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Journal of Crohn's and Colitis (2013) 7, 958–967

Exploring the use of adalimumab for patients withmoderate Crohn's disease: Subanalyses frominduction and maintenance trials☆

William J. Sandborn a,⁎, Jean-Frederic Colombel b, Julian Panés c,Majin Castillo d, Anne M. Robinson d, Qian Zhou d,Mei Yang d, Roopal Thakkar d

a Division of Gastroenterology, University of California San Diego, La Jolla, CA, USAb Hepatogastroenterology, Centre Hospitalier Universitaire de Lille, Lille, Francec Department of Gastroenterology, Hospital Clinic of Barcelona, CIBERehd, Barcelona, Spaind AbbVie, North Chicago, IL, USA

Received 27 June 2012; received in revised form 1 December 2012; accepted 14 February 2013

☆ Conference presentation: PortionsGastroenterology Week 2011 conferen⁎ Corresponding author at: UCSD Inf

Gilman Drive, La Jolla, CA 92093-0956E-mail address: wsandborn@ucsd.e

1873-9946/$ - see front matter © 2013http://dx.doi.org/10.1016/j.crohns.2

KEYWORDSCrohn's disease;C-reactive protein;Adalimumab;Anti-tumor necrosisfactor therapy;Inflammatory boweldisease

Abstract

Background: Anti-TNF agents are often reserved for patients with severe Crohn's disease (CD).Aims: We explored the predictive value of baseline disease activity and C-reactive protein (CRP)for disease course, adalimumab efficacy for remission (induction and maintenance) in patientswith moderate and severe CD, and adalimumab efficacy in moderate CD by CRP category.Methods: Post hoc analyses of remission data were performed for all randomized patients frominduction (CLASSIC I) and maintenance (CHARM, EXTEND) adalimumab trials in patients withmoderate (CDAI≤300) or severe (CDAIN300) CD, and in high (≥10 mg/L) or low (b10 mg/L) CRP

moderate CD subgroups. Placebo-treated CHARM patients were evaluated for disease activityover time and time to CD-related hospitalization, by baseline disease severity and CRP.Results: Moderate CD patients had the highest clinical remission rate and largest treatment effectsize compared with placebo at week 4 after 160/80 mg induction (46.3% adalimumab, 17.4%placebo; versus 22.9%, 3.6% for severe patients). Moderate-CD/high-CRP patients had the mostpronounced efficacy (57.1% adalimumab, 6.7% placebo; versus 40.7%, 20.0% for lower CRP group).Adalimumab maintenance treatment (40 mg every-other-week) achieved superior remission versusplacebo at one year inmoderate (32.9% versus 13.7%) and severe (27.2% versus 7.5%) cohorts. Amongmoderate patients, efficacy was similar by CRP category. Moderate-CD/high-CRP placebo-treated

of the data reported in this manuscript have been previously presented at the United Europeance.lammatory Bowel Disease Center, Division of Gastroenterology, UC San Diego Health System, 9500, USA. Tel.: +1 858 657 5284; fax: +1 858 657 5022.du (W.J. Sandborn).

European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.013.02.016

959Adalimumab for moderate Crohn’s disease

patients experienced disease activity and hospitalization rates at week 56 of CHARM approachingthose of severe CD patients.Conclusions: This analysis suggests that moderate CD patients can be treated effectively withadalimumab, and supports using CRP to identify moderate CD patients at greatest risk of diseaseprogression.© 2013 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

1. Introduction

Crohn's disease (CD) is a chronic condition characterized bya pattern of relapsing and remitting symptoms. Conven-tional treatments for Crohn's disease, including corticoste-roids and immunosuppressants such as thiopurines ormethotrexate, do not adequately control the disease in allpatients. The biologic anti-tumor necrosis factor (TNF)agents adalimumab, infliximab, and certolizumab pegol areeffective for treating patients with moderate to severeCrohn's disease1–5 and have expanded the availabletreatment strategies for CD.

Though not routinely used in clinical practice, the Crohn'sdisease activity index (CDAI) is currently the gold standardfor quantifying Crohn's disease activity in clinical trials ofpatients with luminal disease, and is the basis of regulatoryapproval of treatments for CD.6,7 While the definition ofclinical remission (CDAI b 150 points) is well accepted, thecategorization of disease severity based on the CDAI is not asclear. The investigators who developed the CDAI arbitrarilydesignated a value of 150–219 as “mildly active” disease,220–450 as “moderately active” disease and values greaterthan 450 as “very severe disease”.6,7 A CDAI range of220–450 was used as the enrollment criteria for the pivotalclinical trials for adalimumab, certolizumab pegol, andinfliximab (infliximab trials used a maximum CDAI of400).1–5 In the United States, the prescribing informationfor all three agents specifies use in patients with “moderateto severe” CD who have failed conventional therapy.8–10 InEurope, the prescribing information for adalimumab and,until recently, infliximab, was limited to patients with“severe” CD11,12 (certolizumab pegol is not approved inEurope). The European indication for infliximab was recentlyexpanded to include “moderate” CD.13

In clinical practice anti-TNF agents are often reserved forpatients with more severe symptoms, because of symptom-based “step up” treatment strategies, benefit/risk concernsin patients with less severe disease, approved indication, andcost.14,15 Recent position statements regarding the treatmentof CD have advocated earlier introduction of biologicalor immunosuppressant therapy in patients with a poordisease prognosis defined by demographic, genotypic,serological, or immunological factors, including elevatedC-reactive protein (CRP).16 These recommendations arebased at least in part on the desire to quickly introduceeffective therapy in patients who will eventually experi-ence disease progression, but also on an increasingrecognition of the limited correlation between clinicalsymptoms and inflammation.16,17

CRP is a widely used biomarker of inflammation inCrohn's disease.18–20 Measurement of CRP could be useful

in identifying patients with moderate symptoms for whombiologic therapy may be appropriate, while minimizing theuse of these agents in patients who are less likely to benefit.

