Infliximab Reduces Endoscopic, bu No Clinical, Recu ence o
C ohn’s Disease A e Ileocolonic Resec ion
Miguel Reguei o,
1
B ian G. Feagan,
2
Bin Zou,
3
Jewel Johanns,
3
Ma ion A. Blank,
4
Ma c Che ie ,
3
Sco Ple y,
3
John Popp,
4
F eddy J. Co nillie,
5
Milan Lukas,
6
Sil io Danese,
7
Paolo Gionche i,
8
S ephen B. Hanaue ,
9
Wal e Reinisch,
10,11
William J. Sandbo n,
12
Da io So en ino,
13,14
and Paul Ru gee s,
15
o he PREVENT S udy G oup
1
Inflamma o y Bowel Disease Cen e and Di ision o Gas oen e ology, Hepa ology and Nu i ion, Uni e si y o Pi sbu gh
Medical Cen e , Pi sbu gh, Pennsyl ania;
2
Roba s Resea ch Ins i u e, Uni e si y o Wes e n On a io, London, On a io,
Canada;
3
Janssen Resea ch & De elopmen , LLC, Sp ing House, Pennsyl ania;
4
Janssen Scien ific A ai s, LLC, Ho sham,
Pennsyl ania;
5
MSD In e na ional, Luze n, Swi ze land;
6
Cha les Uni e si y, P ague, Czech Republic;
7
Is i u o Clinico
Humani as, Milan, I aly;
8
S. O sola-Malpighi Hospi al, Uni e si y o Bologna, Bologna, I aly;
9
Feinbe g School o Medicine,
No hwes e n Uni e si y, Chicago, Illinois;
10
McMas e Uni e si y, Hamil on, On a io, Canada;
11
Depa men o In e nal
Medicine III, Medical Uni e si y o Vienna, Vienna, Aus ia;
12
Uni e si y o Cali o nia San Diego, La Jolla, Cali o nia;
13
Vi ginia Tech, Ca ilion School o Medicine, Roanoke, Vi ginia;
14
Depa men o Clinical and Expe imen al Pa hology,
Uni e si y o Udine School o Medicine, Udine, I aly; and
15
Uni e si y Hospi al Gas huisbe g, Leu en, Belgium
See edi o ial on page 1521.
BACKGROUND & AIMS: Mos pa ien s wi h C ohn’s disease
(CD) e en ually equi e an in es inal esec ion. Howe e , CD
equen ly ecu s a e esec ion. We pe o med a andomized
ial o compa e he abili y o infliximab s placebo o p e en
CD ecu ence. METHODS: We e alua ed he e ficacy o
infliximab in p e en ing pos ope a i e ecu ence o CD in
297 pa ien s a 104 si es wo ldwide om No embe 2010
h ough May 2012. All s udy pa ien s had unde gone ileoco-
lonic esec ion wi hin 45 days be o e andomiza ion. Pa ien s
we e andomly assigned (1:1) o g oups gi en infliximab
(5 mg/kg) o placebo e e y 8 weeks o 200 weeks. The
p ima y end poin was clinical ecu ence, defined as a
composi e ou come consis ing o a CD Ac i i y Index sco e
>200 and a 70-poin inc ease om baseline, and endo-
scopic ecu ence (Ru gee s sco e i2, de e mined by a
cen al eade ) o de elopmen o a new o e-d aining fis ula
o abscess, be o e o a week 76. Endoscopic ecu ence was
a majo seconda y end poin . RESULTS: A smalle p opo ion
o pa ien s in he infliximab g oup had a clinical ecu ence
be o e o a week 76 compa ed wi h he placebo g oup, bu
his di e ence was no s a is ically significan (12.9% s
20.0%; absolu e isk educ ion [ARR] wi h infliximab, 7.1%;
95% confidence in e al: 1.3% o 15.5%; P¼.097). A
significan ly smalle p opo ion o pa ien s in he infliximab
g oup had endoscopic ecu ence compa ed wi h he placebo
g oup (30.6% s 60.0%; ARR wi h infliximab, 29.4%; 95%
confidence in e al: 18.6% o 40.2%; P<.001). Addi ionally,
asignifican ly smalle p opo ion o pa ien s in he inflix-
imab g oup had endoscopic ecu ence based only on Ru -
gee s sco es i2 (22.4% s 51.3%; ARR wi h infliximab,
28.9%; 95% confidence in e al: 18.4% o 39.4%; P<.001).
Pa ien s p e iously ea ed wi h an i- umo nec osis ac o
agen s o hose wi h mo e han 1 esec ion we e a g ea e
isk o clinical ecu ence. The sa e y p ofile o infliximab
wassimila o ha omp e ious epo s.CONCLUSIONS:
Infliximab is no supe io o placebo in p e en ing clinical
ecu ence a e CD- ela ed esec ion. Howe e , infliximab
does educe endoscopic ecu ence. ClinicalT ials.go ID
NCT01190839.
Keywo ds: PREVENT; An i-TNF; Inflamma o y Bowel Disease;
CDAI.
C ohn’s disease (CD) o en equi es in es inal esec-
ion, despi e ea men wi h immunosupp essi e
and biologic he apies.
1,2
His o ically, up o 70% o pa ien s
who unde go CD- ela ed esec ion de elop pos ope a i e
endoscopic ecu ence a o p oximal o he su gical anas-
omosis wi hin 1 yea .
3,4
Recen sys ema ic e iews and
me a-analyses ha e shown ha app oxima ely one- hi d o
pa ien s wi h CD who ha e a fi s esec ion equi e a second
wi hin 10 yea s, and he majo i y o hese second in es inal
esec ions occu wi hin 5 yea s o he fi s . Howe e , du ing
he pas ew decades, he isk o a second esec ion has
dec eased.
