Infliximab versus ciclosporin for steroid-resistant acute severe ulcerative colitis (CONSTRUCT): a mixed methods, open-label, pragmatic randomised trial.
Infliximab and ciclosporin are of similar efficacy in treating acute severe ulcerative colitis, but there has been no comparative evaluation of their relative clinical effectiveness and cost-effectiveness.



In this mixed methods, open-label, pragmatic randomised trial, we recruited consenting patients aged 18 years or older at 52 district general and teaching hospitals in England, Scotland, and Wales who had been admitted, unscheduled, with severe ulcerative colitis and failed to respond to intravenous hydrocortisone within about 5 days. Patients were randomly allocated (1:1) to receive either infliximab (5 mg/kg intravenous infusion given over 2 h at baseline, and again at 2 weeks and 6 weeks after the first infusion) or ciclosporin (2 mg/kg per day by continuous infusion for up to 7 days, followed by twice-daily tablets delivering 5·5 mg/kg per day for 12 weeks). Randomisation used a web-based password-protected site, with a dynamic algorithm to generate allocations on request, thus protecting against investigator preference or other subversion, while ensuring that each trial group was balanced by centre, which was the only stratification used. Local investigators and participants were aware of the treatment allocated, but the chief investigator and analysts were masked. Analysis was by treatment allocated. The primary outcome was quality-adjusted survival-ie, the area under the curve (AUC) of scores from the Crohn's and Ulcerative Colitis Questionnaire (CUCQ) completed by participants at baseline, 3 months, and 6 months, then every 6 months from 1 year to 3 years. This trial is registered with the ISRCTN Registry, number ISRCTN22663589.



Between June 17, 2010, and Feb 26, 2013, 270 patients were recruited. 135 patients were allocated to the infliximab group and 135 to the ciclosporin group. 121 (90%) patients in each group were included in the analysis of the primary outcome. There was no significant difference between groups in quality-adjusted survival (mean AUC 564·0 [SD 241·9] in the infliximab groupvs587·0 [226·2] in the ciclosporin group; mean adjusted difference 7·9 [95% CI -22·0 to 37·8]; p=0·603). Likewise, there were no significant differences between groups in the secondary outcomes of CUCQ scores, EQ-5D, or SF-6D scores; frequency of colectomy (55 [41%] of 135 patients in the infliximab groupvs65 [48%] of 135 patients in the ciclosporin group; p=0·223); or mean time to colectomy (811 [95% CI 707-912] days in the infliximab groupvs744 [638-850] days in the ciclosporin group; p=0·251). There were no differences in serious adverse reactions (16 reactions in 14 participants receiving infliximabvsten in nine patients receiving ciclosporin); serious adverse events (21 in 16 patientsvs25 in 17 patients); or deaths (three in the infliximab groupvsnone in the ciclosporin group).



There was no significant difference between ciclosporin and infliximab in clinical effectiveness.



NIHR Health Technology Assessment programme.
Swansea University Medical School, Swansea, UK.
John G
JG
Williams
College of Human and Health Sciences, Swansea University, Swansea, UK.
M Fasih
MF
Alam
Swansea University Medical School, Swansea, UK.
Laith
L
Alrubaiy
NHS Lothian, Western General Hospital, Edinburgh, UK.
Ian
I
Arnott
Swansea University Medical School, Swansea, UK.
Clare
C
Clement
University of South Wales, Pontypridd, UK.
David
D
Cohen
Hampshire Hospitals NHS Foundation Trust, Royal Hampshire County Hospital, Winchester, UK.
John N
JN
Gordon
Cardiff and Vale University Health Board, University Hospital of Wales, Cardiff, UK.
A Barney
AB
Hawthorne
Swansea University Medical School, Swansea, UK.
Mike
M
Hilton
Swansea University Medical School, Swansea, UK.
Hayley A
HA
Hutchings
National Institute for Health Research (NIHR), Nottingham Digestive Diseases Biomedical Research Unit, Nottingham University Hospital NHS Trust, Nottingham, UK.
Aida U
AU
Jawhari
College of Human and Health Sciences, Swansea University, Swansea, UK.
Mirella
M
Longo
The Newcastle upon Tyne Hospitals NHS Foundation Trust, Royal Victoria Infirmary, Newcastle upon Tyne, UK.
John
J
Mansfield
Swansea University Medical School, Swansea, UK.
Jayne M
JM
Morgan
Swansea University Medical School, Swansea, UK.
Frances
F
Rapport
Swansea University Medical School, Swansea, UK.
Anne C
AC
Seagrove
Hull and East Yorkshire Hospitals NHS Trust, Hull, UK.
Shaji
S
Sebastian
Gloucestershire Hospitals NHS Foundation Trust, Gloucester, UK.
Ian
I
Shaw
Translational Gastroenterology Unit, Oxford University Hospitals NHS Trust, Oxford, UK.
Simon P L
SP
Travis
Swansea University Medical School, Swansea, UK.
Alan
A
Watkins
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D003093:Colitis, Ulcerative / Q000188:drug therapy* / Q000191:economics; D003362:Cost-Benefit Analysis; D016572:Cyclosporine / Q000191:economics / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006854:Hydrocortisone / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000191:economics / Q000627:therapeutic use*; D000069285:Infliximab / Q000191:economics / Q000627:therapeutic use*; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D012720:Severity of Illness Index; D016896:Treatment Outcome; D006113:United Kingdom; D055815:Young Adult
D007166:Immunosuppressive Agents; D016572:Cyclosporine; D000069285:Infliximab; D006854:Hydrocortisone