In this post hoc analysis of clinical trial data, we exploredthe efficacy and safety of adalimumab treatment for inductionand maintenance of remission in patients with moderate(CDAI ≤ 300) versus severe (CDAI N 300) Crohn's disease. TheCDAI threshold was selected based upon the Europeanregulatory approval for adalimumab and infliximab, whichdefine severe CD as a CDAI N 300.12,13 To provide informationabout the quality of life in patients with moderate CD, weevaluated baseline Inflammatory Bowel Disease Questionnaire(IBDQ)21,22 scores according to baseline disease severity. Tohelp provide guidance for selection of patients for adalimumabtreatment with consideration of the benefit/risk balance, wealso explored the predictive value of CRP, a serumbiomarker ofinflammation, for disease course and adalimumab efficacy inpatients with moderate CD.

2. Methods

2.1. Induction and maintenance trials

Data from the CLASSIC 1 trial3 was used to explore theefficacy and safety of adalimumab for induction of remissionin patients with moderate to severe CD. The eligibilitycriteria and design of CLASSIC I have been published.3

Briefly, patients with a diagnosis of CD for at least 4 monthsprior to screening and a baseline CDAI of 220–450 wereincluded in the trial. Concomitant treatment with stabledoses of corticosteroids, 5-aminosalicylates, and immuno-suppressants (azathioprine, mercaptopurine, methotrexate)was permitted, but previous exposure to anti-TNF agents wasnot allowed. Eligible patients were randomized (1:1:1:1) toone of four induction regimens: subcutaneous adalimumab40 mg at week 0, 20 mg at week 2; 80 mg at week 0, 40 mgat week 2; 160 mg at week 0, 80 mg at week 2; or placebo atweek 0 and week 2.

Maintenance of clinical remission in patients with moder-ate or severe CD was assessed using data from the CHARM andEXTEND trials, which have been previously described.1,23 Inboth trials, patients with CD for at least 4 months prior toscreening and a baseline CDAI of 220–450 were eligible.Concomitant treatment with stable doses of corticosteroids,5-aminosalicylates, and immunosuppressants was permitted;corticosteroids could be tapered at the investigator'sdiscretion during the trials. Previous exposure to anti-TNFagents was permitted, provided the anti-TNF therapy hadbeen discontinued at least 8 weeks (EXTEND) or 12 weeks(CHARM) prior to screening. In both trials, primarynon-responders to a prior anti-TNF agent were excluded.

960 W.J. Sandborn et al.

In the maintenance trials, patients received 4-week,open-label induction therapy with subcutaneous adalimumab(CHARM: 80 mg at baseline and 40 mg at week 2; EXTEND:160 mg at baseline and 80 mg at week 2.) At week 4, patientsentered the blinded phase, in which all patients werestratified by response (defined as ≥70 point decrease inCDAI [CR-70]) and randomized to blinded treatment withsubcutaneous adalimumab (CHARM: 40 mg every other week[eow], 40 mg weekly, or placebo [1:1:1]; EXTEND: 40 mg eowor placebo [1:1]). At or after week 8 (EXTEND) or week 12(CHARM), patients who experienced disease flare or non-response could move to open-label adalimumab 40 mg eow.Patients with continued flare or non-response could move toopen-label adalimumab 40 mg weekly. Disease flare wasdefined as an increase in CDAI ≥ 70 points compared withweek 4 and a CDAI N 220; non-response was defined as a lackof a CR-70 response compared with baseline.

2.2. Outcomes

Throughout the analyses, moderate CD is defined as baselineCDAI ≤ 300, and severe CD is defined as baseline CDAI N 300.Baseline CRP is defined as either high (≥10 mg/L) or low(b10 mg/L).

2.2.1. Quality of life in moderate compared with severeCrohn's disease

To evaluate the impact of CD on quality of life in patientsaccording to baseline disease activity, we calculated thebaseline median IBDQ scores in patients with moderate orsevere CD in CLASSIC I, CHARM, and EXTEND. An IBDQscore ≤ 135 was considered to reflect severely impairedquality of life. This value was derived by a regression linecalculation that evaluated the correlation between IBDQ andCDAI (IBDQ = 201–0.22*CDAI), using a CDAI value of 300.24

2.2.2. Disease progression and hospitalization risk inplacebo-treated patients

In order to analyze the influence of baseline CRP on diseaseactivity over time in patients not receiving anti-TNF therapy,we evaluated CDAI trends over the course of the trial (at eachstudy visit) in the patients in the CHARM study who receivedplacebo. The last observation carried forward (LOCF) methodwas used to handle missing data after week 4. The visit timesin CHARM and EXTENDwere different, so the larger patient setfrom CHARM was used for the analysis. Patients were groupedaccording to baseline severity of Crohn's disease (moderate orsevere) and high or low baseline CRP. Time to CD-relatedhospitalization for the same groups of placebo-treatedpatients was assessed during the double-blind period.

