Future Clinical Trials: Unanswered
Questions in the Care of IBD Patients
William J. Sandborn, MD
Chief, Division of Gastroenterology
Director, UCSD IBD Center
Unanswered Questions





Step down
Test Versus No Test
Mucosal healing
Prevention of postoperative recurrence
Anti-TNF versus vedolizumab
Step Down
Withdrawal of AZA in 80 Patients
With CD Treated With Scheduled IFX Maintenance:
Clinical Outcomes
No need for early rescue IFX
No need to discontinue IFX
1.0
Continued
Discontinued
0.8
0.6
0.4
Log rank (Cox): P=0.735
0.2
0.0
Proportion of Patients
Proportion of Patients
1.0
0.8
Log rank (Cox): P=0.374
0.6
0.4
0.2
0.0
0 8 16 24 32 40 48 56 64 72 80 88 96
Weeks
0 8 16 24 32 40 48 56 64 72 80 88 96 104
Weeks
Reprinted from Gastroenterology 134(7), Van Assche G, et al. Withdrawal of
immunosuppression in Crohn's disease treated with scheduled infliximab maintenance: a
randomized trial, 1861-1868. Copyright 2008, with permission from the AGA Institute.
Withdrawal of AZA in CD Patients Treated
With Scheduled IFX Maintenance: Serum
CRP and IFX Concentrations Over Time
15
10
P<.005
5
1.6
Trough IFX (μg/mL)
0
2.8
Discontinued
Continued
11
10
9
8
7
6
5
4
3
2
1
0
0
Con
8
16
24
32
P<.0001
2.87
1.65
1
Con
48
56
64
72
80
88
96 104
Weeks
Continued
Discontinued
P=.0046
7
10
40
Dis
[IFX] μg/mL
CRP (mg/L)
20
CRP (mg/L)
**
***
P=.11
6
5
P=.028
P=.043
P=.051
P=.048
P=.15
P=.19
4
3
2
1
0
Dis
0
8
16
24
32
40
48
56
64
72
80
88
96 104
20
18
19
18
18
18
17
18
Weeks
Con
N= Dis
CRP, C-reactive protein
40
40
39
38
32
33
31
28
28 27
25 22
22
20
22
20
20
18
16
18
Reprinted from Gastroenterology 134(7), Van Assche G, et al. Withdrawal of
immunosuppression in Crohn's disease treated with scheduled infliximab maintenance: a
randomized trial, 1861-1868. Copyright 2008, with permission from the AGA Institute.
STORI Trial



Patients with Crohn's disease who were treated for at least 1 year with
scheduled infliximab and an antimetabolite and had been in
corticosteroid-free remission for at least 6 months
Assessed the risk of relapse after discontinuation of infliximab in
patients on combined maintenance therapy with immunosuppressors
and to identify the risk factors for relapse
Results:
 After 1 year of infliximab discontinuation, the relapse rate was 44%
 Patients who relapsed were successfully retreated with infliximab
 Of the 40 evaluable responses to retreatment at 4 weeks, 37 were in
remission
Predictive
Factor
CDEIS >0
hsCRP ≥5 mg/L
Hemoglobin ≤14.5 g/dL
Infliximab trough levels ≥2 μg/mL
CDEIS, Crohn’s Disease Endoscopic Index of
Severity; usCRP, ultrasensitive C-reactive protein
Hazard
Ratio
P Value
2.3
3.2
6.0
2.5
0.04
<0.001
<0.001
0.02
Reprinted from Gastroenterology 141(1), Louis E, et al.
Maintenance of remission among patients with Crohn's disease
on antimetabolite therapy after infliximab therapy is stopped,
63-70. Copyright 2012, with permission from the AGA Institute.
