L-arginine and Vitamin D Adjunctive Therapy in Pulmonary Tuberculosis (TB)

Phase 3

Completed

• Conditions: Smear Positive Pulmonary Tuberculosis
• Interventions: Drug: L-arginine; Drug: Vitamin D; Drug: Placebo L-arginine; Drug: Placebo Vitamin D

• Registration Number: NCT00677339
• Lead Sponsor: Menzies School of Health Research

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

Study Timeline

• Study First Submitted: 2008-05-12
• Study First Submitted QC: 2008-05-13
• Study First Posted: 2008-05-14
• Study Start: 2008-06
• Primary Completion: 2010-02
• Study Completion: 2010-05
• Status Verified: 2012-01
• Last Update Submitted: 2012-01-17
• Last Update Posted: 2012-01-18

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 200

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.

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Exclusion Criteria

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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: FACTORIAL

Arm && Interventions

Group	Intervention	Description
2	Placebo L-arginine	Placebo L-arginine plus active Vitamin D
4	Placebo L-arginine	placebo L-arginine plus placebo vitamin D
3	Placebo Vitamin D	Active L-arginine plus placebo vitamin D
4	Placebo Vitamin D	placebo L-arginine plus placebo vitamin D
1	L-arginine	Active L-arginine plus active vitamin D
2	Vitamin D	Placebo L-arginine plus active Vitamin D
1	Vitamin D	Active L-arginine plus active vitamin D
3	L-arginine	Active L-arginine plus placebo vitamin D

Primary Outcome Measures

Name	Time	Method
Proportion of pulmonary TB patients who are culture negative at 1 month	1 month
Difference in improvement in composite clinical endpoint comprising weight, cough clearance and FEV1 at 2 months.	2 months

Secondary Outcome Measures

Name	Time	Method
Functional improvement measured using six minute walk test	week 0, 4, 8, 24
Quality of life assessment using modified St George Respiratory Questionnaire.	weeks 0, 4, 8, 24
Change in plasma L-arginine concentration	week 0, 2, 4, 8, 24
Change in plasma 25(OH)D3 concentration	week 0, 2, 4, 8, 24
Death, clinical failure and default independently, and 'death or clinical failure or default'.	week 24
Hypercalcaemia	week 0, 2, 4, 8, 24
Gastrointestinal side effects	weekly to week 8 then at week 24
Sputum smear conversion time	weekly to week 8 then at week 24
Radiological improvement (percentage lung involvement on CXR at 2 months).	week 0, 2, 4, 8, 24
Cough clearance	weekly to week 8 then at week 24
Difference in improvement in percent predicted FEV1 at 2 and 6 months.	weeks 0, 4, 8, 24
Weight gain	weekly to week 8 then at week 24
Immunological improvement (exhaled NO)	week 0, 2, 4, 8, 24
Immunological improvement (T cell CD3ζ expression and T cell function)	week 0, 2, 4, 24
Primary end points stratified by HIV status.	weekly to week 8 then at week 24
Primary end points stratified by baseline vitamin D and L-arginine status.	weekly to week 8 then week 24
Primary end points stratified by ethnicity (Papuan and non-Papuan patients).	weekly to week 8 then week 24

Trial Locations

Locations (1)

Timika Tuberculosis Clinic and Community Hospital; 🇮🇩 Timika, Papua Province, Indonesia