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

NCT01580007 | Completed Phase 2 DMC

• 1 other identifier: PR-09068
• Study Type: interventional
• Target: 288
• Locations: 1 country
• Sites: 1

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.

Conditions

Pulmonary Tuberculosis

Keywords

tuberculosis; phenylbutyrate; vitamin D; cathelicidin; antimicrobial peptide; in adults

Outcome Measures

Primary Outcomes (2)

• 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.

  week 4

• 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)

  8 weeks

Secondary Outcomes (11)

• Sputum smear conversion time

  weekly up to week 12; then at week 24

• Radiological improvement (percent lung involvement on CXR)

  week 0, 8, 12 and 24

• Cough clearance

  weekly up to week 12; then at week 24

• Weight gain

  weekly up to week 12, then at week 24

• Change in plasma PBA concentrations

  week 0, 4, 8, 12

Study Arms (4)

Active Sodium Phenylbutyrate and active cholecalciferol

ACTIVE COMPARATOR

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

Drug: Active Sodium Phenylbutyrate and active cholecalciferol

Placebo Sodium Phenylbutyrate plus active cholecalciferol

ACTIVE COMPARATOR

Drug: Cholecalciferol Placebo: Sodium Phenylbutyrate

Drug: Placebo Sodium Phenylbutyrate plus active cholecalciferol

Active Sodium Phenylbutyrate and placebo cholecalciferol

ACTIVE COMPARATOR

Drug: Sodium Phenylbutyrate Placebo: cholecalciferol

Drug: Active Sodium Phenylbutyrate and placebo cholecalciferol

Placebo Sodium Phenylbutyrate plus placebo cholecalciferol

PLACEBO COMPARATOR

Placebo Sodium Phenylbutyrate Placebo cholecalciferol

Drug: Placebo Sodium Phenylbutyrate plus placebo cholecalciferol

Interventions

Active Sodium Phenylbutyrate and active cholecalciferol DRUG

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

Also known as: triButyrate®, Vigantol oil

Active Sodium Phenylbutyrate and active cholecalciferol

Placebo Sodium Phenylbutyrate plus active cholecalciferol DRUG

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

Also known as: Vigantol oil, Placebo Phenylbutyrate

Placebo Sodium Phenylbutyrate plus active cholecalciferol

Active Sodium Phenylbutyrate and placebo cholecalciferol DRUG

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

Also known as: triButyrate®, Placebo vigantol oil

Active Sodium Phenylbutyrate and placebo cholecalciferol

Placebo Sodium Phenylbutyrate plus placebo cholecalciferol DRUG

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

Placebo Sodium Phenylbutyrate plus placebo cholecalciferol

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

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

You may not qualify if:

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

Sponsors & Collaborators

• International Centre for Diarrhoeal Disease Research, Bangladesh: lead
• Karolinska Institutet: collaborator
• National Institute of Diseases of the Chest and Hospital, Bangladesh: collaborator
• University of Iceland: collaborator

Study Sites (1)

National Institute of Diseases of Chest and Hospital (NIDCH)

Dhaka, 1212, Bangladesh

Location

Related Publications (3)

• 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.

  PMID: 29973153 DERIVED

• 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.

  PMID: 26394045 DERIVED

• 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.

  PMID: 23590701 DERIVED

MeSH Terms

Conditions

Tuberculosis, Pulmonary; Tuberculosis

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 17, 2012
• First Posted: April 18, 2012
• Study Start: December 1, 2010
• Primary Completion: December 1, 2014
• Study Completion: December 1, 2014
• Last Updated: February 13, 2015

Record last verified: 2014-01

Locations

BA (1)