5
Addi ionally, a dec easing end has been ound
du ing he pas 6 decades in he cumula i e isk o esec ion
1, 5, and 10 yea s a e CD diagnosis.
6
S udies o p obio ics, aminosalicyla es, and
budesonide
7–13
o p e en ion o pos ope a i e ecu ence
ha e o e all yielded nega i e esul s. S udies o ni o-
imidazole an ibio ics ha e been posi i e o p e en ion o
clinical ecu ence. S udies o hiopu ines ha e had mixed
esul s o he p e en ion o clinical ecu ence. Nei he
ni oimidazole an ibio ics no hiopu ines ha e consis en ly
Abb e ia ions used in his pape : ARR, absolu e isk educ ion; ATI,
an ibodies o infliximab; CD, C ohn’s disease; CDAI, C ohn’s Disease
Ac i i y Index; CI, confidence in e al; TNF, umo nec osis ac o .
Mos cu en a icle
© 2016 by he AGA Ins i u e
0016-5085
h p://dx.doi.o g/10.1053/j.gas o.2016.02.072
Gas oen e ology 2016;150:1568–1578
CLINICAL AT
Open access unde CC BY-NC-ND license.
p e en ed endoscopic ecu ence.
14–16
Ini ial s udies,
17,18
a
small placebo-con olled ial,
19
and subsequen obse a-
ional s udies
20–25
sugges ed ha umo nec osis ac o
(TNF) an agonis s migh be e ec i e o p e en ion o
pos ope a i e ecu ence. In ecen s udies o CD ea men
s a egies a e in es inal esec ion, he apy adjus ed
acco ding o 6-mon h colonoscopy findings led o e ec i e
disease con ol.
26–28
O e all, op imal pos ope a i e man-
agemen is unclea .
Gi en hese conside a ions, we e alua ed he e ficacy
and sa e y o infliximab o p e en ion o pos ope a i e CD
ecu ence.
Me hods
Pa ien s
The PREVENT (P ospec i e, Mul icen e , Randomized,
Double-Blind, Placebo-Con olled T ial Compa ing REMI-
CADE® [infliximab] and Placebo in he P e en ion o
Recu ence in C ohn’s Disease Pa ien s Unde going Su gical
Resec ion Who A e a an Inc eased Risk o Recu ence;
ClinicalT ials.go ID NCT01190839) s udy was a phase 3,
mul icen e , placebo-con olled, double-blind, andomized
s udy conduc ed a 104 si es globally be ween No embe
2010 and May 2012. The Ins i u ional Re iew Boa d o e hics
commi ee a each si e app o ed he p o ocol, and pa ien s
p o ided w i en in o med consen . All au ho s had access o
he s udy da a and had e iewed and app o ed he final
manusc ip .
En olled pa ien s we e a leas 18 yea s old wi h a
confi med diagnosis o CD who had unde gone ileocolonic
esec ion wi h ileocolonic anas omosis. An end o loop
ileos omy wi hin 1 yea was pe mi ed i s oma closu e and
ileocolonic anas omosis occu ed wi hin 45 days o andom-
iza ion. Pa ien s had no e idence o mac oscopic CD, no
known ac i e CD elsewhe e in he gas oin es inal ac , and
we e eligible o andomiza ion wi hin 45 days o esec ion.
Pa ien s we e ineligible i he quali ying su ge y occu ed
mo e han 10 yea s a e CD diagnosis and was pe o med o
s ic u ing disease in ol ing <10 cm o bowel. Pa ien s we e
also equi ed o ha e a baseline CD Ac i i y Index (CDAI)
29
sco e <200 and a leas one o he ollowing isk ac o s o
disease ecu ence: quali ying su ge y ha was hei second
in a-abdominal esec ion wi hin 10 yea s; hi d o mo e
in a-abdominal esec ion; esec ion o a pene a ing CD
complica ion (eg, abscess o fis ula); a his o y o pe ianal
fis ulizing CD, p o ided he e en hadno occu edwi hin3
mon hs; o smoking 10 o mo e ciga e es pe day o he pas
yea . The p especified isk ac o s o smoking, pe o a ing
disease, and p e ious esec ion had been iden ified om
p e ious s udies and we e u ilized in a ecen pos ope a i e
s udy.
28,30–35
Pa ien s ecei ing o al mesalamine o immunosupp essi es
(aza hiop ine, 6-me cap opu ine, o me ho exa e) p e-su ge y
could con inue ea men wi h main enance o s able doses
a e esec ion. Pa ien s no ecei ing hese agen s p e-su ge y
could no ecei e hem pos -su ge y. Rec al mesalamine was
discon inued a leas 2 weeks be o e andomiza ion. Ini ia ion
o co icos e oids o an ibio ics o CD ea men was
p ohibi ed.
S udy Design
Pa ien s we e andomized equally o ecei e infliximab
(Remicade; Janssen Bio ech, Inc., Ho sham Township, PA) 5
mg/kg o placebo e e y 8 weeks. Placebo and infliximab in-
usions we e adminis e ed in a blinded manne . Randomiza-
ion was s a ified by he numbe o isk ac o s o
ecu ence (1 o >1) and cu en use o an immunosup-
p essi e (yes/no). Unlike dosing egimens used p e iously
and hosedesc ibedin hep esc ibingin o ma ion o pa-
ien s wi h CD,
36
e e y-8-weeks dosing wi hou he 3-dose
induc ion egimen was u ilized in his s udy. This dosing
egimen was chosen because pa ien s in his s udy we e in
su gically-induced emission and did no ha e ac i e CD a
he ime hey en e ed he s udy; hus, e e y-8-weeks dosing
o main enance o emission was employed. Also, some pa-
ien s migh no ha e been naï e o infliximab, and da a om
an infliximab ial in pa ien s wi h pso iasis showed a highe
a e o se ious in usion eac ions a he week-2 infliximab
in usion a e a hia us.
