Meta-analysis: remission and response from control arms ofrandomized trials of biological therapies for active luminalCrohn’s diseaseF. T INE* , F . ROSSI� , A . SFERRAZZA� , A . ORLANDO� , F . MOCCIARO� , D . SCIMECA� , M. OLIVO�

& M. COTTONE�

*Divisione di Gastroenterologia,

Azienda Ospedaliera V. Cervello,

Palermo; �Dipartimento di Medicina,

Pneumologia e Fisiologia della

Nutrizione Umana, Universita degli

Studi di Palermo e Azienda

Ospedaliera V. Cervello, Palermo, Italy

Correspondence to:

Dr F. Tine, Divisione di

Gastroenterologia, Azienda

Ospedaliera V. Cervello, Via Trabucco

180, Palermo, Italy.

E-mail: fabiotinemd@virgilio.it

Publication data

Submitted 3 February 2008

First decision 20 February 2008

Resubmitted 28 February 2008

Accepted 5 March 2008

Epub OnlineAccepted 14 March 2008

SUMMARY

BackgroundRemission and response are the main outcomes to evaluate the efficacyof new treatments for Crohn’s disease (CD).

Aim

To explain variation of remission and response rates in active luminal CD.

MethodsWe studied control patients from trials of biological therapies througharticles retrieved by MEDLINE search (from 1997 to 2007) and by bibli-ography review. Thousand nine hundred and thirteen control patientsfrom 28 trials were identified; data were extracted by three independentobservers and pooled by DerSimonian and Laird random effect model;factors influencing remission and clinical response were explored bymetaregression for aggregated data.

ResultsThe pooled control rates of remission and response were 17% and 33%,respectively, both with significant heterogeneity among studies(P < 0.0001). At metaregression, the time of primary outcome evalua-tion was associated with remission, whereas the trial’s criteria for defin-ing response and publication year were predictors of response. CDAIscore, CRP levels or other clinical variables related with disease activityor concomitant medications were not significant factors.

ConclusionsPopulations used as ‘add-on’ treatment comparator in trials of biologi-cal therapies for active luminal CD are poorly characterized and out-comes are heterogeneous. Planning of future trials will require betterdescription of patients and concomitant therapies, blinding of outcomeassessors and homogeneous criteria of outcome definition.

Aliment Pharmacol Ther 27, 1210–1223

Alimentary Pharmacology & Therapeutics

1210 ª 2008 The Authors

Journal compilation ª 2008 Blackwell Publishing Ltd

doi:10.1111/j.1365-2036.2008.03681.x

INTRODUCTION

Recent insights into the pathogenesis of Crohn’s dis-

ease (CD) have led to the development of new treat-

ment options, represented by biologically targeted

treatments.1, 2 Such treatments are aimed at neutraliz-

ing proinflammatory mediators or consist of adminis-

tration of anti-inflammatory molecules.3 Among these

molecules are TNF-a inhibitors, other inflammatory

cytokines inhibitors (IL-6, IL-12), anti-inflammatory

cytokines (IL-10, IL-11), adhesion molecules inhibitors,

cellular signals transduction inhibitors or natural

immunity stimulators. Several randomized controlled

trials (RCTs) of biological molecules in active inflam-

matory CD have been conducted in recent years.4 The

design of these trials has been an ‘add-on’ study

design, in which patients with active CD5 were given

standard therapy such as aminosalicylates, corticoster-

oids and immunosuppressants and were randomly

assigned to receive also either a new agent or a

placebo.

In active CD, the percentage of placebo response

changes with factors such as the site of disease, the

duration of disease and its activity, and also with con-

comitant therapies and a smoking habit.6 In a meta-

analysis of placebo outcomes in active CD patients,

including a large set of trials assaying different drugs

from 1976 to 2000, Su et al.7 identified factors that

influenced the placebo remission rates, such as study

duration, number of study visits and disease severity

at entry. On the other hand, no significant predictor of

response was found.

An accurate estimation of outcome rates in control

populations and the identification of trial and patient

characteristics that are associated with these rates are

of help in interpreting results and for future planning

of trials of medical therapy in active CD.3–5, 7 We car-

ried out a systematic review of RCTs of biological

therapy in active, luminal CD and applied meta-analy-

sis techniques to describe control populations, to

assess their outcome rates and, finally, to explore the

reasons for possible heterogeneity of estimates.

METHODS

A literature search of RCTs of therapies for CD was

carried out starting from 1997, i.e. the year of the

well-known first RCTs of biologicals.14–16 We used the

MEDLINE–PubMed service (clinical study category

search: clinical queries: therapy) and limited our

search to English papers and adult patients. Comments,

editorials and letters were excluded (see Appendix 1

for the combination of MESH terms). EMBASE, Coch-

rane Library and Cochrane Controlled Trials Register

were also consulted. The references from the identified

articles and previously published meta-analyses were

manually searched to identify other potential studies.

Eligible studies were RCTs comparing an active

treatment represented by a biological therapy with a

control group including a placebo in adult patients

with luminal CD in acute phase at baseline [CD Activ-

ity Index (CDAI) > 150]. Endpoints of interest from the

studies were clinical response and remission measured

through the CDAI score, which consists of eight sub-

jective and objective criteria of disease activity, rang-

ing from 0 to 600.8 A higher score generally

represents a more severe disease activity. Remission is

defined as a score that measures £150 points, while

response is defined as a reduction in the score exceed-

ing a predefined value, usually 70 or 100. We consid-

ered as response the reduction of 100 points of the

CDAI score. Only when this measure was not available,

a reduction of 70 points was alternatively considered.

