GASTROENTEROLOGY 2012;142:257265

WILLIAM J. SANDBORN,* GERT VAN ASSCHE, WALTER REINISCH, JEANFREDERIC COLOMBEL,

GEERT DHAENS,,# DOUGLAS C. WOLF,** MARTINA KRON, MARY BETH TIGHE, ANDREAS LAZAR, and
ROOPAL B. THAKKAR
*University of California San Diego, La Jolla, California; University Hospital of Gasthuisberg, Leuven, Belgium; Medical University Vienna, Vienna, Austria; Centre
Hospitalier Universitaire de Lille, Lille, France; Academic Medical Center, Amsterdam, The Netherlands; #Imelda GI Clinical Research Center, Bonheiden, Belgium;
**Atlanta Gastroenterology Associates, Atlanta, Georgia; Abbott GmbH & Co. KG, Ludwigshafen, Germany; Abbott, Abbott Park, Illinois

BACKGROUND & AIMS: Adalimumab is a fully human

monoclonal antibody that binds tumor necrosis factor
(TNF)-. Its efficacy as maintenance therapy for patients
with ulcerative colitis has not been studied in a controlled,
double-blind trial. METHODS: Ulcerative colitis long-term
remission and maintenance with adalimumab 2 (ULTRA 2)
was a randomized, double-blind, placebo-controlled trial to
evaluate the efficacy of adalimumab in induction and maintenance of clinical remission in 494 patients with moderateto-severe ulcerative colitis who received concurrent treatment with oral corticosteroids or immunosuppressants.
Patients were stratified based on prior exposure to TNF-
antagonists (either had or had not been previously treated
with antiTNF-) and randomly assigned to groups given
adalimumab 160 mg at week 0, 80 mg at week 2, and then
40 mg every other week or placebo. Primary end points were
remission at weeks 8 and 52. RESULTS: Overall rates of
clinical remission at week 8 were 16.5% on adalimumab and
9.3% on placebo (P .019); corresponding values for week
52 were 17.3% and 8.5% (P .004). Among antiTNF-
nave patients, rates of remission at week 8 were 21.3% on
adalimumab and 11% on placebo (P .017); corresponding
values for week 52 were 22% and 12.4% (P .029). Among
patients who had previously received anti-TNF agents, rates
of remission at week 8 were 9.2% on adalimumab and 6.9%
on placebo (P .559); corresponding values for week 52
were 10.2% and 3% (P .039). Serious adverse events occurred in 12% of patients given adalimumab or placebo.
Serious infections developed in 1.6% of patients given adalimumab and 1.9% given placebo. In the group given adalimumab, 1 patient developed squamous cell carcinoma and 1
developed gastric cancer. CONCLUSIONS: Adalimumab
was safe and more effective than placebo in inducing
and maintaining clinical remission in patients with
moderate-to-severe ulcerative colitis who did not have an
adequate response to conventional therapy with steroids
or immunosuppressants.
Keywords: Antibody Targeted Therapy; IBD; Clinical Trial
Result; Inflammation; Colon.

he proinflammatory cytokine tumor necrosis factor- (TNF-) plays an important role in the
pathogenesis of ulcerative colitis (UC).1 Intravenous

administration of infliximab, a chimeric IgG1 monoclonal antibody to TNF-, is effective for induction and
maintenance of remission in outpatients with moderate-to-severe UC who fail conventional therapy with
steroids and/or immunosuppressive agents.2 In a related condition, Crohns disease, 2 subcutaneously administered antiTNF- agents are approved in the
United States, and are preferred by some patients because they can be self-administered.37 At present, no
subcutaneously administered antiTNF- agents are
approved for patients with UC.
Adalimumab is a fully human IgG1 monoclonal antibody directed against TNF- that inhibits activity of this
cytokine by blocking the interaction of TNF- with its
p55 and p75 cell surface receptors. Adalimumab is approved in the United States, Europe, and Japan for
Crohns disease, rheumatoid arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, psoriatic arthritis, and
psoriasis. Several small open-label trials and case reports
have suggested that adalimumab might be effective therapy for UC.8 11 Recently, an 8-week randomized controlled trial demonstrated the ability of adalimumab to
induce clinical remission in patients with moderate-tosevere UC, and demonstrated that an induction regimen
of subcutaneous adalimumab 160 mg at week 0, 80 mg at
week 2, and 40 mg every other week (EOW) was more
effective than placebo or adalimumab 80 mg at week 0, 40
mg at week 2, and then 40 mg EOW ulcerative colitis
long-term remission and maintenance with adalimumab
1 (ULTRA 1).12 Although this trial established the safety
and efficacy of adalimumab for inducing clinical remission, higher than expected response rates were seen in
placebo patients for several secondary end points, including clinical response and mucosal healing. To date,
no controlled data regarding long-term (1 year) efficacy
of adalimumab in patients with UC are available, and
Abbreviations used in this paper: EOW, every other week; IBDQ,
Inammatory Bowel Disease Questionnaire; NNT, number needed to
treat; TNF, tumor necrosis factor; UC, ulcerative colitis; ULTRA 1, ulcerative colitis long-term remission and maintenance with adalimumab 1;
ULTRA 2, ulcerative colitis long-term remission and maintenance with
adalimumab 2.
2012 by the AGA Institute
0016-5085/$36.00
doi:10.1053/j.gastro.2011.10.032

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Adalimumab Induces and Maintains Clinical Remission in Patients With

Moderate-to-Severe Ulcerative Colitis

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SANDBORN ET AL

additional data regarding the induction efficacy of

adalimumab for therapy in UC would be of interest.
Accordingly, we designed the ulcerative colitis longterm remission and maintenance with adalimumab 2
(ULTRA 2) trial, a 52-week placebo-controlled induction and long-term treatment study in patients with
moderate-to-severe UC.
CLINICAL AT

