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P465 Indication-specific feasibility assessment of a placebo-controlled randomised mesalazine withdrawal study for paediatric patients with ulcerative colitis

N. Croft1, W. Faubion2, D. Tierens3, J. Dewulf3, D. Bwirire3, D. Stefani-Hunyady4, F. Cataldi*5

1Blizard Institute, Barts and The London School of Medicine and Dentistry, Centre for Immunobiology, London, United Kingdom, 2Mayo Clinic, Department of Gastroenterology and Hepatology, Rochester, Minnesota, United States, 3Shire, Brussels, Belgium, 4Shire, Lexington, Massachusetts, United States, 5Shire, Gastroenterology, Lexington, Massachusetts, United States

Background

Paediatric patients (pts) with ulcerative colitis (UC) are often treated with off-label drugs, and, therefore, clinical trials are essential for establishing the safety, tolerability, and efficacy of medicinal products in children. The safety and efficacy of mesalazine (5-aminosalicylic acid; 5-ASA) in children and adolescents with UC has not been well established, and the use of placebo-controlled trials in paediatric populations may raise ethical concerns. A survey was conducted to understand the potential barriers and ethical issues surrounding a placebo-controlled randomised withdrawal trial in paediatric UC.

Methods

A questionnaire (Indication-Specific Feasibility Profile) was circulated to 34 sites (1 physician per site) from an ongoing phase 3 study protocol for paediatric UC (NCT02093663) across 8 countries. Topics covered included: number and proportion of paediatric UC pts currently being managed with 5-ASA, and disease status (for pts aged 5 to < 12 y and 12 to < 18 y); familiarity with placebo-controlled randomised withdrawal studies; acceptability of this study design for paediatric UC trials; and willingness to participate in a study of this design, and if unwilling, the reasons for declining.

Results

Out of 27 responses received, 17 completed the survey (CS), and 10 declined to complete the full survey (DS) but responded that they did not consider placebo-controlled randomised withdrawal studies ethical in paediatric UC pts. For each site, the median (range) number of pts with UC in the 5 to < 12 y and 12 to <1 8 y age groups was 20 (21–25) and 40 (14–200), respectively, and the proportion treated with mesalazine was 70% and 77%, respectively. Amongst mesalazine-treated pts, the proportion in remission in each age group was 86% and 85%, respectively. Further, 16 of 17 (94%) respondents (CS) were familiar with the placebo-controlled randomised withdrawal study design, and 21 of 27 (78%) respondents (CS + DS) found such studies to be unethical. Other reasons mentioned for not participating in these trials included difficulty obtaining pt consent/parental assent (52%); significant Institutional Review Board/Ethics Committee and/or regulatory agency issues (43%); drugs with proven efficacy available (29%); and other reasons (10%). Only 5 respondents (19%) considered placebo-controlled studies with 5-ASA acceptable in paediatric UC pts, and 1 (4%) found such studies acceptable only in the 12 to < 18 yr age group.

Conclusion

A high proportion of responding physicians considered placebo-controlled randomised withdrawal studies of 5-ASA for paediatric UC either unacceptable and/or unethical. As such, the enrolment of paediatric pts with UC into such studies will be challenging and perhaps not even feasible.