P-142 Meta-analysis of Baseline C-reactive Protein and Clinical Remission in Nine Crohnʼs Disease Clinical Trials

Abstract

The inflammatory response marker C-reactive protein (CRP) has been proposed as a potential biomarker to enrich the patient population for phase III trials in Crohn’s disease (CD). The review of publications showed inconsistencies in selecting CRP cut-off values and the results of enrichment. Therefore, we explored the potential of CRP as an enrichment biomarker in clinical trials for CD by meta-analysis of patient-level data. Meta-analysis was conducted using patient-level data from nine clinical trials (n = 3968). The data was previously submitted to FDA in support of 4 biologic products for CD. In all trials, Crohn’s Disease Activity Index (CDAI) was used as an efficacy endpoint and clinical remission was defined as a score of less than 150. We conducted a meta-analysis employing Spearman’s rank correlations between baseline CRP and clinical remission at pre-specified time after treatment. The optimal cutoff for baseline CRP that could predict clinical remission in response to treatment was explored by the receiver operating characteristic (ROC) curve for the pooled dataset. The proportion of patients in remission was compared between high CRP and low CRP groups by Chi-square test. The odds ratio (OR) of active treatment effect to placebo effect was calculated using logistic regression model. Potential association between CRP and multiple covariates including gender, age, body mass index, ethnicity, and concurrent medications was examined using multiple regression model. At baseline the median CRP levels ranged from 7.6 to 14 mg/L, and the median CDAI scores ranged from 276 to 304 across 9 trials. There was a weak correlation between CRP and CDAI (correlation coefficient: 0.14 [95% CI: 0.11–0.17]). Baseline CRP concentration of 10 mg/L was identified as the optimal cut-off to distinguish clinical remitter and non-remitters after treatment with sensitivity and specificity of 54.7% and 57%, respectively (AUC: 0.564). The positive predictive value for remitters with CRP ≥ 10 mg/L was 28.4% and the negative predictive value for non-remitters with CRP < 10 mg/L was 61.2%. When the proportion of patients achieving clinical remission was compared using the identified baseline CRP cutoff of 10 mg/L, more patients achieved remission after active treatment in the high CRP (≥10 mg/L) group than in the low CRP (<10 mg/L) group (39% versus 28%, P = 1.4e–07). The proportions of remitters were similar between the 2 CRP groups (17% versus 16.9%, P = 0.89) in patients who received placebo treatment. The odds ratio of active treatment effect to placebo treatment effect was significantly greater in the high CRP group (OR = 2.79 [95% CI: 1.93–4.02]) compared to the low CRP group (OR = 1.44 [95% CI: 1.06–1.95]). Our analyses indicate that baseline CRP alone is not a strong predictive biomarker to identify patients who may achieve remission by CDAI in response to biologic therapeutics in CD. However, the baseline CRP at cutoff of 10 mg/L showed a potential as an enrichment biomarker to increase the clinical trial efficiency. Further studies are warranted to determine whether a combination of biomarkers, including CRP, can better identify patients who are most likely to respond to the therapy.