The main reason for exclusion was the absence of

active disease or a not inflammatory pattern of disease

(short bowel syndrome, draining fistulas, stricture with

obstructive symptoms, abdominal abscess). Trials that

considered ‘steroid-sparing’ (defined as discontinuation

of steroid therapy without a disease flare represented

by CDAI score ‡220 points) as primary outcome were

excluded from the present meta-analysis, as well as

reports in which the number of patients in the experi-

mental and in the control groups was not reported or

in which the outcome was the maintenance of remis-

sion and response.

Decisions about which trials to include were

blindly taken by two reviewers (FR, MC) and dis-

agreements were solved by discussion. Excluded trials

were identified with the reason for exclusion. Data

concerning trials and patients characteristics as well

as treatment outcome were abstracted by each study

by three independent reviewers (FT, AS, FR) and dis-

crepancies were settled by consensus. A quality anal-

ysis of each study was conducted independently by

two authors (FT, MC) by computing the Jadad score.9

This is a well-established and validated scale apply-

ing seven criteria (five for good and two for poor

study quality) to obtain a numerical score between

0 and 5 with 0 being the poorest and 5 being the

highest design and reporting quality.

META-ANALYS IS : REMISS ION AND RESPONSE FOR ACTIVE LUMINAL CROHN’S DISEASE 1211

ª 2008 The Authors, Aliment Pharmacol Ther 27, 1210–1223

Journal compilation ª 2008 Blackwell Publishing Ltd

The recorded trial characteristics were: publication

year, journal, nationality of the first author, number of

participating centres, sample-size calculation, number

of arms, number of total patients randomized, number

of patients in control group, class of biological therapy

tested in treatment arm, dose and route of administra-

tion of the experimental drug, duration of treatment

and follow-up, definition of response and remission,

primary and secondary outcomes with relative time of

evaluation (weeks) and quality of trial’s score. The

recorded patient characteristics were: age, gender,

weight, duration of the disease, smoking history, dis-

ease location, previous intestinal resection, previous

and concomitant medications, C-reactive protein

(CRP), CDAI score and minimum CDAI score at entry.

The endpoints from the trials were combined using

the DerSimonian and Laird10 random effect model to

estimate the rate and corresponding 95% confidence

interval (CI) for each clinical outcome. The random

effects model was chosen to provide estimates that

consider variance both between and within studies.

Heterogeneity testing applied the Q-statistic with

P-values <0.10 being considered significant. Studies

that did not mention a specific outcome were excluded

from the analysis for that endpoint. Because of the

aggregated nature of data on outcomes and covariates,

study-level metaregression analyses were performed to

search for reasons of heterogeneity found among the

estimates.11 The dependent variable was the log-odd

from each arm for the outcome of interest. Weights

were assigned according to the estimated variance

from the log-odd. The residual between trial heteroge-

neity was expressed as s2, estimated by a restricted

maximum likelihood method using an iterative proce-

dure.12, 13 To establish which factors and how many

factors would have been included in the metaregres-

sion, we considered either previous knowledge of fac-

tors shown to be associated with remission and

response in patients with active CD7 and the number

of retrieved trials. CDAI score at entry, time of out-

come evaluation (weeks), publication year, number of

study visits, definition of response and activity class

of luminal CD were selected for the analysis. Stratum-

specific pooled estimates of the outcomes of interest

within each stratum of those covariates that resulted

statistically significant were calculated to explore

whether associations of these covariates with the out-

come of interest would account for the heterogeneity

between studies. All analyses were carried out using

STATS DIRECT statistical software version 2.6.1

(19.1.2007) and STATA 8.0 (ª1999 Stata Corporation,

College Station, TX, USA).

RESULTS

A total of 237 potentially relevant articles were identi-

fied (Figure 1). After a review of the abstracts, 166

papers (137 RCTs and 29 prospective studies) were

excluded because active treatment was not a biological

therapy. The remaining 71 articles on biologicals were

analysed for inclusion: 28 fulfilled the selection crite-

ria14–41 and 43 were excluded. The causes of exclusion

were outcome different from induction of remission,

steroid-free remission as outcome, trials on mainte-

nance therapy, trials on fistulizing disease, lack of pla-

cebo arm, studies on ulcerative colitis and rheumatoid

arthritis (Appendix 2).

The degree of agreement between the reviewers

exceeded 95%. The distribution of the main character-

istics of the 28 RCTs considered in this study is

reported in Table 1. The studies included a total of

1913 patients in the control groups, ranging from 5 to

325 per arm. Only seven trials (25%) included more

than 100 patients among controls. Most of the RCTs

(75%) were phase II trials. About 70% of trials were

published by gastroenterology journals after the year

PUBMEDClinical query ontherapy for CD(1997–2007):237 citations

Trial results involving biologicaltherapies for CD:

71 citations

166 citationsexcluded becauseactive Rx is not abiological therapy

43 citations excluded because:– maintenance RCT (9)– lack of a placebo arm (5)– fistulizing disease (5)– steroid-free remission (4) or

other outcome (14)– studies in UC or RA (5)

RCTs ofbiological therapies

28 citations

Figure 1. Flow-diagram of study selection.

1212 F . T IN E et al.

ª 2008 The Authors, Aliment Pharmacol Ther 27, 1210–1223

Journal compilation ª 2008 Blackwell Publishing Ltd

2000. TNF antagonists were evaluated in 12 (43%)

studies, adhesion molecule inhibitors in six (21%)

studies, anti-inflammatory interleukins in five (18%)

studies, inhibitors of Th polarization in four (14%)

studies and growth factors in only one study. Each

trial was sponsored by the pharmaceutical company

manufacturing the experimental drug.