2.2.3. RemissionTo evaluate the effect of baseline disease severity on the

likelihood of success with induction therapy, clinicalremission (CDAI b 150) was assessed at week 4 for patientsin CLASSIC I who received induction with adalimumab(160/80 mg or 80/40 mg) or placebo, according to diseaseseverity subgroups (moderate or severe). An analysis byhigh or low baseline CRP in the moderate subgroup was alsoperformed. Non-responder imputation (NRI) was used tohandle missing data.

To evaluate the likelihood of achieving remission after oneyear of adalimumab therapy in patients with moderate orsevere Crohn's disease, pooled data from all randomizedpatients in CHARM and EXTEND were assessed for the placeboand adalimumab 40 mg eow and 40 mg weekly arms. Clinicalremission at one year (defined as week 56 of CHARM and week52 of EXTEND) was assessed in the intent-to-treat (ITT) andmodified intent-to-treat (mITT) populations according todisease severity at baseline (moderate or severe), and in themoderate cohort by baseline CRP (high or low), using NRI formissing data or data obtained after move to open-labeltherapy. The ITT population included all randomized patients(regardless of response to open-label induction therapy). ThemITT population consisted of the patients who responded(defined as achievement of CR-70 at week 4) to open-labelinduction, and represents patients who are most likely tocontinue on adalimumab in clinical practice.

2.3. Safety

Treatment-emergent adverse events were summarized bydisease severity subgroups throughout each study, until70 days after the last dose of study medication. For thepooled CHARM and EXTEND populations, safety results forthe ITT are reported as events per 100 patient years.

2.4. Statistical analysis

Statistical analyses were performed with SAS statisticalsoftware (version 9.1, SAS Institute Inc., Cary, NC). All analyseswere conducted post hoc. Demographic and baseline charac-teristics were compared using the chi-square test (categoricalvariables) or the Kruskal–Wallis test (continuous variables).Fisher's exact test was used to compare results from placebo-and adalimumab-treated groups. P values b 0.05 were consid-ered significant. The patients in the study were not randomizedaccording to baseline CDAI ≤ or N300; therefore, baselinedifferences may be responsible for differences in outcomes.The statistical significance of treatment differences betweendisease severity groups was evaluated based on Z scoreapproximations.

The time to CD-related hospitalization in the double-blindperiod, beginning at randomization (week 4), was assessedusing Kaplan–Meier analysis. Data were censored for patientswho did not experience a CD-related hospitalization beforecompleting the trial (through 70 days after the last dose ofstudy drug), after receiving the first dose of adalimumab in theextension trial, after moving to open-label adalimumab, orupon dropping out of the study. Survival curves werecompared using the log-rank test.

3. Results

3.1. Baseline demographics andclinical characteristics

With the exception of baseline CDAI, patient demographicsand baseline characteristics were generally similar for thedisease severity subgroups in CLASSIC I (Table 1) and in the

Table 1 Patient demographics and baseline characteristics: CLASSIC I.

CDAI ≤ 300 CDAI N 300

PlaceboN = 46

Adalimumab80/40N = 45

Adalimumab160/80N = 41

PlaceboN = 28

Adalimumab80/40N = 30

Adalimumab160/80N = 35

Female; n (%) 21 (45.7) 28 (62.2) 23 (56.1) 16 (57.1) 22 (73.3) 17 (48.6)Age, years; mean (SD) 36.7 (12.05) 37.1 (11.78) 37.8 (10.66) 37.8 (15.31) 40.2 (11.31) 39.4 (11.78)White race; n (%) 43 (93.5) 42 (93.3) 35 (85.4) 25 (89.3) 22 (73.3) 32 (91.4)Weight, kg; mean (SD) 76.1 (21.3) 75.8 (22.2) 75.2 (16.8) 71.5 (15.7) 72.0 (15.2) 80.2 (18.7)Disease duration, years

Median (range) 5.96 (0.4–31.3) 5.71 (0.1–32.7) 7.07 (0.4–36.7) 5.48 (0.2–23.5) 7.99 (0.5–33.9) 5.67 (0.5–35.2)CDAI; mean (SD) 255.3 (22.96) 259.4 (27.49) 255.0 (23.64) 362.0 (38.37) 363.6 (37.93) 342.2 (32.64)CRP, mg/L; median (range) 6.8 (0.3–84) 12.5 (0.4–125) 6.7 (0.2–50) 10.0 (0.6–173) 7.5 (0.8–149) 8.2 (0.9–93)Concomitant medications, n (%)

Corticosteroids 17 (37.0) 18 (40.0) 14 (34.1) 8 (28.6) 13 (43.3) 8 (22.9)Immunosuppressants 15 (32.6) 14 (31.1) 10 (24.4) 7 (25.0) 7 (23.3) 12 (34.3)Aminosalicylates 22 (47.8) 28 (62.2) 25 (61.0) 14 (50.0) 13 (43.3) 15 (42.9)

CDAI: Crohn's disease activity index; CRP: C–reactive protein.* Statistically significant at 0.05 level.