Materials and Methods

Patients
This phase 3, multicenter, randomized, double-blind,
placebo-controlled trial was conducted at 103 centers in North
America, Europe, Australia, New Zealand, and Israel between
November 2006 and March 2010. The protocol was approved by
the institutional review board for each center. All patients gave
written consent.
Eligible patients were adults with moderately-to-severely active UC for at least 3 months with a Mayo score of 612 points
(endoscopy subscore of at least 2), despite concurrent therapy
with steroids and/or azathioprine or 6-mercaptopurine. The
Mayo score is a composite score of 4 items (ie, rectal bleeding,
stool frequency, physicians global assessment, endoscopy).13 For
the scoring of the rectal bleeding and stool frequency items, the
worst score from the previous 3 days before the study visit was
used. The diagnosis of UC was confirmed by biopsy obtained at
the screening colonoscopy or flexible sigmoidoscopy. Patients
concurrently treated with oral corticosteroids were to receive a
stable dose (prednisone 20 mg/day for at least 2 weeks, or 20
mg/day for at least 40 days) before baseline. Patients treated
with immunomodulators were to receive at least a consecutive
3-month course of azathioprine (at least 1.5 mg/kg/day, or
highest tolerated dosage) or 6-mercaptopurine (at least 1 mg/
kg/day, or highest tolerated dosage) before baseline (with stable
dosage for at least 4 weeks). Concurrent therapy was not required for patients who failed to respond to or could not
tolerate previous corticosteroid or immunomodulator treatment, as judged by the investigator. Previous use of anti-TNF
agents other than adalimumab was permitted if the patient had
discontinued its use due to a loss of response or intolerance to
the agent for longer than 8 weeks. Patients were allowed stable
dosages of 5-aminosalicylates as concurrent therapy, but 5-aminosalicylate use was not an entry criterion for the trial.
Patients were excluded if they had the following: history of
subtotal colectomy with ileorectostomy or colectomy with ileoanal pouch, Koch pouch, or ileostomy for UC, or planned bowel
surgery; previous treatment with adalimumab; receipt of intravenous corticosteroids within 2 weeks of screening; receipt of
cyclosporine, tacrolimus, or mycophenolate mofetil within 1
month of baseline; receipt of therapeutic enema or suppository,
other than required for endoscopy, within 2 weeks of the screening endoscopy and during the screening period; or receipt of any
investigational agent within 30 days or 5 half-lives before baseline. Patients were also excluded for the following: a current
diagnosis of fulminant colitis or toxic megacolon, disease limited to the rectum (ulcerative proctitis), current diagnosis of
indeterminate colitis, or current diagnosis or history of Crohns
disease, current total parenteral nutrition, positive Clostridium
difficile stool assay, previous use of infliximab and no clinical
response at any time (primary nonresponder), history of an
infection requiring intravenous antimicrobial therapy within 1
month or oral antimicrobial therapy within 2 weeks, history of
listeria, histoplasmosis, chronic or active hepatitis B infection,

GASTROENTEROLOGY Vol. 142, No. 2

human immunodeficiency virus, immunodeficiency syndrome,

or untreated tuberculosis, history of central nervous system
demyelinating disease, history of malignancy other than a successfully treated nonmetastatic cutaneous squamous cell or
basal cell carcinoma or localized carcinoma in situ of the cervix,
or evidence of dysplasia or malignancy on the screening colonoscopy/flexible sigmoidoscopy with biopsy.

Study Design
Patients were randomly assigned in a 1:1 ratio to receive
subcutaneous injections of adalimumab 160 mg at week 0, 80
mg at week 2 and then 40 mg EOW beginning at week 4, or
matching placebo. They were followed through week 52. Randomization was performed centrally and was stratified by prior
exposure to infliximab or other anti-TNF agents. Concomitant
medication doses remained constant except steroids, which
could be tapered after week 8 at the discretion of the investigator
in patients who had a satisfactory clinical response. The taper
consisted of reducing the prednisone dosage by 5 mg weekly
until a dosage of 10 mg/day was reached. Thereafter, the dosage
was reduced by 2.5 mg weekly until discontinuation. Patients
demonstrating inadequate response could switch to open-label
adalimumab (40 mg EOW) starting at week 12. Inadequate
response was defined as: (1) partial Mayo score equal to or above
baseline score on 2 consecutive visits at least 14 days apart (for
patients with a partial Mayo score of 47 at baseline); (2) partial
Mayo score 7 on 2 consecutive visits at least 14 days apart (for
patients with a partial Mayo score of 8 or 9 at baseline). Patients
who demonstrated inadequate response at 2 consecutive visits at
least 14 days apart while on open-label administration 40 mg
EOW were permitted to escalate dosage to adalimumab 40 mg
weekly.

Efficacy Evaluations
Patients were evaluated at weeks 0, 2, 4, 8, 12, 16, 20, 26,
32, 38, 44, and 52/early termination. The Mayo score was determined at weeks 0, 8, 32, and 52/early termination. A partial
Mayo Score (Mayo Score without endoscopy) was determined at
all visits. Health-related quality of life, as measured by the
Inflammatory Bowel Disease Questionnaire (IBDQ),14 was determined at weeks 0, 4, 8, 20, 32, and 52/early termination.
Clinical remission was defined as a total Mayo score 2 points,
with no individual subscore exceeding 1 point. Clinical response
was defined as a decrease from baseline in the total Mayo score
by at least 3 points and at least 30% with an accompanying
decrease in rectal bleeding subscore of at least 1 point or an
absolute rectal bleeding subscore of 0 or 1. Mucosal healing was
defined as an endoscopy subscore of 0 or 1. Clinical response,
clinical remission, and mucosal healing were assessed at weeks 8,
32, and 52/early termination. Patients who achieved clinical
remission or clinical response at both weeks 8 and 52 were
considered to be in sustained clinical remission or sustained
clinical response, respectively. Partial Mayo score clinical remission was defined as a partial Mayo score 2 points, with no
individual subscore exceeding 1 point. IBDQ response was defined as an increase from baseline of at least 16 points.