37
CDAI sco es we e de e mined a each isi , and as
equi ed a in e im assessmen s; baseline CDAI e e s o he
CDAI collec ed du ing he sc eening pe iod (ie, no ewe han
10 days and no mo e han 45 days be o e andomiza ion)
ha qualified he pa ien o he s udy. Pa ien s who me
CDAI c i e ia (ie, 200 and an inc ease o 70 poin s om
he baseline CDAI sco e) o clinical ecu ence o eached
week 76 unde wen a ideo ileocolonoscopy. Pa ien s who
discon inued s udy agen be o e week 76 had a ideo ileo-
colonoscopy a he ime o discon inua ion. I clinical ecu -
ence was obse ed, pa ien s could ecei e blinded
infliximab doses a an inc ease o 5 mg/kg o each subse-
quen scheduled in usion isi , such ha pa ien s ecei ing
placebo inc eased o 5 mg/kg and pa ien s ecei ing 5 mg/kg
o 10 mg/kg.
Se um samples we e collec ed a baseline and week 72 o
measu emen o infliximab and an ibodies o infliximab (ATI).
38
Ad e se e en s, concomi an medica ions, and CD- ela ed hos-
pi aliza ions and su ge ies we e eco ded h oughou .
End Poin s
The p ima y end poin was clinical ecu ence be o e o a
week 76, defined by a 70-poin inc ease om baseline wi h a
o al CDAI sco e 200 and e idence o endoscopic ecu ence
defined by a Ru gee s sco e
3
o i2 (i0, no lesions; i1, 5
aph hous lesions; i2, >5 aph hous lesions o anas omo ic ulce
<1 cm; i3, di use aph hous ilei is wi h di usely inflamed mu-
cosa; i4, di use inflamma ion wi h la ge ulce s, nodules, and/o
na owing) a he anas omo ic si e o i s equi alen elsewhe e
in he gas oin es inal ac o fis ula/abscess de elopmen (ie,
new d aining ex e nal fis ula, in e nal fis ula, eopening and
d aining o a p e iously exis ing ex e nal fis ula, pe ianal ab-
scess, o in a-abdominal abscess >3 mon hs a e he index
su ge y). Pa ien s we e conside ed o ha e clinical ecu ence i
hey had a ea men ailu e (ie, ini ia ed a p ohibi ed CD
medica ion, had a p ohibi ed use o a CD medica ion, o had CD-
ela ed su ge y).
The majo seconda y end poin was endoscopic ecu ence
o CD be o e o a week 76, defined as a Ru gee s sco e o i2
ei he a he anas omosis o elsewhe e in he gas oin es inal
ac , whe he his occu ed a he week 76 ideo ileocolono-
scopy, o a a p io ideo ileocolonoscopy. Pa ien s who
June 2016 Infliximab o Pos su gical CD P e en ion 1569
CLINICAL AT
Table 1.Baseline Demog aphics, Disease Cha ac e is ics, and Concomi an C ohn’s Disease Medica ions o
Randomized Pa ien s
Cha ac e is ic Placebo (N ¼150) Infliximab 5 mg/kg (N ¼147) To al (N ¼297)
Sex, n (%)
n 150 147 297
Male 81 (54.0) 77 (52.4) 158 (53.2)
Female 69 (46.0) 70 (47.6) 139 (46.8)
Race, n (%)
n 150 147 297
Whi e 138 (92.0) 138 (93.9) 276 (92.9)
Black o A ican Ame ican 4 (2.7) 3 (2.0) 7 (2.4)
Asian 2 (1.3) 1 (0.7) 3 (1.0)
O he 6 (4.0) 5 (3.4) 11 (3.7)
Age, y
n 150 147 297
Mean (SD) 35.4 (12.41) 37.1 (13.49) 36.3 (12.96)
Median 34.0 35.0 34.0
In e qua ile ange (25.044.0) (26.045.0) (26.044.0)
Range (1869) (1876) (1876)
Weigh , kg
n 150 147 297
Mean (SD) 69.70 (16.083) 69.64 (17.716) 69.67 (16.883)
Median 67.30 66.00 66.80
In e qua ile ange (58.1078.10) (57.2079.50) (58.0078.30)
Range (41.0127.0) (40.0125.7) (40.0127.0)
Disease du a ion, y
n 150 146 296
Mean (SD) 6.39 (7.457) 8.38 (8.651) 7.37 (8.115)
Median 3.32 6.49 5.17
In e qua ile ange (0.749.71) (1.4511.07) (0.8010.61)
Range (0.137.5) (0.145.9) (0.145.9)
CDAI sco e
n 150 146 296
Mean (SD) 109.8 (54.75) 107.7 (52.75) 108.8 (53.69)
Median 109.5 102.5 105.5
In e qua ile ange (66.0153.0) (64.0148.0) (65.0152.5)
Range (4240) (3202) (3240)
In ol ed gas oin es inal a eas, n (%)
n 150 146 296
Ileum 146 (97.3) 144 (98.6) 290 (98.0)
Colon 76 (50.7) 89 (61.0) 165 (55.7)
P oximal small in es ine, s omach and/o esophagus 6 (4.0) 6 (4.1) 12 (4.1)
Pe ianal 13 (8.7) 17 (11.6) 30 (10.1)
Ex a in es inal mani es a ions 15 (10.0) 21 (14.4) 36 (12.2)
Findings a su ge y, n (%)
n 150 146 296
S ic u e 86 (57.3) 84 (57.5) 170 (57.4)
Abscess 41 (27.3) 47 (32.2) 88 (29.7)
In e nal fis ula 86 (57.3) 67 (45.9) 153 (51.7)
Sinus ac s 10 (6.7) 7 (4.8) 17 (5.7)
Pe o a ion 12 (8.0) 19 (13.0) 31 (10.5)
P io in a-abdominal su ge ies, n (%)
n150 146 296
0 91 (60.7) 79 (54.1) 170 (57.4)
12 51 (34.0) 63 (43.2) 114 (38.5)
>2 8 (5.3) 4 (2.7) 12 (4.1)
CD medica ion his o y, n (%)
n 150 146 296
Any CD medica ion 144 (96.0) 136 (93.2) 280 (94.6)
An i- umo nec osis ac o 30 (20.0) 37 (25.3) 67 (22.6)
Adalimumab 17 (11.3) 21 (14.4) 38 (12.8)
Infliximab 15 (10.0) 18 (12.3) 33 (11.1)
Ce olizumab 0 3 (2.1) 3 (1.0)
1570 Reguei o e al Gas oen e ology Vol. 150, No. 7
CLINICAL AT
de eloped a fis ula o abscess, o had a ea men ailu e we e
conside ed o ha e endoscopic ecu ence.
