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

This study has been completed.
Sponsor:
Collaborators:
National Institute of Health Research and Development, Indonesia
Australian National University
Information provided by (Responsible Party):
Dr Anna Ralph, Menzies School of Health Research
ClinicalTrials.gov Identifier:
NCT00677339
First received: May 12, 2008
Last updated: January 17, 2012
Last verified: January 2012
  Purpose

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.


Condition Intervention Phase
Smear Positive Pulmonary Tuberculosis
Drug: L-arginine
Drug: Vitamin D
Drug: Placebo L-arginine
Drug: Placebo Vitamin D
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Factorial Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Phase 3 Trial of Oral L-arginine and / or Vitamin D as Adjunctive Therapies in Pulmonary Tuberculosis in Papua Province, Indonesia.

Resource links provided by NLM:


Further study details as provided by Menzies School of Health Research:

Primary Outcome Measures:
  • Proportion of pulmonary TB patients who are culture negative at 1 month [ Time Frame: 1 month ] [ Designated as safety issue: No ]
  • Difference in improvement in composite clinical endpoint comprising weight, cough clearance and FEV1 at 2 months. [ Time Frame: 2 months ] [ Designated as safety issue: No ]

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

Enrollment: 200
Study Start Date: June 2008
Study Completion Date: May 2010
Primary Completion Date: February 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: 1
Active L-arginine plus active vitamin D
Drug: L-arginine
L-arginine 6g orally daily
Other Name: Argimax
Drug: Vitamin D
Cholecalciferol 50000 IU once monthly orally
Other Name: Calciferol Strong
Active Comparator: 2
Placebo L-arginine plus active Vitamin D
Drug: Vitamin D
Cholecalciferol 50000 IU once monthly orally
Other Name: 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 Name: 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

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

Ages Eligible for Study:   15 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00677339

Locations
Indonesia
Timika Tuberculosis Clinic and Community Hospital
Timika, Papua Province, Indonesia
Sponsors and Collaborators
Menzies School of Health Research
National Institute of Health Research and Development, 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, Indonesia
Principal Investigator: Sandjaja Sandjaja, PhD National Institute of Health Research and Development, 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
  More Information

No publications provided by Menzies School of Health Research

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Dr Anna Ralph, Global and Tropical Health, Menzies School of Health Research
ClinicalTrials.gov Identifier: NCT00677339     History of Changes
Other Study ID Numbers: AVDAPT 1
Study First Received: May 12, 2008
Last Updated: January 17, 2012
Health Authority: Indonesia: Ministry of Health

Keywords provided by Menzies School of Health Research:
Tuberculosis
Adjunctive therapy
L-arginine
Nitric oxide
Vitamin D

Additional relevant MeSH terms:
Tuberculosis
Tuberculosis, Pulmonary
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Vitamin D
Ergocalciferols
Vitamins
Micronutrients
Growth Substances
Physiological Effects of Drugs
Pharmacologic Actions
Bone Density Conservation Agents

ClinicalTrials.gov processed this record on September 18, 2014