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Pulmonary TuberculosisPhase 2NCT01580007

Clinical Trial of Phenylbutyrate and Vitamin D in Tuberculosis (TB)

A Phase 2 study testing Active Sodium Phenylbutyrate and active cholecalciferol in people with Pulmonary Tuberculosis, run by International Centre for Diarrhoeal Disease Research, Bangladesh at 1 site in Bangladesh.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

Vitamin D exerts its effects via the Vitamin D Receptor (VDR) present in activated macrophages and induces expression and release of the cathelicidin, LL-37, a human antimicrobial peptide involved in killing of MTB. Read more about this study

Who is it for?
Ages 18 to 60 years
Conditions the study is for
Pulmonary Tuberculosis
What is being tested?
Active Sodium Phenylbutyrate and active cholecalciferol
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
288 participants
Where
1 siteBangladesh
Study dates
Dec 2010to Dec 2014
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 60 years
  • All sexes
  • No healthy volunteers
  • Adult

Who may be able to join

  • Adults, 18-60 years with sputum smear positive pulmonary TB
  • New cases only
  • Gender, both
  • Consent to enroll in the study

Who cannot join

  • Hypercalcaemia (serum calcium > 2.6 mmol/L) identified at baseline
  • Taking vitamin D
  • Pregnant and lactating
  • Any known liver or kidney function abnormality, malignancy

Trial locations and contacts

1 site in 1 country.

Bangladesh1 site

  • National Institute of Diseases of Chest and Hospital (NIDCH)

    Dhaka, 1212

Other trials in Bangladesh

About this study

Official title: Clinical Trial of Oral Phenylbutyrate and Vitamin D Adjunctive Therapy in Pulmonary Tuberculosis in Bangladesh: a Pilot Study

Vitamin D exerts its effects via the Vitamin D Receptor (VDR) present in activated macrophages and induces expression and release of the cathelicidin, LL-37, a human antimicrobial peptide involved in killing of MTB. We aimed to investigate whether treatment of newly diagnosed pulmonary TB patients for 2 months with adjunctive PBA and vitamin D (Cholecalciferol) in combination with standard DOTS therapy (i) can improve response to standard short course TB therapy towards a rapid recovery; (ii) can induce expression of LL-37 in macrophages; (iii) can enhance killing capacity of macrophages isolated from TB patients infected in vitro with MTB; and (iv) does not evoke any adverse effects.

Read the detailed description

This is a double-blind, randomized, placebo controlled clinical trial on clinical efficacy of phenylbutyrate and vitamin D3 therapy daily for 2 months in newly diagnosed sputum smear positive pulmonary TB patients. The clinical trial will take place in the National Institute of the Diseases of the Chest and Hospital (NIDCH) in Dhaka, Bangladesh.

Our specific aims are:

Objective 1: To determine the optimal oral dose of PBA required for induction of antimicrobial peptide in macrophages from healthy adults.

Objective 2

The second aim of this study is to determine whether adjunctive sodium phenylbutyrate and vitamin D treatment (for 2 months) of newly diagnosed pulmonary TB patients:

  1. Can improve response to standard short course TB therapy towards a rapid recovery (clinical, radiological, mycobacterial).
  2. Can induce expression of LL-37 in macrophages (immunological).
  3. Can enhance killing capacity of macrophages from TB patients infected in vitro with MTB (functional measures of treatment outcome).

Study Design: The study will be a randomized, double blind (Subject, Caregiver, Investigator, Outcomes Assessor), placebo control trial for 2 months. It will also be a safety and efficacy phase III study. The study will have a 4x4 factorial design with 4-cell interventions. Enrolled patients will be randomized into the following four treatment arms in a 1:1:1:1 ratio:

Group 1: PBA Group 2: Vitamin D3 (Cholecalciferol) Group 3: PBA plus vitamin D3 Group 4: Placebo

Being tested
Active Sodium Phenylbutyrate and active cholecalciferol, Placebo Sodium Phenylbutyrate plus active cholecalciferol, Active Sodium Phenylbutyrate and placebo cholecalciferol, Placebo Sodium Phenylbutyrate plus placebo cholecalciferol
Keywords
tuberculosis, phenylbutyrate, vitamin D, cathelicidin, antimicrobial peptide, in adults
Medical subject headings
Tuberculosis, Pulmonary, Tuberculosis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Active Sodium Phenylbutyrate and active cholecalciferolDrug

    Also called triButyrate®, Vigantol oil

    Sodium Phenylbutyrate: 500 mg twice daily orally for 2 months Cholecalciferol: 5000 IU once daily orally for 2 months

  • Placebo Sodium Phenylbutyrate plus active cholecalciferolDrug

    Also called Vigantol oil, Placebo Phenylbutyrate

    Placebo Sodium Phenylbutyrate: twice daily orally for 2 months Cholecalciferol: 5000 IU once daily for 2 months

  • Active Sodium Phenylbutyrate and placebo cholecalciferolDrug

    Also called triButyrate®, Placebo vigantol oil

    Sodium phenylbutyrate: 500 mg twice daily orally for 2 months Placebo cholecalciferol: once daily orally for 2 months

  • Placebo Sodium Phenylbutyrate plus placebo cholecalciferolDrug

    Placebo Sodium Phenylbutyrate: twice daily orally for 2 months Placebo cholecalciferol: once daily orally for 2 months

