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 induction 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 induction, 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 w as 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 subsequently 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 of the entire CHARM cohort (including those who received open-label ADA) found that continuous ADA was a more effective treatment strategy versus induction dosing followed by retreatment for clinical flare [34].

Long-term follow-up studies of ADA from CHARM and the open-label extension, Additional Long-Term Dosing With HUMIRA to Evaluate Sustained Remission and Efficacy in CD (ADHERE) , demonstrated improved rates of steroid-free remission at 2, 3, and 4 years compared to placebo [35–37]. Additionally multiple analyses from these large randomized controlled trials demonstrate that ADA is effective at improving patient-reported outcomes for CD [38–40], reducing costs [38, 41], and reducing all-cause hospitalizations and surgery [42].

The ability for ADA to induce and maintain mucosal healing was assessed in the EXTEND (Extend the Safety and Efficacy of Adalimumab through Endoscopic Healing) trial [43]. This study is notable in that it was the first prospective, randomized, placebo-controlled study with mucosal healing as an end point. All subjects were given open-label ADA for induction (160 mg at week 0 and 80 mg at week 2), and those with a clinical response (decrease in CDAI by at least 70 from baseline) were randomized to maintenance with ADA 40 mg every other week or placebo. Subjects who flared or were nonresponders were given open-label ADA. Ileocolonoscopy was scored using the CDEIS, and while the initial assessment was study site specific, the final assessment was performed by a blinded central reviewer. In the intention to treat analysis, 27% of subjects in the ADA group achieved mucosal healing at week 12 versus 13% with placebo (p < 0.056). At week 52, the mucosal healing rate was 24% for those on ADA, while none of the subjects in the placebo group achieved mucosal healing (p < 0.001). Additionally, using clinical data from EXTEND, ADA was shown to improve a composite outcome including clinical remission and mucosal healing [44]. Similar to mucosal healing rates, no significant difference was noted at week 12, while 19% of those on ADA achieved deep remission at week 52 versus 0% on placebo (p < 0.001).

In the CLASSIC I trial, the rates of fistula improvement and remission for ADA and placebo groups were not significantly different, although only 11% of randomized patients had draining enterocutaneous fistulas [31]. Among those with fistulas at baseline, more patients in CHARM experience complete fistula closure at week 56 on ADA therapy (33%) versus placebo (13%) (p < 0.016) [33]. An open-label Canadian trial, Adalimumab in Canadian Subjects with Moderate to Severe Crohn’s Disease (ACCESS), found that fistula healing rates at week 24 were as high as 60% for anti-TNF-naïve subjects and 28% for those previously treated with IFX [40]. In a randomized controlled trial of ADA plus ciprofloxacin versus ADA alone, those with ADA plus ciprofloxacin had a significantly higher reduction in fistula at 12 weeks versus ADA alone (71% versus 47%, p < 0.047) [45]. Complete fistula close was noted in 33% of ADA subjects at week 12 versus 65% of ADA plus ciprofloxacin (p < 0.009).

The early randomized phase II placebo-controlled trial for CZP consisted of 92 adult subjects with moderate to severe CD who were randomized to CZP at varying doses and placebo [46]. The primary efficacy of clinical response at week 4 was similar for the three CZP treatment groups (5 mg/kg, 10 mg/kg, and 20 mg/kg) and 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 positive antidrug antibody. Similarly to the prior phase II study, this study had an unexpectedly 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 placebo 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 placebo (p < 0.04) [48]. Similar findings were noted in the entire population regardless 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 maintenance 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 placebo arm (p < 0.001). Given the equivocal remission data from PRECISE 1, further 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 primary outcome of clinical remission at week 6 (32% and 25% for CZP and placebo, respectively, p < 0.174) [50]. However as with other CZP trials, when only looking at those with an elevated CRP (>5 mg/L), significant differences between CZP and placebo were noted. In PRECISE 1 and 2, the rates of antidrug antibody formation were 8 and 9%, respectively [48, 49].

PRECISE 3, an open-label extension including participants from PRECISE 1 and 2, demonstrated efficacy for CZP over a longer period as well as established that continuous therapy was superior to interrupted therapy [51]. Those in the placebo arm of PRECISE 1 or 2 were given the option for open-label CZP at the end of the study and then followed for an additional 54 weeks. Similarly to other anti-TNFs, those on continuous CZP had a response rate of 40% versus 27% for those who received interrupted CZP. Twenty percent of those who started the open-label extension completed the 7-year follow-up. At 7 years, a higher proportion of those who started the extension study in remission remained in remission versus those not in remission at the start of the extension, indicating that those who achieved remission on CZP could maintain a long-term remission [52].

PRECISE 1 and 2 did not have mucosal healing end points. The Endoscopic Mucosal Improvement in Patients with Active Crohn’s Disease Treated with CZP (MUSIC) trial was an open-label single-arm study to assess the efficacy of CZP for mucosal healing [53]. Subjects were given CZP 400 mg at weeks 0, 2, 4, and 8 then every 4 weeks, and the primary outcome was endoscopic improvement assessed via CEDIS at week 10 compared to baseline; the main secondary outcome was endoscopic improvement at week 54. Of the 89 subjects enrolled, 88% had a week 10 colonoscopy revealing a significant decrease in mucosal lesions (mean CDEIS decrease of 5.7 from baseline, 95% CI 5.3, 7.6, p < 0.001) with 4% (95% CI 1, 11) being in mucosal healing [53]. At week 54, the mucosal healing rates increased to 13% (95% CI 6, 25). Although this study lacked a control group, a significant decrease in mucosal lesions was noted on CZP that persisted through 1 year.