SPARE
Research type
Research Study
Full title
A proSpective randomized controlled trial comParing infliximAb-antimetabolites combination therapy to anti-metabolites monotheRapy and infliximab monothErapy in Crohn’s disease patients in sustained steroid-free remission on combination therapy (SPARE)
IRAS ID
173327
Contact name
Fiach O'Mahony
Contact email
fiach.o'mahony@ed.ac.uk
Eudract number
2014-002311-41
Duration of Study in the UK
3 years, 7 months, 30 days
Research summary
Research Summary
SPARE is prospective randomised controlled trial with the overall aim of assessing the practicalities of withdrawing immunemodulatory drugs in Crohn's disease. The trial aims to compare three strategies of maintenance therapy within this patient cohort. Patients with a diagnosis of luminal Crohn's disease in sustained steroid-free remission on combination therapy for at least 6 months and having been treated by a combination of anti-metabolites and infliximab for at least 1 year will be recruited to assess the effect of two withdrawal strategies in patients with Crohn’s disease. Each recruited patient will be randomised to one of three parallel arms: continuing infliximab treatment and anti-metabolite at the same dosage, discontinuing infliximab and continuing anti-metabolite at the same dosage or discontinuing anti-metabolites. Patients will be followed up every 8 weeks for a period of 2 years (24 months) with regular assessments including the Crohn’s Disease Activity Index (CDAI), adverse events, clinical examination, blood and stool samples and patient reported outcomes. In the event of a clinical relapse, the infliximab and/or anti-metabolites treatment will be adapted specifically in each study arm according to protocol. The trial addresses a question that is of daily relevance to patients and clinicians, for which there is no strong evidence.
Summary of Results
Crohn’s disease is a chronic inflammatory illness affecting the small and large intestine, which is increasingly prevalent in the developed and developing world. The cause of Crohn’s disease is uncertain, and no cure is possible - disease management is aimed at controlling inflammation, controlling symptoms, increasing quality of life. Long term or indefinite immunosuppression therapy is commonly required; and there are inevitably concerns regarding safety, costs and acceptability.
The use of drugs directed against TNF, which is an inflammatory protein involved in many inflammatory pathways, has been remarkably effective in Crohn’s disease. The first anti-TNF drug licensed in Crohn’s disease, infliximab, is still widely used, although a number of new therapies have been developed over recent years. Data generated approximately 15 years ago had suggested that the optimum effects of infliximab in Crohn’s disease was achieved if infliximab were used in combination with an immunosuppressant agent, either a thiopurine agent or methotrexate. This has become common practice throughout the world and the use of two drugs together has become known as combination therapy.
The present study aims to address a number of uncertainties in the use of combination therapy in Crohn’s disease. The primary question is whether, after a period of stable remission, patients will stay in remission and free of relapse of Crohn’s disease if either the infliximab or the immunosuppressant agent were to be discontinued.
In the present study, 211 patients with Crohn’s disease, who had been stable and free of corticosteroid therapy for more than six months on combination treatment of infliximab and an immunosuppressant were included. These patients were randomised either to continue combination therapy; or to discontinue azathioprine, remaining on infliximab alone; or to discontinue infliximab and to continue only on the immunosuppressant drug. Patients were followed up for a total period of two years. Two primary endpoints of the trial were identified – assessment of the rate of clinical relapse; and of the time spent in remission over two years. Further analyses of the data aimed at identifying those patients in whom infliximab therapy could be withdrawn with the lowest risk of relapse.
Of the 211 patients randomised, 67 were randomised to continue on combination therapy, 71 were randomised to infliximab withdrawal, continuing on immunosuppressants alone, and 69 to therapy with infliximab after stopping immunosuppressants and 4 withdrew their consent. The results demonstrated that whilst 12% of patients in the combination therapy group experienced clinical relapse in a 2 year period and 9% of the patients continuing on infliximab alone experienced relapse, the relapse rates were very significantly higher in the patients in whom infliximab was withdrawn as 36% patients in this group relapsed in this group. However, in those patients in who infliximab was withdrawn, who relapsed, the majority were then treated successfully with infliximab once again even after a period off therapy and the Crohn’s disease activity was successfully brought under control.
Formal analysis of the time spent in remission over the two years of the trial also demonstrated that the group who had the least favourable outcome were those in whom infliximab was withdrawn.
Overall, the investigators concluded that in patients with Crohn’s disease who are stable and in steroid-free remission for at least six months on a combination of infliximab and immunosuppression therapy, withdrawal of immunosuppression therapy, rather than withdrawal of infliximab may represent a preferable plan for long-term management.
This study is novel in Crohn’s disease in comparing the withdrawal of infliximab with withdrawal of immunosuppressive therapy and with continuing on combination therapy. The rate of relapse in patients stopping infliximab is broadly similar to that reported in other studies, and it does demonstrate that real thought needs to be given as to whether and when drug withdrawal of infliximab is appropriate and timely.REC name
Scotland B REC
REC reference
15/SS/0107
Date of REC Opinion
14 Jul 2015
REC opinion
Further Information Favourable Opinion