Endoscopic ecu ence be o e o a week 76 defined by
endoscopic sco e only (Ru gee s sco e i2) was also analyzed.
Endoscopy end poin s be o e o a week 76, including hose o
he p ima y end poin , we e e alua ed by a cen al eade
(P.R.).
A seconda y e ficacy end poin was clinical ecu ence
be o e o a week 104.
S udy Du a ion
Al hough ea men was planned o a maximum o 208
weeks, he s udy was e mina ed a e week 104 because he
p ima y ou come was no me .
S a is ical Analysis
All andomized pa ien s we e included in e ficacy analyses
acco ding o assigned ea men , ega dless o ac ual ea men
ecei ed. All pa ien s who ecei ed a leas 1 dose o s udy
agen we e included in sa e y and pha macokine ic analyses
based on ac ual ea men ecei ed.
Fo con inuous ou comes, he las alue be o e ea men
ailu e was ca ied o wa d.
Se en sensi i i y analyses we e pe o med (5 p especified
and 2 pos -hoc) on he p ima y end poin .
Odds a ios o p especified subg oup analyses (eg, de-
mog aphics, disease cha ac e is ics, concomi an medica ions)
o clinical ecu ence we e summa ized.
Ca ego ical da a (eg, clinical o endoscopic ecu ence)
we e compa ed using he Coch an-Man el-Haenszel c
2
es .
Con inuous measu es we e compa ed using analysis o a i-
ance on he an de Wae den no mal sco es. Time- o-e en
end poin s we e analyzed using he log- ank es . A Cox
model was used o e alua e p edic o s o clinical ecu ence.
S a is ical es ing was pe o med a a¼.05 (2-sided) le el o
significance.
Afixed-sequence es ing p ocedu e con olled he o e all
ype I e o a e a he .05 le el. I he es o he p ima y end
poin was no posi i e, s a is ical es s o o he end poin s
we e no conside ed posi i e, e en i he nominal P alue
eached he .05 le el o significance.
In a s udy conduc ed wi h a pa ien popula ion simila o
ha p oposed o his s udy, app oxima ely 40% o pa ien s in
he placebo g oup expe ienced clinical ecu ence by week
52.
19
Fo calcula ion o sample size, 50% and 30% o placebo-
and infliximab- ea ed pa ien s, espec i ely, we e expec ed o
de elop clinical ecu ence by week 76. A sample size o 290
pa ien s, 145 pe ea men , p o ided 93% powe o de ec a
20% be ween-g oup di e ence in clinical ecu ence be o e o
a week 76.
Resul s
Pa ien s
Demog aphics, quali ying cha ac e is ics, and isk ac-
o s o he 297 andomized pa ien s (placebo, N ¼150;
infliximab, N ¼147) we e simila be ween ea men
g oups. The mos common isk ac o o in es inal esec ion
was pene a ing complica ion (Table 1,Supplemen a y
Tables 2 and 3). App oxima ely 20% o andomized pa-
ien s ecei ed concomi an immunosupp essi es (Table 1).
An ibio ics we e adminis e ed o CD o 6 pa ien s in he
placebo g oup and 2 pa ien s in he infliximab 5 mg/kg
g oup; hese pa ien s we e conside ed ea men ailu es.
Pa ien disposi ion is shown in Supplemen a y Figu e 1.
App oxima ely one- hi d o andomized pa ien s dis-
con inued s udy d ug be o e week 76, mos commonly o
ad e se e en s.
Table 1.Con inued
Cha ac e is ic Placebo (N ¼150) Infliximab 5 mg/kg (N ¼147) To al (N ¼297)
Co icos e oid (excluding budesonide) 96 (64.0) 104 (71.2) 200 (67.6)
Budesonide 67 (44.7) 63 (43.2) 130 (43.9)
Immunosupp essi e d ugs 88 (58.7) 85 (58.2) 173 (58.4)
6-MP 22 (14.7) 19 (13.0) 41 (13.9)
AZA 77 (51.3) 73 (50.0) 150 (50.7)
Me ho exa e 7 (4.7) 11 (7.5) 18 (6.1)
Mesalamine 101 (67.3) 100 (68.5) 201 (67.9)
An ibio ics 88 (58.7) 94 (64.4) 182 (61.5)
Concomi an CD medica ions, n (%)
n 150 147 297
Any CD medica ion 47 (31.3) 53 (36.1) 100 (33.7)
Co icos e oid (excluding budesonide) 4 (2.7) 10 (6.8) 14 (4.7)
20 mg/d P.Eq 0 1 (0.7) 1 (0.3)
<20 mg/d P.Eq 4 (2.7) 9 (6.1) 13 (4.4)
Budesonide 2 (1.3) 2 (1.4) 4 (1.3)
Immunosupp essi e d ugs 27 (18.0) 25 (17.0) 52 (17.5)
6-MP/AZA 27 (18.0) 21 (14.3) 48 (16.2)
Me ho exa e 0 4 (2.7) 4 (1.3)
Mesalamine 27 (18.0) 28 (19.0) 55 (18.5)
AZA, aza hiop ine; 6-MP, 6-me cap opu ine; P.Eq, p ednisone equi alen .
