Predictors of response to anti-IL6 monoclonal antibody therapy (siltuximab) in idiopathic multicentric Castleman disease: secondary analyses of phase II clinical trial data.

Siltuximab is the only US Food and Drug Administration-approved treatment for idiopathic multicentric Castleman disease (iMCD), a rare haematological disorder associated with substantial morbidity and mortality. Although siltuximab induces a response in a significant proportion of iMCD patients via interleukin 6 (IL6) neutralization, it is not universally effective. To develop a predictive model of response, we performed an in-depth analysis of 38 baseline laboratory parameters in iMCD patients from the phase II siltuximab trial who met criteria for treatment response or treatment failure. Univariate analyses identified eight baseline laboratory parameters that were significantly different between responders and treatment failures: albumin, immunoglobulin G (IgG), immunoglobulin A, C reactive protein (CRP), fibrinogen, haemoglobin, sodium and triglycerides. Stepwise logistic regression analysis of these candidate parameters identified a top performing model that included fibrinogen, IgG, haemoglobin and CRP. Based on cross-validation of the final multivariate logistic regression model, the model accurately discriminated responders from those who failed treatment (area under the receiver operator characteristic curve 0·86, 95% confidence interval: 0·73-0·95). All four laboratory parameters associated with response to siltuximab have biological relationships with IL6 and acute inflammation. Our model suggests that iMCD patients with laboratory evidence of an inflammatory syndrome are the best candidates for siltuximab therapy.

Trial registration in pediatric surgery trials.

BACKGROUND: Prospective clinical trial registration serves to increase transparency and to mitigate selective reporting bias. An assessment of adult surgical trials revealed poor trial registration practice with incomplete provision of information in registries and inconsistent information in the corresponding publication. The extent and completeness of pediatric surgical trial registration are unknown. We aimed to determine the proportion and adequacy of clinical trial registration in pediatric surgery trials published in 2014. METHODS: Using sensitive search strategies in MEDLINE, abstracts and full-texts of prospective pediatric intervention studies published in 2014 were screened in duplicate. Pediatric surgical trials were included. Clinical trial registration numbers obtained from publications were searched in trial registries. Data were extracted based on WHO 20-item minimum data set to determine the completeness of registration data. The proportion of registered trials was recorded and registration data were compared to reported data in the corresponding publication. RESULTS: Our search and abstract screening identified 3375 articles for full text review. Following coding, a total of 54 pediatric surgical trials were included and analyzed; 28% (15/54) of which published a registration number. In trials which reported a registration number, 40% (6/15) were retrospectively registered and 40% (6/15) had made changes to their registered primary and/or secondary outcome measures. One included published trial reported an incorrect registration number. CONCLUSIONS: Analysis of pediatric surgery trials published in 2014 revealed a poor prospective trial registration rate and incomplete registration data. Our study supports future initiatives for improved registration behaviors in pediatric surgery trials to ensure high-quality, transparent, reproducible evidence is generated. STUDY TYPE: Therapeutic (clinical trials), level II.