961Adalimumab for moderate Crohn’s disease

pooled CHARM and EXTEND ITT population (Table 2; baselinecharacteristics and demographics for the mITT populationare included in the supplemental material). The placebopatients in the severe CD group in CHARM/EXTEND had aslightly longer disease duration and higher baseline CRP thanthe other groups. The patients with severe CD in CHARM/EXTEND were slightly more likely to have received prioranti-TNF therapy than those with moderate disease activity.Median IBDQ values were higher in the patients withmoderate disease, compared with those in the severedisease activity category in each trial, but there wassubstantial overlap in IBDQ scores between the moderateand severe cohorts (Fig. 1). Baseline median IBDQ scoresfor patients with moderate CD in each trial were near 135(dotted line; CLASSIC I, median = 140; CHARM, median = 131;

Table 2 Patient Demographics and Baseline Characteristics: CHAgroup.

CDAI ≤ 300

PlaceboN = 139

Adalimumab40 mg eowN = 155

Ad40N

Female; n (%) 84 (60.4) 94 (60.6) 73Age, years; mean (SD) 37.8 (12.65) 37.1 (11.69) 37White race; n (%) 134 (96.4) 144 (92.9) 11Weight, kg; mean (SD) 73.4 (18.4) 71.0 (16.1) 72Disease duration, years

Median (range) 6.57 (0.1–40.3) 8.30 (0.4–37.0) 7.CDAI; mean (SD) 256.6 (26.63) 257.5 (24.64) 26CRP, mg/L; median (range) 7.3 (0.2–118) 8.7 (0.3–182) 8.Prior anti-TNF use; n (%) 68 (48.9) 72 (46.5) 64Concomitant medications, n (%)

Corticosteroids 58 (41.7) 64 (41.3) 54Immunosuppressants 70 (50.4) 64 (41.3) 59Aminosalicylates 53 (38.1) 45 (29.0) 51

CDAI: Crohn's disease activity index; CRP: C-reactive protein; eow: eve⁎ Statistically significant at 0.05 level.

EXTEND, median = 132), indicating severely impaired qualityof life in a substantial proportion of patients with “moderate”CD.

3.2. Effect of CRP on disease progression andhospitalization risk

In the cohort of patients treated with placebo in themaintenance period of CHARM, the mean CDAI droppedfrom week 0 to week 4 in all subgroups as a result ofinduction therapy (Fig. 2). By week 12 and through week 56,mean CDAI increased from week 4 in all placebo subgroups.Patients with moderate Crohn's disease and high baselineCRP experienced a rapid recurrence of disease activity based

RM and EXTEND ITT, pooled data, including CHARM weekly dose

CDAI N 300

alimumabmg weekly= 131

PlaceboN = 187

Adalimumab40 mg eowN = 169

Adalimumab40 mg weeklyN = 126

(55.7) 119 (63.6) 109 (64.5) 84 (66.7).9 (12.46) 36.4 (10.85) 36.6 (11.13) 37.7 (11.75)9 (90.8) 172 (92.0) 160 (94.7) 112 (88.9).9 (19.3) 69.5 (17.6) 70.1 (17.3) 69.0 (17.4)

00 (0.0–32.7) 9.60 (0.4–32.6) 7.90 (0.4–44.1) 9.25 (0.2–38.7)4.1 (21.38) 361.6 (50.78) 360.8 (42.06) 354.1 (40.26)1 (0.2–95) 14.7 (0.1–287) 9.7 (0.2–182) 9.1 (0.3–350)(48.9) 99 (52.9) 91 (53.8) 63 (50.0)

(41.2) 85 (45.5) ⁎ 57 (33.7) ⁎ 62 (49.2) ⁎

(45.0) 88 (47.1) 76 (45.0) 62 (49.2)(38.9) 82 (43.9) 60 (35.5) 43 (34.1)

ry other week; TNF: tumor necrosis factor.

Bas

elin

e IB

DQ

0

50

100

150

200

250

CLASSIC I CHARM EXTEND

Moderate

Severe

IBDQ: Inflammatory Bowel Disease Questionnaire.

Figure 1 Baseline IBDQ scores, with median, 25th and 75thpercentiles indicated (middle, lower, and upper horizontal lines,respectively), for CLASSIC I, CHARM, and EXTEND. Dotted line atIBDQ = 135 indicates threshold for severely impaired quality of life.

962 W.J. Sandborn et al.

on a mean CDAI similar to their baseline activity, andapproaching that of patients with severe Crohn's disease andlow CRP, despite differences in baseline CDAI of more than90 points.

In placebo-treated patients with moderate Crohn'sdisease and baseline CRP b 10 mg/L, 94.7% had not expe-rienced a CD-related hospitalization by week 56 (Fig. 3). Bycontrast, in patients with moderate CD and CRP ≥ 10 mg/L,78.8% were free of CD-related hospitalization at week 56,similar to results for the patients with severe CD (81.8% for

7069 69 69 69 70 Moderate Low

4241 40 44 44 44 Moderate High

6060 59 57 59 60 Severe Low

8686 84 87 87 87 Severe High

1286420Week:

Number of patients in each grou

Weeks

CD

AI s

core

0 2 4 6 8 12 16 20 26 32150

200

250

300

350

400

Figure 2 Mean (SD) CDAI over time in placeb

severe CD and low CRP; 79.0% for severe CD and high CRP).The hospitalization-free rates by week 56 were notstatistically different among the 4 groups (log-rank test,P = 0.235).

