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NIHR Signal Two injections are equally effective for treating flare ups of severe ulcerative colitis

Published on 6 September 2016

doi: 10.3310/signal-000295

There is little difference between the newer drug infliximab and the older ciclosporin for treating adults with severe ulcerative colitis that has become resistant to the usual treatment with steroids. Infliximab was more expensive.

Ulcerative colitis is a chronic disease where the colon and rectum become inflamed. For severe flare-ups, the standard treatment is steroids. But these do not work for almost a third of patients. In this case, NICE recommend ciclosporin, an immunosuppressant or infliximab, another drug given intravenously in hospital, if ciclosporin is contraindicated.

This NIHR-funded trial of 270 adults compared the two drugs over one to three years for treating steroid-resistant acute severe ulcerative colitis. Although infliximab was more expensive and at the time of this trial less cost effective, the patent has since expired so there may in the future be less of a cost difference.

Nurses and patients preferred infliximab as it is given intravenously over two hours on three occasions rather than ciclosporin which is given continuously over seven days before switching to tablets.

This trial is on-going, and will follow participants for ten years which will provide further insights on effectiveness over the long-term.

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Why was this study needed?

Ulcerative colitis is a chronic debilitating disease that can present rapidly and with severe symptoms, flare-ups. It affects around 150,000 people in the UK. A quarter of these people have acute severe ulcerative colitis flare-ups which require hospitalisation and usually treatment with intravenous steroids. Approximately 30% of people with acute severe ulcerative colitis do not respond to steroid treatment. This is often referred to as steroid-resistant ulcerative colitis. Many people end up requiring an ileostomy, where the damaged section of the bowel is removed and a stoma is created. This can have profound implications for patients and so any drug treatment that can avoid the need for surgery is of importance.

Infliximab and ciclosporin are known to be effective for improving severe ulcerative colitis when steroids have failed. This trial aimed to directly compare whether one is more clinically effective or cost effective than the other.

What did this study do?

This was a randomised controlled trial (CONSTRUCT) of 270 UK adults with ulcerative colitis who failed to respond to two to five days of intravenous steroids. The trial looked at quality adjusted survival, quality of life, adverse events, rates of colectomy and death.

Half the participants received intravenous infliximab over two hours at the start of the trial and at two and six weeks. The other half received continuous intravenous ciclosporin for seven days followed by oral ciclosporin up to 12 weeks.

Interviews were conducted with nurses, consultants and 20 participants about their preferences between the drugs.

Due to slow recruitment, results are based on most participants at one year, half at two years and 34 people by three years.

What did it find?

  • There was no difference between infliximab and ciclosporin on quality-adjusted survival or quality of life measures.
  • There was no difference in number of colectomies, (41% on infliximab versus 48% on ciclosporin) or mean time to colectomy (odds ratio 1.35, 95% confidence interval 0.83 to 2.19).
  • The number of serious adverse reactions was similar (16 reactions in 14 people on infliximab versus 10 in 9 people on ciclosporin) as were serious adverse events (21 in 16 people on infliximab versus 25 in 17 people on ciclosporin). There were two deaths from sepsis and one from colorectal cancer in the infliximab group and none in the ciclosporin group.
  • At 30 months, the total health service costs for ciclosporin of £14,609 were lower than £20,241 for infliximab (mean adjusted difference -£5,632, 95% confidence interval [CI] ‑£8,305 to ‑£2,773). QALY gains were similar and so ciclosporin was good value for money and had an 85% chance of being cost-effective at a wide range of willingness to pay thresholds. Technically, ciclosporin dominates infliximab at the price in 2010/13.
  • Participants were more positive about infliximab and nurses preferred it due to the resource-intensive infusion protocol for ciclosporin. Consultant views were mixed though most perceived both drugs to be effective.

What does current guidance say on this issue?

Treatment for ulcerative colitis aims to relieve symptoms during flare-ups and prevent symptoms from returning.

NICE’s 2013 ulcerative colitis guidance recommends acute severe ulcerative colitis is initially treated with intravenous corticosteroids. If this is not tolerated or contraindicated, the guidance recommends considering intravenous ciclosporin or surgery. For people who have little improvement or whose symptoms worsen within 72 hours intravenous ciclosporin can be added to intravenous corticosteroids.

