<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/NCT03011580</url>
  </required_header>
  <id_info>
    <org_study_id>011410</org_study_id>
    <nct_id>NCT03011580</nct_id>
  </id_info>
  <brief_title>Vitamin D to Resolve Inflammation After Tuberculosis (ResolveD-TB)</brief_title>
  <acronym>ResolveD-TB</acronym>
  <official_title>Vitamin D3 to Enhance Resolution of Residual Pulmonary Inflammation in Patients Completing Antituberculosis Treatment (ResolveD-TB): a Proof-of-concept Intervention Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Queen Mary University of London</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Queen Mary University of London</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This Strategic Research Project is a translational proof-of-concept study that will determine&#xD;
      whether vitamin D3 has potential to prevent recurrent tuberculosis (TB), as indicated by&#xD;
      enhanced resolution of pulmonary inflammation detected using 18F-FDG PET-CT scanning. The&#xD;
      extent of pulmonary inflammation detectable on PET-CT scanning is a validated biomarker that&#xD;
      has previously been shown to predict risk of TB recurrence in patients taking anti-TB&#xD;
      treatment. The investigators propose to explore whether vitamin D3 can enhance resolution of&#xD;
      PET-CT-detectable pulmonary inflammation, on the basis of extensive preliminary data from in&#xD;
      vitro studies and a Phase 2b clinical trial that the investigators have conducted, showing&#xD;
      that high-dose vitamin D3 accelerates resolution of peripheral blood inflammatory responses&#xD;
      in patients with pulmonary TB.&#xD;
&#xD;
      Forty vitamin D-deficient patients who have completed 6 months' TB treatment, but who still&#xD;
      have residual pulmonary inflammation detectable on PET-CT scanning, will be allocated to&#xD;
      receive either an 8-week course of high-dose oral vitamin D3 supplementation or placebo&#xD;
      during the study period. The extent of pulmonary inflammation on PET-CT scanning will be&#xD;
      compared between intervention vs. control groups at 8-week follow-up.&#xD;
&#xD;
      If the study shows a positive result, it will generate valuable proof-of-concept data that&#xD;
      could be used to support an application to conduct a large phase 3 trial of vitamin D&#xD;
      supplementation to prevent TB recurrence.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Study design and its justification:&#xD;
&#xD;
      This is an exploratory study to compare the effects of vitamin D supplementation against&#xD;
      placebo (capsules with no active drug) on residual pulmonary inflammation detectable with&#xD;
      PET-CT scanning. If the study demonstrates that vitamin D supplementation can dampen down&#xD;
      lung inflammation in patients who still have such inflammation at the end of antibiotic&#xD;
      treatment, it will provide the basis for bigger and more rigorous studies. Half of the&#xD;
      participants will be asked to take capsules containing vitamin D (the immediate&#xD;
      supplementation group) and the other half placebo (the delayed supplementation group) for a&#xD;
      duration of 8 weeks, once they have completed anti-tuberculosis treatment. There is an equal&#xD;
      chance (1 in 2) that participants will be given either study medication - this allows the two&#xD;
      groups to be fairly similar in background characteristics so that any differences in&#xD;
      inflammation after 8 weeks would be put down to vitamin D supplementation.&#xD;
&#xD;
      The study will adopt a 'double-blind' approach, meaning that neither participants nor&#xD;
      researchers will know which study medication each participant is taking for the duration of&#xD;
      the study. This allows to minimise the influence that knowing the type of study medication&#xD;
      each participant is taking might have on researchers' or participants' behaviour during the&#xD;
      study, as these behaviours might affect the results of the study. This is also one of the&#xD;
      reasons that the investigators have chosen to use placebo in this study, rather than&#xD;
      comparing participants taking vitamin D to those who are not taking any study medication. In&#xD;
      addition, the use of placebo may encourage participants to take the study medication. It is&#xD;
      unlikely that the delay in starting vitamin D replacement for participants in the delayed&#xD;
      supplementation arm would be harmful, as vitamin D deficiency is very unlikely to be&#xD;
      associated with any acute medical problem, and the delay in its correction (8 weeks) is very&#xD;
      short in relation to the likely duration of deficiency preceding the study, which is likely&#xD;
      to have been longstanding (e.g. over years).&#xD;
&#xD;
      Study procedures:&#xD;
&#xD;
        -  Attend up to three visits to hospital after they have completed a course of antibiotics&#xD;
           for pulmonary tuberculosis. Visit 2 may be conducted via telephone with posting of study&#xD;
           medication (by registered mail or courier)&#xD;
&#xD;
        -  Take three capsules of study medication (each is 3,200 IU so a total of 9,600 IU) every&#xD;
           day, using the dispenser provided by the investigators&#xD;
&#xD;
        -  Give two blood samples: first =19 ml (~4 tsp), second =25 ml (~5 tsp)&#xD;
&#xD;
        -  Give two coughing samples&#xD;
&#xD;
        -  Have two chest PET-CT scans&#xD;
&#xD;
        -  Receive five telephone calls, each lasting about five minutes&#xD;
&#xD;
        -  Receive additional telephone calls if any doses are missed&#xD;
&#xD;
      Potential participants will be given a copy of the Patient Information Sheet (PIS) by a&#xD;
      member of their usual care team at their scheduled clinic appointment after completing TB&#xD;
      treatment and ample time (at least 24 hours) to decide whether they want to take part in the&#xD;
      study. Those taking a PIS will be asked to complete a contact slip providing their contact&#xD;
      details and authorising the research team to make contact with them once they have had a&#xD;
      chance to read the information; this contact slip will be forwarded to the research team by&#xD;
      the participant's usual care team.&#xD;
&#xD;
      Telephone call 1 - This will feed back results of tests of vitamin D status, calcium and&#xD;