3.3. Induction (week 4)

Adalimumab 160/80 was effective at inducing remission inpatients with moderate or severe Crohn's disease (Fig. 4A).The remission rates achieved with the 80/40 dose were notstatistically different compared with placebo for eithercohort. Numerically higher rates of clinical remission andthe greatest separation from placebo were seen in themoderate Crohn's disease cohort (29.0%) compared with thesevere Crohn's disease cohort (19.3%) for the 160/80 dosegroup, with nearly one-half of moderate patients achievingremission at week 4; the P-value for comparison of theseeffect sizes was 0.437. Patients with moderate Crohn'sdisease and high CRP had the best chance of achievingremission, compared with patients with low CRP (Fig. 4B).The greatest efficacy and effect size compared with placebofor this high-risk group was observed with adalimumab160/80 treatment (50.5%); the comparable value for theeffect size in the low CRP group was 20.7%; P = 0.117 forthe comparisons of the effect sizes.

3.4. Maintenance (week 52/56)

Maintenance treatment with adalimumab 40 mg eow orweekly was superior to placebo for achieving clinicalremission in patients at one year, regardless of diseaseactivity at baseline, with the moderate cohort achieving the

70 70 70 70 70 70 70

42 42 42 42 42 42 42

60 60 60 60 60 60 60

86 86 86 86 86 86 86

56484032262016

p at each time point:

40 48 56

Severe High

Severe Low

Moderate High

Moderate Low

o subgroups of CHARM (LOCF after week 4).

Time, days

Per

cent

Sur

viva

lF

ree

of C

D-r

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ospi

taliz

atio

n

0 100 200 300 400 5000

10

50

60

70

80

90

100Moderate Low

Moderate High

Severe Low

Severe High

Figure 3 Kaplan–Meier plot for time to CD-related hospitalization in the double-blind period, placebo group only, by baseline CDAIand baseline CRP.

*P <0.05 vs. placebo. **P <0.01 vs. placebo. ADA: adalimumab; CDAI: Crohn’s disease activity index.

Per

cent

age

of P

atie

nts

in C

linic

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emis

sion

CDAI CDAI >3000

20

40

60

80

100

ADA 80/40ADA 160/80

Placebo

3.6%

16.7%22.9%*

17.4%

28.9%

46.3%**

**P <0.01 vs. placebo. ADA: adalimumab; CRP: C-reactive protein.

Per

cent

age

of P

atie

nts

in C

linic

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emis

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CRP CRP <10mg/L0

20

40

60

80

100

20.0%

31.8%

40.7%

6.7%

26.1%

57.1%**

N= 46 45 41 28 30 35

N= 15 23 14 30 22 27

PlaceboADA 80/40ADA 160/80

A

B

300

10mg/L

Figure 4 Clinical remission at week 4 in CLASSIC I: A) bybaseline Crohn's disease activity, and B) by baseline CRP inpatients with moderate Crohn's disease.

***P<0.001 vs. placebo. ADA: adalimumab; CDAI: Crohn’s disease activity index; eow: every other week.

Per

cent

age

of P

atie

nts

in C

linic

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emis

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CDAI CDAI >3000

20

40

60

80

100PlaceboADA eow

13.7%

32.9%***

7.5%

26.2%***

N=

ADA weekly

34.4%***

27.2%***

139 131 187 126196155

*P <0.05 vs. placebo. **P <0.01 vs. placebo ; ***P<0.001 vs. placebo. ADA: adalimumab; CRP: C-reactive protein; eow: every other week.

Per

cent

age

of P

atie

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in C

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CRP CRP <10mg/dL0

20

40

60

80

100

15.5%

37.2%**30.7%*

10.9%

27.9%*

39.3%***

N= 55 68 56 84 86 75

PlaceboADA eowADA weekly

A

B

≤300

10mg/dL

Figure 5 Clinical remission at week 56 (CHARM) or week 52(EXTEND): A) by baseline Crohn's disease activity, and B) bybaseline CRP in patients with moderate Crohn's disease. Placeboand ADA eow groups include CHARM and EXTEND pooled data;ADA weekly group is from CHARM only.

963Adalimumab for moderate Crohn’s disease

964 W.J. Sandborn et al.

highest rates (Fig. 5A). The results for weekly adalimumabwere similar to those for adalimumab eow treatment.Adalimumab was superior to placebo in the moderate groupsanalyzed by baseline CRP for both doses. Patients withmoderate Crohn's disease and elevated CRP treated withweekly dosing had the highest remission rates, and thegreatest effect size compared with placebo treatment(Fig. 5B). The P-value for the comparison of effect sizesbetween adalimumab and placebo treatment in each CRPcohort was 0.620 for eow dosing (17.0% versus 21.7%) and0.196 (28.4% versus 15.2%) for weekly dosing. Correspondingdata for the mITT population are shown in Supplemental Fig.1A and 1B.

3.5. Safety

Treatment-emergent adverse events for the induction trial(Table 3) and events per 100 patient years for the pooledmaintenance trials (ITT, Table 4) were summarized bydisease severity subgroups. Event rates are reported forthe maintenance double-blind period due to differentdurations of follow up in the placebo compared toadalimumab groups. The safety profiles were consistentwith the known safety of adalimumab in patients withCrohn's disease and other conditions. In CLASSIC I, overallAEs, serious AEs, and serious infections were more likely tooccur in the severe cohort. In the pooled maintenancestudies, the overall rate of events was lower in the moderatecohort, as were the rates of serious infections. The rate ofadverse events leading to discontinuation of the study drugwas higher in the moderate than the severe cohort forpatients receiving adalimumab. There were no cases oftuberculosis, demyelinating disease, or congestive heartfailure, and no deaths in CLASSIC I, CHARM, or EXTEND.Events per 100 patient years for the mITT population in thepooled maintenance trials are included in the supplementalmaterial.

