Clinical trial NCT01580007: Clinical Trial of Phenylbutyrate and Vitamin D in Tuberculosis (TB)
Official title: Clinical Trial of Oral Phenylbutyrate and Vitamin D Adjunctive Therapy in Pulmonary Tuberculosis in Bangladesh: a Pilot Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Pulmonary Tuberculosis
Keywords: tuberculosis
phenylbutyrate
vitamin D
cathelicidin
antimicrobial peptide
in adults
Lead sponsor: International Centre for Diarrhoeal Disease Research, Bangladesh
Sponsor class: OTHER
Collaborators: name: Karolinska Institutet
name: National Institute of Diseases of the Chest and Hospital, Bangladesh
name: University of Iceland
First posted: 2012-04-18
Enrollment: 288
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

Brief 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. 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.

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

Eligibility criteria: Inclusion Criteria:

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

Exclusion Criteria:

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

Primary outcomes:
measure: Proportion of pulmonary TB patients who are culture negative in sputum in week 4
timeFrame: week 4
measure: Difference in improvement in clinical endpoints consisting of cough clearance, percentage chest x-ray clearance, fever remission and weight increase upto 8 weeks.
timeFrame: 8 weeks
Secondary outcomes:
measure: Sputum smear conversion time
timeFrame: weekly up to week 12; then at week 24
measure: Radiological improvement (percent lung involvement on CXR)
timeFrame: week 0, 8, 12 and 24
measure: Cough clearance
timeFrame: weekly up to week 12; then at week 24
measure: Weight gain
timeFrame: weekly up to week 12, then at week 24
measure: Change in plasma PBA concentrations
timeFrame: week 0, 4, 8, 12
measure: Change in plasma 25(OH)D3 concentration
timeFrame: week 0, 4, 8, 12, 24
measure: Clinical failure and default independently and 'death or clinical failure or default'
timeFrame: week 24
measure: Hypercalcaemia (serum calcium > 2.6 mmol/L)
timeFrame: week 0, 2, 4, 8, 12
measure: Gastrointestinal side effects
timeFrame: weekly to week 12 then at week 24
measure: Immunological improvement (LL-37 in macrophages)
timeFrame: week 0, 4, 8, 12
measure: Functional immunological improvement (killing by macrophages)
timeFrame: week 0, 4, 8, 12
Other outcomes:
Locations:
city: Dhaka
country: Bangladesh
facility: National Institute of Diseases of Chest and Hospital (NIDCH)
Study officials:
References:
citation: 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.
citation: 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.
citation: 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.