With regard to the definition of disease activity, five

(18%) trials included patients who were considered to

have a mild-to-moderate disease (CDAI at entry

between 150 and 220), four (14%) included patients

with a moderate disease (CDAI at entry between 221

and 450) and 19 (68%) included patients with a

Table 1. Distribution of main characteristics of 28selected RCTs

VariablesNumberof trials

PC-RCTs (number of studies) 28Total patients randomized 6732Total patients under placebo ‘add on’ 1913Arms

2 11 (39%)3 6 (21%)4 7 (25%)5 4 (14%)Total number of arms 68

Trial phase2 21 (75%)3 7 (25%)

Publication year‡2000 23 (82%)<2000 5 (18%)

JournalGeneral 8 (29%)Specialistic 20 (71%)

Prime author nationalityEurope 9 (32%)US 14 (50%)Canada 4 (14%)Japan 1 (4%)

Biologic therapyTNF antagonists 12 (43%)Adhesion molecule inhibitors 6 (21%)Anti-inflammatory interleukins 4 (14%)Inhibitors of Th1 polarization 4 (14%)Granulokines 1 (4%)Inhibitors of proinflammatorycytokine receptors

1 (4%)

Patient selectionMild–moderate 5 (18%)Moderate 4 (14%)Moderate–severe 19 (68%)

Primary outcomeRemission 9 (32%)Response 9 (32%)Remission and response 4 (14%)Safety 6 (21%)

Remission definitionCDAI £150 22 (78%)CDAI £150 and other criteria 6 (21%)

Response definitionCDAI ‡70 4 (16%)CDAI ‡70 and other criteria 2 (8%)CDAI ‡100 9 (37%)CDAI ‡100 and ‡70 9 (37%)

Trial analysisPer protocol 4 (14%)Intention to treat 24 (86%)z

Table 1. Continued

VariablesNumberof trials

Primary outcomeRemission 9 (32%)Response 9 (32%)Remission and response 4 (14%)Safety 6 (21%)

Concurrent steroid therapyYes 25 (89%)No 3 (11%)

Concurrent immunosuppressorsYes 24 (86%)No 4 (14%)

Drug routeIntravenous 15 (53%)Subcutaneous 12 (43%)Oral 1 (4%)

Number of placebo administrations(i.v., s.c. or oral) (s.d.)

11 (15)

Number of study visits (s.d.) 6.5 (1.9)Sample-size calculation

Yes 20 (71%)No 8 (29%)

Blinding descriptionYes 15 (54%)No 13 (46%)

Randomization descriptionYes 21 (75%)No 7 (25%)

Withdrawals and dropouts descriptionYes 23 (82%)No 5 (18%)

Jadad score‡3 23 (82%)<3 5 (18%)

CDAI, Crohn’s Disease Activity Index.

META-ANALYS IS : REMISS ION AND RESPONSE FOR ACTIVE LUMINAL CROHN’S DISEASE 1213

ª 2008 The Authors, Aliment Pharmacol Ther 27, 1210–1223

Journal compilation ª 2008 Blackwell Publishing Ltd

moderate-to-severe disease (CDAI at entry between at

least 220 and also more than 450).

About 80% of the RCTs considered remission and ⁄ or

response as the primary outcome. All the 28 included

articles reported remission data, whereas response data

were available in only 24 papers (Table 2). In 22 stud-

ies (79%), remission was defined as having a CDAI

score of <150 or £150, while in six RCTs (21%) addi-

tional criteria were used in combination with the defi-

nition of remission, including the decrease in the CDAI

score of ‡100 points or ‡70 points from baseline, the

steroid-free remission or the corticosteroid dosage £the level at baseline.

In eight trials, response was defined as having a

decrease in the CDAI score of ‡70; in 10 trials, it was

defined as a decrease in the CDAI score of ‡100

points. In six trials, the data of response were reported

for a reduction of both 70 and 100 points (in this case,

we considered only the results according to the more

restrictive criteria). Of the eight trials in which

response was defined as having a decrease in the CDAI

score of ‡70, two used additional criteria in combina-

tion with the definition of response (e.g. response not

accompanied by a change in any concomitant medica-

tions, or response defined as having a decrease in the

CDAI score of ‡70 or, also, a CDAI score of <150

points).

The evaluation of the outcomes was performed

within 6 weeks in 64% of the trials. The time at which

outcomes were evaluated for pooling was that reported

when remission or response were the primary out-

comes (Table 2). Most of the drugs (54%) were admin-

istered by intravenous injection.

With regard to their quality, although all trials

reported a statement on randomization and all trials

except one32 were declared double-blinding, the ran-

domization method was not described in 11 trials

(39%) and the blinding method was not described in

13 trials (46%). No study reported a statement on

blinding of outcome assessment. The description of

withdrawals and dropouts was reported in 23 trials

(82%). A sample-size calculation was reported in 20

(71%) of trials. Anyway, a Jadad score of at least 3

was attributed to 22 (79%) studies.

The distribution of main characteristics of patients

per arm is reported in Table 3. In most of the trials, the

proportion of patients assuming steroid and immuno-

suppressor therapy simultaneously was not available.

All studies but one reported mean or median CDAI at

entry (mean 294, s.d. 18). Data on CRP levels at entry

were available from 14 studies.15, 21, 26, 28, 30–33, 35–39, 41

In nine trials, data were given through mean change

of CRP levels with time between treated and con-

trols. Very few studies reported a subgroup analysis

on remission and response based on patients with

CRP levels lower or higher than 10 mg ⁄ L. A cor-

relation between entry CDAI and CRP levels was

absent in the 13 studies in which both data were

available.

Figure 2 shows remission data: rates ranged from

0% to 34% and the pooled estimate was 17% (95% CI:

13–21%). Statistically significant heterogeneity among

the studies (Q-test: 103.4, P < 0.0001) was found, with

residual between study heterogeneity (s2 = 0.043). Uni-

variate metaregression identified time of primary out-

come evaluation as unique factor positively associated

with remission (Table 4). The final multivariate met-

aregression model, adjusted for the other variables,

included only trial’s time of primary outcome evalua-

tion as a study level factor associated with remission

(Table 4).