Table 3 Adverse events in CLASSIC I, according to baseline disea

CDAI ≤ 300

PlaceboN = 46 n (%)

ADA 80/40N = 45 n (%)

Any adverse event (AE) 33 (71.7) 29 (64.4)Serious AE 1 (2.2) 1 (2.2)Severe AE 1 (2.2) 4 (8.9)AE leading to discontinuation 1 (2.2) 1 (2.2)AE at least possibly drug-related 16 (34.8) 18 (40.0)Infection 8 (17.4) 7 (15.6)Serious infection 0 0Opportunistic infection 0 0Allergic reaction 1 (2.2) 1 (2.2)Injection site pain 3 (6.5) 4 (8.9)Malignancy 0 0Congestive heart failure 0 0Demyelinating disease 0 0Death 0 0

ADA: Adalimumab; AE: Adverse event; CDAI: Crohn's disease activity in* and ** Statistically significant vs. placebo at 0.05 and 0.01 levels, res

4. Discussion

Subanalyses of data from the CLASSIC I, CHARM, and EXTENDclinical trials support the safety and efficacy of adalimumabfor induction and maintenance of clinical remission inpatients with moderate or severe Crohn's disease, as definedusing baseline CDAI. Induction of clinical remission wasnumerically greater in patients with moderate versus severeCrohn's disease, with nearly one-half (46%) of patients in themoderate cohort who received the 160/80 induction doseachieving remission at week 4 (compared with 17% ofpatients receiving placebo); the corresponding values forsevere CD were 23% and 4%. The one-year remission rates inpatients who responded to induction therapy were numer-ically greater in the moderate cohort, with a similar effectsize (adalimumab minus placebo) for maintenance ofremission between patients with moderate versus severe CD.

Sole reliance on clinical symptoms to quantify or monitorCD activity is problematic due to the lack of a strongcorrelation between symptoms and inflammation. Recentanalyses found that fecal and serum biomarkers (includingCRP) were significantly associated with endoscopic Crohn'sdisease activity but not clinical symptoms as measured byCDAI.17,25 Additionally, most patients will progress tofibrostenotic or penetrating complications which may beirreversible and contribute to the need for costly surgery andhospitalization.26,27 Earlier treatment with anti-TNF agentsmay potentially prevent or reduce complications andintestinal resections, which reduce the effectiveness ofsubsequent therapy and adversely affect patient quality oflife and productivity.28 Treatment with adalimumab orcertolizumab pegol early in duration of Crohn's disease(regardless of disease severity at baseline) was reported tolead to better outcomes.29,30

Prescribers may be unwilling to introduce anti-TNFtherapy in patients who are not severely symptomatic,because of concerns about safety and/or cost, and a beliefthat such patients do not require anti-TNF treatment.

se activity.

CDAI N 300

ADA 160/80N = 41 n (%)

PlaceboN = 28 n (%)

ADA 80/40N = 30 n (%)

ADA 160/80N = 35 n (%)

28 (68.3) 22 (78.6) 22 (73.3) 29 (82.9)0 2 (7.1) 0 3 (8.6)6 (14.6)* 6 (21.4) 0** 6 (17.1)0 1 (3.6) 0 020 (48.8) 11 (39.3) 13 (43.3) 17 (48.6)3 (7.3) 4 (14.3) 5 (16.7) 9 (25.7)0 0 0 2 (5.7)0 0 0 01 (2.4) 2 (7.1) 0 02 (4.9) 2 (7.1) 0 3 (8.6)0 0 0 00 0 0 00 0 0 00 0 0 0

dex.pectively.

Table 4 Adverse events per 100 patient years during double-blind period, according to baseline disease activity; pooled datafrom CHARM and EXTEND, including CHARM weekly dose group.

CDAI ≤ 300 CDAI N 300

Placebo N = 139PYs = 54.1 E (E/100PY)

Any ADA N = 286PYs = 162.4 E (E/100PY)

Placebo N = 187PYs = 59.7 E (E/100PY)

Any ADA N = 295PYs = 160.1 E (E/100PY)

Any adverse event (AE) 535 (988.9) 1307 (804.8) 660 (1105.5) 1334 (833.2)Serious AE 19 (35.1) 34 (20.9) 34 (57.0) 31 (19.4)Severe AE 42 (77.6) 67 (41.3) 69 (115.6) 66 (41.2)AE leading to discontinuation 16 (29.6) 36 (22.2) 25 (41.9) 15 (9.4)AE at least possibly drug-related 142 (262.5) 319 (196.4) 121 (202.7) 268 (167.4)Infection 104 (192.2) 255 (157.0) 104 (174.2) 255 (159.3)Serious infection 3 (5.5) 5 (3.1) 6 (10.1) 9 (5.6)Opportunistic infection 3 (5.5) 4 (2.5) 0 3 (1.9)Allergic reaction 6 (11.1) 6 (3.7) 0 8 (5.0)Injection site pain 1 (1.8) 5 (3.1) 2 (3.4) 4 (2.5)Malignancy 1 (1.8) 0 0 0Congestive heart failure 0 0 0 0Demyelinating disease 0 0 0 0Death 0 0 0 0

ADA: adalimumab; AE: adverse event; CDAI: Crohn's disease activity index; E/100PY: events per 100 patient years.

