[Overview and therapy update Crohn's disease].

INTRODUCTION: Crohn's disease (CD) is a chronic inflammatory bowel disease that can affect the entire gastrointestinal tract. The pathophysiology of CD includes a disrupted interplay of intestinal bacteria, the intestinal immune system and the intestinal surface in genetically susceptible individuals, which remains incompletely understood. Conventional therapies include steroids, but numerous advanced therapies are also available. Three tumor necrosis factor (TNF) inhibitors (infliximab, adalimumab and certolizumab pegol (Switzerland)) have been approved for MC. Additional treatment options include the interleukin (IL)-12/23 inhibitors ustekinumab and the integrin inhibitors vedolizumab. With risankizumab, a first selective IL-23 inhibitor for CD has been approved by the EMA in 2022. Moreover, the Janus kinase-1 inhibitor upadacitinib has been available for the treatment of CD in the EU since 2023. For localized CD, elective surgical resection also remains a valid option with good long-term outcomes. Perianal and fistulizing CD are difficult to treat and require a close interdisciplinary collaboration between gastroenterologists and colorectal surgeons. Surgical fistula treatment with curative intent should only be performed in well-controlled CD. The recent increase in therapeutic options in CD is encouraging, since more safe and effective therapies are now available to patients. Nevertheless, CD remains an incurable disease and so far, for all existing treatments only a fraction of patients responds to the therapy. Therefore, the development of new therapies should continue.

Early Initiation of Anti-TNF is Associated with Favourable Long-term Outcome in Crohn's Disease: 10-Year-Follow-up Data from the Swiss IBD Cohort Study.

BACKGROUND AND AIMS: The optimal timing of treatment escalation in Crohn's disease [CD] remains a challenging issue, and very little is known about its long-term development following early versus late administration of anti-TNF antibodies. The long-term outcome of Swiss CD patients was comparatively assessed in an up to 10-year follow-up, using patients participating in the Swiss Inflammatory Bowel Disease Cohort Study [SIBDCS]. METHODS: Prospectively collected SIBDCS patient data, including disease history, baseline characteristics at enrolment, and course of disease, were analysed in patients with early versus late [<24 versus ≥24 months after diagnosis] and no anti-TNF treatment. RESULTS: A reduced risk of developing bowel stenosis was found in patients who received early anti-TNF treatment. This association was seen in patients overall and also in the subgroups of CD patients without pre-existing complications [Log-rank test: p < 0.001].Furthermore, osteoporosis and anaemia were observed significantly less frequently in patients who received early anti-TNF treatment, compared with either patients who received treatment late [p < 0.001 and p = 0.046, respectively] or were never [p < 0.001 for both] treated with anti-TNF antibodies. Patients with early anti-TNF administration sought medical consultations significantly less often, including gastroenterologists in private practice [p = 0.017], ambulatory [outpatient] hospital visits [p = 0.038], and a composite of any medical visits [p = 0.001]. The percentage of patients unable to work was lowest for early-anti-TNF-treated patients, in comparison with patients who were treated late or never [3.6% vs 8.8% vs 3.7%, p = 0.016]. CONCLUSIONS: In CD patients within the SIBDCS, early anti-TNF administration was found to be associated with several indicators of a more favourable long-term outcome.

Funding characteristics of randomised clinical trials supported by the Swiss National Science Foundation: a retrospective cohort study.

AIMS OF THE STUDY: Failure to publish publicly funded research represents a waste of scarce research resources across medical disciplines and countries. In Switzerland, about 40% of randomised clinical trials (RCTs) supported by the Swiss National Science Foundation (SNSF) were not published. We aimed to describe funding characteristics of published and unpublished RCTs supported by the SNSF, to quantify the amount of money spent for unpublished studies, and to compare our results to a similar study performed in the UK. METHODS: We established a retrospective cohort of RCTs funded by the SNSF up to 2015. For each RCT proposal, two investigators independently identified corresponding publications in electronic databases and trial registries. Teams of two investigators independently extracted details from the original SNSF proposal and, if available, from trial registries or publications. In addition, we surveyed principal investigators about trial costs and additional sources of funding. RESULTS: We included 101 RCTs supported by the SNSF between 1986 and 2015. Most were single-centre RCTs with a median of 138 participants (interquartile range [IQR] 76-400). Overall, 67 (67%) principal investigators responded to our main survey questions. Median total costs per RCT were CHF 428 000 (IQR 282 000-900 000) of which the SNSF provided a median CHF 222 000 (67% of total costs, IQR 40-80%). Most investigators (70%) mentioned additional funding, mainly from their own institution or private foundations. A total of CHF 6.7 million was granted to RCTs that remained unpublished. Funding characteristics were similar to publicly funded trials in the UK. CONCLUSIONS: A third of the total SNSF grant sum spent on healthcare RCTs between 1986 and 2015 did not result in peer-reviewed scientific publications. New SNSF grant schemes might improve publication outcomes but their effectiveness needs to be evaluated.

