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

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

Karolinska Institutet, National Institute of Diseases of the Chest and Hospital, Bangladesh, University of Iceland

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.

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: Can improve response to standard short course TB therapy towards a rapid recovery (clinical, radiological, mycobacterial). Can induce expression of LL-37 in macrophages (immunological). 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

500 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

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

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

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

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

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.

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)

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

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.

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.

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.