965Adalimumab for moderate Crohn’s disease

Nevertheless, published data have shown that even patientswith less severe Crohn's-related symptoms experience poorquality of life compared with the general population orpatients with other chronic conditions.31,32 These findingsare supported by the results of this study's analysis of patientquality of life as quantified by IBDQ. Although baselinemedian IBDQ scores were higher in patients with moderateCrohn's disease versus severe CD (indicating less impairmentin quality of life), there was substantial impact on quality oflife in patients with moderate CD, as evidenced by thesignificant overlap in baseline scores between patients inthe moderate and severe CD cohorts.

It is challenging, though desirable, to identify individualswith a poor long-term disease prognosis in order to selectthose with the best benefit/risk balance for treatment.Demographic factors have been suggested to identifypatients more likely to suffer a complicated disease course,including young age at diagnosis, perianal disease atdiagnosis, and early need for steroid therapy.33 Thepresence of high inflammatory burden, as indicated byserum CRP, may also help identify patients more likely toprogress and eventually need more intensive therapy. CRP,an acute phase reactant produced mainly by hepatocytes viacytokine IL-6 stimulation,34 is a well-accepted and easilymeasured biomarker for inflammation, and elevated CRPvalues correlate with Crohn's disease activity and predictdisease relapses.25,35 Kiss et al.36 reported that CRP atdiagnosis aided in identification of patients with a morecomplicated disease phenotype. The current analysis sup-ports the association of elevated CRP and negative outcomesin patients with moderate CD, as patients with moderate CDand elevated baseline CRP who were randomized to placeboexperienced rapid recurrence of disease activity. Thisresult was not surprising, based on pharmacokinetics andthe progressive nature of CD. As the drug is eliminated,recrudescence would be expected. The symptomaticactivity in the moderate CD and high CRP groupapproached that of patients with severe CD and low CRPby week 12, after an initial decline in activity following

receipt of two induction doses of adalimumab. Additionally,among placebo-treated patients, those with moderate CD andhigh CRP had a similar risk of CD-related hospitalization aspatients with severe CD.

The value of using CRP to identify patients most likely tobenefit from anti-TNF treatment is also supported by thefact that factors such as irritable bowel syndrome (IBS) andbile acid malabsorption may mimic symptoms of CD withoutelevation of CRP,37,38 and up to 57% of CD patients who arein remission may experience IBS-like symptoms.39,40 InCLASSIC I, patients with elevated baseline CRP achievedhigher rates of remission at week 4 than those with lowerCRP.3 In the ITT population in CHARM, higher baseline CRPconcentration (as well as lower baseline CDAI) was asignificant factor in predicting maintenance of remission atweek 26 and week 56.30 This is consistent with our results, inwhich patients with moderate CD and elevated baseline CRPhad numerically higher rates of remission after inductionthan patients with low CRP. Among the moderate cohort,one-year efficacy with adalimumab maintenance therapywas superior to placebo regardless of baseline CRP, andbroadly similar across dosing groups. The slightly higherremission rate in the weekly dosing group in the high CRPcohort is consistent with the finding of slightly higherefficacy for remission maintenance in patients with elevatedbaseline CRP in the primary CHARM results.1

The safety profiles of adalimumab in patients withmoderate or severe CD were consistent with the knownsafety of adalimumab in patients with Crohn's disease andother conditions. The results of the safety analysis in themoderate and severe cohorts did not raise new concernsabout the use of adalimumab in these subgroups of patientswith CD.

This was a post hoc analysis, and patients were notrandomized according to baseline disease activity, sodifferences in other baseline variables between groups mayhave influenced the outcomes. In addition, it is possible thatachievement of remission, a dichotomous endpoint, is easierfor patients with moderate disease, since a lesser change in

966 W.J. Sandborn et al.

CDAI is needed to reach b150. Furthermore, all patients whowere randomized to placebo received open-label inductionwith adalimumab, an approach that is not consistent withclinical practice. Due to the relatively long half-life ofadalimumab, it is likely that the hospitalization and CDAIanalyses in the placebo arm may have been influenced by alingering therapeutic effect of adalimumab for severalweeks after induction dosing. Finally, the clinical trials andthe post hoc analyses were not powered to determinestatistically significant differences between the effect sizesobserved in the different subgroups. Though the effect sizesbetween the high and low CRP subgroups or the moderateand severe subgroups may have clinical relevance, arandomized controlled trial would be required to establishstatistical significance.

In summary, the evidence suggests that patients withmoderate Crohn's disease can be treated safely andeffectively with adalimumab. Use of CRP to identify patientswith moderate CD symptoms who are at greatest risk ofdisease progression may aid in selection of patients forearlier intervention with anti-TNF therapy, before severesymptoms and complications occur.

Supplementary data to this article can be found online athttp://dx.doi.org/10.1016/j.crohns.2013.02.016.

Specific author contributions

WJS, J-FC, JP: Conception and design, collection of data,interpretation of results, development of manuscript, andapproval of final manuscript version. MC, AMR, RT: Conceptionand design, interpretation of results, development of manu-script, and approval of final manuscript version.

