Comparative Effectiveness of Anti-TNF in Combination With Low-Dose Methotrexate vs Anti-TNF Monotherapy in Pediatric Crohn's Disease: A Pragmatic Randomized Trial.

BACKGROUND & AIMS: Tumor necrosis factor inhibitors, including infliximab and adalimumab, are a mainstay of pediatric Crohn's disease therapy; however, nonresponse and loss of response are common. As combination therapy with methotrexate may improve response, we performed a multicenter, randomized, double-blind, placebo-controlled pragmatic trial to compare tumor necrosis factor inhibitors with oral methotrexate to tumor necrosis factor inhibitor monotherapy. METHODS: Patients with pediatric Crohn's disease initiating infliximab or adalimumab were randomized in 1:1 allocation to methotrexate or placebo and followed for 12-36 months. The primary outcome was a composite indicator of treatment failure. Secondary outcomes included anti-drug antibodies and patient-reported outcomes of pain interference and fatigue. Adverse events (AEs) and serious AEs (SAEs) were collected. RESULTS: Of 297 participants (mean age, 13.9 years, 35% were female), 156 were assigned to methotrexate (110 infliximab initiators and 46 adalimumab initiators) and 141 to placebo (102 infliximab initiators and 39 adalimumab initiators). In the overall population, time to treatment failure did not differ by study arm (hazard ratio, 0.69; 95% CI, 0.45-1.05). Among infliximab initiators, there were no differences between combination and monotherapy (hazard ratio, 0.93; 95% CI, 0.55-1.56). Among adalimumab initiators, combination therapy was associated with longer time to treatment failure (hazard ratio, 0.40; 95% CI, 0.19-0.81). A trend toward lower anti-drug antibody development in the combination therapy arm was not significant (infliximab: odds ratio, 0.72; 95% CI, 0.49-1.07; adalimumab: odds ratio, 0.71; 95% CI, 0.24-2.07). No differences in patient-reported outcomes were observed. Combination therapy resulted in more AEs but fewer SAEs. CONCLUSIONS: Among adalimumab but not infliximab initiators, patients with pediatric Crohn's disease treated with methotrexate combination therapy experienced a 2-fold reduction in treatment failure with a tolerable safety profile. CLINICALTRIALS: gov, Number: NCT02772965.

Measuring PROMIS® Global Health in Early Childhood.

OBJECTIVE: Assessing general ("global") health is important to clinicians caring for patients, researchers studying patient subgroups, and epidemiologists tracking population trends. The Patient-Reported Outcomes Measurement Information System® (PROMIS®) introduced an adult self-report Global Health measure (ages 18+) in 2009 and pediatric versions (ages 5-17 years) in 2014. Our aim was to extend global health assessment to 1-5-year olds. METHODS: We used the PROMIS mixed-methods approach to develop PROMIS Early Childhood (EC) Global Health, emphasizing qualitative measure development guidance utilizing input from experts and parents. Quantitatively, we conducted two data collection waves with parents of 1-5-year olds and applied state-of-the-science measure development methods, including exploratory, confirmatory, and bi-factor analytics, particularly regarding potentially multi-dimensional Global Health item content. We conducted a series of hypothesis-based across-domain association analyses, which were more exploratory in nature, and known-groups validity analyses. RESULTS: Experts emphasized the physical, mental, and social facets of global health, and parents described the broader, overarching construct. Using Waves 1 (N = 1,400) and 2 (N = 1,057) data, we retained six items directly sourced from the age 5-17 version and two new items. The resulting 8-item PROMIS EC Global Health was sufficiently unidimensional, so we fit item responses to the graded response model for parameter estimation. This produced an 8-item scale with one total score. Across-domain associations and known-groups validity analyses largely supported our hypotheses. CONCLUSIONS: We achieved our aim to extend global health assessment to 1-5-year olds and to thereby expand the range of PROMIS life course global health assessment from children aged 1-17 years, to adults of all ages.