title: L-arginine and vitamin D adjunctive therapies in pulmonary tuberculosis: a randomised, double-blind, placebo-controlled trial.
abstract: BACKGROUND
  Vitamin D (vitD) and L-arginine have important antimycobacterial effects in humans. Adjunctive therapy with these agents has the potential to improve outcomes in active tuberculosis (TB).
  
  
  METHODS
  In a 4-arm randomised, double-blind, placebo-controlled factorial trial in adults with smear-positive pulmonary tuberculosis (PTB) in Timika, Indonesia, we tested the effect of oral adjunctive vitD 50,000 IU 4-weekly or matching placebo, and L-arginine 6.0 g daily or matching placebo, for 8 weeks, on proportions of participants with negative 4-week sputum culture, and on an 8-week clinical score (weight, FEV1, cough, sputum, haemoptysis). All participants with available endpoints were included in analyses according to the study arm to which they were originally assigned. Adults with new smear-positive PTB were eligible. The trial was registered at ClinicalTrials.gov NCT00677339.
  
  
  RESULTS
  200 participants were enrolled, less than the intended sample size: 50 received L-arginine + active vitD, 49 received L-arginine + placebo vit D, 51 received placebo L-arginine + active vitD and 50 received placebo L-arginine + placebo vitD. According to the factorial model, 99 people received arginine, 101 placebo arginine, 101 vitamin D, 99 placebo vitamin D. Results for the primary endpoints were available in 155 (4-week culture) and 167 (clinical score) participants. Sputum culture conversion was achieved by week 4 in 48/76 (63%) participants in the active L-arginine versus 48/79 (61%) in placebo L-arginine arms (risk difference -3%, 95% CI -19 to 13%), and in 44/75 (59%) in the active vitD versus 52/80 (65%) in the placebo vitD arms (risk difference 7%, 95% CI -9 to 22%). The mean clinical outcome score also did not differ between study arms. There were no effects of the interventions on adverse event rates including hypercalcaemia, or other secondary outcomes.
  
