Original article
Oral p38 Mitogen-Activated Protein Kinase Inhibition With BIRB 796 for Active Crohn’s Disease: A Randomized, Double-Blind, Placebo-Controlled Trial

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Background & Aims: The p38 mitogen-activated protein kinase (MAPK) regulates the expression of proinflammatory cytokines, which play a critical role in the pathophysiology of Crohn’s disease (CD). This study investigated the efficacy and safety of BIRB 796, a highly potent inhibitor of p38 MAPK, in chronic active CD. Methods: In a multicenter, multinational trial, 284 patients with moderate to severe CD were randomized to receive placebo, or 10, 20, 30, or 60 mg of BIRB 796 twice daily for 8 weeks. Clinical endpoints were based on standard safety assessments, CD Activity Index, C-reactive protein levels, and quality of life (Inflammatory Bowel Disease Questionnaire). In a substudy, the Crohn’s Disease Endoscopic Index of Severity and histologic results of biopsy specimens were assessed. Results: No clinical efficacy (primary end point, clinical remission; secondary end point, clinical response; Inflammatory Bowel Disease Questionnaire; Crohn’s Disease Endoscopic Index of Severity) was seen for BIRB 796 in comparison with placebo. A significant, dose-dependent decrease of C-reactive protein level was observed transiently after BIRB 796 after 1 week with a return to baseline level over time. The incidence of adverse events was comparable between all treatment groups, with the exception of a mild increase of transaminase levels that was seen more frequently in the BIRB 796 groups. Geographic center effects were observed with Russian centers producing distinctly higher remission and response rates and lower adverse event rates than in other countries in both placebo and active treatment groups. Conclusions: There was no evidence for clinical efficacy of BIRB 796 in CD. A remarkable difference in the course of CD exists between Russia and non-Russian centers.

Section snippets

Patients and Concomitant Medications

Screened patients were 18–65 years old with documented chronic active CD for at least 6 months and moderate to severe activity (Crohn’s disease activity index [CDAI] ≥220 to ≤450) at baseline. The following concomitant therapies were allowed if administered in a stable dose and for at least the following time intervals before baseline: prednisone or other systemic corticosteroids (12 weeks and stable oral dosage ≤25 mg/day or equivalent for the past 2 weeks), budesonide (stable dose ≤9 mg/day

Study Population and Patient Characteristics

A total of 354 patients (108 in Russia) were screened for inclusion at 47 sites (7 in Russia), which led to randomization of 284 patients. One patient randomized to 60-mg BIRB 796 was excluded from the efficacy analysis populations because no postbaseline efficacy data were available for this patient.

Patients who were randomized to the 7 Russian centers (n = 96) showed different demographic and baseline disease characteristics than patients (n = 188) from the other countries, indicating less

Discussion

Preclinical data suggest that p38 MAPK plays an important role in the regulation of inflammatory mediators in CD.15, 17 Furthermore, in a recent pilot study, administration of the Janus kinase (JNK)/p38 inhibitor CNI-1493 (Cytokine Pharma Sciences, King of Prussia, PA) resulted in a significant decrease in CDAI scores and mucosal healing.23 Therefore, the use of the highly selective p38 MAPK inhibitor BIRB 79618 seemed to be a promising approach in patients suffering from CD.

However, none of

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  • Cited by (0)

    Supported by Boehringer Ingelheim (trial 1175.12) in accordance with the principles laid out in the International Convention of Helsinki and Good Clinical Practice. Also supported in part by the publicly funded competence network for inflammatory bowel disease in Germany through Bundesministerium fur Bildung und Forschung (BMBF).

    Drs C. Yong, Ulrich Meier, and J. Steffgen are employees of Boehringer Ingelheim. Dr Colombel has served as a consultant for Boehringer Ingelheim.

    Present address for T.W.: Division of Digestive Diseases and Nutrition, University of Kentucky, Lexington, Kentucky.

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