June 2016 Infliximab o Pos su gical CD P e en ion 1571
CLINICAL AT
P ima y End Poin
Clinical ecu ence a es be o e o a week 76 we e
12.9% and 20.0% o he infliximab and placebo g oups,
espec i ely (absolu e isk educ ion [ARR] wi h infliximab,
7.1%; 95% confidence in e al [CI]: 1.3% o 15.5%); hese
esul s we e no s a is ically significan (P¼.097)
(Figu e 1). O no e, clinical ecu ence a es be o e o a
week 76 among pa ien s who me bo h CDAI and endo-
scopic c i e ia we e 4.1% and 9.3% (P¼.056) o he
infliximab and placebo g oups, espec i ely (Table 2).
In gene al, he esul s o he sensi i i y analyses we e
consis en wi h he esul s o he p ima y end poin analysis
(Supplemen a y Table 1).
Time o clinical ecu ence is summa ized in Figu e 2 o
he infliximab and placebo g oups (log ank P¼.141).
Resul s obse ed in p especified subg oups we e
gene ally consis en wi h he o e all esul s, wi h a ew
excep ions, including CD du a ion, baseline CDAI sco e,
p io TNF he apy, ace, geog aphic loca ion, disease loca-
ion in gas oin es inal ac , and pa ien s unde going hei
second in a-abdominal ope a ion (Supplemen a y
Figu e S2AD).
Seconda y End Poin s
Endoscopic ecu ence. Endoscopic ecu ence, as
defined by Ru gee s sco e i2; o abscess, fis ula ecu -
ence, o de elopmen ; o ea men ailu e, be o e o a
week 76 o he infliximab and placebo g oups was 30.6%
and 60.0%, espec i ely (ARR wi h infliximab ¼29.4%;
95% CI: 18.6%40.2%; P<.001; Figu e 3A).
Simila ly, endoscopic ecu ence defined only by Ru -
gee s sco es i2 o he infliximab and placebo g oups was
22.4% and 51.3%, espec i ely (ARR wi h infliximab ¼
28.9%; 95% CI: 18.4% 39.4%; P<.001; Figu e 3A).
Classifica ion o pa ien s by Ru gee s sco e i1 (<5
aph hous ulce s) and i2 (5 aph hous ulce s o anas omo ic
ulce <1 cm) endoscopic ecu ence may be o negligible
clinical significance and po en ially sepa a ed by only 1
aph hous ulce . Classi ying pa ien s by no mal mucosa (i0)
o agg essi e endoscopic ecu ence (i3/i4) p o ides a
mo e meaning ul dis inc ion.
Cen al endoscopic esul s be o e o a week 76 a e
p esen ed in Figu e 3B. O 73 pa ien s wi h an i0 Ru gee s
sco e be o e o a week 76, 54 (74.0%) and 19 (26.0%)
pa ien s we e in infliximab and placebo g oups, espec i ely
(Supplemen a y Figu e S3). O 59 pa ien s wi h an i3 o i4
Ru gee s sco e be o e o a week 76, 11 (18.6%) and 48
(81.4%) pa ien s we e in he infliximab and placebo g oups,
espec i ely (Supplemen a y Figu e S3).
Among pa ien s wi h endoscopy esul s be o e o a
week 76, he dis ibu ion o Ru gee s sco es a e summa-
ized in Figu e 3B.
Clinical ecu ence a week 104. Clinical ecu ence
a es be o e o a week 104 we e 17.7% and 25.3% o he
Figu e 1. Clinical ecu ence be o e o a week 76 and be o e
o a week 104. P alues based on he Coch an-Man el-
Haenszel c
2
es s a ified by he numbe o isk ac o s o
ecu ence o ac i e C ohn’s disease (1 o >1) and baseline
use (yes/no) o an immunosupp essi es (ie, aza hiop ine,
6-me cap opu ine, o me ho exa e).
a
Nominal P alue.
Table 2.Reasons o Clinical Recu ence
a
Be o e o a
Week 76
Reasons
Placebo
(N ¼150)
Infliximab,
5 mg/kg
(N¼147)
Me CDAI and endoscopic c i e ia 14 (9.3) 6 (4.1)
Me fis ula/abscess c i e ia 7 (4.7) 3 (2.0)
De eloped a new d aining ex e nal
fis ula
2 (1.3) 0
Reopened and d ained a p e iously
exis ing ex e nal fis ula
0 1 (0.7)
De eloped a new in e nal fis ula 3 (2.0) 2 (1.4)
De eloped a new pe ianal abscess 6 (4.0) 1 (0.7)
De eloped a new in a-abdominal
abscess >3 mo a e he da e o
he index su ge y
0 1 (0.7)
Had a ea men ailu e 14 (9.3) 14 (9.5)
Ini ia ed a p ohibi ed CD medica ion 7 (4.7) 4 (2.7)
Had a p ohibi ed use o a CD
medica ion
12 (8.0) 12 (8.2)
Had a su ge y o CD 2 (1.3) 2 (1.4)
Me a leas 1 o he ollowing c i e ia 1 (0.7) 0
Discon inued s udy agen due o
ecu en symp oms o CD
00
Me CDAI c i e ia a he ime o
discon inua ion o s udy agen
1 (0.7) 0
Did no ha e su ficien da a o e alua e
clinical ecu ence s a us a bo h wk
72 and wk 76
00
NOTE. Values a e n (%).
a
Pa ien s could ha e mo e han one eason o clinical
ecu ence.
1572 Reguei o e al Gas oen e ology Vol. 150, No. 7
CLINICAL AT

infliximab and placebo g oups, espec i ely (ARR wi h
infliximab ¼7.6%, 95% CI: 1.7%, o 17.0%; P¼.098)
(Figu e 1).