Safety Evaluations
At each clinic visit from baseline (week 0) through week
52/early termination, patients underwent physical examination,
vital signs, previous (at baseline) and concomitant medications,
and adverse events were recorded, and general laboratory tests
including C-reactive protein and urinalysis were performed. Sera

ADALIMUMAB FOR INDUCTION AND MAINTENANCE OF REMISSION IN UC

were collected for determination of antibodies to adalimumab

(weeks 0, 8, 32, and 52/early termination), adalimumab concentrations (weeks 0, 2, 4, 8, 32, and 52/early termination), antinuclear antibodies (weeks 0, 32, and 52/early termination), and
double-stranded DNA antibodies (weeks 0, 32, and 52/early
termination, performed only if antinuclear antibody was positive).

Statistical Methods
The primary efficacy analysis was performed on the
intent-to-treat population and consisted of 2 co-primary efficacy
end points: (1) proportion of patients achieving clinical remission at week 8 and (2) proportion of patients achieving clinical
remission at week 52. Clinical remission per Mayo score was
defined as Mayo score 2 with no subscore 1. Ranked secondary efficacy variables included: (1) the proportion of patients
who achieved clinical remission at both weeks 8 and 52 (sustained); (24) clinical response (decrease in Mayo score of 3
points from baseline and decrease in Mayo score of 30% from
baseline and decrease in the rectal bleeding score 1 or an
absolute rectal bleeding score of 0 or 1) at week 8, week 52, and
both weeks 8 and 52 (sustained); (57) mucosal healing (endoscopy subscore of 0 or 1) at week 8, week 52, and both weeks 8
and 52 (sustained); (8) proportion of patients who achieved
remission at week 52 and discontinued corticosteroid use before
week 52; or (12) for 90 days before week 52; (13) proportion of
patients who discontinued corticosteroid use and achieved remission (sustained) at both weeks 32 and 52; (9) physicians
global assessment subscore; (10) stool frequency subscore; and
(11) proportion of patients with a rectal bleeding subscore
indicative of mild disease (1) at week 8; (15) proportion of
patients who were IBDQ responders (defined as an increase 16
points) at week 8; and (14) at week 52. Additionally, ranked
primary and secondary end points were analyzed after stratification by use of prior anti-TNF agent.
Demographic and baseline characteristics were summarized
using descriptive statistics. Efficacy analyses were done in the
intent-to-treat population. Exclusion of 3 sites from efficacy
analyses occurred due to site noncompliance with good clinical
practice and protocol requirements. Hypothesis testing for the
ranked primary and secondary end points was carried out in a
hierarchical order using a 2-sided Cochran-Mantel-Haenszel test
adjusted for earlier exposure to infliximab or other anti-TNF
agents at a significance level of .05. The confirmatory multiple
testing procedure stopped at the first hypothesis that could not
be rejected. This ensured that the multiple significance level was
controlled at .05. Missing or incomplete data as well as values at
or after switch to open-label treatment of adalimumab were
handled using the nonresponder imputation methods. Comparison of treatment groups in subgroups of patients with or
without prior anti-TNF treatment use were carried out using the
2 test or Fishers exact test. Analyses of treatment-emergent
adverse events were determined in the safety population, which
included all patients who received at least 1 injection of study
drug during the study. The numbers of patients experiencing
adverse events were compared between the treatment groups
using Fishers exact test.

Sample Size
Assuming a remission rate of 5% in the placebo group at
week 8 or week 52, a difference of at least 7 percentage points
from the adalimumab group, and a 2-sided test at the .05 level,
a sample size of 250 patients provided power of .80 to detect a

259

difference between the treatment groups. Thus, a total of 500

patients were to be randomized in this study.

Results
Patients
Supplementary Figure 1 shows the disposition of
patients. The baseline characteristics were similar in the 2
groups (Table 1). Seventy-five percent (368 of 494) of
patients in the overall population were currently receiving
steroids and/or azathioprine/6-mercaptopurine. The remaining 25% of patients had previously failed and discontinued one or both of these agents, in the opinion of the
investigator. Forty percent (199 of 494) of patients in the
overall population had previously received and discontinued an anti-TNF agent.

Efficacy
Co-primary end points. At week 8, 16.5% of patients receiving adalimumab were in clinical remission as
compared with 9.3% on placebo (P .019; absolute difference 7.2; 95% confidence interval: 1.212.9) (Figure
1A). At week 52, the corresponding values were 17.3% and
8.5%, respectively (P .004; absolute difference 8.8;
95% CI: 2.814.5) (Figure 1A). The efficacy of adalimumab was generally consistent among demographic and
baseline disease characteristics (Supplementary Figures
2A and B).
Secondary endpoints and exploratory analyses.

Clinical response was achieved at week 8 in 50.4% of

patients receiving adalimumab and 34.6% on placebo (P
.001) (Figure 1B). The corresponding values at week 52
were 30.2% and 18.3%, respectively (P .002) (Figure 1B).
Mucosal healing was achieved at week 8 in 41.1% of
patients receiving adalimumab and 31.7% of patients receiving placebo (P .032) (Figure 1C). The corresponding
values at week 52 were 25% and 15.4%, respectively (P
.009) (Figure 1C). For other secondary end points, differences also favored adalimumab over placebo, and all but
one of the comparisons were significant at the P .05
level (Table 2).

Prior Anti-TNF Use

Among patients who were nave to anti-TNF
agents, 21.3% of patients receiving adalimumab achieved
clinical remission at week 8 as compared with 11% on
placebo (P .017). The corresponding values at week 52
were 22% and 12.4% (P .029). At week 52, for antiTNFnave patients, the number needed to treat (NNT)
for clinical remission was 11 and the NNT for clinical
response was 8. For other secondary end points, differences also favored adalimumab over placebo, and all but
3 of the comparisons were significant at the P .05 level
(Table 3). Among the anti-TNFexperienced patients,
9.2% of patients receiving adalimumab achieved clinical
remission at week 8 as compared with 6.9% on placebo
(P .559). The corresponding values at week 52 were
10.2% and 3%, respectively (P .039). For anti-TNFex-

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February 2012

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SANDBORN ET AL

GASTROENTEROLOGY Vol. 142, No. 2

Table 1. Baseline Demographics and Clinical Characteristicsa

CLINICAL AT

Characteristic

Placebo (n 246)

Adalimumab (n 248)

Total (n 494)

