A PROSPECTIVE,OPEN RANDOMIZED,PARALLEL-GROUP STUDY TO EVALUATE THE OUTCOME OF DISCONTINUING vs CONTINUING antiTNF IN UC PATIENTS IN REMISS

Ulcerative colitis is a chronic inflammatory disease of the colon. The main symptom of the disease is diarrhoea, which can be bloody if the inflammation is severe. The majority of patients have mild inflammation that can be treated with mild anti-inflammatory medications such as mesalazine tablets or short courses of cortisone tablets. 30-40% may have more severe inflammation in periods and then need additional treatment with immunosuppressive drugs such as azathioprine and biological drugs. The most widely used biological drugs are TNF inhibitors that block Tumor necrosis factor alpha, an important inflammatory signaling substance in the body. In Norway, 3 different TNF alpha inhibitors are available for ulcerative colitis: Intravenous hospital treatment with infliximab, as well as subcutaneous home treatment with adalimumab and golimumab. Immunosuppressive drugs are expensive and can have unwanted side effects, such as an increased risk of infections and cancer. There is therefore a desire both among patients and healthcare personnel to end such treatment in a safe way in patients who have achieved freedom from the disease. The aim of the BIOSTOP study is to find out more about who can safely stop treatment with TNF inhibitors, as well as how and when in the course of the disease such treatment should be stopped. The study will also map how many people have a relapse of ulcerative colitis inflammation of the bowel, how many have to restart TNF inhibitors and the effect of restarting treatment. Through a wide range of samples - from blood, faeces, intestinal mucosa - we hope to find good future predictors for who can stop treatment and who should have maintenance treatment for several years. We hope that the study can help form the basis for new international guidelines for the use of TNF inhibitor treatment in ulcerative colitis. Current study participants are ulcerative colitis patients who have used TNF inhibitors for at least 1 year, and have been disease-free for the last 3 months on stable doses of TNF inhibitors and other anti-inflammatory medications. In order to be included in the study, a binocular examination of the patient's large intestine (colonoscopy) must be carried out, which confirms that the mucosa is free of inflammation. The included patients will be randomized to either continue with or to stop TNF inhibitors for the next 2 years. Both patient groups will be followed up closely at the hospital outpatient clinic and receive rapid examination and treatment in case of recurrence of bowel inflammation. In the BIOSTOP study, we will examine whether after 2 years the patients who stop taking TNF inhibitors do just as well as those who continue. Those who restart TNF inhibitors due to relapse are also included in the assessment. After 2 years, patients in both groups who have been persistently disease-free since the start of the study must continue without TNF inhibitor treatment for a further 2 years. They will be followed up in the same way as in the first randomized part of the study until the final evaluation after a total inclusion period of 4 years. Participation is of course voluntary. Those patients who refuse will receive the same good follow-up at their local gastroenterology department as before. But if they want to stop the medicine outside the study, we currently do not know how to advise our patients if they ask. International guidelines will not be published until the results of BIOSTOP and/or other similar studies are available. Status for the BIOSTOP study as of 01.07.23: The inclusion period was extended with REK approval, from the planned end date 31/12/2019 to 28/02/2021, due to the closure of both research activity and endoscopy activity at the inclusive Norwegian centers during the corona pandemic in 2020-21. A total of 174 patients were randomized in the period 01.06.2017-28.02.2021. 19 centers were actively inclusive. The plan was originally to randomize 200 patients. However, statistical calculations before the start of the study showed that it is sufficient if 170 patients complete the study to be able to prove the study's primary endpoint: That the proportion of patients in endoscopic remission after 2 years is as large in the intervention group as in the control group. We therefore still have good hope that the study has enough strength to prove this endpoint The last study participant finished the 2-year randomized part of the study at the end of March 2023. 100 of the 174 included study participants have also completed the 4-year end-of-study visit. As of today, it is still waiting for all participating centers to finish recording all data for the first 2 years of the study, the study management and the monitor group are following this work closely. We hope that we can close the database for data from part 1 of the study just above the summer of 2023. Article writing and publication are planned as soon as the data files are available.

Dette må avvente resultatene i studien.

In the BIOSTOP Study ulcerative colitis patients in remission after at least one year anti-TNF maintenance therapy will be included. If clinical remission is confirmed by symptom score and faecal calprotectin, a full ileocolonoscopy is performed. Mucosal healing defined as Mayo endoscopic score (MES) of 0-1 is the major inclusion criterion. Patients will be openly randomized to either discontinuing anti-TNF (intervention group) or continuing anti-TNF (control group) for 2 years. During the randomization period, patients will be monitored by repeated symptom scoring and faecal calprotectin. If suspected relapse a rectosigmoidoscopy will be done, and if confirmed endoscopic relapse defined as MES > 1, anti-TNF therapy restarted. Patient Report Outcome is registered every 6 months, and at the end of the 2 year randomization period all patients will be thoroughly evaluated including a scheduled ileocolonoscopy. Control group patients, and intervention group patients who has restarted anti-TNF, will in addition be regularly monitored by anti-TNF drug concentration and antibody measurements. Subgroup analyses of baseline endoscopic and histological scoring will be performed, to explore these factors as major predictive factors for the outcome of discontinuing anti-TNF therapy. Standardized biopsies will be obtained at every endoscopy procedure during the study. At inclusion additional mucosal, faecal and blood samples will be obtained for examination of mucosal and serologic gene expression of cytokines, possible alterations in gut microbiome and predictive genetic factors. The primary endpoint is defined as the proportion of patients in remission at 2 years in the intervention group, including the proportion of relapse patients achieving remission after restarting therapy, compared to those in remission in the control group (non-inferiority study design).