Study groups in NCT01580007
Study groupRoleWhat they receive
Active Sodium Phenylbutyrate and active cholecalciferolActive comparator500 mg sodium phenylbutyrate (4-phenylbutyric acid, sodium salt) in tablet form twice daily and 5000 IU of cholecalciferol once daily will be given orally for 2 months
Receives: Drug: Active Sodium Phenylbutyrate and active cholecalciferol
Placebo Sodium Phenylbutyrate plus active cholecalciferolActive comparatorDrug: Cholecalciferol Placebo: Sodium Phenylbutyrate
Receives: Drug: Placebo Sodium Phenylbutyrate plus active cholecalciferol
Active Sodium Phenylbutyrate and placebo cholecalciferolActive comparatorDrug: Sodium Phenylbutyrate Placebo: cholecalciferol
Receives: Drug: Active Sodium Phenylbutyrate and placebo cholecalciferol
Placebo Sodium Phenylbutyrate plus placebo cholecalciferolPlacebo comparatorPlacebo Sodium Phenylbutyrate Placebo cholecalciferol
Receives: Drug: Placebo Sodium Phenylbutyrate plus placebo cholecalciferol

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Proportion of pulmonary TB patients who are culture negative in sputum in week 4

    To determine the proportion of sputum culture positive patients becoming culture negative at 1 and 2 months after adjunctive sodium phenylbutyrate and vitamin D treatment of patients for 2 months.

    Measured: week 4

  2. Difference in improvement in clinical endpoints consisting of cough clearance, percentage chest x-ray clearance, fever remission and weight increase upto 8 weeks.

    Difference in improvement in clinical endpoints consisting of:

    cough clearance (weekly to week-8 then at week 24) chest x-ray impovement (percentage lung involvement on CXR at week 8) fever remission (weekly to week-8 then at week 24) weight increase (weekly to week-8 then at week 24)

    Measured: 8 weeks

Secondary outcomes (11)

  1. Sputum smear conversion time

    Measured: weekly up to week 12; then at week 24

  2. Radiological improvement (percent lung involvement on CXR)

    Measured: week 0, 8, 12 and 24

  3. Cough clearance

    Measured: weekly up to week 12; then at week 24

  4. Weight gain

    Measured: weekly up to week 12, then at week 24

  5. Change in plasma PBA concentrations

    Measured: week 0, 4, 8, 12

  6. Change in plasma 25(OH)D3 concentration

    Measured: week 0, 4, 8, 12, 24

  7. Clinical failure and default independently and 'death or clinical failure or default'

    Measured: week 24

  8. Hypercalcaemia (serum calcium > 2.6 mmol/L)

    Measured: week 0, 2, 4, 8, 12

  9. Gastrointestinal side effects

    Measured: weekly to week 12 then at week 24

  10. Immunological improvement (LL-37 in macrophages)

    Measured: week 0, 4, 8, 12

  11. Functional immunological improvement (killing by macrophages)

    Measured: week 0, 4, 8, 12

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted18 Apr 2012 (estimated)
  2. Study startDec 2010
  3. Primary completionDec 2014
  4. Study completionDec 2014

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Factorial
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
288 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01580007
Sponsor's protocol ID
PR-09068
Status last verified
Jan 2014
First submitted
17 Apr 2012
Last updated
13 Feb 2015
Results posted
No
Data monitoring committee
Yes

Publications

  • Rekha RS, Mily A, Sultana T, Haq A, Ahmed S, Mostafa Kamal SM, van Schadewijk A, Hiemstra PS, Gudmundsson GH, Agerberth B, Raqib R. Immune responses in the treatment of drug-sensitive pulmonary tuberculosis with phenylbutyrate and vitamin D3 as host directed therapy. BMC Infect Dis. 2018 Jul 4;18(1):303. doi: 10.1186/s12879-018-3203-9.

    PubMed 29973153

  • Mily A, Rekha RS, Kamal SM, Arifuzzaman AS, Rahim Z, Khan L, Haq MA, Zaman K, Bergman P, Brighenti S, Gudmundsson GH, Agerberth B, Raqib R. Significant Effects of Oral Phenylbutyrate and Vitamin D3 Adjunctive Therapy in Pulmonary Tuberculosis: A Randomized Controlled Trial. PLoS One. 2015 Sep 22;10(9):e0138340. doi: 10.1371/journal.pone.0138340. eCollection 2015.

    PubMed 26394045

  • Mily A, Rekha RS, Kamal SM, Akhtar E, Sarker P, Rahim Z, Gudmundsson GH, Agerberth B, Raqib R. Oral intake of phenylbutyrate with or without vitamin D3 upregulates the cathelicidin LL-37 in human macrophages: a dose finding study for treatment of tuberculosis. BMC Pulm Med. 2013 Apr 16;13:23. doi: 10.1186/1471-2466-13-23.

    PubMed 23590701

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Active Sodium Phenylbutyrate and active cholecalciferol in people with Pulmonary Tuberculosis, run by International Centre for Diarrhoeal Disease Research, Bangladesh at 1 site in Bangladesh.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 13 Feb 2015. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Bangladesh. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Proportion of pulmonary TB patients who are culture negative in sputum in week 4 (time frame: week 4). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01580007, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Feb 2015.

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