Response data were reported in 24 out of 28 studies.

The pooled estimate of response rate was 33% (95%

CI: 28–38%), with evidence of heterogeneity among

the studies and residual between study heterogeneity

(Q-test: 115.4, P < 0.0001; s2 = 0.0535) (Figure 3). At

univariate metaregression, trial’s criteria for defining

response (CDAI reduction of at least 70 points vs. of at

least 100 points) and trial’s publication year (after

2002 vs. previous to 2002) were the factors marginally

associated with response (Table 4). These two factors

remained significant at multivariate metaregression.

After stratifying across various categories of these

variables (Table 5), heterogeneity remained statistically

significant in all the strata.

DISCUSSION

In this study, we looked at outcomes of placebo ‘add-

on treatment’ controls from trials of biological thera-

pies for CD published in the last 10 years. Efficacy

was not of interest because we considered it not

appropriate to combine data from molecules character-

ized by different mechanisms of action. We found

large heterogeneity in both remission and response

rates assessed by conventional CDAI’s criteria in

patients with active CD. A few design characteristics

of trials, but not patient-related variables were found

to be factors explaining such heterogeneity. A poor

characterization of patients in terms of disease activity

1214 F . T IN E et al.

ª 2008 The Authors, Aliment Pharmacol Ther 27, 1210–1223

Journal compilation ª 2008 Blackwell Publishing Ltd

Tabl

e2.

Char

acte

rist

ics

of

28

studie

sco

nta

inin

gre

mis

sion

and

⁄or

resp

onse

dat

a

Auth

or

(yea

r)Bio

logic

alth

erap

y

Tim

eof

outc

om

e(w

eeks

)Pla

cebo

size

(n)

CD

AI

score

atbas

elin

e*D

efinitio

nof

rem

issi

on

Rem

issi

on

rate

(%)

Defi

nitio

nof

resp

onse

Res

ponse

rate

(%)

Sta

cket

al.

(1997)1

4CD

P571

210

253

CD

AI

£150

0–

–Tar

gan

etal

.(1

997)1

5In

flix

imab

425

288

CD

AI

£150

+IB

DQ

score

170–190

8‡7

0+

no

chan

ge

inan

yco

nco

mitan

tm

edic

atio

ns

16

Van

Dev

ente

ret

al.

(1997)1

6IL

-10

413

292

CD

AI

£150

+re

duct

ion

‡100

23.1

‡100

23.1

Yac

ysh

yn

etal

.(1

998)1

7IS

IS-2

302

45

291

CD

AI

£150

20

––

San

ds

etal

.(1

999)1

8IL

-11

315

308.5

CD

AI

£150

+re

duct

ion

‡70

0‡1

00

13.3

Fed

ora

ket

al.

(2000)1

9IL

-10

423

261

CD

AI

£150

0–

–Sch

reib

eret

al.

(2000)2

0IL

-10

466

271

CD

AI

£150

+re

duct

ion

‡100

18.2

>100

27.3

Gord

on

etal

.(2

001)2

1N

atal

izum

ab2

12

273

CD

AI

<150

8.3

––

San

dborn

etal

.(2

001)2

2CD

P571

258

332

CD

AI

£150

6.9

‡70

‡100

27

13.8

San

dborn

etal

.(2

001)2

3Eta

ner

cept

420

265

CD

AI

<150

20

‡70

or

CD

AI

<150

45

San

ds

etal

.(2

002)2

4IL

-11

649

310

CD

AI

<150

+re

duct

ion

‡100

16.3

‡70

‡100

39

32.6

Ghosh

etal

.(2

003)2

5N

atal

izum

ab6

63

300

CD

AI

£150

27

‡70

38.1

Ito

etal

.(2

004)2

6A

nti-I

L-6

12

13

295

CD

AI

£150

0‡7

030.8

Man

non

etal

.(2

004)2

7A

nti-I

L-12

18

8279

CD

AI

£150

12.5

‡100

25

San

dborn

etal

.(2

004)2

8CD

P571

28

132

301

CD

AI

£150

20.4

‡70

‡100

27

23.5

Win

ter

etal

.(2

004)2

9Cer

tolizu

mab

peg

ol

425

310

CD

AI

£150

20.

‡100

56

San

dborn

etal

.(2

005)3

0N

atal

izum

ab10

181

303

CD

AI

£150

30.4

‡70

48.6

Sch

reib

eret

al.

(2005)3

1Cer

tolizu

mab

peg

ol

12

73

–CD

AI

£150

23.3

‡100

35.6

Korz

enik

etal

.(2

005)3

2Sar

gra

most

in8

43

300

CD

AI

£150

19

‡70

‡100

44

26

Han

auer

etal

.(2

006)3

3A

dal

imum

ab4

74

296

CD

AI

£150

12.2

‡70

‡100

37

24.3

Hom

mes

etal

.(2

006)3

4Fonto

lizu

mab

443

303

CD

AI

£150

11.6

‡100

32.5

Rei

nis

chet

al.

(2006)3

5Fonto

lizu

mab

410

304

CD

AI

£150

30

‡70

‡100

60

60

Rutg

eert

set

al.

(2006)3

6O

ner

cept

838

306

CD

AI

£150

23.7

‡100

36.8

Sch

reib

eret

al.

(2006)3

7p38

862

306

CD

AI

£150

30.6

‡70

56.4

Tar

gan

etal

.(2

007)3

8N

atal

izum

ab12

250

299

CD

AI

£150

16

‡70

‡100

32

22

META-ANALYS IS : REMISS ION AND RESPONSE FOR ACTIVE LUMINAL CROHN’S DISEASE 1215

ª 2008 The Authors, Aliment Pharmacol Ther 27, 1210–1223

Journal compilation ª 2008 Blackwell Publishing Ltd

and an inadequate description of concomitant thera-

pies was a typical aspect of these trials.