Male, n (%)
Age, y, mean SD
Weight, kg, mean SD
Disease location, n (%)
Pancolitis
Descending colon
Other
Disease duration, y, mean SD
High-sensitivity CRP, mg/L
Mean SD
Median
ULN 4.94 mg/L,b n (%)
Mayo score, mean SD
Partial Mayo scorec
Endoscopy subscored
Rectal bleeding subscorec
PGA subscorec
Stool frequency subscore
Concomitant medication, n (%)
Corticosteroids
Azathioprine/6-MP
Aminosalicylatese
Azathioprine/6-MP and/or steroids
Azathioprine/6-MP steroids
Prior anti-TNF therapy

152 (61.8)
41.3 13.22
77.1 17.31

142 (57.3)
39.6 12.47
75.3 17.71

294 (59.5)
40.4 12.86
76.2 17.52

120 (48.8)
96 (39.0)
30 (12.2)
8.5 7.37

120 (48.4)
96 (38.7)
32 (12.9)
8.1 7.09

240 (48.6)
192 (38.9)
62 (12.6)
8.3 7.23

13.1 36.78
4.2
116 (47.2)
8.9 1.75
6.5 1.55
2.5 0.50
1.7 0.94
2.2 0.57
2.6 0.66

14.5 32.07
4.1
113 (45.7)
8.9 1.50
6.5 1.39
2.5 0.50
1.7 0.85
2.2 0.55
2.5 0.71

13.8 34.48
4.1
229 (46.5)
8.9 1.63
6.5 1.47
2.5 0.50
1.7 0.89
2.2 0.56
2.5 0.69

140 (56.9)
80 (32.5)
155 (63.0)
175 (71.1)
45 (18.3)
101 (41.1)

150 (60.5)
93 (37.5)
146 (58.9)
193 (77.8)
50 (20.2)
98 (39.1)

290 (58.7)
173 (35.0)
301 (60.9)
368 (74.5)
95 (19.2)
199 (40.3)

CRP, C-reactive protein; ITT, intent-to-treat; PGA, Physicians Global Assessment; 6-MP, 6-mercaptopurine; ULN, upper limit of normal.
patients (14 placebo 10 adalimumab) were excluded due to site noncompliance.
bn 246, placebo; n 247, adalimumab; n 493, total.
cn 245, placebo; n 247, adalimumab; n 492, total.
dn 247, adalimumab; n 493, total.
eIncludes mesalazine, sulphasalazine, balsalazide, aminosalicyclic acid, and olsalazine.
a24

perienced patients, week 52 NNT for clinical remission

was 14 and week 52 NNT for clinical response was 10. For
other secondary end points, differences generally favored
adalimumab over placebo, but a majority of the comparisons were not significant (Table 3).

Additional Analyses
Using the nonresponder imputation method, the
proportion of patients achieving clinical remission based on
the partial Mayo score was statistically significantly higher
for adalimumab patients compared with placebo from week
2 on throughout the study (except for week 38; Figure 1D)
and the proportion of patients using corticosteroids at baseline who discontinued corticosteroid use (Figure 1E) tended
to progressively increase over study visits. No patients underwent colectomy during the placebo-controlled trial. A
subsequent publication will integrate the colectomy results
from the current trial with the colectomy results from companion open-label extension studies.

Safety
Adalimumab treatment was generally well-tolerated
and the overall safety profile of adalimumab was comparable
with that of placebo. A similar proportion of patients in each
study group experienced treatment emergent adverse events
(Table 4); the incidence rate during double-blind treatment
was numerically greater in the placebo group vs the adali-

mumab treatment group (846.1 events/100 patient-years vs

743.3 events/100 patient-years, respectively). The majority of
patients experienced treatment emergent adverse events that
were nonserious, mild, or moderate in severity, and were
considered not related or probably not related to study drug
by the investigator. A statistically significantly greater proportion of adalimumab-treated patients reported injection
site-related and hematologic-related adverse events compared with placebo-treated patients. The latter adverse events
(mostly leukopenia) were reported in adalimumab-treated
patients who were all receiving concomitant immunosuppressants at baseline; all events were resolved by the end of
the study.
There were no statistically significant differences between
treatment groups for any of the other adverse events of
special interest. However, the incidence of serious adverse
events, severe adverse events, infectious adverse events, and
adverse events leading to discontinuation tended to be
higher in placebo-treated compared with adalimumabtreated patients (Table 4). During double-blind treatment, 2
adalimumab-treated patients experienced malignancies (1
squamous cell carcinoma, 1 gastric cancer). There were no
deaths or cases of demyelinating disease, lymphoma, or tuberculosis reported in this study. Analyses of laboratory
parameters and vital signs did not reveal any additional
safety issues.

ADALIMUMAB FOR INDUCTION AND MAINTENANCE OF REMISSION IN UC

261

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February 2012

Figure 1. (A) Proportion of patients with clinical remission at week 8 and week 52. Proportion of patients with (B) clinical response and (C) mucosal
healing at week 8 and week 52. (D) Proportion of patients achieving remission per partial mayo score over time. (E) Corticosteroid discontinuation by
visit among baseline corticosteroid users. Intent-to-treat population; nonresponder imputation method. *P .05; **P .005 based on Cochran
MantelHaenszel test.

Antibodies to Adalimumab and Adalimumab

Concentrations
Antibodies to adalimumab were detected in 2.9%
(7 of 245) of patients in the adalimumab group with
evaluable data on anti-adalimumab antibody status
during double-blind treatment; all patients positive for
antibodies to adalimumab received adalimumab monotherapy. The median serum trough concentrations for

remitters vs nonremitters at weeks 8, 32, and 52/early

termination are shown in Table 5.

