40
placebo with all ranging between 45% and 60% response (defined as decrease in
CDAI ≥ 100). A post hoc analysis of the data revealed that the 10 mg/kg dose had a
statistically significant week 2 remission rate versus placebo. Additionally, subjects
treated with CZP 20 mg/kg had the lowest geometric mean of CRP at week 2. This
trial was performed with an infusion of CZP in order to optimize the assessment of
the pharmacokinetics. Overall the trial was thought to be negative due to the placebo
response rate of 52–60% over the study period. Given this finding, a subsequent
phase II trial was designed to assess efficacy and safety and dose response in a
larger population [ 47 ]. Two hundred and sixty subjects were randomized into CZP
100 mg, 200 mg, 400 mg, or placebo. Similar to the initial phase II study, this study
failed to reach its primary end point of clinical response (CDAI ≥ 100) at week 12.
At every other time point, CZP at any dose was numerically superior to placebo;
additionally CZP 400 mg was significantly superior to placebo at all time points
aside from week 12. Week 4 remission rates were superior for all CZP treatment
arms, and the higher doses of CZP suppressed CRP more although this was not
statistically significant. Over the 12 weeks, 12.3% of subjects had at least one posi-
tive antidrug antibody. Similarly to the prior phase II study, this study had an unex-
pectedly high placebo response rate of 15–36% over the study period. Further post
hoc assessments identified that the greatest benefit between CZP 400 mg and pla-
cebo was in those with a high baseline CRP.
Given the phase II experience with CZP and the high placebo response rate,
the phase III induction trials for CZP were specifically designed to stratify for
those with an elevated CRP. The Pegylated Antibody Fragment Evaluation in
Crohn’s Disease: Safety and Efficacy (PRECISE 1 and 2) trials measured the
efficacy for induction and maintenance of remission for moderate to severe CD
[ 48 , 49 ]. The PRECISE trials were unique from other anti-TNF trials in that they
did not only randomize short-term responders but rather designed a 26-week
induction/maintenance study. In PRECISE 1, the primary outcome of CDAI
decrease by 100 or more in subjects with CRP > 10 mg/L was met in 37% of
those on CZP 400 mg (0, 2, 4, then every 4 weeks) versus 26% of those on pla-
cebo (p < 0.04) [ 48 ]. Similar findings were noted in the entire population regard-
less of CRP level (clinical response of 35% for CZP and 27% for placebo,
p < 0.02). The rates of remission at week 6 and remission at week 6 and 26 were
similar for both CZP and placebo regardless of CRP strata (Fig. 3.1, week 6 data).
When examining remission at every time point, significantly more patients on
CZP were in remission at week 4 and week 26. PRECISE 2 evaluated mainte-
nance CZP over 26 weeks as well as CZP withdraw among those with a clinical
response to open-label CZP [ 49 ]. Following open-label induction with three
doses of CZP 400 mg (weeks 0, 2, and 4), 64% had a clinical response (CDAI
decrease of 100 or more) and 48% were in remission (CDAI < 150) (Fig. 3.2).
Among week 6 responders who had a CRP > 10 mg/L, 62% had a clinical
response at week 26 in the CZP arm, while only 34% had a response in the pla-
cebo arm (p < 0.001). Given the equivocal remission data from PRECISE 1, fur-
ther data were needed for efficacy in induction. However, a subsequent trial of
CZP versus placebo in 439 adults with moderate to severe CD failed to meet the
B. P. Va u g h n