A 2008 NICE technology assessment recommends infliximab for treating acute exacerbations of severely active ulcerative colitis only in people where ciclosporin is contraindicated or clinically inappropriate. NICE is currently consulting on the use of infliximab for severe ulcerative colitis.

What are the implications?

This trial of adults not responding to steroids found no significant difference between infliximab or ciclosporin for treating flare ups when looking at quality adjusted survival, quality of life, adverse events, rates of colectomy and death. Findings are consistent with a similar smaller trial of 115 participants conducted in France- the CySIF trial.

Ciclosporin was more cost-effective than infliximab, due in part to the higher cost of acquiring infliximab and continuation of the drug beyond the initial treatment regime. However, the cost of infliximab will since have reduced following the patent expiry in 2015.

This trial is on-going, and will follow participants for 10 years which will provide more detailed analysis of quality of life scores, adverse event rates and long-term survival.

Citation and Funding

Williams JG, Alam MF, Alrubaiy L, et al. Comparison Of iNfliximab and ciclosporin in Steroid Resistant Ulcerative Colitis: pragmatic randomised Trial and economic evaluation (CONSTRUCT). Health Technol Assess. 2016;20(44).

This project was funded by the National Institute for Health Research Health Technology Assessment programme (project number 06/78/03).

Bibliography

Alrubaiy L, Cheung WY, Dodds P et al. Development of a short questionnaire to assess the quality of life in Crohn's disease and ulcerative colitis. J Crohns Colitis. 2015.

NICE. Infliximab for acute exacerbations of ulcerative colitis. TA163.London: National Institute for Health and Care Excellence; 2008.

NICE. Ulcerative Colitis: management. CG166. London: National Institute for Health and Care Excellence; 2013.

NHS Choices. Ileostomy. London: Department of Health; 2016.

NHS Choices. Ulcerative colitis. London: Department of Health; 2016.

Why was this study needed?

Ulcerative colitis is a chronic debilitating disease that can present rapidly and with severe symptoms, flare-ups. It affects around 150,000 people in the UK. A quarter of these people have acute severe ulcerative colitis flare-ups which require hospitalisation and usually treatment with intravenous steroids. Approximately 30% of people with acute severe ulcerative colitis do not respond to steroid treatment. This is often referred to as steroid-resistant ulcerative colitis. Many people end up requiring an ileostomy, where the damaged section of the bowel is removed and a stoma is created. This can have profound implications for patients and so any drug treatment that can avoid the need for surgery is of importance.

Infliximab and ciclosporin are known to be effective for improving severe ulcerative colitis when steroids have failed. This trial aimed to directly compare whether one is more clinically effective or cost effective than the other.

What did this study do?

This was a randomised controlled trial (CONSTRUCT) of 270 UK adults with ulcerative colitis who failed to respond to two to five days of intravenous steroids. The trial looked at quality adjusted survival, quality of life, adverse events, rates of colectomy and death.

Half the participants received intravenous infliximab over two hours at the start of the trial and at two and six weeks. The other half received continuous intravenous ciclosporin for seven days followed by oral ciclosporin up to 12 weeks.

Interviews were conducted with nurses, consultants and 20 participants about their preferences between the drugs.

Due to slow recruitment, results are based on most participants at one year, half at two years and 34 people by three years.

What did it find?

  • There was no difference between infliximab and ciclosporin on quality-adjusted survival or quality of life measures.
  • There was no difference in number of colectomies, (41% on infliximab versus 48% on ciclosporin) or mean time to colectomy (odds ratio 1.35, 95% confidence interval 0.83 to 2.19).
  • The number of serious adverse reactions was similar (16 reactions in 14 people on infliximab versus 10 in 9 people on ciclosporin) as were serious adverse events (21 in 16 people on infliximab versus 25 in 17 people on ciclosporin). There were two deaths from sepsis and one from colorectal cancer in the infliximab group and none in the ciclosporin group.
  • At 30 months, the total health service costs for ciclosporin of £14,609 were lower than £20,241 for infliximab (mean adjusted difference -£5,632, 95% confidence interval [CI] ‑£8,305 to ‑£2,773). QALY gains were similar and so ciclosporin was good value for money and had an 85% chance of being cost-effective at a wide range of willingness to pay thresholds. Technically, ciclosporin dominates infliximab at the price in 2010/13.
  • Participants were more positive about infliximab and nurses preferred it due to the resource-intensive infusion protocol for ciclosporin. Consultant views were mixed though most perceived both drugs to be effective.