      renal function performed as part of usual care.&#xD;
&#xD;
      Potential participants who are found to be vitamin D deficient (serum 25[OH]D &lt;50 nmol/L),&#xD;
      normocalcaemic (serum corrected calcium &lt;2.65 mmol/L) and to have eGFR &gt;30 ml/min/1.73 m2&#xD;
      will be invited to attend Visit 1 (-2 weeks) for screening.&#xD;
&#xD;
      Visit 1 - Potential participants attending Visit 1 will be asked to give written informed&#xD;
      consent to participate in the study. A PET-CT scan will be performed at the Department of&#xD;
      Nuclear Medicine, Barts Health NHS Trust (radiation exposure for a PET-CT scan is 4.6 mSv).&#xD;
      All women of childbearing age will be asked to do a urine pregnancy test before the PET-CT&#xD;
      scan ; the scan will not proceed unless a negative pregnancy test result is obtained at this&#xD;
      time. Blood samples (volume of 19 ml) for immunological testing and an induced sputum sample&#xD;
      will also be taken during this visit. Participants' GPs will be notified by post about their&#xD;
      involvement in the study at this stage, where consent has been given to do so.&#xD;
&#xD;
      Telephone call 2 - This will feed back results of tests of the PET-CT scan performed at Visit&#xD;
      1. Participants who are found to have significant residual PET-hot pulmonary inflammation on&#xD;
      this scan (SUVmax ≥3 g/ml) will be invited to attend Visit 2 (0 weeks).&#xD;
&#xD;
      Visit 2 (0 weeks) - At this visit, eligible participants will be allocated to oral vitamin D&#xD;
      replacement therapy at a daily dose of 9,600 IU of Fultium-D3 (cholecalciferol or vitamin D3)&#xD;
      for 8 weeks for the immediate supplementation arm (n=20) or oral placebo for 8 weeks for the&#xD;
      delayed supplementation arm (n=20). Fultium-D3 and placebo will be identical in appearance&#xD;
      and taste and both will be given at a dose of three capsules once daily (each Fultium-D3&#xD;
      capsules contains 3,200 IU vitamin D3). Participants may also be given a CE-marked Sensemedic&#xD;
      dispenser each for real-time adherence monitoring and shown how to use it. Participants will&#xD;
      be advised of the symptoms of high blood calcium levels (nausea, vomiting, thirst, passing&#xD;
      excessive amounts of urine or feeling generally unwell) and asked to contact a designated&#xD;
      member of the study team if they develop these symptoms so that a blood test to check for&#xD;
      high blood calcium levels can be arranged urgently. Any new symptoms reported between Visit 2&#xD;
      and Visit 3 will be assessed by a study doctor for potential association with the study&#xD;
      medication. Arrangements will be made during this visit for telephone follow-up sessions.&#xD;
      Visit 2 may be conducted via telephone with posting of study medication (by registered mail&#xD;
      or courier) at an investigator's discretion.&#xD;
&#xD;
      Follow-up telephone calls (T3-5 and for missed doses) - Follow-up telephone calls will be&#xD;
      made at 1 week (T3), 3 weeks (T4) and 5 weeks (T5) post-randomisation for all participants. A&#xD;
      member of the study team will telephone participants at a pre-arranged time to check&#xD;
      adherence to study medication and if there have been any problems with using the Sensemedic&#xD;
      dispenser. Telephone calls will also be made to participants when a non-adherence is logged&#xD;
      on the Sensemedic system. Additional intermediate study face-to-face visits will be arranged&#xD;
      as necessary if any adherence issues are identified.&#xD;
&#xD;
      Visit 3 - PET-CT scans and measurement of whole blood (volume of 25 ml) and induced sputum&#xD;
      inflammatory markers will be repeated at Visit 3 (+8 weeks). All women of childbearing age&#xD;
      will be asked to do a urine pregnancy test before the PET-CT scan ; the scan will not proceed&#xD;
      unless a negative pregnancy test result is obtained at this time. All radiological read-outs&#xD;
      will be assessed by radiologists blinded to allocation, and compared between supplemented vs.&#xD;
      unsupplemented patients using analysis of covariance to adjust for baseline values. All&#xD;
      participants will be offered vitamin D supplementation after their 8-week follow-up&#xD;
      assessment, prior to discharge from the study. Participants'GPs will be informed by post that&#xD;
      their participation in the study has ended. All participants will be informed by post at the&#xD;
      end of the study of whether they received vitamin D supplements or placebo between Visit 2&#xD;
      and Visit 3.&#xD;
&#xD;
      Discontinuation of study medication:&#xD;
&#xD;
      Participants whose study medication is discontinued will remain in follow-up as long as they&#xD;
      consent to do so, and data will continue to be collected for them.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">March 14, 2017</start_date>
  <completion_date type="Actual">August 1, 2019</completion_date>
  <primary_completion_date type="Actual">April 1, 2019</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>Prevention</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Mean maximum standardised uptake value (SUVmax) on PET-CT scanning at 8-week follow-up.</measure>
    <time_frame>8 weeks in total</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Inflammation Score on PET-CT at 8-week follow-up.</measure>
    <time_frame>8 weeks in total</time_frame>
    <description>A single composite outcome score derived from the following components: total glycolytic activity, total cavitary air, total volume of lesions with radiodensity ranging from -100 to +200 Houndsfield Units</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of PET-hot lesions resolving over the course of the study</measure>
    <time_frame>8 weeks in total</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total and differential white cell counts</measure>
    <time_frame>8 weeks in total</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Concentrations of inflammatory mediators in serum at 8-week follow-up.</measure>
    <time_frame>8 weeks in total</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Concentrations of inflammatory mediators in plasma at 8-week follow-up.</measure>
    <time_frame>8 weeks in total</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Concentrations of inflammatory mediators in induced sputum supernatants at 8-week follow-up.</measure>