QZ, MY: Conception and design, performance of statisti-cal analyses, interpretation of results, development ofmanuscript, and approval of final manuscript version.

Role of the sponsor

AbbVie reviewed and approved the manuscript; the authorsmaintained control over the final content. AbbVie fundedthe research and provided writing support. The authorsthank Laurinda Cooker, PhD, of AbbVie, for writing the firstdraft and for editorial assistance.

Conflict of interest

WJS: Consultant: AbbVie (formerly Abbott), ActoGeniX NV,AGI Therapeutics, Inc., Alba Therapeutics Corporation,Albireo, Alfa Wasserman, Amgen, AM-Pharma BV, Anaphore,Astellas Pharma, Athersys, Inc., Atlantic Healthcare Limited,Axcan Pharma (now Aptalis), BioBalance Corporation,Boehringer-Ingelheim Inc., Bristol Meyers Squibb, Celgene,Celek Pharmaceuticals, Cellerix SL, Cerimon Pharmaceuticals,ChemoCentryx, CoMentis, Cosmo Technologies, CoronadoBiosciences, Cytokine Pharmasciences, Eagle Pharmaceuti-cals, Eisai Medical Research Inc., Elan Pharmaceuticals,EnGene, Inc., Eli Lilly, Enteromedics, Exagen Diagnostics,Inc., Ferring Pharmaceuticals, Flexion Therapeutics, Inc.,Funxional Therapeutics Limited, Genzyme Corporation,Genentech (now Roche), Gilead Sciences, Given Imaging,

Glaxo Smith Kline, Human Genome Sciences, IronwoodPharmaceuticals (previously Microbia Inc.), Janssen (previous-ly Centocor), KaloBios Pharmaceuticals, Inc., Lexicon Phar-maceuticals, Lycera Corporation, Meda Pharmaceuticals(previously Alaven Pharmaceuticals), Merck Research Labora-tories, MerckSerono, Millennium Pharmaceuticals (subsequent-ly merged with Takeda), Nisshin Kyorin Pharmaceuticals Co.,Ltd., Novo Nordisk A/S, NPS Pharmaceuticals, OptimerPharmaceuticals, Orexigen Therapeutics, Inc., PDL Biopharma,Pfizer, Procter and Gamble, Prometheus Laboratories, ProtAbLimited, Purgenesis Technologies, Inc., Receptos, Relypsa,Inc., Salient Pharmaceuticals, Salix Pharmaceuticals, Inc.,Santarus, Schering Plough Corporation (acquired by Merck),Shire Pharmaceuticals, Sigmoid Pharma Limited, Sirtris Phar-maceuticals, Inc. (a GSK company), S.L.A. Pharma (UK)Limited, Targacept, Teva Pharmaceuticals, Therakos, TillottsPharma AG (acquired by Zeria Pharmaceutical Co., Ltd.),TxCell SA, UCB Pharma, Viamet Pharmaceuticals, VascularBiogenics Limited (VBL), Warner Chilcott UK Limited, Wyeth(now Pfizer). Speakers fees: AbbVie (formerly Abbott), BristolMeyers Squibb, and Janssen (previously Centocor). Grants/Research support: AbbVie (formerly Abbott), Bristol MeyersSquibb, Genentech, Glaxo Smith Kline, Janssen (previous-ly Centocor), Millennium Pharmaceuticals (now Takeda),Novartis, Pfizer, Procter and Gamble Pharmaceuticals,Shire Pharmaceuticals, and UCB Pharma.

J-FC: Consultant: AbbVie (formerly Abbott), Amgen,Biogen Idec Inc., Boehringer-Ingelheim, Inc., Bristol MeyersSquibb, Cellerix SL, Chemocentryx, Inc., Centocor, CosmoTechnologies, Ltd., Elan Pharmaceuticals, Inc., Genentech,Giuliani SPA, Given Imaging, Glaxo Smith Kline, ImmunePharmaceuticals Ltd., Merck & Co., Inc., Millenium Pharma-ceuticals Inc., Neovacs SA, Ocerra Therapeutics, Inc.(previously named Renovia, Inc.), Pfizer Inc. Prometheus,Sanofi, Schering Plough Corporation, Shire Pharmaceuticals,Synta Pharmaceutical Corporation, Takeda, Teva Pharma-ceuticals, Therakos, TXcell, UCB Pharma (previously namedCelltech Therapeutics, Ltd.), Wyeth Pharmaceuticals;Speakers fees: AbbVie (formerly Abbott), Centocor, FalkPharma, Ferring, Given Imaging, Merck & Co., Inc., ScheringPlough Corporation, Shire Pharmaceuticals, UCB Pharma;Grants/Research support: AbbVie (formerly Abbott), Ferring,Schering Plough Corporation, UCB Pharma, Giuliani SPA,;Stock ownership: Intestinal Biotech Development.

JP: Consultant: AbbVie (formerly Abbott), Bristol-MyersSquibb, Genentech Inc., MSD Laboratories, Pfizer Inc.,Takeda Pharmaceutical Co, Ltd., UCB, Inc. Speakers fees:AbbVie (formerly Abbott), Ferring, Schering-Plough, Shireand UCB. Grant/Research support from AbbVie (formerlyAbbott) and MSD Laboratories.

MC, AMR, QZ, MY, RT: Employed by AbbVie (formerlyAbbott); shareholders of Abbott stock.

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