AST-120 (Spherical Carbon Adsorbent) in the Treatment of Perianal Fistulae in Mild-to-Moderate Crohnʼs Disease

Abstract

Background AST-120 (spherical carbon adsorbent) was previously reported to be effective for perianal fistula healing in Japanese patients with mild-to-moderate Crohn’s disease. Methods To evaluate the efficacy and safety of AST-120 in a Western population, a phase 3, multicenter, randomized, double-blind, placebocontrolled, study (FHAST-1) was conducted in adult patients with at least 1 draining perianal fistula and a Crohn’s disease activity index <400. Patients received either AST-120 or matching placebo at a dose of 2 g 3 times daily for 8 weeks. The primary endpoint was the proportion of patients with treatment success, defined as a 50% reduction in the number of draining fistulae, at both weeks 4 and 8. A multivariate model was generated to assess covariates for treatment success among baseline variables. Results Two hundred forty-nine patients were randomized (AST-120; n = 122; placebo, n = 127). The proportions of patients achieving the primary endpoint were no different between treatment groups (13.9% versus 16.5%, P = 0.6). No differences in fistula response were noted at week 4 (23.0% versus 25.2%, P = 0.77) or week 8 (27.0 versus 34.6%, P = 0.22). Serum C-reactive protein concentrations >0.6 mg/dL and Crohn’s disease activity index scores >151 at baseline were associated with a reduced likelihood of treatment success (odds ratio, 0.40; confidence interval, 0.19–0.87; P = 0.02; and odds ratio, 0.45; confidence interval, 0.21–0.97; P = 0.04, respectively). Conclusions In this largest placebo-controlled trial to date to evaluate the impact of a therapeutic agent on perianal fistulae in Crohn’s disease, the efficacy of AST-120 could not be confirmed. An inverse relationship was observed between both inflammatory and clinical disease activity and fistula response.

Placebo Response Rate in Clinical Trials of Fistulizing Crohn's Disease: Systematic Review and Meta-analysis

“…Characteristics of individual RCTs, including the magnitude of the placebo response in each trial, are provided in Table 1. Three trials included only patients with perianal fistulizing disease with fistula closure as the primary endpoint, 17,18,28 three trials recruited patients with fistulizing disease exclusively, but at any location, 20,22,26 again reporting fistula closure as the primary endpoint, and seven trials reported fistula closure as a secondary endpoint within a mixed population of patients with either luminal or fistulizing CD. 16,19,21,[23][24][25]27 Six trials were at low risk of bias.…”

“…Of these 44 RCTs, 31 were excluded for the reasons listed, leaving 13 eligible trials, [16][17][18][19][20][21][22][23][24][25][26][27][28] containing 579 individuals with fistulizing CD who were randomized to receive placebo. Agreement between reviewers for assessment of trial eligibility was good (kappa statistic = 0.90).…”

“…This would also allow the impact of baseline disease activity or inflammatory markers on rates of fistula closure or response with placebo to be studied, something we were unable to examine in our meta-analysis. This issue was examined in one of the included RCTs, 28 and it appeared that patients with lower clinical and inflammatory activity were more likely to experience closure of fistulae with placebo.…”

“…There were seven RCTs that reported the proportion of placebo patients receiving concomitant therapy at trial entry with 5-ASAs, glucocorticosteroids, or immunosuppressants, 16-18, 20, 22, 26, 28 and six that reported use of concomitant antibiotics. 17,18,20,22,26,28 We used a threshold of ≥30% of the placebo arm using these drugs to distinguish between individual trials for all of these analyses. There were no significant differences observed between placebo response rates according to use of 5-ASAs, glucocorticosteroids, immunosuppressants, or antibiotics, although the placebo response rates in trials where ≥30% of the placebo arm were using glucorticosteroids were generally higher (16.8% vs. 10.0%, Cochran Q = 3.87, P = 0.05) ( Table 3).…”

An open prospective study evaluating efficacy and safety of a new medical device for rectal application of activated carbon in the treatment of chronic, uncomplicated perianal fistulas

“…Previously orally administered activated carbon (AST-120) has been investigated on anal fistulas in CD, however, with conflicting results [6, 7], as its passage through the intestinal tract may possibly influence the adsorptive capacity. Thus, by using oral administration of activated carbon, it is uncertain how much adsorption power is actually available when it reaches the rectal ampulla.…”