Report from IIS Award Winner 2022: Dan Turner
Dan Turner, ECCO Member
© Dan Turner
Academia can generate high-quality paediatric data during off-label use of drugs: the example of the prospective multicentre VEDOKIDS study
Remarkably, of the numerous biologics approved in adults with IBD, only infliximab and adalimumab have been approved in children. The long delay between approval of new drugs in adults versus children leads to their extensive off-label use, in the absence of appropriate dosing and safety data. Prospective paediatric data regarding vedolizumab are limited to a small phase 2 study (n=88; HUBBLE trial) focusing on pharmacokinetics. A paediatric phase 3 trial is underway but its completion is long overdue, also since vedolizumab is easily accessible in most countries without the constraints of study protocols. With that challenge in mind, once vedolizumab received approval in adults we initiated a prospective cohort study to explore the effectiveness, dosing and safety of vedolizumab in children. The VEDOKIDS study was sponsored by ECCO, The Paediatric Porto group of ESPGHAN and Takeda. Explicit demographic, clinical and safety data were prospectively recorded, and serum was collected for drug levels and stool for faecal calprotectin.
A total of 142 children were enrolled from 17 paediatric centres, 65 (46%) with CD and 77 (54%) with UC, and are being followed through 3 years [44 (31%) children had a body weight below 40 kg]. Vedolizumab was the first biologic in 37 (26%) children, while in 105 (74%) vedolizumab was initiated after failure of another biologic agent. Disease activity improved significantly as early as week 6, with 33% and 45% of CD and UC patients, respectively, achieving clinical remission. The corresponding rates of steroid-free remission (SFR) at week 14 were 32% and 43%, respectively. SFR with calprotectin <250 was noted in 26% of UC children. In CD, 19% had a MINI score <8, a validated multi-item measure to reflect endoscopic healing (including CRP/ESR, calprotectin and a stool item).
The best predictor of week 14 remission in UC was the Paediatric Ulcerative Colitis Activity Index (PUCAI) at diagnosis, with better prediction seen at week 6 [AUC=0.85 (95% CI 0.75–0.95)]. Every 10-point increase in the PUCAI at baseline was associated with a 7% reduction in the likelihood of achieving SFR [OR=0.93 (95% CI 0.88–0.99)]; the likelihood of achieving SFR at week 14 was twice as high in those achieving SFR at week 6 [OR=2.0 (95% CI 1.6–2.5)]. In CD, the best predictors were the MINI score at baseline [AUC=0.79 (95% CI 0.64–0.94)] and clinical remission as evaluated by the weighted Paediatric Crohn Disease Activity Index at week 6 [AUC=0.78 (95% CI 0.65–0.93)], indicating that in both CD and UC the effectiveness of vedolizumab increases as the severity of disease decreases. In CD, effectiveness was not better with colonic distribution compared with small bowel disease.
The best cut-off trough drug levels in children <40 kg were >30 μg/mL at week 6 and >10 μg/mL at week 14. The dosing associated with these levels was either 200 mg/BSA or 10 mg/kg in children weighing <30 kg whereas others could be dosed as adults (300 mg). A total of 114 adverse events were reported, 32 of which were classified as possibly related to vedolizumab, but only two children (1.4%) discontinued treatment (owing to infusion reaction and leukocytoclastic vasculitis).
In the era of delayed registration trials in paediatric IBD, collaborative efforts of academic institutes with respect to prospective data collection in children treated off-label may provide the clinical data necessary to bridge the gap until the results of the phase 3 trial are available.