35ability to detect subtle differences in dose response. Over 12 weeks, the difference
in clinical response for IFX versus placebo remained significant (41% versus 12%,
respectively, p < 0.008), while remission rates on the other hand were numerically
better, but not statistically different (24% versus 8%, respectively, p < 0.31).
Given the early data demonstrating recurrence of disease weeks to months after
a single infusion, patients who met the week 4 primary end point (70-point reduc-
tion in CDAI) were randomized to an extension study of IFX 10 mg/kg or placebo
every 8 weeks for four infusions [ 11 ]. Seventy-three subjects were randomized, and
at the end of 44 weeks, those on IFX were more likely to be in remission versus
placebo (53% vs. 20%, respectively, p < 0.013). However, despite a significant dif-
ference for remission rates, the primary outcome of maintenance of clinical response
was numerically superior and not statistically significant.
At this point in the early 2000s, IFX was being used on an intermittent basis for
active CD given the mixed results for maintenance of remission. However it was
hypothesized that this was an artifact from the small trials and thus ACCENT I (A
Crohn’s Disease Clinical Trial Evaluating Infliximab in a New Long-Term
Treatment Regimen) was designed to assess the efficacy and safety of repeated
infusions of IFX in those who responded to an initial infusion [ 12 ]. All participants
received a single infusion of IFX 5 mg/kg and were randomized to one of three
treatment groups (placebo, IFX 5 mg/kg or IFX 10mg/kg every 8 weeks) and then
stratified by clinical response (defined as CDAI decrease of ≥70). The co-primary
end points were clinical remission at week 30 and time to loss of response up to
week 54. Five hundred and seventy-three patients were given IFX 5 mg/kg, and
335 (58%) had a week 2 clinical response. Subjects exposed to IFX were more
likely to be in clinical remission at week 30 (OR: 2.7, 95% CI: 1.6, 4.6) and had a
significantly longer time to loss of response versus those who received placebo.
While no statistically significant differences were noted between IFX 5 mg/kg and
10 mg/kg, there was a numerical dose response for both remission and response at
week 30 and week 54 favoring the higher dose. Additionally the median time to
loss of response in the 5 mg/kg group was 38 weeks, while the 10 mg/kg group
was >54 weeks. Among those initially randomized to the placebo group (including
both responders and nonresponders at week 2), 49% crossed over to infliximab
5 mg/kg [ 13 ]. The episodic dosing arm (i.e., placebo arm) had higher CDAI scores
and lower remission scores. These data from the ACCENT study group established
the role of infliximab maintenance therapy following an initial response and addi-
tionally demonstrated the superiority of scheduled, rather than episodic,
treatment.
A more extensive discussion of combination therapy with IFX and an immuno-
modulator is presented in a later chapter; however, the efficacy of IFX was con-
firmed in the SONIC trial (the Study of Biologic and Immunomodulator Naïve
Patients in Crohn’s Disease) [ 14 ]. The SONIC trial remains one of the most infor-
mative trials for CD as it directly compared azathioprine monotherapy to IFX
monotherapy to the combination of azathioprine and infliximab for patients with
treatment-naïve, moderately to severely active CD. Forty-four percent of subjects
on IFX monotherapy achieved steroid-free clinical remission at week 26 compared
to 30% on azathioprine monotherapy (p < 0.006), although combination therapy
was superior to both arms.
3 Antitumor Necrosis Factor Agents in Crohn’s Disease