Adalimumab Induces Deep Remission in Patients With Crohn's Disease Jean–Frédéric Colombel, Paul J. Rutgeerts, William J. Sandborn, Mei Yang, Anne Camez, Paul F. Pollack, Roopal B. Thakkar, Anne M. Robinson, Naijun Chen, Parvez M. Mulani, Jingdong Chao  Clinical Gastroenterology and Hepatology  Volume 12, Issue 3, Pages 414-422.e5 (March 2014) DOI: 10.1016/j.cgh.2013.06.019 Copyright © 2014 AGA Institute Terms and Conditions

Figure 1 DR at weeks 12 and week 52 (A) overall and (B) by disease duration. Patients with baseline mucosal ulceration per blinded/central review (N = 61 for induction-only/placebo; N = 62 for continuous adalimumab). aCochran–Mantel–Haenszel test for adalimumab vs placebo. bP = .19 for adalimumab vs placebo, adjusted for baseline disease duration (Cochran–Mantel–Haenszel test). cP < .001 for adalimumab vs placebo, adjusted for baseline disease duration (Cochran–Mantel–Haenszel test). dFisher exact test for adalimumab vs placebo within disease duration group. Clinical Gastroenterology and Hepatology 2014 12, 414-422.e5DOI: (10.1016/j.cgh.2013.06.019) Copyright © 2014 AGA Institute Terms and Conditions

Figure 2 Quality of life and productivity at week 52: adalimumab-treated patients with and without week-12 DR. (A) IBDQ remission and normal SF-36 MCS/PCS. (B) Mean WPAI component scores. N = 64 ITT adalimumab patients regardless of baseline mucosal healing status; 11 patients achieved DR at week 12, according to site assessment. aIBDQ score of 170 points or greater. bSF-36 MCS/PCS score of 50 or greater. cLower absenteeism scores indicate fewer work days missed. dLower presenteeism scores indicate less work productivity impairment. eLower TWPI scores indicate greater work productivity. fLower total activity impairment (TAI) scores indicate less daily nonwork activity impairment. Clinical Gastroenterology and Hepatology 2014 12, 414-422.e5DOI: (10.1016/j.cgh.2013.06.019) Copyright © 2014 AGA Institute Terms and Conditions

Figure 3 Comparison of outcomes for patients achieving DR (N = 11) vs absence of mucosal ulceration only (N = 8) or clinical remission only (N = 19). (A) Quality-of-life scores at week 52, hospitalization, and treatment adjustment. (B) Work productivity scores at week 52. aFor each end point except CD-related hospitalization, P < .05 for patients achieving DR vs absence of mucosal ulceration only; there were no statistically significant differences for patients with DR vs clinical remission only. bIBDQ score of 170 points or greater. cSF-36 MCS/PCS score of 50 or greater. dLower TWPI and total activity impairment (TAI) scores indicate less impairment. OL, open label. Clinical Gastroenterology and Hepatology 2014 12, 414-422.e5DOI: (10.1016/j.cgh.2013.06.019) Copyright © 2014 AGA Institute Terms and Conditions

Figure 4 Cost estimates at week 52: adalimumab-treated patients with and without week-12 DR. aTotal costs (indirect + direct); difference between groups = $10,360. bTotal direct costs; difference between groups = $6117. cIndirect costs; difference between groups = $4243. Clinical Gastroenterology and Hepatology 2014 12, 414-422.e5DOI: (10.1016/j.cgh.2013.06.019) Copyright © 2014 AGA Institute Terms and Conditions

Supplementary Figure 1 EXTEND study design. The study was conducted from August 2006 to September 2008 at 19 sites (Europe, the United States, and Canada). The primary efficacy end point was mucosal healing (ie, absence of mucosal ulceration in patients with baseline ulceration) as determined by the review committee’s visual assessment of the week-12 ileocolonoscopies.11 Starting at week 8, patients with symptomatic flare (increase in the CDAI of ≥70 points compared with week 4 and a CDAI of >220) or nonresponse (failure to achieve a CDAI decrease of ≥70 points compared with baseline [CR-70]) could receive open-label adalimumab 40 mg EOW with subsequent adjustment to open-label adalimumab 40 mg weekly at or after week 10 for ongoing flare/nonresponse. CD-related concomitant medications were permitted, provided that patients were receiving stable dosages before baseline as specified in the protocol. Patients could have received prior anti-TNF therapy for CD, provided that the other agent was discontinued at least 8 weeks before baseline and the reason for discontinuation was not primary nonresponse. Patients who continued on blinded therapy for the full duration of the trial or who moved to open-label therapy before week 12 had 3 ileocolonoscopies (baseline, week 12/move to open-label, and week 52/termination). Patients who remained on their randomized treatment until week 12 and subsequently moved to open-label therapy had 4 ileocolonoscopies (baseline, week 12, move to open-label EOW, and week 52/termination). aAdalimumab induction-only with placebo maintenance; reinitiation of adalimumab for flare/nonresponse. Clinical Gastroenterology and Hepatology 2014 12, 414-422.e5DOI: (10.1016/j.cgh.2013.06.019) Copyright © 2014 AGA Institute Terms and Conditions

Supplementary Figure 2 EXTEND patient disposition. A total of 135 patients entered the induction phase and received adalimumab 160 mg at baseline/week 0 and 80 mg at week 2; 129 patients were randomized at week 4 (65 to induction only/placebo and 64 to continuous adalimumab). Five (8%) patients randomized to induction only/placebo and 10 (16%) patients randomized to continuous adalimumab discontinued from the study during the double-blind phase. Clinical Gastroenterology and Hepatology 2014 12, 414-422.e5DOI: (10.1016/j.cgh.2013.06.019) Copyright © 2014 AGA Institute Terms and Conditions

Supplementary Figure 3 Kaplan-Meier analysis of time to open-label dosing: patients with and without early DR. There were 64 ITT adalimumab patients regardless of baseline mucosal ulceration status. Eleven patients had achieved DR at week 12, according to site assessment. Patients were censored if they dropped out of the study early or completed the study without moving to open-label EOW or weekly dosing. (A) Moved to open-label EOW therapy within 1 year. Cumulative probability of moving to open-label EOW therapy within 1 year was significantly lower for patients who achieved DR at week 12 (10%) vs patients who did not (54%; P < .02 from log-rank test). For patients not in DR at week 12, the average time to transition from blinded to open-label EOW therapy was 206 days; the 1 patient who achieved week-12 DR and moved to open-label EOW therapy did so on day 325. (B) Moved to open-label weekly therapy within 1 year. The cumulative probability of a dosage increase to weekly therapy within 1 year was 33% for patients who did not achieve DR at week 12 (P < .05 from log-rank test). The average time from blinded EOW therapy to dosage adjustment to weekly open-label therapy was 264 days. aN = number of patients remaining in the respective group at each time point. Clinical Gastroenterology and Hepatology 2014 12, 414-422.e5DOI: (10.1016/j.cgh.2013.06.019) Copyright © 2014 AGA Institute Terms and Conditions

Supplementary Figure 4 Cost calculations during the 40 weeks from determination of early DR at week 12 to end of study. There were 64 ITT adalimumab patients (N = 11 in DR; N = 53 not in DR), regardless of baseline mucosal healing status; of the 11 patients with DR at week 12, there was 1 patient who had baseline mucosal ulceration based on the site’s assessment, but not the central review of the ileocolonoscopy. Clinical Gastroenterology and Hepatology 2014 12, 414-422.e5DOI: (10.1016/j.cgh.2013.06.019) Copyright © 2014 AGA Institute Terms and Conditions