It should be noted that the quality assessment of

included trials revealed methodological limitations.

Among these limitations, those regarding the report of

blinding are of particular concern by considering the

known variation among researchers in the administra-

tion and implementation of the CDAI score.42 Any

conclusion about the factors that drive the placebo out-

come when this instrument is used under circumstances

similar to those described in the trials included in our

study should be arrived at with caution because of the

risk of assessment bias. A limitation of the trials we

included in our study was also represented by an insuf-

ficient characterization of patients regarding response

Tabl

e2.

Continued

Auth

or

(yea

r)Bio

logic

alth

erap

y

Tim

eof

outc

om

e(w

eeks

)Pla

cebo

size

(n)

CD

AI

score

atbas

elin

e*D

efinitio

nof

rem

issi

on

Rem

issi

on

rate

(%)

Defi

nitio

nof

resp

onse

Res

ponse

rate

(%)

San

dborn

etal

.(2

007)3

9A

dal

imum

ab4

166

313

CD

AI

£150

7‡7

0‡1

00

34

25

Yac

ysh

yn

etal

.(2

007)4

0IS

IS-2

302

12

110

–CD

AI

£150

+re

duct

ion

‡70

34.5

‡100

54

San

dborn

etal

.(2

007)4

1Cer

tulizu

mab

peg

ol

6325

297

CD

AI

£150

17

‡100

‡70

27

38

CD

AI,

Cro

hn’s

Dis

ease

Act

ivity

Index

;IB

DQ

,in

flam

mat

ory

bow

eldis

ease

qual

ity

score

.*

Mea

nor

med

ian.

Table 3. Distribution of main characteristics of patientsper arm in 28 selected randomized controlled trials

Numberof placeboarms Mean (s.d.)

Rangeof means

Age (years) 28 36.3 (3.7) 26–42Male (%) 28 45.9 (11.4) 24–77Weight (kg) 17 69.4 (6.3) 53–75Duration of disease (years) 23 8.7 (1.6) 5.7–11Disease location

Ileum 22 39.3 (23.9) 0–80Colon 20 30.1 (16.2) 8–41Ileum–colon 18 46.4 (20.6) 9–92Perianal 7 22.8 (12.4) 0–33

Previous intestinalresection

12 45.4 (8.7) 33–61

Percentage of patientswith steroids therapy

25 45.9 (24.6) 0–100

Percentage of patientswith immunosuppressivetherapy

25 30.9 (12.9) 0–47

Percentage of patientswith aminosalycilatetherapy

26 55.6 (19.8) 23–100

Percentage of patientswith prior anti-TNFtherapy

11 40.4 (23.9) 12–100

CDAI score at baseline 27 294 (18) 253–332CRP (mg ⁄ L) at baseline 13 14.1 (10.9) 0.9–35Number of study visits 27 14.1 (10.9) 3–10Number of placeboadministrations(i.v., oral or s.c.)

28 14.1 (10.9) 1–56

CDAI, Crohn’s Disease Activity Index; CRP, C-reactiveprotein.

1216 F . T IN E et al.

ª 2008 The Authors, Aliment Pharmacol Ther 27, 1210–1223

Journal compilation ª 2008 Blackwell Publishing Ltd

to previous therapies and regarding concomitant treat-

ment during the study. The criteria for definition of

efficacy of conventional therapy were often vague and

variable between the studies. In fact, in many cases,

patients were defined as resistant to steroids, despite the

fact that the dose was below 40 mg daily. In some stud-

ies, immunosuppressive therapy was started 3 months

before the beginning of the study, although the action

of these drugs requires at least 4 months of treatment.

Moreover, the rate at entry of patients taking concomi-

tant steroids, immunosuppressive therapy and aminos-

alycilates varied between studies and often the real

proportion of patients assuming more than one of these

concomitant therapies was not defined. This wide vari-

ability produces a heterogeneous population within

studies and it makes it difficult to interpret any possible

influence of concomitant therapies on ‘placebo-add-on’

outcomes. Although only 11 trials reported data on the

proportion of control patients at entry with prior anti-

TNF therapy (range 12–100%), a subgroup analysis

based on this characteristic was possible in four trials

alone and it did not show significant differences in the

pooled response rates.

We report a pooled estimate of remission rate of

17%. Heterogeneity of rates among trials was evident,

ranging from 0% to 34%; it was statistically explained

by time of primary outcome evaluation within 6 weeks

as the most important factor. Because patients are

more likely to enter spontaneous remission with time,

a positive correlation between the time of primary out-

come evaluation and control outcome rate could be

expected even if these patients take other drugs.

Among factors that may influence such correlation

there are, apart from a true placebo effect, the natural

history of CD itself, the patient’s conviction that par-

ticipating in the trial is better than usual care (more

frequent contacts) and regression to the mean of mea-

sures of disease activity. Also, in the Su et al.’s study7

that reported a very similar pooled remission rate, a

similar time-related variable, the study duration (per

month increment), was shown to be a factor positively

associated with remission. However, in that study as

well in our study, there was a significant heterogeneity

within strata. Such kind of heterogeneity that weakens

our results is shown in Figure 4 in which the range of

reported remission rates at 4 weeks as well as at

0.0 0.2Proportion (95% confidence interval)

0.4 0.6 0.8

Combined 0.168 (0.133, 0.207)Sandborn, 2007; certolizumab pegol 0.175 (0.135, 0.221)

Yacyshyn, 2007; ICAM-1 0.345 (0.257, 0.442)Sandborn, 2007; adalimumab 0.072 (0.038, 0.123)

Targan, 2007; natalizumab 0.160 (0.117, 0.211)Schreiber, 2006; p38 0.306 (0.196, 0.437)

Rutgeers, 2006; onercept 0.237 (0.114, 0.402)Reinish, 2006; fontolizumab 0.300 (0.067, 0.652)

