Clinical trial NCT00677339: L-arginine and Vitamin D Adjunctive Therapy in Pulmonary Tuberculosis (TB)
Official title: Phase 3 Trial of Oral L-arginine and / or Vitamin D as Adjunctive Therapies in Pulmonary Tuberculosis in Papua Province, Indonesia.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Smear Positive Pulmonary Tuberculosis
Keywords: Tuberculosis
Adjunctive therapy
L-arginine
Nitric oxide
Vitamin D
Lead sponsor: Menzies School of Health Research
Sponsor class: OTHER
Collaborators: name: National Institute of Health Research and Development, Ministry of Health Republic of Indonesia
name: Australian National University
First posted: 2008-05-14
Enrollment: 200
Sex: ALL
Minimum age (years): 15
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine whether adjunctive L-arginine and vitamin D can improve response to standard short course TB therapy in people with newly diagnosed pulmonary TB.

Detailed description: The two major pathways proposed to mediate macrophage mycobacterial killing in humans are the arginine-nitric oxide and Vitamin D-1,25 dihydroxyvitamin D pathways. Our aim is to determine if the key immunomodulatory agents L-arginine and vitamin D can improve the rapidity and magnitude of the microbiological and clinical response in pulmonary TB. We will test the following hypotheses in newly-diagnosed TB patients in Timika, Papua, Indonesia:

Our specific aims are to:

1. Determine whether supplementation with L-arginine and/or vitamin D is safe, and results in more rapid improvement in clinical, mycobacterial, immunological, radiological, physiological and functional measures of treatment outcome. We will randomise patients with pulmonary TB to receive, in addition to standard TB therapy, adjunctive arginine, vitamin D and / or placebo in a randomised, double-blind factorial 2x2 design. We will relate serial measurements of plasma concentrations of L-arginine and vitamin D, and immunological responses (pulmonary NO production, T cell function and phenotype) to measures of treatment outcome \[mycobacterial (sputum smear clearance and culture conversion), physiological (spirometry), clinical (symptoms and weight), radiological (chest Xray) and functional (six-minute walk test, modified St George Respiratory Questionnaire)\].
2. Determine whether pulmonary production of NO is inversely related to disease severity at presentation. Baseline and serial measures of NO production will be related to disease severity and the magnitude and rapidity of clinical response

Eligibility criteria: Inclusion Criteria:

* Adults \>15 years with sputum smear positive pulmonary TB
* New cases only
* Agree to continue treatment in Timika for the full six month course of treatment -Not pregnant
* Consent to enroll in the study.

Exclusion Criteria:

* hypercalcaemia (ionized calcium \>1.32 mmol/L) identified at baseline
* taking arginine or vitamin D

Primary outcomes:
measure: Proportion of pulmonary TB patients who are culture negative at 1 month
timeFrame: 1 month
measure: Difference in improvement in composite clinical endpoint comprising weight, cough clearance and FEV1 at 2 months.
timeFrame: 2 months
Secondary outcomes:
measure: Change in plasma L-arginine concentration
timeFrame: week 0, 2, 4, 8, 24
measure: Change in plasma 25(OH)D3 concentration
timeFrame: week 0, 2, 4, 8, 24
measure: Death, clinical failure and default independently, and 'death or clinical failure or default'.
timeFrame: week 24
measure: Hypercalcaemia
timeFrame: week 0, 2, 4, 8, 24
measure: Gastrointestinal side effects
timeFrame: weekly to week 8 then at week 24
measure: Sputum smear conversion time
timeFrame: weekly to week 8 then at week 24
measure: Radiological improvement (percentage lung involvement on CXR at 2 months).
timeFrame: week 0, 2, 4, 8, 24
measure: Cough clearance
timeFrame: weekly to week 8 then at week 24
measure: Difference in improvement in percent predicted FEV1 at 2 and 6 months.
timeFrame: weeks 0, 4, 8, 24
measure: Weight gain
timeFrame: weekly to week 8 then at week 24
measure: Immunological improvement (exhaled NO)
timeFrame: week 0, 2, 4, 8, 24
measure: Immunological improvement (T cell CD3ζ expression and T cell function)
timeFrame: week 0, 2, 4, 24
measure: Functional improvement measured using six minute walk test
timeFrame: week 0, 4, 8, 24
measure: Quality of life assessment using modified St George Respiratory Questionnaire.
timeFrame: weeks 0, 4, 8, 24
measure: Primary end points stratified by HIV status.
timeFrame: weekly to week 8 then at week 24
measure: Primary end points stratified by baseline vitamin D and L-arginine status.
timeFrame: weekly to week 8 then week 24
measure: Primary end points stratified by ethnicity (Papuan and non-Papuan patients).
timeFrame: weekly to week 8 then week 24
Other outcomes:
Locations:
city: Timika
country: Indonesia
facility: Timika Tuberculosis Clinic and Community Hospital
state: Papua Province
Study officials:
affiliation: Menzies School of Helath Research
name: Nicholas M Anstey, MBBS
role: STUDY_DIRECTOR
affiliation: Australian National University, Canberra, Australia
name: Anna P Ralph, MBBS
role: PRINCIPAL_INVESTIGATOR
affiliation: District Ministry of Health, Timika
name: Franciscus Thio, MPPM
role: PRINCIPAL_INVESTIGATOR
affiliation: Menzies School of Health Research, Northern Territory, Australia
name: Peter Morris, MBBS
role: PRINCIPAL_INVESTIGATOR
affiliation: Papuan Community Health and Development Foundation
name: Enny Kenangalem, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Mimika District Health Authority
name: Jeanne R Poespoprodjo, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Menzies School of Health Research
name: Richard N Price, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Menzies School of Health Research
name: Tonia Woodberry, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Australian Capital Territory Department of Health
name: Paul M Kelly, MBBS
role: PRINCIPAL_INVESTIGATOR
affiliation: National Institute of Health Research and Development, Ministry of Health Republic of Indonesia
name: Emiliana Tjitra, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: National Institute of Health Research and Development, Ministry of Health Republic of Indonesia
name: Sandjaja Sandjaja, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: National Institute of Health Research and Development
name: Dina B Lolong, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: National Health and Medical Research Council (Australia) Clinical Trials Centre
name: Mark Chatfield, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Institute of Medical and Veterinary Pathology, South Australia
name: Ivan Bastian, MBBS
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ralph AP, Waramori G, Pontororing GJ, Kenangalem E, Wiguna A, Tjitra E, Sandjaja, Lolong DB, Yeo TW, Chatfield MD, Soemanto RK, Bastian I, Lumb R, Maguire GP, Eisman J, Price RN, Morris PS, Kelly PM, Anstey NM. L-arginine and vitamin D adjunctive therapies in pulmonary tuberculosis: a randomised, double-blind, placebo-controlled trial. PLoS One. 2013 Aug 14;8(8):e70032. doi: 10.1371/journal.pone.0070032. eCollection 2013.