    <time_frame>8 weeks in total</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Concentrations of inflammatory mediators in supernatants of antigen-stimulated whole blood at 8-week follow-up.</measure>
    <time_frame>8 weeks in total</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Induced sputum transcriptional profiles at 8-week follow-up.</measure>
    <time_frame>8 weeks in total</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Whole blood transcriptional profiles at 8-week follow-up.</measure>
    <time_frame>8 weeks in total</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Sputum microbiology at 8-week follow-up.</measure>
    <time_frame>8 weeks in total</time_frame>
    <description>To assess the proportion of samples in which Mycobacterium tuberculosis can be detected after 8 weeks.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">15</enrollment>
  <condition>Recurrent Tuberculosis</condition>
  <arm_group>
    <arm_group_label>Immediate supplementation arm</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Fultium-D3 (oral cholecalciferol or vitamin D3) will be given at a dose of 9,600 IU/day for 8 weeks (three capsules once daily as each Fulitium D-3 capsules contains 3,200 IU vitamin D3). Participants may also be given a Sensemedic dispenser each for real-time adherence monitoring and shown how to use it.&#xD;
All participants will be given a supply of Fultium-D3 at a dose of 3,200 IU/day at the end of the study.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Delayed supplementation arm</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Oral placebo will be given for 8 weeks at a dose of three capsules once daily. Fultium-D3 and placebo will be identical in appearance and taste. Participants may also be given a Sensemedic dispenser each for real-time adherence monitoring and shown how to use it. All participants will be given a supply of Fultium-D3 at a dose of 3,200 IU/day at the end of the study.</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Fultium-D3</intervention_name>
    <description>Fultium-D3 (oral cholecalciferol or vitamin D3) will be given to participants in the immediate supplementation arm at a dose of 9,600 IU/day for 8 weeks at V2. At V3, all participants will be given a supply of Fultium-D3 at a dose of 3,200 IU/day.</description>
    <arm_group_label>Immediate supplementation arm</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>3 capsules of placebo will be given daily to participants in the delayed supplementation arm for 8 weeks at V2.</description>
    <arm_group_label>Delayed supplementation arm</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age 20 years or more at enrolment&#xD;
&#xD;
          -  Baseline serum 25-hydroxyvitamin D &lt;50 nmol/L&#xD;
&#xD;
          -  Maximum standardised uptake value (SUVmax) on baseline PET-CT ≥3 g/ml&#xD;
&#xD;
          -  Completing antimicrobial therapy for pulmonary tuberculosis&#xD;
&#xD;
          -  If a woman of child-bearing potential, has negative pregnancy test immediately prior&#xD;
             to each PET-CT scan and agrees to use reliable form of contraception until she has&#xD;
             completed the study&#xD;
&#xD;
          -  Gives written informed consent to participate&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pregnant, breastfeeding or planning a pregnancy&#xD;
&#xD;
          -  Baseline serum corrected calcium concentration ≥2.65 mmol/L&#xD;
&#xD;
          -  Baseline eGFR ≤ 30 ml/min/1.73 m2&#xD;
&#xD;
          -  Other contra-indication to vitamin D supplementation: known sarcoidosis, known&#xD;
             hyperparathyroidism or known nephrolithiasis&#xD;
&#xD;
          -  Taking concomitant phenytoin, barbiturate, cardiac glycoside, oral glucocorticoid or&#xD;
             vitamin D supplement&#xD;
&#xD;
          -  Known allergy to vitamin D or its excipients&#xD;
&#xD;
          -  Currently taking part in another interventional research study&#xD;
&#xD;
          -  PET-CT scan within the previous 6 months&#xD;
&#xD;
          -  Any inclusion criteria not met&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>20 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Adrian Martineau, Prof</last_name>
    <role>Principal Investigator</role>
    <affiliation>Barts and The London School of Medicine and Dentistry, Queen Mary University, University of London</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Barts Health NHS Trust</name>
      <address>
        <city>London</city>
        <zip>E1 1BB</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>July 2019</verification_date>
  <study_first_submitted>November 15, 2016</study_first_submitted>
  <study_first_submitted_qc>January 3, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 5, 2017</study_first_posted>
  <last_update_submitted>September 13, 2019</last_update_submitted>
  <last_update_submitted_qc>September 13, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">September 16, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Vitamin D</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tuberculosis</mesh_term>
    <mesh_term>Inflammation</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>No individual participant data will be available. Non-patient identifiable data will be presented in paper, abstract and presentation to conferences.</ipd_description>
  </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/NCT03011580
org study id: 011410
nct id: NCT03011580
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
This Strategic Research Project is a translational proof-of-concept study that will determine
      whether vitamin D3 has potential to prevent recurrent tuberculosis (TB), as indicated by
      enhanced resolution of pulmonary inflammation detected using 18F-FDG PET-CT scanning. The
      extent of pulmonary inflammation detectable on PET-CT scanning is a validated biomarker that
      has previously been shown to predict risk of TB recurrence in patients taking anti-TB
      treatment. The investigators propose to explore whether vitamin D3 can enhance resolution of
      PET-CT-detectable pulmonary inflammation, on the basis of extensive preliminary data from in
      vitro studies and a Phase 2b clinical trial that the investigators have conducted, showing
      that high-dose vitamin D3 accelerates resolution of peripheral blood inflammatory responses
      in patients with pulmonary TB.