Hommes, 2006; fontolizumab 0.116 (0.039, 0.251)Hanauer, 2006; adalimumab 0.122 (0.057, 0.218)Korzenig, 2005; sagramostin 0.186 (0.084, 0.334)

Schreiber, 2005; certolizumab pegol 0.233 (0.142, 0.346)Sandborn, 2005; natalizumab 0.304 (0.238, 0.376)

Winter, 2004; certolizumab pegol 0.200 (0.068, 0.407)Sandborn, 2004; CDP571 0.205 (0.139, 0.283)Mannon, 2004; anti-IL-12 0.125 (0.003, 0.527)

Ito, 2004; anti-IL-6 0.000 (0.000, 0.247)Ghosh, 2003; natalizumab 0.270 (0.166, 0.397)

Sands, 2002; IL-11 0.163 (0.073, 0.297)Sandborn, 2001; etanercept 0.200 (0.057, 0.437)

Sandborn, 2001; CDP571 0.052 (0.011, 0.144)Gordon, 2001; natalizumab 0.083 (0.002, 0.385)

Schreiber, 2000; IL-10 0.182 (0.098, 0.296)Fedorak, 2000; IL-10 0.000 (0.000, 0.148)

Sands, 1999; IL-11 0.000 (0.000, 0.218)Yacyshyn, 1998; ISIS-2302 0.200 (0.005, 0.716)Van Deventer, 1997; IL-10 0.231 (0.050, 0.538)

Targan, 1997; infliximab 0.080 (0.010, 0.260)Stack, 1997; CDP571 0.000 (0.000, 0.308)

Figure 2. Rates of remissionin controls of biological trialsusing placebo as ‘add-on’treatment.

META-ANALYS IS : REMISS ION AND RESPONSE FOR ACTIVE LUMINAL CROHN’S DISEASE 1217

ª 2008 The Authors, Aliment Pharmacol Ther 27, 1210–1223

Journal compilation ª 2008 Blackwell Publishing Ltd

Table 4. Metaregression analysis for the arm-placebo effect on remission (28 trials) and on response (24 trials)

Variables Coefficient S.E. P-value s2 Coefficient S.E. P-value s2

Univariate metaregression for remission Multivariate metaregression forremission

Time of primary outcome evaluation(>6 vs. £6 weeks)

0.596 0.205 0.004 0.113 0.487 0.212 0.022 0.102

Publication year* 0.062 0.044 0.159 0.202 Not includedMild-to-moderate CD (yes vs. no) )1.455 0.785 0.064 0.191CDAI score at entry* )0.002 0.008 0.759 0.162Number of study visits 0.076 0.059 0.202 0.149Univariate metaregression for response Multivariate metaregression for responseDefinition of response (‡70 vs. ‡100 points) 0.453 0.254 0.074 0.199 0.586 0.240 0.015 0.158�Publication year (‡2002 vs. <2002) 0.080 0.045 0.076 0.240 0.631 0.261 0.016Time of primary outcome evaluation(>6 vs. £6 weeks)

0.001 0.218 0.959 0.264 Not included

Mild-to-moderate CD (yes vs. no) )0.230 0.427 0.590 0.262Number of study visits )0.002 0.069 0.973 0.254CDAI score at entry )0.003 0.008 0.706 0.222

The dependent variable is the observed log-odd from each trial for remission. Weights have been assigned according to theestimated variance from the log-odd.S.E., standard error of the coefficient.s2 is a measure of residual between trial heterogeneity, estimated by a restricted maximum likelihood method using aniterative procedure.* Continuous.� In multivariate analysis, s2 refers to the final model including only two variables.

0.0 0.3 0.6 0.9

Combined 0.33 (0.28, 0.38)Sandborn, 2007; certolizumab pegol 0.27 (0.22, 0.32)

Yacyshyn, 2007; ICAM-1 0.54 (0.44, 0.63)Sandborn, 2007; adalimumab 0.25 (0.18, 0.32)

Targan, 2007; natalizumab 0.22 (0.17, 0.28)Schreiber, 2006; p38 0.56 (0.43, 0.69)*

Rutgeers, 2006; onercept 0.37 (0.22, 0.54)Reinish, 2006; fontolizumab 0.60 (0.26, 0.88)

Hommes, 2006; fontolizumab 0.33 (0.19, 0.49)Hanauer, 2006; adalimumab 0.24 (0.15, 0.36)Korzenig, 2005; sagramostin 0.26 (0.14, 0.41)

Schreiber, 2005; certolizumab pegol 0.36 (0.25, 0.48)Sandborn, 2005; natalizumab 0.49 (0.41, 0.56)*

Winter, 2004; certolizumab pegol 0.56 (0.35, 0.76)Sandborn, 2004; CDP571 0.23 (0.17, 0.32)Mannon, 2004; anti-IL-12 0.25 (0.03, 0.65)

Ito, 2004; anti-IL-6 0.31 (0.09, 0.61)*Ghosh, 2003; natalizumab 0.38 (0.26, 0.51)*

Sands, 2002; IL-11 0.33 (0.20, 0.48)Sandborn, 2001; etanercept 0.45 (0.23, 0.68)*

Sandborn, 2001; CDP571 0.14 (0.06, 0.25)Schreiber, 2000; IL-10 0.27 (0.17, 0.40)

Sands, 1999; IL-11 0.13 (0.02, 0.40)Van Deventer, 1997; IL-10 0.23 (0.05, 0.54)

Targan, 1997; infliximab 0.16 (0.05, 0.36)*

Proportion (95% confidence interval)

Figure 3. Rates of response,defined as a reduction of 100points of Crohn’s DiseaseActivity Index (CDAI) score, incontrols of biological trialsusing placebo as ‘add-on’treatment. * Rates of responsedefined exclusively as a reduc-tion of 70 points of CDAIscore.

