Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03011580 |
| Other study ID # |
011410 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
March 14, 2017 |
| Est. completion date |
August 1, 2019 |
Study information
| Verified date |
July 2019 |
| Source |
Queen Mary University of London |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
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.
Description:
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.
