title: GI-REASONS: a novel 6-month, prospective, randomized, open-label, blinded endpoint (PROBE) trial.
abstract: OBJECTIVE
  Because of the limitations of randomized controlled trials (RCTs) and observational studies, a prospective, randomized, open-label, blinded endpoint (PROBE) study may be an appropriate alternative, as the design allows the assessment of clinical outcomes in clinical practice settings. The Gastrointestinal (GI) Randomized Event and Safety Open-Label Nonsteroidal Anti-inflammatory Drug (NSAID) Study (GI-REASONS) was designed to reflect standard clinical practice while including endpoints rigorously evaluated by a blinded adjudication committee. The objective of this study was to assess if celecoxib is associated with a lower incidence of clinically significant upper and/or lower GI events than nonselective NSAIDs (nsNSAIDs) in standard clinical practice.
  
  
  METHODS
  This was a PROBE study carried out at 783 centers in the United States, where a total of 8,067 individuals aged ≥ 55 years, requiring daily NSAIDs to treat osteoarthritis, participated. The participants were randomized to celecoxib or nsNSAIDs (1:1) for 6 months and stratified by Helicobacter pylori status. Treatment doses could be adjusted as per the United States prescribing information; patients randomized to nsNSAIDs could switch between nsNSAIDs; crossover between treatment arms was not allowed, and patients requiring aspirin at baseline were excluded. The primary outcome was the incidence of clinically significant upper and/or lower GI events.
  
  
  RESULTS
  Significantly more nsNSAID users met the primary endpoint (2.4% (98/4,032) nsNSAID patients and 1.3% (54/4,035) celecoxib patients; odds ratio, 1.82 (95% confidence interval, 1.31-2.55); P = 0.0003). Moderate to severe abdominal symptoms were experienced by 94 (2.3%) celecoxib and 138 (3.4%) nsNSAID patients (P=0.0035). Other non-GI adverse events were similar between treatment groups. One limitation is the open-label design, which presents the possibility of interpretive bias.
  
  
  CONCLUSIONS
  Celecoxib was associated with a lower risk of clinically significant upper and/or lower GI events than nsNSAIDs. Furthermore, this trial represents a successful execution of a PROBE study, where therapeutic options and management strategies available in clinical practice were incorporated into the rigor of a prospective RCT.
authors: University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. Byron.Cryer@UTSouthwestern.edu
authors: Byron
authors: B
authors: Cryer
authors: Chunming
authors: C
authors: Li
authors: Lee S
authors: LS
authors: Simon
authors: Gurkirpal
authors: G
authors: Singh
authors: Martin J
authors: MJ
authors: Stillman
authors: Manuela F
authors: MF
authors: Berger
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects* / Q000627:therapeutic use; D000068579:Celecoxib; D052246:Cyclooxygenase 2 Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D005260:Female; D006471:Gastrointestinal Hemorrhage / Q000139:chemically induced*; D041981:Gastrointestinal Tract / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D010003:Osteoarthritis / Q000188:drug therapy*; D011446:Prospective Studies; D011720:Pyrazoles / Q000009:adverse effects* / Q000627:therapeutic use; D013276:Stomach Ulcer / Q000139:chemically induced*; D013449:Sulfonamides / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D000068579:Celecoxib
references: Ann Intern Med. 1995 Aug 15;123(4):241-9
references: 7611589
references: Arch Intern Med. 1994 Feb 14;154(3):311-6
references: 8297198
references: Epidemiology. 2004 Sep;15(5):615-25
references: 15308962
references: Blood Press. 1992 Aug;1(2):113-9
references: 1366259
references: N Engl J Med. 1999 Jun 17;340(24):1888-99
references: 10369853
references: Hypertens Res. 2009 Feb;32(2):109-14
references: 19262468
references: Am Heart J. 2009 Apr;157(4):606-12
references: 19332185
references: Gut. 2006 Dec;55(12):1731-8
references: 16687434
references: World J Gastroenterol. 2006 Jun 28;12(24):3789-92
references: 16804960
references: Epidemiology. 1997 Jan;8(1):18-24
references: 9116088
references: Aliment Pharmacol Ther. 2007 May 15;25(10):1211-22
references: 17451567
references: Lancet. 2010 Jul 17;376(9736):173-9
references: 20638563
references: Arch Intern Med. 1996 Jul 22;156(14):1530-6
references: 8687261
references: Pain. 2004 Dec;112(3):254-266
references: 15561380
references: Pharmacoepidemiol Drug Saf. 2001 Oct-Nov;10(6):517-24
references: 11828834
references: Lancet. 2004 Aug 21-27;364(9435):665-74
references: 15325831
references: Lancet. 2006 Nov 18;368(9549):1771-81
references: 17113426
references: Am J Med. 2006 Mar;119(3):255-66
references: 16490472
references: Clin Gastroenterol Hepatol. 2005 Feb;3(2):133-41
references: 15704047
references: Am J Gastroenterol. 2009 Jul;104(7):1633-41
references: 19574968
references: N Engl J Med. 2000 Nov 23;343(21):1520-8, 2 p following 1528
references: 11087881
references: J Rheumatol. 2010 Jan;37(1):167-74
references: 19884267
references: JAMA. 2000 Sep 13;284(10):1247-55
references: 10979111
references: Lancet. 2007 Feb 10;369(9560):465-73
references: 17292766
references: Gastroenterology. 2001 Feb;120(3):594-606
references: 11179238