What does current guidance say on this issue?

Treatment for ulcerative colitis aims to relieve symptoms during flare-ups and prevent symptoms from returning.

NICE’s 2013 ulcerative colitis guidance recommends acute severe ulcerative colitis is initially treated with intravenous corticosteroids. If this is not tolerated or contraindicated, the guidance recommends considering intravenous ciclosporin or surgery. For people who have little improvement or whose symptoms worsen within 72 hours intravenous ciclosporin can be added to intravenous corticosteroids.

A 2008 NICE technology assessment recommends infliximab for treating acute exacerbations of severely active ulcerative colitis only in people where ciclosporin is contraindicated or clinically inappropriate. NICE is currently consulting on the use of infliximab for severe ulcerative colitis.

What are the implications?

This trial of adults not responding to steroids found no significant difference between infliximab or ciclosporin for treating flare ups when looking at quality adjusted survival, quality of life, adverse events, rates of colectomy and death. Findings are consistent with a similar smaller trial of 115 participants conducted in France- the CySIF trial.

Ciclosporin was more cost-effective than infliximab, due in part to the higher cost of acquiring infliximab and continuation of the drug beyond the initial treatment regime. However, the cost of infliximab will since have reduced following the patent expiry in 2015.

This trial is on-going, and will follow participants for 10 years which will provide more detailed analysis of quality of life scores, adverse event rates and long-term survival.

Citation and Funding

Williams JG, Alam MF, Alrubaiy L, et al. Comparison Of iNfliximab and ciclosporin in Steroid Resistant Ulcerative Colitis: pragmatic randomised Trial and economic evaluation (CONSTRUCT). Health Technol Assess. 2016;20(44).

This project was funded by the National Institute for Health Research Health Technology Assessment programme (project number 06/78/03).

Bibliography

Alrubaiy L, Cheung WY, Dodds P et al. Development of a short questionnaire to assess the quality of life in Crohn's disease and ulcerative colitis. J Crohns Colitis. 2015.

NICE. Infliximab for acute exacerbations of ulcerative colitis. TA163.London: National Institute for Health and Care Excellence; 2008.

NICE. Ulcerative Colitis: management. CG166. London: National Institute for Health and Care Excellence; 2013.

NHS Choices. Ileostomy. London: Department of Health; 2016.

NHS Choices. Ulcerative colitis. London: Department of Health; 2016.

Infliximab or ciclosporin for steroid-resistant acute severe ulcerative colitis? Results of a pragmatic randomised trial and economic evaluation

Published on 22 June 2016

Williams JG, Alam MF, Alrubaiy L, Arnott I, Clement C, Cohen D, Gordon JN, Hawthorne AB, Hilton M, Hutchings HA, Jawhari A, Longo M, Mansfield J, Morgan JM, Rapport F, Seagrove AC, Sebastian S, Shaw I, Travis SPL, Watkins A, for the CONSTRUCT investigators

Lancet The , 2016

Background 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. Methods 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. Findings 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 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). Interpretation There was no significant difference between ciclosporin and infliximab in clinical effectiveness. Funding NIHR Health Technology Assessment programme.

The severity of Ulcerative colitis was judged by the following criteria:

  • criteria from Truelove and Witts (which include more than six bowel movements da day, presence of blood in the stools and other signs of illness such as rapid pulse),
  • a Mayo score of at least 2 on endoscopic finding (where 0 is healthy, 2 represents moderate disease and 12 is severe disease)
  • or clinical judgement.

Quality-adjusted survival was determined using the area under the curve of scores from Crohn’s and Ulcerative Colitis Questionnaires completed by participants at three and six months and then six-monthly over one to three years and more frequently after surgery.

Expert commentary

This multicentre study of 270 patients with severe ulcerative colitis unresponsive to intravenous hydrocortisone shows no statistically significant difference in colectomy rate, hospital stay or quality of life in those treated with ciclosporin compared with infliximab over a three year follow-up period. Nurses found the infliximab infusions easier to administer. However, in the infliximab group, there were two deaths from “perioperative pneumonia with sepsis” out of the 28 patients who had early colectomies. Ciclosporin is less expensive and on this data still remains the preferred treatment for severe ulcerative colitis after intravenous steroids.

Dr Jeremy Nightingale, Consultant Gastroenterologist and General Physician, St Mark’s Hospital