Personalizing treatment selection in Crohn’s disease: a meta-analysis of individual participant data from fifteen randomized controlled trials

Abstract

ABSTRACTBACKGROUNDMeta-analyses have found anti-TNF drugs to be the best treatment, on average, for Crohn’s disease. We performed a subgroup analysis to determine if it is possible to achieve more efficacious outcomes by individualizing treatment selection.METHODSWe obtained participant-level data from 15 trials of FDA-approved treatments (N=5703). We used sequential regression and simulation to model week six disease activity as a function of drug class, demographics, and disease-related features. We performed hypothesis testing to define subgroups based on rank-ordered preferences for treatments. We queried health records from University of California Health (UCH) to estimate the impacts these models could have on practice. We computed the sample size needed to prospectively test a prediction of our models.RESULTS45% of the participants (N=2561) showed greater efficacy with at least one drug class (anti-TNF, anti-IL-12/23, anti-integrin) over another. They were classifiable into 6 subgroups, two showing greatest efficacy with anti-TNFs (36%, N=2064). Women over 50 showed superior responses with anti-IL-12/23s. Although they represented only 2% of the trial-based cohort, 25% of Crohn’s patients at UCH are women over 50 (N=5,647), consistent with potential selection bias in trials. Moreover, 75% of biologic-exposed women over 50 did not receive an anti-IL12/23 first-line, supporting the potential value of these models. A future trial with 250 patients per arm will have 97% power to confirm the superiority of anti-IL-12/23s over anti-TNFs in these patients. A treatment recommendation tool is available athttps://crohnsrx.org.CONCLUSIONSPersonalizing treatment can improve outcomes in Crohn’s disease. Future work is needed to confirm these findings, and improve representativeness in Crohn’s trials.WHAT YOU NEED TO KNOWBACKGROUND AND CONTEXTPatients with Crohn’s disease likely harbor different underlying susceptibilities to different treatments. Yet, clinical practice today is guided by cohort-averaging studies that ignore patient-level variation. Personalized treatment strategies are needed.NEW FINDINGSWe re-analyzed data from 15 trials to model individual outcomes to different treatments. We found 6 subgroups, including women over 50 whose superior responses to anti-IL-12/23s deviate from the majority trend.LIMITATIONSThis was a meta-analysis of trial data; confirmatory prospective studies are needed. Our models need to be updated to include recently approved treatments.CLINICAL RESEACH RELEVANCEOur findings confirm that heterogeneity of treatment effect does exist in Crohn’s disease. A future trial with 250 patients per arm is 97% powered to show that anti-IL-12/23s are more efficacious than anti-TNFs in women over 50. Incidentally, we also found evidence of possible selection bias into Crohn’s trials. Future work is needed to study and rectify this.BASIC RESEARCH RELEVANCEWe found that patients do in fact harbor different underlying susceptibilities to different treatment mechanisms of action. But the biological basis of this is unknown. Future studies designed to elucidate this may reveal new therapeutic targets in Crohn’s disease.