  
  CONCLUSIONS
  Neither vitD nor L-arginine supplementation, at the doses administered and with the power attained, affected TB outcomes.
  ClinicalTrials.gov. Registry number: NCT00677339.
authors: Global and Tropical Health Division, Menzies School of Health Research, Darwin, Northern Territory, Australia. anna.ralph@menzies.edu.au
authors: Anna P
authors: AP
authors: Ralph
authors: Govert
authors: G
authors: Waramori
authors: Gysje J
authors: GJ
authors: Pontororing
authors: Enny
authors: E
authors: Kenangalem
authors: Andri
authors: A
authors: Wiguna
authors: Emiliana
authors: E
authors: Tjitra
authors: Sandjaja
authors: Dina B
authors: DB
authors: Lolong
authors: Tsin W
authors: TW
authors: Yeo
authors: Mark D
authors: MD
authors: Chatfield
authors: Retno K
authors: RK
authors: Soemanto
authors: Ivan
authors: I
authors: Bastian
authors: Richard
authors: R
authors: Lumb
authors: Graeme P
authors: GP
authors: Maguire
authors: John
authors: J
authors: Eisman
authors: Ric N
authors: RN
authors: Price
authors: Peter S
authors: PS
authors: Morris
authors: Paul M
authors: PM
authors: Kelly
authors: Nicholas M
authors: NM
authors: Anstey
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001120:Arginine / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004311:Double-Blind Method; D004338:Drug Combinations; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000096:biosynthesis; D010919:Placebos; D016896:Treatment Outcome; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000378:metabolism; D014807:Vitamin D / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D004338:Drug Combinations; D010919:Placebos; D014807:Vitamin D; D009569:Nitric Oxide; D001120:Arginine
references: Am J Respir Crit Care Med. 2006 Jul 15;174(2):208-12
references: 16627863
references: Lancet Infect Dis. 2013 Jan;13(1):77-88
references: 23257233
references: Mol Aspects Med. 2008 Dec;29(6):361-8
references: 18801384
references: COPD. 2005 Mar;2(1):75-9
references: 17136966
references: Lancet. 2011 Jan 15;377(9761):242-50
references: 21215445
references: Antimicrob Agents Chemother. 1999 Feb;43(2):403-5
references: 9925545
references: Thorax. 2010 Oct;65(10):863-9
references: 20861290
references: J Cell Sci. 2004 Apr 15;117(Pt 10):2131-40
references: 15090599
references: Front Immunol. 2011 Sep 15;2:43
references: 22566833
references: J Asthma. 2006 Dec;43(10):731-4
references: 17169823
references: J Infect Dis. 2013 Aug 15;208(4):616-26
references: 23737604
references: Am J Respir Crit Care Med. 2007 Jul 15;176(2):208-13
references: 17463418
references: Emerg Infect Dis. 2010 May;16(5):853-5
references: 20409383
references: Trends Microbiol. 2008 Jul;16(7):336-44
references: 18513971
references: Int J Tuberc Lung Dis. 2007 Oct;11(10):1101-7
references: 17945067
references: Dermatoendocrinol. 2012 Apr 1;4(2):95-100
references: 22928064
references: Int J Clin Pract. 2007 Feb;61(2):231-5
references: 17166185
references: Med J Aust. 2005 Mar 21;182(6):281-5
references: 15777143
references: Cochrane Database Syst Rev. 2008 Oct 08;(4):CD006086
references: 18843702
references: Int J Tuberc Lung Dis. 2006 Feb;10(2):172-7
references: 16499256
references: Int J Epidemiol. 2008 Feb;37(1):113-9
references: 18245055
references: BMC Infect Dis. 2013 Jan 19;13:22
references: 23331510
references: Am J Respir Crit Care Med. 2006 Aug 1;174(3):344-8
references: 16709935
references: Int J Tuberc Lung Dis. 2009 Dec;13(12):1500-6
references: 19919767
references: Annu Rev Pharmacol Toxicol. 2001;41:79-99
references: 11264451
references: Int J Tuberc Lung Dis. 2009 Jan;13(1):119-25
references: 19105889
references: Am J Respir Crit Care Med. 2005 Apr 15;171(8):912-30
references: 15817806
references: Int J Clin Pract. 2006 Aug;60(8):1013-9
references: 16893446
references: Indian J Tuberc. 2009 Jan;56(1):5-9
references: 19402266
references: Tuberculosis (Edinb). 2011 Sep;91(5):370-7
references: 21813328
references: Clin Infect Dis. 1997 Sep;25(3):666-70
references: 9314458
references: Lancet. 2011 Jan 15;377(9761):189-90
references: 21215444
references: J Infect Dis. 2006 Nov 15;194(10):1385-93
references: 17054067
references: Clin Infect Dis. 2012 Oct;55(7):1004-11
references: 22715179
references: Sci Transl Med. 2011 Oct 12;3(104):104ra102
references: 21998409
references: Clin Trials. 2004;1(3):315-25
references: 16279257
references: Public Health Nutr. 2009 Oct;12(10):1893-901
references: 19232150
references: J Exp Med. 2007 Oct 29;204(11):2693-704
references: 17954570
references: PLoS One. 2011 Apr 08;6(4):e18474
references: 21494617
references: Proc Natl Acad Sci U S A. 2012 Sep 18;109(38):15449-54
references: 22949664
references: Clin Infect Dis. 2008 Feb 1;46(3):443-6
references: 18173355
references: J Lab Clin Med. 2004 Jan;143(1):14-22
references: 14749681
references: Int J Tuberc Lung Dis. 2013 Jan;17(1):61-6
references: 23146565
references: Am J Respir Crit Care Med. 2006 Aug 1;174(3):236-7
references: 16864715
references: Int J Tuberc Lung Dis. 2010 Sep;14(9):1147-52
references: 20819260
references: J Assoc Physicians India. 1984 Feb;32(2):185-8
references: 6746514
references: FEMS Immunol Med Microbiol. 2012 Nov;66(2):265-8
references: 22827286
references: J Immunol. 2007 Jun 1;178(11):7190-8
references: 17513768
references: BMC Infect Dis. 2010;10:362
references: 21605474
references: Am J Respir Crit Care Med. 2010 Jan 1;181(1):94, author reply 95
references: 20026752
references: Science. 2006 Mar 24;311(5768):1770-3
references: 16497887
references: Lancet. 2006 Mar 18;367(9514):940-2
references: 16546543
references: Nat Immunol. 2008 Dec;9(12):1399-406
references: 18978793
references: Cell Host Microbe. 2009 Sep 17;6(3):231-43
references: 19748465
references: Am J Clin Nutr. 2005 Aug;82(2):477-82
references: 16087996
references: Am J Clin Nutr. 2007 Nov;86(5):1376-83
references: 17991649
references: Eur Respir J. 2003 Mar;21(3):483-8
references: 12662006
references: Am J Respir Crit Care Med. 2009 May 1;179(9):843-50
references: 19179490
references: Clin Sci (Lond). 1995 Feb;88(2):135-9
references: 7720336