Discussion
Treatment with adalimumab demonstrated significant benefits over placebo in the rates of clinical remission at weeks 8 and 52 among patients with moderate-tosevere UC who had previously failed or were currently

Table 2. Additional Efficacy Results

End points

Placebo (n 246)

Adalimumab (n 248)

P valuea

Sustained remission per Mayo score at week 8 and week 52

Sustained response per Mayo score at week 8 and week 52
Sustained mucosal healing at week 8 and week 52
PGA 1 at week 8
SFS 1 at week 8
RBS 1 at week 8
Discontinued corticosteroid use before week 52 and achieved
remission at week 52b
Discontinued corticosteroid use for 90 days before week 52 and
achieved remission at week 52b
Discontinued corticosteroid use and achieved sustained remission
at both weeks 32 and 52b
IBDQ responders at week 52
IBDQ responders at week 8

10 (4.1)
30 (12.2)
26 (10.6)
92 (37.4)
70 (28.5)
143 (58.1)
8 (5.7)

21 (8.5)
59 (23.8)
46 (18.5)
114 (46.0)
94 (37.9)
174 (70.2)
20 (13.3)

.047
.001
.013
.058
.028
.006
.035

8 (5.7)

20 (13.3)

.035

2 (1.4)

15 (10.0)

.002

65 (26.2)
144 (58.1)

.007
.006

40 (16.3)
112 (45.5)

NOTE. Data are n (%).

IBDQ, inflammatory bowel disease questionnaire; PGA, Physicians Global Assessment subscore; RBS, Rectal Bleeding Subscore; SFS, Stool
Frequency Subscore.
aP value to compare treatment groups was based on CochranMantelHaenszel test.
bRestricted to patients using corticosteroids at baseline (placebo, n 140; adalimumab, n 150).

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GASTROENTEROLOGY Vol. 142, No. 2

Table 3. Efficacy Results Stratified by Prior Anti-TNF Treatment

No prior anti-TNF

End points

CLINICAL AT

Clinical remission per Mayo score at week 8b

Clinical remission per Mayo score at week 52b
Sustained clinical remission per Mayo score at week 8
and week 52
Clinical response per Mayo score at week 8c
Clinical response per Mayo score at week 52c
Sustained clinical response per Mayo score at week 8
and week 52
Mucosal healing at week 8d
Mucosal healing at week 52d
Sustained mucosal healing at week 8 and week 52d
Discontinued corticosteroid use before week 52 and
achieved clinical remission at week 52e
PGA 1 at week 8
SFS 1 at week 8
RBS 1 at week 8
Discontinued corticosteroid use for 90 days before
week 52 and achieved remission at week 52e
Discontinued corticosteroid use and achieved sustained
clinical remission at both weeks 32 and 52e
IBDQ responders at week 52
IBDQ responders at week 8

Prior anti-TNF

Placebo
(n 145)

Adalimumab
(n 150)

Placebo
(n 101)

Adalimumab
(n 98)

P valuea

16 (11.0)
18 (12.4)
9 (6.2)

32 (21.3)
33 (22.0)
16 (10.7)

.017
.029
.169

7 (6.9)
3 (3.0)
1 (1.0)

9 (9.2)
10 (10.2)
5 (5.1)

.559
.039
.115

56 (38.6)
35 (24.1)
24 (16.6)

89 (59.3)
55 (36.7)
44 (29.3)

.001
.019
.009

29 (28.7)
10 (9.9)
6 (5.9)

36 (36.7)
20 (20.4)
15 (15.3)

.228
.038
.032

51 (35.2)
28 (19.3)
20 (13.8)
5 (6.2)

74 (49.3)
47 (31.3)
36 (24.0)
15 (13.6)

.014
.018
.025
.096

27 (26.7)
10 (9.9)
6 (5.9)
3 (5.1)

28 (28.6)
15 (15.3)
10 (10.2)
5 (12.5)

.772
.250
.269
.263

63 (43.4)
43 (29.7)
86 (59.3)
5 (6.2)

88 (58.7)
69 (46.0)
116 (77.3)
15 (13.6)

.009
.004
.001
.096

29 (28.7)
27 (26.7)
57 (56.4)
3 (5.1)

26 (26.5)
25 (25.5)
58 (59.2)
5 (12.5)

.731
.844
.695
.263

1 (1.2)

11 (10.0)

.014

1 (1.7)

4 (10.0)

.155

31 (21.4)
75 (51.7)

48 (32.0)
102 (68.0)

.039
.004

9 (8.9)
37 (36.6)

17 (17.3)
42 (42.9)

.078
.370

P valuea

NOTE. Data are n (%).

IBDQ, inflammatory bowel disease questionnaire; PGA, Physicians Global Assessment subscore; RBS, rectal bleeding subscore; SFS, stool
frequency subscore.
aP values to compare adalimumab treatment group with placebo were based on 2 test (or Fishers exact test if 20% of the cells had an
expected cell count 5).
bMayo score 2 with no individual subscore 1.
cDecrease from baseline in Mayo score 3 points and 30%, rectal bleeding subscore 0 or 1 or decrease from baseline 1 point.
dEndoscopy subscore 0 or 1.
eAmong patients with baseline corticosteroid use: n 81 for placebo and n 110 for adalimumab (no prior anti-TNF); n 59 for placebo and
n 40 for adalimumab (prior anti-TNF).

failing steroids and/or immunosuppressive therapy with

azathioprine or 6-mercaptopurine (75% of patients were
currently failing these medications). Substantial benefits
were also seen for clinical response, mucosal healing,
steroid discontinuation, IBDQ response, and other secondary end points. Incidence rates of treatment-emergent
adverse events were similar across treatment groups, and
no clinically important safety trends were identified.
Our results confirm the findings of ULTRA 1, an
8-week induction trial with adalimumab in patients with
UC, which demonstrated that adalimumab 160 mg at
week 0, 80 mg at week 2, and then 40 mg EOW beginning
at week 4 was effective for inducing clinical remission.12
Of note, in the earlier study conducted by Reinisch and
colleagues,12 significant differences between the adalimumab and placebo groups were only achieved for 2 of
the secondary end points at week 8, ie, rectal bleeding and
Physicians Global Assessment subscores. In contrast, in
ULTRA 2, significantly greater proportions of adalimumab-treated patients achieved almost all secondary
end points at week 8. The discrepancy between the 2 trials
might be due to the relatively high placebo response rates
that were observed during ULTRA 1; whereas the placebo
response rates observed in ULTRA 2 are generally similar