1218 F . T IN E et al.

ª 2008 The Authors, Aliment Pharmacol Ther 27, 1210–1223

Journal compilation ª 2008 Blackwell Publishing Ltd

12 weeks is from 0% to more than 30%. It should be

noted that in our study, there was a trend towards

increase in placebo remission rates with longer periods

of follow-up,27, 28 as observed in other studies.7, 45

Moreover, it should be noted that only one40 of

the five trials showing rates of more than

27%25, 30, 35, 37, 40 did use as outcome criteria a

CDAI £150 points plus a score reduction of at least 70

points. Yet, almost all the trials included in our study

were multinational trials, and in only one trial25 was

the small size a possible cause of false positive result.

It is possible that other factors that are not available

from published papers may be associated with the

placebo remission rates and thus influence the hetero-

geneity. For example, the prior response to corticoste-

roid or other therapy or the smoking status of patients

receiving placebo may be related to spontaneous

remission in the short term.

The pooled estimate of response rate in our study

was 33% by considering the 24 trials reporting data

on this outcome. In the 18 trials, using the more strin-

gent criterion of ‡100 points, the response was 30%.

In Su’s analysis, the response rate was 19% in the

eight studies containing data with response defined as

a ‡100 points decrease in the CDAI score. We specu-

late that the higher response rate in placebo group in

our study could depend on concomitant therapies to

which placebo was added in recent trials of biological

therapies. When a 70-point reduction in CDAI score

was considered a response criterion, patients

responded better to the placebo (average response rate

was around 40%), indicating that less restrictive crite-

ria allow a more favourable response, but could be

prone to phenomena such as regression to mean. The

variability in the definition of response complicates

the interpretation of results of our meta-analysis. The

at least 100-point reduction in CDAI score definition

is preferable in evaluating response rates,43 consider-

ing that in a majority of patients with moderate-severe

disease (CDAI from 220 to 400), a reduction of only

70 points in CDAI score would not correspond to a

real clinical benefit. Anyway, the response rate of at

least 30% in control arms, mainly in the large and

more recent trials, suggests that the sample of future

Table 5. Stratum-specific remission and response rates inthe placebo group for statistically significant predictors

Variables nPooledestimate 95% CI

P-value fortest ofheterogeneity

RemissionTime of primary outcome evaluation (weeks)

>6 10 13 7–18 0.0003£6 18 23 18–26 0.0003

ResponseDefinition of response

‡70 6 41 31–50 0.016‡100 18 30 25–35 <0.0001

Publication year‡2002 17 36 30–42 <0.0001<2002 7 25 17–33 0.069

0 10 20 300

10

20

30

40

% R

emis

sion

Time of outcome evaluation (weeks)

Sandborn 2004(CDP571)

Mannon 2004(anti-IL-12)

Ghosh 2003(natalizumab)

Reinish 2006(fontolizumab)

Yacyshyn 2007(ICAM-1)

Sandborn 2005(natalizumab)

Schreiber 2006(p38 MAPK)

Figure 4. Rates of remissionin controls of 28 biologicaltrials using placebo as ‘add-ontreatment’, according to timeof primary outcome evalua-tion. Circle’s dimension isproportional to placebo armsize. Trial first author whenremission rate outweighs 25%or time is higher than12 weeks.

META-ANALYS IS : REMISS ION AND RESPONSE FOR ACTIVE LUMINAL CROHN’S DISEASE 1219

ª 2008 The Authors, Aliment Pharmacol Ther 27, 1210–1223

Journal compilation ª 2008 Blackwell Publishing Ltd

trials needs to be sized according to this baseline

expected rate. Consider as an example that if the

expected placebo response rate (‡70 points) is 20%,

the required sample size (power 90%, delta + 15%) is

181 patients per group. In a large trial of natal-

izumab,38 the sample size increased up to 231 patients

per group under similar circumstances (power 90%,

delta + 15%) when the placebo rate was considered

40%.

We found high heterogeneity (Q-test: P < 0.0001)

both in response and in remission rates. This heteroge-

neity remained statistically significant also after strati-

fying across various categories of variables. It has

been suggested that use of metaregression should be

restricted to investigation of differences between trials

that relate to trial features and patient characteristics

that vary substantially across trials and not within tri-

als, when these features have been prespecified and

many trials are available.44 Moreover, to provide a

way of investigating patient characteristics, it is neces-

sary to move to inspection of relations within trials

and to compare subgroups of patients within every

trial and then combine these results over trials.

Because of lack of subgroup data from each trial, it

was impossible to perform this kind of analysis in our

study. In addition, even the suggestions derived from

metaregression of aggregated trial level data should be

considered exploratory. In fact, aggregation bias has

the potential to cause spurious results when covariates

relating to average patient characteristics, such as age

or weight, are used. Hence, caution is required. Our

results are not directly comparable with Su et al.’s

meta-analysis7 that looked at all trials on active dis-

ease starting from 1966, including various drugs such

as mesalamine and immunosuppressive therapies. In

that meta-analysis, the trials included a larger spec-

trum of disease activity than in our analysis: the med-

ian CDAI score at baseline was 256 (range 190–287) in

the trials testing therapies other than biological and

278 (range 253–311) in the subgroup of the biological

trials. The Su’s study showed an inverse relationship

between CDAI score at entry and remission rate, and a

positive association between CDAI score at entry and

response rate. These opposite findings were explained

suggesting that patients with more severe disease may

be more likely to have spontaneously a decrease in

CDAI score of 70–100 points with placebo alone than

patients with less severe disease. We did not find an

association between CDAI at baseline and response or

remission rates in spite of the fact that median CDAI

score at baseline was typical of severe disease. A

meta-analysis based on individual patient data would

have been more appropriate, although not feasible, to

manage the large variability underlying the use of the

CDAI score both as a tool to characterize patients at

entry and as a measure of outcome.

