baseline b. CRP
measure: Quantiferon gold in tube
time frame: day 56
description: change from baseline
measure: Gene expression profiles (exploratory)
time frame: days 56 and 180
description: Change from baseline to 2 and 6 months in gene expression profiles
measure: PD-1 expression (exploratory)
time frame: days 56 and 180
description: PD-1 expression on CD4 and CD8 lymphocytes
arm group label: 2HRbEZ/4HRb
arm group type: Active Comparator
description: 2HRbZE
arm group label: Everolimus
arm group type: Experimental
description: Everolimus 0.5 MG
arm group label: Auranofin
arm group type: Experimental
description: Auranofin 6 MG
arm group label: Vitamin D
arm group type: Experimental
description: Vitamin D3
arm group label: CC-11050
arm group type: Experimental
description: CC-11050
intervention type: Drug
intervention name: Everolimus 0.5 MG
arm group label: Everolimus
intervention type: Drug
intervention name: Auranofin 6 MG
arm group label: Auranofin
intervention type: Drug
intervention name: Vitamin D3
arm group label: Vitamin D
intervention type: Drug
intervention name: CC-11050
arm group label: CC-11050
intervention type: Drug
intervention name: 2HRbZE/4HRb
arm group label: 2HRbEZ/4HRb
arm group label: Auranofin
arm group label: CC-11050
arm group label: Everolimus
arm group label: Vitamin D
other name: rifabutin-modified TB therapy
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Robert S Wallis, MD,FIDSA
role: Principal Investigator
affiliation: The Aurum Institute NPC
facility: 
country: South Africa
responsible party type: Sponsor
mesh term: Tuberculosis
mesh term: Vitamin D
mesh term: Cholecalciferol
mesh term: Rifabutin
mesh term: Everolimus
mesh term: Auranofin
mesh term: CC-11050
sharing ipd: Undecided