Adalimumab for the treatment of fistulas in patients with Crohn's disease

Abstract

Objective: To evaluate the efficacy of adalimumab in the healing of draining fistulas in patients with active Crohn's disease (CD).

Design: A phase III, multicentre, randomised, double-blind, placebo controlled study with an open-label extension was conducted in 92 sites.

Patients: A subgroup of adults with moderate to severely active CD (CD activity index 220-450) for >or=4 months who had draining fistulas at baseline.

Interventions: All patients received initial open-label adalimumab induction therapy (80 mg/40 mg at weeks 0/2). At week 4, all patients were randomly assigned to receive double-blind placebo or adalimumab 40 mg every other week or weekly to week 56 (irrespective of fistula status). Patients completing week 56 of therapy were then eligible to enroll in an open-label extension.

Main outcome measures: Complete fistula healing/closure (assessed at every visit) was defined as no drainage, either spontaneous or with gentle compression.

Results: Of 854 patients enrolled, 117 had draining fistulas at both screening and baseline (70 randomly assigned to adalimumab and 47 to placebo). The mean number of draining fistulas per day was significantly decreased in adalimumab-treated patients compared with placebo-treated patients during the double-blind treatment period. Of all patients with healed fistulas at week 56 (both adalimumab and placebo groups), 90% (28/31) maintained healing following 1 year of open-label adalimumab therapy (observed analysis).

Conclusions: In patients with active CD, adalimumab therapy was more effective than placebo for inducing fistula healing. Complete fistula healing was sustained for up to 2 years by most patients in an open-label extension trial.

Trial registration: ClinicalTrials.gov NCT00077779 NCT00195715.

Figure 1

Study design. Flare was defined as a recurrence of very active disease (Crohn’s disease activity index (CDAI) increase ⩾70 points after week 4 and a CDAI >220). Non-response was defined as a failure to achieve 70-point response at any visit on or after week 12. *Option to adjust dosage to weekly for flare/non-response. ADHERE, Additional Long-Term Dosing with HUMIRA to Evaluate Sustained Remission and Efficacy in Crohn’s disease; CHARM, Crohn’s Trial of the Fully Human Antibody Adalimumab for Remission Maintenance; eow, every other week.

Figure 2

Patient disposition. (A) Patient disposition to week 56 of the Crohn’s Trial of the Fully Human Antibody Adalimumab for Remission Maintenance (CHARM). Randomly assigned responders achieved a 70-point or greater decrease in the Crohn’s disease activity index score at week 4 in CHARM. (B) Patient disposition for sustained fistula response over 2 years of adalimumab therapy in patients randomly assigned to adalimumab in CHARM and who enrolled in the Additional Long-Term Dosing with HUMIRA to Evaluate Sustained Remission and Efficacy in Crohn’s disease (ADHERE) study (analysis 1). (C) Patient disposition for sustained fistula response in all patients with healed fistulas at the end of CHARM (includes adalimumab and placebo-treated patients who entered ADHERE) (analysis 2). *Denominator for non-responder imputation (NRI) analyses. †Denominator for observed-case analysis at the end of CHARM. ‡Denominator for observed-case analysis to 2 years of therapy. eow, every other week.

Figure 2

Patient disposition. (A) Patient disposition to week 56 of the Crohn’s Trial of the Fully Human Antibody Adalimumab for Remission Maintenance (CHARM). Randomly assigned responders achieved a 70-point or greater decrease in the Crohn’s disease activity index score at week 4 in CHARM. (B) Patient disposition for sustained fistula response over 2 years of adalimumab therapy in patients randomly assigned to adalimumab in CHARM and who enrolled in the Additional Long-Term Dosing with HUMIRA to Evaluate Sustained Remission and Efficacy in Crohn’s disease (ADHERE) study (analysis 1). (C) Patient disposition for sustained fistula response in all patients with healed fistulas at the end of CHARM (includes adalimumab and placebo-treated patients who entered ADHERE) (analysis 2). *Denominator for non-responder imputation (NRI) analyses. †Denominator for observed-case analysis at the end of CHARM. ‡Denominator for observed-case analysis to 2 years of therapy. eow, every other week.

Figure 2

Patient disposition. (A) Patient disposition to week 56 of the Crohn’s Trial of the Fully Human Antibody Adalimumab for Remission Maintenance (CHARM). Randomly assigned responders achieved a 70-point or greater decrease in the Crohn’s disease activity index score at week 4 in CHARM. (B) Patient disposition for sustained fistula response over 2 years of adalimumab therapy in patients randomly assigned to adalimumab in CHARM and who enrolled in the Additional Long-Term Dosing with HUMIRA to Evaluate Sustained Remission and Efficacy in Crohn’s disease (ADHERE) study (analysis 1). (C) Patient disposition for sustained fistula response in all patients with healed fistulas at the end of CHARM (includes adalimumab and placebo-treated patients who entered ADHERE) (analysis 2). *Denominator for non-responder imputation (NRI) analyses. †Denominator for observed-case analysis at the end of CHARM. ‡Denominator for observed-case analysis to 2 years of therapy. eow, every other week.

Figure 5

Long-term maintenance of fistula healing (absence of drainage from all fistulas, either spontaneously or upon gentle compression) in patients with healed fistulas at the end of the Crohn’s Trial of the fully Human Antibody Adalimumab for Remission Maintenance (CHARM; placebo, every other week (eow) and weekly; n  =  40).*Observed analysis: two placebo-treated patients with healed fistulas did not enter Additional Long-Term Dosing with HUMIRA to Evaluate Sustained Remission and Efficacy in Crohn’s disease (ADHERE) study; data on fistula outcomes were missing for four patients at 24 weeks in ADHERE and seven patients at 60 weeks in ADHERE. †Non-responder imputation analysis: two placebo-treated patients with healed fistulas did not enter ADHERE.

Figure 3

Percentage of patients with fistulas at baseline (adalimumab every other week (eow) and weekly combined, n  =  70; placebo, n  =  47) who had complete fistula healing over time in the Crohn’s Trial of the Fully Human Antibody Adalimumab for Remission Maintenance (CHARM; non-responder imputation analysis). *p<0.05 for combined adalimumab groups (40 eow and 40 mg weekly) compared with placebo for the intention-to-treat population. Fistula efficacy defined as no draining fistulas at the last two consecutive post-baseline evaluations in the double-blind period before and on that visit.

Figure 6

Sample calculation of the mean number of draining fistulas per day. (A) Hypothetical patient 1—minimal disease activity yet not achieving complete healing* at either week 26 or week 56. (B) Hypothetical patient 2—significant disease activity yet achievement of complete healing* at week 56. *Complete healing, no draining fistulas for at least the last two post-baseline evaluations in the double-blind period.

Figure 6

Sample calculation of the mean number of draining fistulas per day. (A) Hypothetical patient 1—minimal disease activity yet not achieving complete healing* at either week 26 or week 56. (B) Hypothetical patient 2—significant disease activity yet achievement of complete healing* at week 56. *Complete healing, no draining fistulas for at least the last two post-baseline evaluations in the double-blind period.

Figure 4

Mean number of draining fistulas per day during double-blind period. *Statistical analyses were not performed on individual adalimumab groups, per prespecified statistical plan. †Intention-to-treat population of patients with draining fistulas at screening and baseline visits. ‡Randomised responder population (⩾70 point decrease in Crohn’s disease activity index score at week 4 in the Crohn’s Trial of the Fully Human Antibody Adalimumab for Remission Maintenance) of patients with draining fistulas at screening and baseline visits. eow, every other week; n, number of patients with fistulas at baseline.