      Forty vitamin D-deficient patients who have completed 6 months' TB treatment, but who still
      have residual pulmonary inflammation detectable on PET-CT scanning, will be allocated to
      receive either an 8-week course of high-dose oral vitamin D3 supplementation or placebo
      during the study period. The extent of pulmonary inflammation on PET-CT scanning will be
      compared between intervention vs. control groups at 8-week follow-up.

      If the study shows a positive result, it will generate valuable proof-of-concept data that
      could be used to support an application to conduct a large phase 3 trial of vitamin D
      supplementation to prevent TB recurrence.
Study design and its justification:

      This is an exploratory study to compare the effects of vitamin D supplementation against
      placebo (capsules with no active drug) on residual pulmonary inflammation detectable with
      PET-CT scanning. If the study demonstrates that vitamin D supplementation can dampen down
      lung inflammation in patients who still have such inflammation at the end of antibiotic
      treatment, it will provide the basis for bigger and more rigorous studies. Half of the
      participants will be asked to take capsules containing vitamin D (the immediate
      supplementation group) and the other half placebo (the delayed supplementation group) for a
      duration of 8 weeks, once they have completed anti-tuberculosis treatment. There is an equal
      chance (1 in 2) that participants will be given either study medication - this allows the two
      groups to be fairly similar in background characteristics so that any differences in
      inflammation after 8 weeks would be put down to vitamin D supplementation.