In summary, our study shows large heterogeneity

both in response and in remission rate in the placebo

used as ‘add-on’ treatment comparator in trials of bio-

logical therapy for active CD. The response rate of at

least 30% in these control arms, mainly in the large

and more recent trials, suggests that the sample of

future trials needs to be sized according to this base-

line expected rate. A better characterization of patients

in terms of disease activity maybe combining CDAI

with objective markers of inflammation such as CRP

levels or with endoscopic data on mucosal appearance,

and in terms of adequate description of concomitant

therapies could be helpful from a clinical point of

view. Moreover, other aspect of design should be

improved, particularly those regarding all the blinding

aspects of the trial and the agreement among out-

comes assessors. The prevention of these sources of

variability is a future effort for both clinicians and

study sponsors.

ACKNOWLEDGEMENT

Declaration of personal and funding interests: None.

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META-ANALYS IS : REMISS ION AND RESPONSE FOR ACTIVE LUMINAL CROHN’S DISEASE 1221

ª 2008 The Authors, Aliment Pharmacol Ther 27, 1210–1223

Journal compilation ª 2008 Blackwell Publishing Ltd

APPENDIX 1

((‘‘crohn disease’’[TIAB] NOT Medline[SB]) OR ‘‘crohn

disease’’[MeSH Terms] OR crohn’s disease[Text Word])

AND (randomized controlled trial [Publication Type]

OR (randomized [Title ⁄ Abstract] AND controlled

[Title ⁄ Abstract] AND trial [Title ⁄ Abstract]) AND

(‘‘humans’’[MeSH Terms] AND English [la] AND

‘‘adult’’[MeSH Terms]) NOT (‘‘letter’’[pt] OR editorial

[pt] OR comment [pt])) AND (‘‘1997 ⁄ 01 ⁄ 01’’[EDAT] :

‘‘2007 ⁄ 12 ⁄ 31’’[EDAT])

APPENDIX 2

Excluded papers (number)

Maintenance therapy (nine).

Rutgeerts P, D’Haens G, Targan S, Vasiliauskas E, Hanauer SB,

Present DH, Mayer L, Van Hogezand RA, Braakman T, DeWoody KL,

Schaible TF, Van Deventer SJ. Efficacy and safety of retreatment

with anti-tumor necrosis factor antibody (infliximab) to maintain

remission in Crohn’s disease. Gastroenterology 1999; 117: 761–9.

Hanauer SB, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S,

Colombel JF, Rachmilewitz D, Wolf DC, Olson A, Bao W, Rutgeerts P,

ACCENT I Study Group. Maintenance infliximab for Crohn’s disease:

the ACCENT I randomised trial. Lancet 2002; 359: 1541–9.

Feagan BG, Yan S, Bala M, Bao W, Lichtenstein GR. The effects of

infliximab maintenance therapy on health-related quality of life. Am

J Gastroenterol 2003; 98: 2232–8.

Sands BE, Anderson FH, Bernstein CN, Chey WY, Feagan BG, Fedo-

rak RN, Kamm MA, Korzenik JR, Lashner BA, Onken JE, Rachmilewitz

D, Rutgeerts P, Wild G, Wolf DC, Marsters PA, Travers SB, Blank MA,

van Deventer SJ. Infliximab maintenance therapy for fistulizing Cro-

hn’s disease. N Engl J Med 2004; 350: 876–85.

Rutgeerts P, Diamond RH, Bala M, Olson A, Lichtenstein GR, Bao

W, Patel K, Wolf DC, Safdi M, Colombel JF, Lashner B, Hanauer SB.

Scheduled maintenance treatment with infliximab is superior to epi-

sodic treatment for the healing of mucosal ulceration associated with

Crohn’s disease. Gastrointest Endosc 2006; 63: 433–42.

Sands BE, Blank MA, Diamond RH, Barrett JP, Van Deventer SJ.

Maintenance infliximab does not result in increased abscess develop-

ment in fistulizing Crohn’s disease: results from the ACCENT II

study. Aliment Pharmacol Ther 2006; 23: 1127–36.

Colombel JF, Sandborn WJ, Rutgeerts P, Enns R, Hanauer SB,

Panaccione R, Schreiber S, Byczkowski D, Li J, Kent JD, Pollack PF.

Adalimumab for maintenance of clinical response and remission in

patients with Crohn’s disease: the CHARM trial. Gastroenterology

2007; 132: 52–65.

Sandborn WJ, Hanauer SB, Rutgeerts P, Fedorak RN, Lukas M,

MacIntosh DG, Panaccione R, Wolf D, Kent JD, Bittle B, Li J, Pollack

PF. Adalimumab for maintenance treatment of Crohn’s disease:

results of the CLASSIC II trial. Gut 2007; 56: 1232–9.

Schreiber S, Khaliq-Kareemi M, Lawrance IC, Thomsen OØ, Han-

auer SB, McColm J, Bloomfield R, Sandborn WJ; PRECISE 2 Study

Investigators. Maintenance therapy with certolizumab pegol for Cro-

hn’s disease. N Engl J Med 2007; 357: 239–50.

Fistulizing disease (five).

Present DH, Rutgeerts P, Targan S, Hanauer SB, Mayer L, van

Hogezand RA, Podolsky DK, Sands BE, Braakman T, DeWoody KL,

Schaible TF, van Deventer SJ. Infliximab for the treatment of fistulas

in patients with Crohn’s disease. N Engl J Med 1999; 340: 1398–405.

Gao Q, Hogezand RA, Lamers CB, Verspaget HW. Basic fibroblast

growth factor as a response parameter to infliximab in fistulizing

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Journal compilation ª 2008 Blackwell Publishing Ltd