to those reported in 2 large placebo-controlled trials of

infliximab for UC.2 When taken together, the results of
ULTRA 1 and ULTRA 2 clearly demonstrate that adalimumab 160 mg at week 0, 80 mg at week 2, and then 40
mg EOW is an effective induction regimen for patients
with UC. Because a plateau in the dose-response curve was
not achieved in the dose-finding ULTRA 1 trial, it is
unknown whether even higher induction doses of adalimumab might have greater efficacy.
The 52-week primary and secondary end points in
ULTRA 2 provide evidence that adalimumab 40 mg EOW is
effective for long-term/maintenance treatment of UC. Important long-term outcomes, including improved quality
of life, steroid discontinuation, and achievement of steroid-free remission, also occurred more frequently during
maintenance therapy with adalimumab. Additional information regarding other long-term outcomes such as reduction in the rates of hospitalization and colectomy,
improved work productivity, etc, with adalimumab maintenance therapy is needed. These data will be reported in
subsequent publications that will integrate the results of
the current controlled trial with the results of companion
open-label extension and induction studies to provide a
greater likelihood of observing relatively rare events like

February 2012

ADALIMUMAB FOR INDUCTION AND MAINTENANCE OF REMISSION IN UC

263

Table 4. Summary of Treatment-Emergent Adverse Events

Adalimumab (n 257),
PYs 146.1

Patients with

n (%)

E (E/100 PY)

n (%)

E (E/100 PY)

Any AE
Any AE at least possibly drug-relatedb
Any severe AE
Any serious AE
Any AE leading to discontinuation
Any allergic reaction-related AE
Any injection site reaction-related AE
Any opportunistic infection-related AE (excluding TB)
Any CHF-related AE
Any demyelinating disease AE
Any lupus-like syndrome AE
Any malignant AE
Any lymphomas AE
Any infectious AE
Any serious infectious AE
Any hematologic-related AE
Deaths

218 (83.8)
86 (33.1)
37 (14.2)
32 (12.3)
34 (13.1)
1 (0.4)
10 (3.8)
3 (1.2)
0
0
0
0
0
103 (39.6)
5 (1.9)
0
0

1016 (846.1)
202 (168.2)
53 (44.1)
44 (36.6)
48 (40.0)
1 (0.8)
17 (14.2)
3 (2.5)
0
0
0
0
0
177 (147.4)
7 (5.8)
0
0

213 (82.9)
101 (39.3)
41 (16.0)
31 (12.1)
23 (8.9)
4 (1.6)
31 (12.1)
5 (1.9)
1 (0.4)
0
1 (0.4)
2 (0.8)
0
116 (45.1)
4 (1.6)
5 (1.9)
0

1086 (743.3)
273 (186.9)
56 (38.3)
45 (30.8)
25 (17.1)
4 (2.7)
58 (39.7)
6 (4.1)
1 (0.7)
0
1 (0.7)
2 (1.4)
0
212 (145.1)
4 (2.7)
5 (3.4)
0

P value for
n (%)a

.001

.030

NOTE. Safety population: All patients who received at least 1 dose of study drug or placebo.
AE, adverse event; CHF, congestive heart failure; E, event; PY, patient-year; TB, tuberculosis.
aP value for comparisons of n (%) between placebo and adalimumab using Fishers exact test.
bAs assessed by investigator.

colectomy. Whether even higher maintenance doses of

adalimumab, such as 40 mg weekly, might have greater
efficacy is unknown. Of interest, a dose-finding maintenance trial with adalimumab in another form of inflammatory bowel disease, Crohns disease, did not
demonstrate a difference between 40 mg EOW and 40
mg weekly.5
Forty percent of patients in ULTRA 2 had previously
used anti-TNF therapy (excluding adalimumab) for the
treatment of UC. Although earlier anti-TNF therapy was a
stratification variable for randomization, the study was
not powered to assess the efficacy of adalimumab in
subgroups of patients who were nave to anti-TNF therapy and who had received earlier anti-TNF therapy.
Among the larger subgroup of patients who were nave to
anti-TNF therapy, both of the co-primary end points and
a majority of the secondary end points were statistically
significant, and the magnitude of effect was broadly comparable to the effects reported with infliximab in patients
with UC who were nave to anti-TNF therapy. Among the
smaller subgroup of patients who had previously received
anti-TNF therapy (predominantly with infliximab), there
were numeric differences in favor of adalimumab, with

statistically significantly higher week 52 remission and

response rates in adalimumab-treated patients. The magnitude of effect was generally small for other end points,
and for many of the comparisons was not significant.
These observations should be interpreted with caution
because it is a subgroup analysis, the total number of
patients in this subgroup is small, and in other disease
settings such as Crohns disease the absolute treatment
effect after prior anti-TNF therapy is smaller than the
effect observed in anti-TNF nave patients.3,4
The absolute differences in remission rates between
adalimumab and placebo observed in our study are somewhat smaller than those observed in 2 trials of infliximab
that had a somewhat similar design.15 Direct comparison
across different studies is complicated for several reasons.
First, the infliximab trials were conducted 810 years ago,
when no approved medication option was available to
patients with UC who had failed conventional therapy.
Second, the infliximab trials did not allow patients with
inadequate response or flare to leave the blinded trial and
receive open-label rescue therapy. Thus, patients had to
remain in the study or be discontinued. In the present
trial, rescue therapy with open-label adalimumab was per-

Table 5. Median Serum Trough Concentrations Over Time by Remission Status at Week 52
Mean SD (minmax), Nnmiss
Treatment groups
40 mg EOW patients who were
remitters (n 43)
40 mg EOW patients who were
nonremitters (n 153)