C ohn’s Disease Ac i i y Index sco es a week
104. Median changes om baseline in CDAI sco e a he
las isi be o e o a week 104 we e 15.0 and 22.0 o
placebo and infliximab 5 mg/kg, espec i ely (P¼.058).
Median CDAI sco es h ough week 104 a e shown in
Supplemen a y Figu e S4.
Hospi aliza ions and Su ge ies
Hospi aliza ions and su ge ies we e uncommon, wi h no
s a is ically significan di e ences obse ed be ween g oups
h ough week 104 (Supplemen a y Table 4).
P edic o s o Clinical Recu ence
Pa ien s wi h mo e han one esec ion o who ecei ed
an i-TNF he apy p e-su ge y we e mo e likely o ha e a
clinical ecu ence (Supplemen a y Table 5).
Sa e y
Among 297 andomized pa ien s, 291 ecei ed a leas
1 dose o s udy d ug. The a e age du a ion o ea men
be o eadoseinc easewassimila o infliximab and
placebo (74.3 weeks and 75.9 weeks, espec i ely;
Table 3).
Ad e se and se ious ad e se e en a es we e simila
be ween g oups. In ec ion a es, including se ious in-
ec ions, we e also simila . Mo e pa ien s in he infliximab
han placebo g oup discon inued he apy because o an
ad e se e en h ough he final isi , mos commonly o
ad e se e en s ela ed o he gas oin es inal o in ec ion
and in es a ion sys em o gan class (Supplemen a y Table 6).
The e we e no dea hs o malignancies (excluding non-
melanoma skin cance ) in infliximab- ea ed pa ien s
(Table 3).
In usion eac ions occu ed in 8.2% o placebo- ea ed
compa ed wi h 19.4% o infliximab- ea ed pa ien s
(Table 3).
Pha macokine ics and Immunogenici y
Fo pa ien s in he infliximab 5 mg/kg g oup, me-
dian ough se um infliximab concen a ions we e 0.00
mg/mL and 2.18 mg/mL a week 0 and week 72,
espec i ely.
A week 72, median se um infliximab concen a ion o
pa ien s ecei ing immunosupp essi es was nume ically
g ea e han hose no ecei ing immunosupp essi es (4.89
mg/mL s 1.83 mg/mL, espec i ely). The p opo ion o
infliximab- ea ed pa ien s wi h endoscopic ecu ence
be o e o a week 76 dec eased wi h inc easing se um
infliximab concen a ion. This e ec was no obse ed o
clinical ecu ence (Supplemen a y Figu e S5).
O e all, ATIs we e p esen in 16.2% o pa ien s, none o
whom we e ecei ing immunosupp essi es a baseline. This
ATI incidence was based on an an igen-b idging enzyme
immunoassay in which de ec able le els o ci cula ing
infliximab can in e e e wi h he abili y o assess he p es-
ence o ATI. Endoscopic ecu ence be o e o a week 76
was seen in 64.7% (11 o 17), 46.7% (7 o 15), and 30.1%
(22 o 73) o pa ien s who we e posi i e, nega i e, o
inconclusi e o ATI, espec i ely. This e ec was no
obse ed o clinical ecu ence.
Discussion
This s udy e alua ing infliximab o p e en ion o
pos -su gical CD ecu ence a e ileocolonic esec ion
did no mee he p ima y end poin o clinical ecu ence
and was p ema u ely e mina ed a week 104. The
endoscopic ecu ence a e in infliximab- ea ed pa ien s
is consis en wi h hose o small andomized con olled
ials.
18,19
We also ound ha pa ien s wi h a p io esec ion and
use o an i-TNF he apy p e-su ge y we e a highe isk o
pos ope a i e CD ecu ence. Howe e , i is possible ha
hese ac o s eflec disease se e i y and/o complica ed
disease cou se a he han independen isk ac o s o
ecu ence. These esul s should be in e p e ed wi h
cau ion due o he small sample size.
The PREVENT ial is he fi s la ge, mul icen e ,
placebo-con olled pos ope a i e CD s udy wi h a bio-
logic. Assump ions on pos ope a i e clinical and endo-
scopic ecu ence we e ex apola ed om he collec i e
esul s o se e al smalle s udies, including he ial by
Reguei o e al.
19
Pa ien s en olled in ha small s udy may
ha e had a highe isk o pos ope a i e CD ecu ence,
mos wi h pene a ing disease and a high p opo ion
ha ing unde gone a leas 2 esec ions. The in en o he
PREVENT s udy was o en oll a simila high- isk popula-
ion o pa ien s; howe e , 69.6% had only one isk ac o
o ecu ence, and 57.4% we e unde going hei fi s
Figu e 2. Time o fi s clinical ecu ence be o e o a week
76; all andomized pa ien s.
June 2016 Infliximab o Pos su gical CD P e en ion 1573
CLINICAL AT
in es inal esec ion. This may accoun o he di e ence in
he placebo clinical ecu ence a e be o e o a week 76
in PREVENT (20.0%) and he 12-mon h a e epo ed
p e iously (38.5%).
19
I should be no ed ha al hough he isk ac o s o
pos ope a i e ecu ence, ha is, ciga e e smoking,
ecu en su ge y, and pene a ing disease, ha e been
included in nume ous p e ious s udies,
4,26,30–35
hese ac-
o s ha e ne e been o mally alida ed o eplica ed.
Likewise, he combina ion o ac o s would p esume a
highe isk o pos ope a i e ecu ence; his addi i e e ec
has also no been eplica ed. The e o e, he s a ifica ion o
isk based on he small sample size o he Reguei o ial may
ha e esul ed in an o e es ima ion o e ec in PREVENT.
