Randomised controlled trial. Comparison Of iNfliximab and ciclosporin in STeroid Resistant Ulcerative Colitis: Trial design and protocol (CONSTRUCT)

Seagrove, Anne C; Alam, M Fasihul; Alrubaiy, Laith; Cheung, WY; Clement, Clare; Cohen, David; Grey, Michelle; Hilton, Mike; Hutchings, Hayley; Morgan, Jamie; Rapport, Frances; Roberts, Stephen E.; Russell, Daphne; Russell, Ian; Thomas, Linzi; Thorne, Kymberley; Watkins, Alan; Williams, John

doi:10.1136/bmjopen-2014-005091

Cited by 31 publications

(52 citation statements)

References 48 publications

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“…We did a mixed methods, open-label, parallel-group, pragmatic randomised trial in 52 district general and teaching hospitals across England, Scotland, and Wales 10 . Potential participants were identified after unscheduled admission with severe ulcerative colitis.…”

Section: Methodsmentioning

confidence: 99%

Infliximab versus ciclosporin for steroid-resistant acute severe ulcerative colitis (CONSTRUCT): a mixed methods, open-label, pragmatic randomised trial

Williams

Alam

Alrubaiy

et al. 2016

The Lancet Gastroenterology & Hepatology

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SummaryBackgroundInfliximab 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.MethodsIn 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.FindingsBetween 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 group vs 587·0 [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 group vs 65 [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 group vs 744 [638–850] days in the ciclosporin group; p=0·251). There were no differences in serious adverse reactions (16 reactions in 14 participants receiving infliximab vs ten in nine patients receiving ciclosporin); serious adverse events (21 in 16 patients vs 25 in 17 patients); or deaths (three in the infliximab group vs none in the ciclosporin group).InterpretationThere was no significant difference between ciclosporin and infliximab in clinical effectiveness.FundingNIHR Health Technology Assessment programme.

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Section: Methodsmentioning

confidence: 99%

Infliximab versus ciclosporin for steroid-resistant acute severe ulcerative colitis (CONSTRUCT): a mixed methods, open-label, pragmatic randomised trial

Williams

Alam

Alrubaiy

et al. 2016

The Lancet Gastroenterology & Hepatology

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196

149

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“…54 However, in 2012 slower recruitment than predicted led us to seek agreement from the Trial Steering Committee (TSC), Data Monitoring and Ethics Committee (DMEC) and Health Technology Assessment (HTA) programme to revise the primary outcome and reduce the analysable sample size to 250. We also proposed to analyse the area under the curve (AUC) of scores on the CUCQ collected every 6 months up to 3 years from randomisation; and to include participants who had undergone colectomy by developing and validating a post-colectomy extension to the CUCQ, which we termed the Crohn's and Ulcerative Colitis Questionnaire with post-colectomy extension (CUCQ+).…”

Section: Sample Size and Powermentioning

confidence: 99%

“…unpredictable, more cumbersome) (54,66) that infliximab is seen as better rightly or wrongly (144, 146) necessarily know cic (211,214)…”

Section: Consultants' Views On Nurses' Preferencesmentioning

confidence: 99%

“…54 Our primary outcome measure was quality-adjusted survival (QAS) 55 weighted by participants' scores on the Crohn's and Ulcerative Colitis Questionnaire (CUCQ), our extension of the validated UK-IBDQ to include severe colitis and post-colectomy states. Secondary outcomes included two generic measures of QoL [European Quality of Life-5 Dimensions (EQ-5D) and Short Form questionnaire-12 items (SF-12)], emergency and planned colectomy rates, AEs and mortality.…”

Section: Trial Designmentioning

confidence: 99%

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Comparison Of iNfliximab and ciclosporin in STeroid Resistant Ulcerative Colitis: pragmatic randomised Trial and economic evaluation (CONSTRUCT)

