Early combined immunosuppression for the management of Crohn's disease (REACT): a cluster randomised controlled trial.
BACKGROUND
Conventional management of Crohn's disease features incremental use of therapies. However, early combined immunosuppression (ECI), with a TNF antagonist and antimetabolite might be a more effective strategy. We compared the efficacy of ECI with that of conventional management for treatment of Crohn's disease.


METHODS
In this open-label cluster randomised controlled trial (Randomised Evaluation of an Algorithm for Crohn's Treatment, REACT), we included community gastroenterology practices from Belgium and Canada that were willing to be assigned to either of the study groups, participate in all aspects of the study, and provide data on up to 60 patients with Crohn's disease. These practices were randomly assigned (1:1) to either ECI or conventional management. The computer-generated randomisation was minimised by country and practice size. Up to 60 consecutive adult patients were assessed within practices. Patients who were aged 18 years or older; documented to have Crohn's disease; able to speak or understand English, French, or Dutch; able to access a telephone; and able to provide written informed consent were followed up for 2 years. The primary outcome was the proportion of patients in corticosteroid-free remission (Harvey-Bradshaw Index score ≤ 4) at 12 months at the practice level. This trial is registered with ClinicalTrials.gov, number NCT01030809.


RESULTS
This study took place between March 15, 2010, and Oct 1, 2013. Of the 60 practices screened, 41 were randomly assigned to either ECI (n=22) or conventional management (n=19). Two practices (one in each group) discontinued because of insufficient resources. 921 (85%) of the 1084 patients at ECI practices and 806 (90%) of 898 patients at conventional management practices completed 12 months follow-up and were included in an intention-to-treat analysis. The 12 month practice-level remission rates were similar at ECI and conventional management practices (66·0% [SD 14·0] and 61·9% [16·9]; adjusted difference 2·5%, 95% CI -5·2% to 10·2%, p=0·5169). The 24 month patient-level composite rate of major adverse outcomes defined as occurrence of surgery, hospital admission, or serious disease-related complications was lower at ECI practices than at conventional management practices (27·7% and 35·1%, absolute difference [AD] 7·3%, hazard ratio [HR]: 0·73, 95% CI 0·62 to 0·86, p=0·0003). There were no differences in serious drug-related adverse events.


CONCLUSIONS
Although ECI was not more effective than conventional management for controlling Crohn's disease symptoms, the risk of major adverse outcomes was lower. The latter finding should be considered hypothesis-generating for future trials. ECI was not associated with an increased risk of serious drug-related adverse events or mortality.


BACKGROUND
AbbVie Pharmaceuticals.
Robarts Clinical Trials Inc, Robarts Research Institute, London, ON, Canada; Department of Medicine, University of Western Ontario, London, ON, Canada.
Reena
R
Khanna
Department of Gastroenterology, St Paul's Hospital, Vancouver, BC, Canada.
Brian
B
Bressler
Robarts Clinical Trials Inc, Robarts Research Institute, London, ON, Canada; Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA.
Barrett G
BG
Levesque
Robarts Clinical Trials Inc, Robarts Research Institute, London, ON, Canada; Department of Epidemiology and Biostatistics, University of Western Ontario, London, ON, Canada.
Guangyong
G
Zou
Robarts Clinical Trials Inc, Robarts Research Institute, London, ON, Canada.
Larry W
LW
Stitt
Division of Gastroenterology, Mount Sinai Hospital, Toronto, ON, Canada.
Gordon R
GR
Greenberg
Division of Gastroenterology and Hepatology, Department of Medicine, University of Calgary, Calgary, AB, Canada.
Remo
R
Panaccione
Division of Gastroenterology, McGill University Health Centre, McGill University, Montreal, QC, Canada.
Alain
A
Bitton
Laval University, CHAUQ, Hôpital du St-Sacrement, Quebec City, QC, Canada.
Pierre
P
Paré
Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders, Leuven, Belgium.
Séverine
S
Vermeire
Robarts Clinical Trials Inc, Robarts Research Institute, London, ON, Canada; Department of Gastroenterology, Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands.
Geert
G
D'Haens
Division of Gastroenterology, Dalhousie University, Halifax, NS, Canada.
Donald
D
MacIntosh
Robarts Clinical Trials Inc, Robarts Research Institute, London, ON, Canada; Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA.
William J
WJ
Sandborn
Robarts Clinical Trials Inc, Robarts Research Institute, London, ON, Canada; Department of Epidemiology and Biostatistics, University of Western Ontario, London, ON, Canada.
Allan
A
Donner
Robarts Clinical Trials Inc, Robarts Research Institute, London, ON, Canada.
Margaret K
MK
Vandervoort
Robarts Clinical Trials Inc, Robarts Research Institute, London, ON, Canada.
Joan C
JC
Morris
Robarts Clinical Trials Inc, Robarts Research Institute, London, ON, Canada; Department of Medicine, University of Western Ontario, London, ON, Canada; Department of Epidemiology and Biostatistics, University of Western Ontario, London, ON, Canada. Electronic address: brian.feagan@robartsinc.com.
Brian G
BG
Feagan
D000068879:Adalimumab / Q000008:administration & dosage / Q000627:therapeutic use; D000328:Adult; D000963:Antimetabolites / Q000008:administration & dosage / Q000627:therapeutic use; D001379:Azathioprine / Q000008:administration & dosage / Q000627:therapeutic use; D003424:Crohn Disease / Q000628:therapy*; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy / Q000379:methods*; D000069285:Infliximab / Q000008:administration & dosage / Q000627:therapeutic use; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage / Q000627:therapeutic use; D008727:Methotrexate / Q000008:administration & dosage / Q000627:therapeutic use; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
D000963:Antimetabolites; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D015122:Mercaptopurine; D000068879:Adalimumab; D001379:Azathioprine; D008727:Methotrexate