      The study will adopt a 'double-blind' approach, meaning that neither participants nor
      researchers will know which study medication each participant is taking for the duration of
      the study. This allows to minimise the influence that knowing the type of study medication
      each participant is taking might have on researchers' or participants' behaviour during the
      study, as these behaviours might affect the results of the study. This is also one of the
      reasons that the investigators have chosen to use placebo in this study, rather than
      comparing participants taking vitamin D to those who are not taking any study medication. In
      addition, the use of placebo may encourage participants to take the study medication. It is
      unlikely that the delay in starting vitamin D replacement for participants in the delayed
      supplementation arm would be harmful, as vitamin D deficiency is very unlikely to be
      associated with any acute medical problem, and the delay in its correction (8 weeks) is very
      short in relation to the likely duration of deficiency preceding the study, which is likely
      to have been longstanding (e.g. over years).

      Study procedures:

        -  Attend up to three visits to hospital after they have completed a course of antibiotics
           for pulmonary tuberculosis. Visit 2 may be conducted via telephone with posting of study
           medication (by registered mail or courier)

        -  Take three capsules of study medication (each is 3,200 IU so a total of 9,600 IU) every
           day, using the dispenser provided by the investigators

        -  Give two blood samples: first =19 ml (~4 tsp), second =25 ml (~5 tsp)

        -  Give two coughing samples

        -  Have two chest PET-CT scans

        -  Receive five telephone calls, each lasting about five minutes

        -  Receive additional telephone calls if any doses are missed

      Potential participants will be given a copy of the Patient Information Sheet (PIS) by a
      member of their usual care team at their scheduled clinic appointment after completing TB
      treatment and ample time (at least 24 hours) to decide whether they want to take part in the
      study. Those taking a PIS will be asked to complete a contact slip providing their contact
      details and authorising the research team to make contact with them once they have had a
      chance to read the information; this contact slip will be forwarded to the research team by
      the participant's usual care team.