Discontinuation and non-publication of randomised clinical trials supported by the main public funding body in Switzerland: a retrospective cohort study.

OBJECTIVE: The Swiss National Science Foundation (SNSF) promotes academic excellence through competitive selection of study proposals and rigorous evaluation of feasibility, but completion status and publication history of SNSF-supported randomised clinical trials (RCTs) remain unclear. The main objectives were to review all healthcare RCTs supported by the SNSF for trial discontinuation and non-publication, to investigate potential risk factors for trial discontinuation due to poor recruitment and non-publication, and to compare findings to other Swiss RCTs not supported by the SNSF. DESIGN: We established a retrospective cohort of all SNSF-supported RCTs for which recruitment and funding had ended in 2015 or earlier. For each RCT, two investigators independently searched corresponding publications in electronic databases. In addition, we approached all principal investigators to ask for additional publications and information about trial discontinuation. Teams of two investigators independently extracted details about study design, recruitment of participants, outcomes, analysis and sample size from the original proposal and, if available, from trial registries and publications. We used multivariable regression analysis to explore potential risk factors associated with discontinuation due to poor recruitment and with non-publication, and to compare our results with data from a previous cohort of Swiss RCTs not supported by the SNSF. RESULTS: We included 101 RCTs supported by the SNSF between 1986 and 2015. Eighty-seven (86%) principal investigators responded to our survey. Overall, 69 (68%) RCTs were completed, 26 (26%) RCTs were prematurely discontinued (all due to slow recruitment) and the completion status remained unclear for 6 (6%) RCTs. For analysing publication status, we excluded 4 RCTs for which follow-up was still ongoing and 9 for which manuscripts were still in preparation. Of the remaining 88 RCTs, 53 (60%) were published as full articles in peer-reviewed journals. Multivariable regression models suggested that discontinued trials were at higher risk for non-publication than completed trials (adjusted OR 7.61; 95% CI 2.44 to 27.09). Compared with other Swiss RCTs, the risk of discontinuation for SNSF-supported RCTs was higher than in industry-initiated RCTs (adjusted OR 3.84; 95% CI 1.68 to 8.74), but not significantly different from investigator-initiated RCTs not supported by the SNSF (adjusted OR 1.05; 95% CI 0.51 to 2.11). We found no evidence that the proportion of discontinued or unpublished RCTs decreased over the last 20 years. CONCLUSIONS: One out of four SNSF-supported RCTs were prematurely discontinued due to slow recruitment, 40% of all included RCTs and 70% of all discontinued RCTs were not published in peer-reviewed journals. There is a case to reconsider how public funding bodies such as the SNSF could improve their feasibility assessment and promote publication of RCTs irrespective of completion status.

Premature trial discontinuation often not accurately reflected in registries: comparison of registry records with publications.

BACKGROUND: One quarter of randomized clinical trials (RCTs) are prematurely discontinued and frequently remain unpublished. Trial registries can document whether a trial is ongoing, suspended, discontinued, or completed and therefore represent an important source for trial status information. The accuracy of this information is unclear. OBJECTIVE: To examine the accuracy of completion status and reasons for discontinuation documented in trial registries as compared to corresponding publications of discontinued RCTs and to investigate potential predictors for accurate trial status information in registries. METHODS: We conducted a cross-sectional study comparing information provided in publications (reference standard) to corresponding registry entries. First, we reviewed publications of RCTs providing information on both discontinuation and registration. We identified eligible publications through systematic searches of MEDLINE and EMBASE (2010-2014) and an international cohort of 1,017 RCTs initiated between 2000 and 2003. Second, pairs of investigators independently and in duplicate extracted data from publications and corresponding registry records. Third, for each discontinued RCT, we compared publication information to registry information. We used multivariable regression to examine whether accurate labeling of trials as discontinued (vs. other status) in the registry was associated with recent initiation of RCT, industry sponsorship, multicenter design, or larger sample size. RESULTS: We identified 173 publications of RCTs that were discontinued due to slow recruitment (55%), harm (16%), futility (11%), benefit (5%), other reasons (3%), or multiple reasons (9%). Trials were registered with clinicaltrials.gov (77%), isrctn.com (14%), or other registries (8%). Of the 173 corresponding registry records, 77 (45%) trials were labeled as discontinued and 57 (33%) provided a reason for discontinuation (of which 53, 93%, provided the same reason as in the publication). Labeling of discontinued trials as discontinued (vs. other label) in corresponding trial registry records improved over time (adjusted odds ratio 1.16 per year, confidence interval 1.04-1.30) and was possibly associated with industry sponsorship (2.01, 0.99-4.07) but unlikely with multicenter status (0.81, 0.32-2.04) or sample size (1.07, 0.89-1.29). CONCLUSIONS: Less than half of published discontinued RCTs were accurately labelled as discontinued in corresponding registry records. One-third of registry records provided a reason for discontinuation. Current trial status information in registries should be viewed with caution.