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.
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).
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.
Produced by the University of Southampton and Bazian on behalf of NIHR through the NIHR Dissemination Centre