The low baseline median CDAI sco e o 105.5 equi ed
many pa ien s o double hei CDAI sco e du ing he cou se
o he s udy o mee he clinical ecu ence c i e ion o CDAI
200. This possibly con ibu ed o he small p opo ions o
pa ien s (infliximab, 4.1%; placebo, 9.3%) who me bo h
CDAI and endoscopic c i e ia o clinical ecu ence be o e
o a week 76. Fu he mo e, only 17.5% o pa ien s ecei ed
concomi an immunosupp essi es compa ed wi h 45.8% o
pa ien s in he Reguei o ial.
19
Adminis a ion o immu-
nosupp essi es inc eases infliximab le els, educes immu-
nogenici y, and inc eases e ficacy o infliximab.
39
Pa ien s in PREVENT unde wen a ideo ileocolonoscopy
a week 76, when CDAI c i e ia me he defini ion o clinical
ecu ence, o when hey discon inued he s udy. Week 76,
a he han week 24 o 48, was selec ed as he p ima y ime
poin due o he combined clinical and endoscopic end
poin . Clinical ecu ence wi hin he fi s yea a e esec-
ion is low, as endoscopic ecu ence o en occu s ini ially
wi hou clinical symp oms.
3,40–43
We hypo hesized ha wai ing 18 mon hs a e
esec ion o p ima y composi e end poin assessmen
would be su ficien o de ec clinical ecu ence wi hou
endoscopic ecu ence causing se e e, i e e sible
bowel damage. Addi ionally, when he PREVENT s udy
was designed (2009), only one small p oo -o -concep
s udy
19
and an open-label expe ience
18
in pos ope a i e
pa ien s wi h CD ea ed wi h an i-TNF he apies we e
published o guide he iming and defini ion o clinical
end poin s.
Ou selec ion o a composi e end poin appea ed o be
suppo ed by a subsequen publica ion by Wal e s e al,
44
who explo ed he u ili y o he CDAI in de e mining symp-
oma ic disease ecu ence in pa ien s ha ing p e iously
unde gone ileocolonic esec ion o CD, and concluded ha
“a combina ion o symp om assessmen plus endoscopic
e idence o ecu ence should emain he gold s anda d
defini ion o assessing ou comes in pos ope a i e CD i-
als.”Howe e , i mus be acknowledged ha he composi e
end poin p ospec i ely implemen ed he e was no o mally
alida ed in his clinical se ing.
Because ea ly endoscopic ecu ence appea s o co e-
la e wi h u u e clinical ecu ence and he need o esec-
ion,
3
i is cu en ly ecommended ha pa ien s wi h CD
unde go a su eillance ileocolonoscopy 6 o 12 mon hs
pos ope a i ely o assess o endoscopic ecu ence.
40–43
Recen s udies ha e sugges ed ha TNF-an agonis s a e
e ec i e in his se ing based on he apy adjus ed
acco ding o 6-mon h pos ope a i e colonoscopy
findings.
26–28
The e a e limi a ions o he s udy. Infliximab migh ha e
been s a ed as la e as 45 days a e esec ion, by which
Figu e 3. Endoscopic ecu ence be o e o a week 76; all
andomized pa ien s (A) and cen al endoscopic esul s
be o e o a week 76 (Ru gee s sco e i0, i1, i2, i3, i4) (B). P
alues based on he Coch an-Man el-Haenszel c
2
es
s a ified by he numbe o isk ac o s o ecu ence o ac i e
C ohn’s disease (1 o >1) and baseline use (yes/no) o an
immunosupp essi es (ie, aza hiop ine, 6-me cap opu ine, o
me ho exa e).
a
Nominal P alue. i0, no lesions; i1, 5 aph-
hous lesions; i2, >5 aph hous lesions o anas omo ic ulce
<1 cm; i3, di use aph hous ilei is wi h di usely inflamed
mucosa; i4, di use inflamma ion wi h la ge ulce s, nodules,
and/o na owing.
1574 Reguei o e al Gas oen e ology Vol. 150, No. 7
CLINICAL AT
ime he e could ha e been ea ly endoscopic ecu ence.
This would mean ha ea men was ini ia ed in esponse o
ac i e inflamma ion a he han p e en ion o CD ecu -
ence. The a ionale o wai ing 45 days was o ensu e a
leas 14 o 21 days passed wi h no su gical esec ion
complica ion, and o allow enough ime o he CDAI
collec ion and addi ional pa ien sc eening. The median ime
be ween esec ion and fi s s udy in usion was 36.5 days o
placebo and 35 days o infliximab 5 mg/kg, and is unlikely
o ha e al e ed he esul s significan ly. While we designed
he s udy o use e e y-8-weeks main enance in usions a e
esec ion, i is possible ha he 3-dose induc ion and
concomi an use o immunosupp essan s could ha e led o
e en lowe ecu ence a es, as desc ibed p e iously,
40
and
educed immunogenici y.
While p e en ion o clinical ecu ence was no ach-
ie ed, infliximab- ea ed pa ien s achie ed a lowe endo-
scopic ecu ence a e han hose assigned o placebo.
Consis en wi h o he s udies using an i-TNF he a-
pies,
17,18,25,45
infliximab- ea ed pa ien s had lowe ecu -
ence defined by endoscopic c i e ia only.
The p ima y end poin o clinical ecu ence may be
influenced by symp om-based CDAI sco e, which consis s o
dia hea, abdominal pain, and gene al well-being compo-
nen s ha migh be nei he sensi i e no specific o
mucosal inflamma ion, which is in eg al o disease ecu -
ence.
46
Reguei o and colleagues
47
also ound no co ela ion
be ween CDAI sco es and endoscopic disease ac i i y 1 yea
a e ileocolonic esec ion, wi h he majo i y o pa ien s in
clinical emission (CDAI <150) despi e endoscopic
ecu ence.
