Vitamin D to Resolve Inflammation After Tuberculosis (ResolveD-TB)

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.