Williams

Alam

Alrubaiy

et al. 2016

Health Technol Assess

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BackgroundThe efficacy of infliximab and ciclosporin in treating severe ulcerative colitis (UC) is proven, but there has been no comparative evaluation of effectiveness.ObjectiveTo compare the clinical effectiveness and cost-effectiveness of infliximab and ciclosporin in treating steroid-resistant acute severe UC.MethodBetween May 2010 and February 2013 we recruited 270 participants from 52 hospitals in England, Scotland and Wales to an open-label parallel-group, pragmatic randomised trial. Consented patients admitted with severe colitis completed baseline quality-of-life questionnaires before receiving intravenous hydrocortisone. If they failed to respond within about 5 days, and met other inclusion criteria, we invited them to participate and used a web-based adaptive randomisation algorithm to allocate them in equal proportions between 5 mg/kg of intravenous infliximab at 0, 2 and 6 weeks or 2 mg/kg/day of intravenous ciclosporin for 7 days followed by 5.5 mg/kg/day of oral ciclosporin until 12 weeks from randomisation. Further treatment was at the discretion of physicians responsible for clinical management. The primary outcome was quality-adjusted survival (QAS): the area under the curve (AUC) of scores derived from Crohn’s and Ulcerative Colitis Questionnaires completed by participants at 3 and 6 months, and then 6-monthly over 1–3 years, more frequently after surgery. Secondary outcomes collected simultaneously included European Quality of Life-5 Dimensions (EQ-5D) scores and NHS resource use to estimate cost-effectiveness. Blinding was possible only for data analysts. We interviewed 20 trial participants and 23 participating professionals. Funded data collection finished in March 2014. Most participants consented to complete annual questionnaires and for us to analyse their routinely collected health data over 10 years.ResultsThe 135 participants in each group were well matched at baseline. In 121 participants analysed in each group, we found no significant difference between infliximab and ciclosporin in QAS [mean difference in AUC/day 0.0297 favouring ciclosporin, 95% confidence interval (CI) –0.0088 to 0.0682;p = 0.129]; EQ-5D scores (quality-adjusted life-year mean difference 0.021 favouring ciclosporin, 95% CI –0.032 to 0.096;p = 0.350); Short Form questionnaire-6 Dimensions scores (mean difference 0.0051 favouring ciclosporin, 95% CI –0.0250 to 0.0353;p = 0.737). There was no statistically significant difference in colectomy rates [odds ratio (OR) 1.350 favouring infliximab, 95% CI 0.832 to 2.188;p = 0.223]; numbers of serious adverse reactions (event ratio = 0.938 favouring ciclosporin, 95% CI 0.590 to 1.493;p = 0.788); participants with serious adverse reactions (OR 0.660 favouring ciclosporin, 95% CI 0.282 to 1.546;p = 0.338); numbers of serious adverse events (event ratio 1.075 favouring infliximab, 95% CI 0.603 to 1.917;p = 0.807); participants with serious adverse events (OR 0.999 favouring infliximab, 95% CI 0.473 to 2.114;p = 0.998); deaths (all three who died received infliximab;p = 0.247) or concomitant use of immunosuppressants. The lower cost of ciclosporin led to lower total NHS costs (mean difference –£5632, 95% CI –£8305 to –£2773;p < 0.001). Interviews highlighted the debilitating effect of UC; participants were more positive about infliximab than ciclosporin. Professionals reported advantages and disadvantages with both drugs, but nurses disliked the intravenous ciclosporin.ConclusionsTotal cost to the NHS was considerably higher for infliximab than ciclosporin. Nevertheless, there was no significant difference between the two drugs in clinical effectiveness, colectomy rates, incidence of SAEs or reactions, or mortality, when measured 1–3 years post treatment. To assess long-term outcome participants will be followed up for 10 years post randomisation, using questionnaires and routinely collected data. Further studies will be needed to evaluate the efficacy and effectiveness of new anti-tumour necrosis factor drugs and formulations of ciclosporin.Trial registrationCurrent Controlled Trials ISRCTN22663589.FundingThis project was funded by the NIHR Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 20, No. 44. See the NIHR Journals Library website for further project information.

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“…The economic evaluation component was subcontracted to the Health Economics and Policy Research Unit, University of South Wales. The protocol and the results of the trial have been reported by Seagrove et al . and Williams et al .…”

Section: Introductionmentioning

confidence: 99%

Estimation of Quality-adjusted Life Years alongside clinical trials: the impact of ‘time-effects’ on trial results

Touray

2018

J Pharm Health Serv Res

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ObjectivesThe objectives were to investigate the impact of ‘time‐effect’ on the estimation of quality‐adjusted life years (QALYs) along prospective clinical trials’ outcomes using an assumed fixed time duration versus the actual time durations for each case. The ‘time’ duration is the length of time in a health state.MethodsTwo methods were used in the estimation of QALYs based using EQ‐5D 3L scores collected at specific time‐point intervals. One method used the actual time durations for each case based on CRF records, and the other used an assumed time duration and globally applied it to all the cases. Using SPSS ® software program, we used paired‐sample t‐tests to assess whether the ‘time‐effect’ can potentially affect trial results using CONSTRUCT trial data as reported in the trial results publications. The trial compared use of Infliximab with Cyclosporine for patients with Ulcerative Colitis and it involved some 270 participants.Key findingsThe results largely indicate statistically significant differences between the two methods of QALY estimations. QALYs at the respective time‐points indicate no statistical difference between the two approaches. However, the difference in terms of total QALYs between the two QALY estimation approaches is statistically significant with considerable impact on costs/QALY.ConclusionsConsidering the possible impact of the time‐effect on QALY estimations, the result implies that it can have significant implications for resources allocations decisions. In this respect, researchers have to pay due considerations to the approach they use and where possible, actual time durations must be used in QALY estimations along prospective clinical trials.

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Randomised controlled trial. Comparison Of iNfliximab and ciclosporin in STeroid Resistant Ulcerative Colitis: Trial design and protocol (CONSTRUCT)

Cited by 31 publications

References 48 publications

Infliximab versus ciclosporin for steroid-resistant acute severe ulcerative colitis (CONSTRUCT): a mixed methods, open-label, pragmatic randomised trial

Infliximab versus ciclosporin for steroid-resistant acute severe ulcerative colitis (CONSTRUCT): a mixed methods, open-label, pragmatic randomised trial

Comparison Of iNfliximab and ciclosporin in STeroid Resistant Ulcerative Colitis: pragmatic randomised Trial and economic evaluation (CONSTRUCT)

Estimation of Quality-adjusted Life Years alongside clinical trials: the impact of ‘time-effects’ on trial results

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