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

Phase 3 Trial of Oral L-arginine and / or Vitamin D as Adjunctive Therapies in Pulmonary Tuberculosis in Papua Province, Indonesia.

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.

Study Overview

• Status: Completed
• Conditions: Smear Positive Pulmonary Tuberculosis
• Intervention / Treatment: Drug: L-arginine; Drug: Vitamin D; Drug: Placebo L-arginine; Drug: Placebo Vitamin D

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 Type: Interventional
• Enrollment (Actual): 200
• Phase: Phase 3

Contacts and Locations

Study Locations

• Indonesia
  • Papua Province
    • Timika, Papua Province, Indonesia
      • Timika Tuberculosis Clinic and Community Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 1; Active L-arginine plus active vitamin D	Drug: L-arginine; L-arginine 6g orally daily; Other Names: Argimax; Drug: Vitamin D; Cholecalciferol 50000 IU once monthly orally; Other Names: Calciferol Strong
Active Comparator: 2; Placebo L-arginine plus active Vitamin D	Drug: Vitamin D; Cholecalciferol 50000 IU once monthly orally; Other Names: Calciferol Strong; Drug: Placebo L-arginine; placebo L-arginine once daily
Active Comparator: 3; Active L-arginine plus placebo vitamin D	Drug: L-arginine; L-arginine 6g orally daily; Other Names: Argimax; Drug: Placebo Vitamin D; placebo vitamin D orally once monthly
Placebo Comparator: 4; placebo L-arginine plus placebo vitamin D	Drug: Placebo L-arginine; placebo L-arginine once daily; Drug: Placebo Vitamin D; placebo vitamin D orally once monthly

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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

Outcome Measure	Time Frame
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
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
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

Collaborators and Investigators

• Sponsor: Menzies School of Health Research
• Collaborators: National Institute of Health Research and Development, Ministry of Health Republic of Indonesia; Australian National University
• Investigators: Study Director: Nicholas M Anstey, MBBS, Menzies School of Helath Research; Principal Investigator: Anna P Ralph, MBBS, Australian National University, Canberra, Australia; Principal Investigator: Franciscus Thio, MPPM, District Ministry of Health, Timika; Principal Investigator: Peter Morris, MBBS, Menzies School of Health Research, Northern Territory, Australia; Principal Investigator: Enny Kenangalem, MD, Papuan Community Health and Development Foundation; Principal Investigator: Jeanne R Poespoprodjo, MD, Mimika District Health Authority; Principal Investigator: Richard N Price, MD, Menzies School of Health Research; Principal Investigator: Tonia Woodberry, PhD, Menzies School of Health Research; Principal Investigator: Paul M Kelly, MBBS, Australian Capital Territory Department of Health; Principal Investigator: Emiliana Tjitra, MD, PhD, National Institute of Health Research and Development, Ministry of Health Republic of Indonesia; Principal Investigator: Sandjaja Sandjaja, PhD, National Institute of Health Research and Development, Ministry of Health Republic of Indonesia; Principal Investigator: Dina B Lolong, MD, National Institute of Health Research and Development; Principal Investigator: Mark Chatfield, PhD, National Health and Medical Research Council (Australia) Clinical Trials Centre; Principal Investigator: Ivan Bastian, MBBS, Institute of Medical and Veterinary Pathology, South Australia

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: June 1, 2008
• Primary Completion (Actual): February 1, 2010
• Study Completion (Actual): May 1, 2010

Study Registration Dates

• First Submitted: May 12, 2008
• First Submitted That Met QC Criteria: May 13, 2008
• First Posted (Estimate): May 14, 2008

Study Record Updates

• Last Update Posted (Estimate): January 18, 2012
• Last Update Submitted That Met QC Criteria: January 17, 2012
• Last Verified: January 1, 2012

More Information

Terms related to this study

• Keywords: Vitamin D; Nitric oxide; Tuberculosis; Adjunctive therapy; L-arginine
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Tuberculosis, Pulmonary; Physiological Effects of Drugs; Micronutrients; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Vitamin D; Cholecalciferol; Vitamins; Ergocalciferols
• Other Study ID Numbers: AVDAPT 1

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No