      Telephone call 1 - This will feed back results of tests of vitamin D status, calcium and
      renal function performed as part of usual care.

      Potential participants who are found to be vitamin D deficient (serum 25[OH]D <50 nmol/L),
      normocalcaemic (serum corrected calcium <2.65 mmol/L) and to have eGFR >30 ml/min/1.73 m2
      will be invited to attend Visit 1 (-2 weeks) for screening.

      Visit 1 - Potential participants attending Visit 1 will be asked to give written informed
      consent to participate in the study. A PET-CT scan will be performed at the Department of
      Nuclear Medicine, Barts Health NHS Trust (radiation exposure for a PET-CT scan is 4.6 mSv).
      All women of childbearing age will be asked to do a urine pregnancy test before the PET-CT
      scan ; the scan will not proceed unless a negative pregnancy test result is obtained at this
      time. Blood samples (volume of 19 ml) for immunological testing and an induced sputum sample
      will also be taken during this visit. Participants' GPs will be notified by post about their
      involvement in the study at this stage, where consent has been given to do so.

      Telephone call 2 - This will feed back results of tests of the PET-CT scan performed at Visit
      1. Participants who are found to have significant residual PET-hot pulmonary inflammation on
      this scan (SUVmax ≥3 g/ml) will be invited to attend Visit 2 (0 weeks).

      Visit 2 (0 weeks) - At this visit, eligible participants will be allocated to oral vitamin D
      replacement therapy at a daily dose of 9,600 IU of Fultium-D3 (cholecalciferol or vitamin D3)
      for 8 weeks for the immediate supplementation arm (n=20) or oral placebo for 8 weeks for the
      delayed supplementation arm (n=20). Fultium-D3 and placebo will be identical in appearance
      and taste and both will be given at a dose of three capsules once daily (each Fultium-D3
      capsules contains 3,200 IU vitamin D3). Participants may also be given a CE-marked Sensemedic
      dispenser each for real-time adherence monitoring and shown how to use it. Participants will
      be advised of the symptoms of high blood calcium levels (nausea, vomiting, thirst, passing
      excessive amounts of urine or feeling generally unwell) and asked to contact a designated
      member of the study team if they develop these symptoms so that a blood test to check for
      high blood calcium levels can be arranged urgently. Any new symptoms reported between Visit 2
      and Visit 3 will be assessed by a study doctor for potential association with the study
      medication. Arrangements will be made during this visit for telephone follow-up sessions.
      Visit 2 may be conducted via telephone with posting of study medication (by registered mail
      or courier) at an investigator's discretion.

      Follow-up telephone calls (T3-5 and for missed doses) - Follow-up telephone calls will be
      made at 1 week (T3), 3 weeks (T4) and 5 weeks (T5) post-randomisation for all participants. A
      member of the study team will telephone participants at a pre-arranged time to check
      adherence to study medication and if there have been any problems with using the Sensemedic
      dispenser. Telephone calls will also be made to participants when a non-adherence is logged
      on the Sensemedic system. Additional intermediate study face-to-face visits will be arranged
      as necessary if any adherence issues are identified.

      Visit 3 - PET-CT scans and measurement of whole blood (volume of 25 ml) and induced sputum
      inflammatory markers will be repeated at Visit 3 (+8 weeks). All women of childbearing age
      will be asked to do a urine pregnancy test before the PET-CT scan ; the scan will not proceed
      unless a negative pregnancy test result is obtained at this time. All radiological read-outs
      will be assessed by radiologists blinded to allocation, and compared between supplemented vs.
      unsupplemented patients using analysis of covariance to adjust for baseline values. All
      participants will be offered vitamin D supplementation after their 8-week follow-up
      assessment, prior to discharge from the study. Participants'GPs will be informed by post that
      their participation in the study has ended. All participants will be informed by post at the
      end of the study of whether they received vitamin D supplements or placebo between Visit 2
      and Visit 3.

