Optimizing Treatment Selection in Crohn's Disease Using Patient-Specific Features: An Individual Participant Data Meta-Analysis of Fifteen Randomized Controlled Trials
The American Journal of Gastroenterology(2023)
Abstract
Introduction: Crohn’s disease is characterized by diverse clinical manifestations that likely reflect differences in disease biology and thus treatment susceptibility. Prior studies have found anti-tumor necrosis factor (anti-TNF) drugs to be more efficacious than other drugs based on their cohort-averaged effects. We performed a subgroup analysis to determine if it is possible to achieve even more efficacious outcomes by personalizing treatment selection. Methods: See Figure 1A-D for an overview. We obtained participant-level data from 15 trials of FDA-approved treatments (N=5703). We used sequential regression and simulation to model the week 6 Crohn’s Disease Activity Index as a function of drug class, demographics, and disease-related features. We performed post-hoc statistical hypothesis testing to classify participants into treatment subgroups, defined by distinct rank orderings of treatment efficacy for 3 drug classes (anti-TNF, anti-Integrin, anti-IL12/23). We queried health records data from University of California Health (UCH; 2012-2023) to estimate the potential impacts these could have on practice. We computed the sample size needed to prospectively test a key prediction of our models. Lastly, we prototyped a treatment recommendation tool that uses patient features as inputs. Results: 55% of all participants did not show superior efficacy with any one drug class. We classified the remainder into 6 subgroups (Table 1), 2 of which showed greatest efficacy with anti-TNFs (36%, N=2061). We also identified a subgroup of women over 50 with superior responses to anti-IL12/23s (Figure 1E). Although they represent 2% of the trial-based cohort, 25% of Crohn’s patients at UCH are women over 50 (n=5,647). During the period when all 3 drug classes were FDA-approved, 75% of biologic exposed women over 50 did not receive an anti-IL12/23 first line. We calculate that a trial with 250 subjects per arm will have 97% power to show anti-IL12/23s as being superior to anti-TNFs in this subgroup. Conclusion: Patients with Crohn’s disease likely harbor different underlying tendencies to benefit from different treatments. Prior results suggesting the superiority of anti-TNFs may reflect majority-vote methods, where many would not benefit from that drug class. Crohn’s trials appear to under-enroll many patient subgroups, including women over 50 who may benefit from anti-IL12/23s. We are releasing a decision support tool (crohnsrx.org) to facilitate early user testing in advance of confirmatory studies.Figure 1.: Study overview (A-D) and summary of subgroup analyses (E). A. Clinical trials were found using clinicaltrials.gov and sought for retrieval on the YODA and Vivli platforms. Individual participant data (IPD) from trials that collected CDAI scores at week 6 visits were then aggregated and harmonized. B. Using sequential regression and simulation, a method for normalizing clinical trial data against a common placebo rate, a placebo-attributable model and 3 drug-attributable models - anti-integrin, anti-interleukin-12/23, and anti-TNF - were developed. Disease activity reduction was partitioned into placebo attributable (square), and drug-attributable (circle) effects based on baseline covariates (age, sex, BMI, etc.). IPD (solid lines) were used to predict or simulate data (dashed lines). C. The drug-attributable models were utilized to simulate patient-level outcomes post-treatment (counterfactuals). Pairwise t-tests (p < 0·05) were conducted to compare and rank the mean responses for all drug classes - anti-integrin vs anti-interleukin-12/23, anti-integrin vs anti-TNF, and anti-interleukin-12/23 vs anti-TNF - and assign patients into 1 of 7 subgroup memberships (see Table 3). D. Lastly, the models were re-packaged into a prototype decision support tool that uses manual inputs and optionally, OMOP-formatted data, to recommend treatments for individual patients. E. Detailed comparison of 3 major subgroup cohorts found in the trial-based cohort (N=5703): prefer anti-TNF only (N = 2061, red), prefer anti-TNF or anti-IL-12/23 (N = 355, blue), and prefer anti-IL-12/23 only (N = 139, green). The first row of bar plots show the average placebo (P) and drug-class (D) attributable effects for each subgroup. Superior drug classes (left of bolded vertical line) reduce disease activity (CDAI reduction) by 30-40 points more on average compared to non-superior drug-classes (right of bolded vertical line). The second and third rows of plots compare the proportions and distributions of covariates for each subgroup. Table 1. - Treatment subgroups Drug Class Preference Subgroup N (%) Anti-TNF TNF > IL > INT 44 (0.8) TNF > (IL = INT) 2,017 (35) Anti-TNF, Anti-Interleukin-12/23 (IL = TNF) > INT 355 (6) Anti-Interleukin-12/23 IL > (TNF = INT) 138 (2.5) IL > TNF > INT 1 (0.02) Other (TNF = INT) > IL 4 (0.07) No Preference (TNF = IL = INT) 3,144 We calculated the potential outcomes (mean response, residual uncertainty) for every patient under scenarios where they were assigned to different drug classes, and pairwise compared treatment scenarios to define preference orderings (treatment subgroups). TNF = anti-tumor necrosis factor, IL = anti-interleukin-12/23, INT = anti-integrin.
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Key words
crohns,fifteen randomized controlled trials,patient-specific,meta-analysis
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