Week 8

Week 32

Week 52

11.4 5.15 (0.00022.8), 41

10.6 5.64 (0.00026.9), 39

10.8 7.45 (0.00039.3), 39

8.49 4.35 (0.00021.8), 110

6.95 3.98 (0.00018.1), 70

6.18 4.22 (0.00016.1), 62

CLINICAL AT

Placebo (n 260),
PYs 120.1

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SANDBORN ET AL

CLINICAL AT

mitted. These patients were conservatively analyzed as

failures, although they continued on adalimumab treatment in the trial. Bias could have been introduced if
patients and or investigators judged the patients to have
an inadequate response or flare in order for the patient to
receive open-label therapy. Third, in the adalimumab trial,
the Mayo score was calculated based on the worst score
from the last 3 days for stool frequency and rectal bleeding. In contrast, in the infliximab trials and other UC
trials, the average score for stool frequency and rectal
bleeding from the last 3 days was used to calculate the
Mayo score. Finally, the patients in the infliximab trials
were anti-TNFnave patients, whereas 40% of patients in
the adalimumab trials had previously been exposed to
anti-TNF agents. These differences in clinical trial design
and patient populations limit across-trial comparisons.
How should the results of this trial be incorporated
into clinical practice? We studied outpatients with moderate-to-severe UC failing therapy with steroids and/or
immunosuppressives. Subgroup analysis showed the
strongest effect in patients who were nave to anti-TNF
therapy. Thus, the results of ULTRA 2 suggest that the
ideal patient population for adalimumab is outpatients
with moderate-to-severe UC, failing steroids and/or immunosuppressives, who are anti-TNF therapynave, and
who desire the convenience of subcutaneous dosing. However, statistically significant benefit for anti-TNF experienced patients receiving adalimumab over placebo in
terms of clinical remission and response at week 52, as
well as sustained clinical response, might offer an additional treatment option to patients who have already
failed or did not tolerate infliximab. Adalimumab has not
been studied in hospitalized patients with severe UC who
are failing intravenous steroids.
The overall safety profile of adalimumab observed in
this study was similar to that seen in other trials of
adalimumab in patients with inflammatory bowel disease.12,16 Notably, higher incidence rates were observed for
adverse events, severe adverse events, serious adverse
events, serious infectious adverse events, and serious infectious adverse events in patients receiving placebo as
compared with those receiving adalimumab. A significantly greater proportion of adalimumab-treated patients
experienced injection-site reactions. Almost all events were
mild and none required discontinuation of study drug
therapy. In addition, 2 malignancies were reported in
adalimumab-treated patients, 1 squamous cell carcinoma
and 1 gastric cancer in a patient with known risk factors.
Similar to reports with other anti-TNF antibodies administered systematically without dose interruption,1,17
the rate of formation of antibodies to adalimumab (antidrug antibodies) during 1 year was lower in patients
receiving combination therapy with adalimumab and an
immunosuppressive agent as compared with patients
receiving monotherapy with adalimumab. The median
trough serum adalimumab concentrations were higher in
patients who achieved remission at week 8 and week 52 as
compared with patients who did not achieve remission.

GASTROENTEROLOGY Vol. 142, No. 2

These findings raise the possibilities that adalimumab

therapy for UC could be further optimized by the concomitant administration of azathioprine and by the use of
therapeutic drug monitoring to customize adalimumab
dosing to achieve the higher median trough concentrations observed among patients who responded to adalimumab therapy. However, as this study was not designed
to prospectively treat to a target serum drug concentration, these results should be interpreted with caution.
In conclusion, adalimumab was more effective than
placebo for inducing and maintaining clinical remission
in patients with moderate-to-severe UC who did not adequately respond to conventional therapy with oral corticosteroids or immunosuppressive agents.

Supplementary Material
Note: To access the supplementary material
accompanying this article, visit the online version of
Gastroenterology at www.gastrojournal.org, and at doi:
10.1053/j.gastro.2011.10.032.
References
1. Baumgart DC, Carding SR. Inflammatory bowel disease: cause
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2. Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab induction
and maintenance therapy for ulcerative colitis. N Engl J Med
2005;353:24622476.
3. Hanauer SB, Sandborn WJ, Rutgeerts P, et al. Human anti-tumor
necrosis factor monoclonal antibody (adalimumab) in Crohns disease: the CLASSIC I trial. Gastroenterology 2006;130:323333.
4. Sandborn WJ, Rutgeerts P, Enns R, et al. Adalimumab induction
therapy for Crohns disease previously treated with infliximab: a
randomized trial. Ann Int Med 2007;146:829 838.
5. Colombel JF, Sandborn WJ, Rutgeerts P, et al. Adalimumab for
maintenance of clinical response and remission in patients with
Crohns disease: the CHARM trial. Gastroenterology 2007;132:
56 65.
6. Sandborn WJ, Feagan BG, Stoinov S, et al. Certolizumab pegol for
the treatment of Crohns disease. N Engl J Med 2007;357:228
238.
7. Schreiber S, Khaliq-Kareemi M, Lawrance I, et al. Certolizumab
pegol maintenance therapy for Crohns disease. N Engl J Med
2007;357:239 250.
8. Peyrin-Biroulet L, Laclotte C, Roblin X, Bigard MA. Adalimumab
induction therapy for ulcerative colitis with intolerance or lost
response to infliximab: an open-label study. World J Gastroenterol
2007;13:2328 2332.
9. Afif W, Leighton JA, Hanauer SB, et al. Open-label study of adalimumab in patients with ulcerative colitis including those with prior
loss of response or intolerance to infliximab. Inflamm Bowel Dis
2009;15:13021307.
10. Barreiro-de Acosta M, Lorenzo A, Dominguez-Munoz JE. Adalimumab in ulcerative colitis: two cases of mucosal healing and
clinical response at two years. World J Gastroenterol 2009;15:
3814 3816.
11. Taxonera C, Estelles J, Fernandez-Blanco I, et al. Adalimumab
induction and maintenance therapy for patients with ulcerative
colitis previously treated with infliximab. Aliment Pharmacol Ther
2011;33:340 348.
12. Reinisch W, Sandborn WJ, Hommes DW, et al. Adalimumab for
induction of clinical remission in moderately to severely active
ulcerative colitis: results of a randomised controlled trial. Gut
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13. Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis.
A randomized study. N Engl J Med 1987;317:16251629.
14. Irvine EJ, Feagan B, Rochon J, et al. Quality of life: a valid and
reliable measure of therapeutic efficacy in the treatment of inflammatory bowel disease. Canadian Crohns Relapse Prevention Trial
Study Group. Gastroenterology 1994;106:287296.
15. Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med
2005;353:24622476.
16. Colombel JF, Sandborn WJ, Panaccione R, et al. Adalimumab
safety in global clinical trials of patients with Crohns disease.
Inflamm Bowel Dis 2009;15:1308 1319.
17. Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohns disease. N Engl J Med
2010;362:13831395.