      Discontinuation of study medication:

      Participants whose study medication is discontinued will remain in follow-up as long as they
      consent to do so, and data will continue to be collected for them.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: Double (Participant, Investigator)
measure: Mean maximum standardised uptake value (SUVmax) on PET-CT scanning at 8-week follow-up.
time frame: 8 weeks in total
measure: Inflammation Score on PET-CT at 8-week follow-up.
time frame: 8 weeks in total
description: A single composite outcome score derived from the following components: total glycolytic activity, total cavitary air, total volume of lesions with radiodensity ranging from -100 to +200 Houndsfield Units
measure: Proportion of PET-hot lesions resolving over the course of the study
time frame: 8 weeks in total
measure: Total and differential white cell counts
time frame: 8 weeks in total
measure: Concentrations of inflammatory mediators in serum at 8-week follow-up.
time frame: 8 weeks in total
measure: Concentrations of inflammatory mediators in plasma at 8-week follow-up.
time frame: 8 weeks in total
measure: Concentrations of inflammatory mediators in induced sputum supernatants at 8-week follow-up.
time frame: 8 weeks in total
measure: Concentrations of inflammatory mediators in supernatants of antigen-stimulated whole blood at 8-week follow-up.
time frame: 8 weeks in total
measure: Induced sputum transcriptional profiles at 8-week follow-up.
time frame: 8 weeks in total
measure: Whole blood transcriptional profiles at 8-week follow-up.
time frame: 8 weeks in total
measure: Sputum microbiology at 8-week follow-up.
time frame: 8 weeks in total
description: To assess the proportion of samples in which Mycobacterium tuberculosis can be detected after 8 weeks.
arm group label: Immediate supplementation arm
arm group type: Experimental
description: Fultium-D3 (oral cholecalciferol or vitamin D3) will be given at a dose of 9,600 IU/day for 8 weeks (three capsules once daily as each Fulitium D-3 capsules contains 3,200 IU vitamin D3). Participants may also be given a Sensemedic dispenser each for real-time adherence monitoring and shown how to use it.
All participants will be given a supply of Fultium-D3 at a dose of 3,200 IU/day at the end of the study.
arm group label: Delayed supplementation arm
arm group type: Placebo Comparator
description: Oral placebo will be given for 8 weeks at a dose of three capsules once daily. Fultium-D3 and placebo will be identical in appearance and taste. Participants may also be given a Sensemedic dispenser each for real-time adherence monitoring and shown how to use it. All participants will be given a supply of Fultium-D3 at a dose of 3,200 IU/day at the end of the study.
intervention type: Dietary Supplement
intervention name: Fultium-D3
description: Fultium-D3 (oral cholecalciferol or vitamin D3) will be given to participants in the immediate supplementation arm at a dose of 9,600 IU/day for 8 weeks at V2. At V3, all participants will be given a supply of Fultium-D3 at a dose of 3,200 IU/day.
arm group label: Immediate supplementation arm
intervention type: Dietary Supplement
intervention name: Placebo
description: 3 capsules of placebo will be given daily to participants in the delayed supplementation arm for 8 weeks at V2.
arm group label: Delayed supplementation arm
criteria: 
gender: All
minimum age: 20 Years
maximum age: N/A
healthy volunteers: No
last name: Adrian Martineau, Prof
role: Principal Investigator
affiliation: Barts and The London School of Medicine and Dentistry, Queen Mary University, University of London
facility: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Tuberculosis
mesh term: Inflammation
sharing ipd: No
ipd description: No individual participant data will be available. Non-patient identifiable data will be presented in paper, abstract and presentation to conferences.