The se e i y o endoscopic ecu ence has a high p e-
dic i e alue o he need o u u e esec ion.
3,48
I he
goal o mucosal healing and main enance o in es inal
no malcy, a he han symp om con ol alone, a e ele an
inflamma o y bowel disease managemen a ge s, hen a
pos ope a i e s a egy o p e en ion o endoscopic
ecu ence may be clinically ele an , especially o high-
isk pa ien s.
49,50
Gi en he high a es o clinically silen ,
bu endoscopically ac i e, CD wi hin 2 yea s o esec ion,
we sugges ha u u e pos ope a i e s udies u ilize
objec i e a he han subjec i e c i e ia o ac i e CD, and
ha e he p ima y assessmen no mo e han 1 yea a e
esec ion.
A pos ope a i e s a egy o escala ing ea men o
endoscopic ecu ence a 6 mon hs was e alua ed in he
POCER (Pos -Ope a i e C ohn’s Disease Endoscopic
Recu ence) s udy.
28
Pa ien s we e isk-s a ified (high s
low) o CD ecu ence hen andomized o ha e an ini ial
colonoscopy a 6 mon hs o no colonoscopy un il 18
mon hs. All pa ien s ecei ed 3 mon hs o me onidazole, i
ole a ed, and high- isk pa ien s we e ea ed wi h pos -
ope a i e hiopu ine, o i p e iously in ole an , adalimu-
mab. Pa ien s unde going a 6-mon h colonoscopy we e
Table 3.Key Sa e y Findings Th ough Week 104 o T ea ed Pa ien s
Va iable
Placebo
a
(N ¼146)
Infliximab,
5 mg/kg
a,b
(N ¼145)
Infliximab (dose inc ease)
All infliximab
d
(N ¼170)
Placebo/infliximab,
5 mg/kg
c
(n ¼25)
Infliximab
5 mg/kg/infliximab,
10 mg/kg
c
(n ¼9)
Mean du a ion o ollow-up, wk 85.4 85.7 50.6 39.4 82.6
Mean du a ion o ea men , wk 75.9 74.3 32.4 13.9 68.9
Pa ien s wi h 1 ad e se e en s, n (%) 132 (90.4) 133 (91.7) 19 (76.0) 7 (77.8) 152 (89.4)
Pa ien s wi h 1 se ious ad e se
e en s, n (%)
32 (21.9) 28 (19.3) 3 (12.0) 2 (22.2) 32 (18.8)
Pa ien s who discon inued s udy agen
because o 1 ad e se e en s, n (%)
13 (8.9) 35 (24.1) 10 (40.0) 5 (55.6) 50 (29.4)
Pa ien s who died, n (%) 1 (0.7) 0 0 0 0
Pa ien s wi h 1 o mo e
malignancies,
e
n(%)
2 (1.4) 0 0 0 0
Pa ien s wi h 1 in ec ions, n (%) 85 (58.2) 84 (57.9) 8 (32.0) 4 (44.4) 93 (54.7)
Pa ien s wi h 1 se ious in ec ions, n (%) 9 (6.2) 7 (4.8) 1 (4.0) 1 (11.1) 9 (5.3)
Pa ien s wi h 1 in usion eac ion,
n(%) 12 (8.2) 26 (17.9) 7 (28.0) 1 (11.1) 33 (19.4)
a
Includes da a up o he ime o dose inc ease o hose who inc eased dose. Six pa ien s we e andomized bu no ea ed and
analyzed o e ficacy only, and 2 pa ien s inad e en ly ecei ed infliximab 5 mg/kg and analyzed o sa e y as infliximab-
ea ed pa ien s.
b
Two pa ien s we e andomized o he placebo g oup, bu ecei ed one in usion o infliximab. These pa ien s we e analyzed in
he infliximab 5 mg/kg g oup o sa e y.
c
Includes da a om he ime o dose inc ease onwa d.
d
Includes da a om he ime o he fi s infliximab dose onwa d.
e
Malignancies excluding nonmelanoma skin cance s we e defined by indi idual e en e ms in neoplasms benign, malignan ,
and unspecified (including cys s and polyps) sys em o gan class.
An in usion eac ion was defined as any ad e se e en ha occu ed du ing o wi hin 1 hou o he adminis a ion o he s udy
agen in usion.
June 2016 Infliximab o Pos su gical CD P e en ion 1575
CLINICAL AT
s a ed on o ecei ed addi ional ea men o endoscopic
ecu ence. The p ima y end poin o he POCER s udy was
pos ope a i e endoscopic ecu ence a 18 mon hs. The
18-mon h endoscopic ecu ence a e in pa ien s p e i-
ously unde going a colonoscopy a 6 mon hs was 49%
compa ed wi h 67% in hose who had no had a 6-mon h
colonoscopy. The 6-mon h endoscopic ecu ence a e in
high- isk pa ien s ecei ing hiopu ine was 45% compa ed
wi h 21% wi h an i-TNF he apy and is simila o he 18-
mon h endoscopic ecu ence a e in he PREVENT ial
(51.3% in placebo and 22.4% in infliximab). The e o e, i
may be easonable o app oach low- isk pa ien s unde -
going hei fi s esec ion o CD conse a i ely and ini ia e
ea men only i he e is endoscopic ecu ence a 6
mon hs. High- isk pa ien s wi h ecu en in es inal
esec ion o CD should be conside ed o pos ope a i e
an i-TNF he apy.
In conclusion, infliximab was no significan ly supe io
o p e en ion o clinical ecu ence a e CD ileocolonic
esec ion, bu did educe endoscopic ecu ence.
Supplemen a y Ma e ial
No e: To access he supplemen a y ma e ial accompanying
his a icle, isi he online e sion o Gas oen e ology a
www.gas ojou nal.o g, and a h p://dx.doi.o g/10.1053/
j.gas o.2016.02.072.
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