Received July 13, 2011 Accepted October 24, 2011.

Reprint requests
Address requests for reprints to: William J. Sandborn, MD, Division
of Gastroenterology, University of California San Diego, 9500
Gilman Drive, Building UC 303, Room 220, La Jolla, California
92093-0063. e-mail: wsandborn@ucsd.edu; fax: (858) 534-3338.
Acknowledgments
Medical writing support was provided in the development and
revision of this article by Amy Gamelli, PhD, and Eileen-BurkhartHartman, PhD, of Abbott Laboratories.
Conicts of interest
The authors disclose the following: Dr Sandborn reports having
been a consultant, study investigator, and received grant and/or
research support from Abbott Laboratories, Janssen (previously
CentocorOrthoBiotech), and UCB Pharma, and a consultant for Merck
(previously Schering Plough). Dr Van Assche reports having been a
study investigator, consultant, and received grant and/or research
support from Abbott Laboratories. In addition, Dr Van Assche has
served as consultant for Biogen Idec, Centocor, Ferring, JanssenCilag, Novartis, NovoNordisk, PDL BioPharma, Sano-aventis,
Schering-Plough, UCB Pharma, and Zealand Pharma; has served on
advisory committees for Biogen Idec, Centocor, Novartis,
NovoNordisk, PDL BioPharma, and Zealand Pharma; has received
research support from Ferring; and has received speaking fees from
Janssen-Cilag and Schering-Plough. Dr Reinisch reports having served
as an advisory board member and speaker for Abbott Laboratories.
In addition, Dr Reinisch has received consulting fees from Aesca,

265

Biogen Idec, Centocor, Ferring, Genentech, Millennium Research

Group, MSD, Novartis, Schering-Plough, Shire Pharmaceuticals, and
UCB Pharma; has served on advisory committees for Aesca, Biogen
Idec, Centocor, Genentech, Millennium Research Group, MSD,
Novartis, Schering-Plough, Shire Pharmaceuticals, and UCB; and has
received speaking fees from Ferring. Dr Colombel reports having
served as a study investigator, consultant, advisory board member
and speaker for Abbott Laboratories. In addition, Dr Colombel has
received consulting fees from ActoGeniX, Albireo Pharma, Amgen,
AstraZeneca, Bayer AG, Biogen Idec, Boehringer Ingelheim GmbH,
Bristol-Myers Squibb, Cellerix, Centocor, Chemocentryx, Cosmo
Technologies, Danone Research, Elan Pharmaceuticals, Genentech,
Giuliani SpA, Given Imaging, Glaxo Smith Kline, Hutchison
MediPharma, Merck Sharp and Dohme Corp., Millennium
Pharmaceuticals Inc. (now Takeda), Neovacs, Ocera Therapeutics,
Inc., Pzer, Shire Pharmaceuticals, Schering-Plough, Prometheus
Laboratories, Sano-Aventis, Synta Pharmaceuticals Corp, Teva,
Therakos, UCB Pharma, and Wyeth; has served on advisory
committees for Centocor, Danone, Elan, Merck Sharp and Dohme
Corp., Millennium Pharmaceuticals Inc. (now Takeda), ScheringPlough, and UCB Pharma; has received speaking fees from Centocor,
Elan Pharmaceuticals, Given Imaging, Otsuka America
Pharmaceutical, Merck Sharp and Dohme Corp., Schering-Plough,
Shire Pharmaceuticals, Tillotts Pharma and UCB Pharma; and has
received grant support from Astra-Zeneca, Ferring, Schering-Plough,
and UCB Pharma. Dr DHaens reports having been a consultant,
study investigator, and received grant and/or research support from
Abbott Laboratories. In addition, Dr DHaens has received consulting
fees from ActoGeniX, Centocor, Chemocentryx, Cosmo Technologies,
Elan Pharmaceuticals, Ferring, Given Imaging, Glaxo Smith Kline,
Merck Research Laboratories, MerckSerono, Millennium
Pharmaceuticals Inc. (now Takeda), Pzer, Schering-Plough, Shire
Pharmaceuticals, Vifor and UCB Pharma. Dr Wolf reports having
served as a study investigator and consultant and received grant
and/or research support and speaking fees from Abbott
Laboratories. In addition, Dr Wolf has received consulting fees from
Bristol-Myers Squibb, Centocor, Millennium Research Group, Ortho
McNeil, Prometheus Laboratories, Salix Pharmaceuticals, and UCB
Pharma; has received research support from Bristol-Myers Squibb,
Centocor, Millennium Research Group, Prometheus Laboratories, and
UCB Pharma; has served on advisory committees for Millennium
Research Group; and has received speaking fees from Ortho McNeil,
Prometheus Laboratories, and UCB Pharma. Drs Kron, Tighe, Lazar,
and Thakkar are employees of and own stock in Abbott.
Funding
This study was sponsored by Abbott Laboratories.

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February 2012

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GASTROENTEROLOGY Vol. 142, No. 2

Supplementary Figure 1. Patient flow. OL, open-label; eow, every other week. aSites were noncompliant with good clinical practices and protocol
requirements.

February 2012

ADALIMUMAB FOR INDUCTION AND MAINTENANCE OF REMISSION IN UC

265.e2

Supplementary Figure 2. (A) Summary of odds ratios for the proportion of patients achieving clinical remission at week 8 for adalimumab vs
placebo by subgroup. (B) Summary of odds ratios for the proportion of patients achieving clinical remission at week 52 for adalimumab vs placebo
by subgroup. aMedian age, 39 years. bOdds ratio could not be calculated for other race category. cOdds ratio could not be calculated for 64
age category. dOdds ratio could not be calculated for current user prior tobacco use category.

265.e3

SANDBORN ET AL

GASTROENTEROLOGY Vol. 142, No. 2

Supplementary Figure 2. Continued