37for up to 16 weeks. Seventy-three percent of subjects had an improvement in fistula
symptoms with 36% in remission [ 27 ]. Additionally, very high trough concentra-
tions of IFX are associated with fistula healing: in one study, an IFX trough >20.2
was associated with 86% fistula healing rate [ 28 ].
Adalimumab
In order to overcome the immunogenicity of IFX that was recognized as an impor-
tant contributor to infusion reactions [ 29 , 30 ], a recombinant humanized monoclo-
nal antibody was developed, adalimumab (Humira, Abbott Laboratories, Chicago,
IL). Adalimumab (ADA) has a high affinity for soluble TNF but, unlike IFX, is
administered subcutaneously.
Clinical Efficacy
The clinical efficacy for induction of remission was established in the Clinical
Assessment of Adalimumab Safety and Efficacy Studied as Induction Therapy in
Crohn’s disease (CLASSIC I) [ 31 ]. This trial measured the effect of varying induc-
tion doses (time zero/week 2) on patients with moderate to severe CD naïve to anti-
TNF therapy. Subjects were given a loading dose at time 0 and week 2, and the
primary outcome was remission at week 4. The study met its primary end point with
36% of those receiving the highest dose (160 mg/80 mg) in remission at week 4
versus 24% of the lower dose (80 mg/40 mg) and 12% of placebo (p < 0.004)
(Fig. 3.1). Over the 4-week induction course, antibodies to ADA were seen on only
two subjects, one in the ADA treatment group and one in placebo. Following induc-
tion, a small phase II trial, CLASSIC II demonstrated that every other week ADA at
40 mg subcutaneously was superior to placebo for maintaining remission [ 32 ].
Given the strict remission criteria for CLASSIC II, only 55 subjects from CLASSIC
I were randomized. However despite these small numbers, those on ADA were
1.5–2 times more likely to maintain remission at week 56 compared to placebo.
Given the positive signal for maintenance of remission in CLASSIC II, the
Crohn’s Trial of the Fully Human Antibody Adalimumab for Remission Maintenance
(CHARM) study was performed to determine the optimal dosing regimen for ADA
for maintenance of remission in moderate to severe CD [ 33 ]. Subjects were given
open-label ADA for induction at weeks 0 and 2 80 mg and 40 mg, respectively, and
were randomized to ADA 40 mg every other week, ADA every week, or placebo.
Notably, subjects did not have to be anti-TNF naïve. Eight hundred and fifty-four
subjects were enrolled, and 499 (58%) responded to ADA at week 4 and were subse-
quently randomized. Those receiving ADA were statistically more likely to be in
remission at weeks 26 and 56 compared to placebo (Fig. 3.2, week 26 data).
Unfortunately ADA concentrations and antibodies to ADA were not measured in
CHARM. Consistent with episodic versus scheduled IFX treatment, a larger analysis
3 Antitumor Necrosis Factor Agents in Crohn’s Disease