Test Versus No Test
Factors Affecting the Pharmacokinetics of
Monoclonal Antibodies
IMPACT on PK
Presence of ADAs
Decreases serum [mAbs]
Three fold-increased clearance
Worse clinical outcomes
Concomitant use of IS
Reduces formation
Increases serum [mAbs]
Decreases mAbs clearance
Better clinical outcomes
High Baseline [TNF-α]
May decrease [mAbs] by increasing clearance
Low Albumin
High Baseline CRP
Body size
Gender
Increases clearance
Worse clinical outcomes
Increases clearance
High BMI may increase clearance
Males have higher clearance
Ordas I, Feagan B, Mould D, Sandborn WJ. Clin Pharmacol Ther 2012
Proportion of patients (%)
ACT 1+2: Proportions of Patients with Ulcerative Colitis
Achieving Efficacy Endpoints by Serum Infliximab
Concentrations
<21.3
≥21.3 –
< 33.0
≥33.0 –
< 47.9
> 47.9
Reinisch W, et al., Digestive Disease Week 2012; Abstract # 566
<0.11
≥0.11<2.4
≥2.4<6.8
> 6.8
Elevating Infliximab Concentration from SubTherapeutic Levels is Effective in Regaining Response
in HACA (-) Patients
Clinical Outcomes of Patients with Detectable Antibodies to Infliximab or
Sub-therapeutic Infliximab Concentrations
Response to test
Detectable HACA
Subtherapeutic
concentration
Complete/partial
response (%)
Increase infliximab
1/6 (17)
Change anti-TNF
11/12 (92)
Increase infliximab
25/29 (86)
Change anti-TNF
2/6 (33)
Afif W, Sandborn WJ. Am J Gastroenterol 2010;105:1133-9.
P value
P<0.004
P<0.016
Treatment Algorithm in IBD
Patients With Clinical Symptoms
(Infliximab and HACA Concentrations)
Positive HACA
Change to another
anti-TNF agent
Therapeutic IFX
concentration
Active disease on
endoscopy/radiology?
yes
no
Subtherapeutic IFX
concentration
Increase
infliximab
dose or
frequency
Change to
different
anti-TNF
agent
Change to
different
anti-TNF
agent
Change to
nonanti-TNF
agent
persistent
disease
Change to nonanti-TNF agent
Change to
different
anti-TNF
agent
Afif W, et al. Am J Gastroenterol 2010;105:1133-9.
Investigate
alternate
etiologies
Mucosal Healing
MUCOSAL HEALING AND TIME TO COLECTOMY IN
INFLIXIMAB-TREATED PATIENTS
0 = NORMAL
1 = MILD
2 = MODERATE
3 = SEVERE
Colombel JF, et al. Gastroenterology. 2011.
Association Between Week 8 Mayo Endoscopy Subscore and and Corticosteroid-Free Symptomatic
Remission at Week 30 During Anti-TNF Antibody
Therapy
Week 8 Mayo
endoscopy subscore
Corticosteroid-free
symptomatic
remission, %
P value
0
46
< 0.001
1
34
2
11
3
6.5
Colombel JF, et al. Gastroenterology 2011
Working Definition of Deep Remission
Overall, aiming for deep remission (DR) is managing
disease beyond symptom control
– In patients with no bowel damage or disability, DR is
resolution of one or more objective measures of
inflammation (endoscopy, markers, imaging) AND
resolution of symptoms
• To prevent damage and disability
– In patients with existing bowel damage and disability,
DR is resolution of one or more objective measures of
inflammation (endoscopy, markers, imaging) AND
improvement of symptoms if possible
• To prevent further damage and disability, and
reverse damage if possible
Development of the Crohn’s Disease Digestive
Damage Score, the Le´mann Score
Benjamin Pariente, Jacques Cosnes, Silvio Danese, William J Sandborn, Maı¨te´ Lewin, Joel
G Fletcher, Yehuda Chowers, Geert D’Haens, Brian G Feagan, Toshifumi Hibi, Daniel W
Hommes, E. Jan Irvine, Michael A. Kamm, Edward V Loftus, Edouard Louis, Pierre Michetti,
Pia Munkholm, Tom Oresland, Julian Pane´s, Laurent Peyrin-Biroulet, Walter Reinisch,
Bruce E Sands, Juergen Schoelmerich, Stefan Schreiber, Herbert Tilg, Simon Travis, Gert
van Assche, Maurizio Vecchi, Jean-Yves Mary, Jean-Fre´de´ric Colombel, Marc Le´mann
Pariente B et al. Inflamm Bowel Dis. 2011;17(6):1415.
Peyrin-Biroulet L et al. GUT. 2011.
Inflammatory Activity and Progression of
Damage in a Theoretical Patient with CD
Digestive damage
Surgery
Fistula/abscess
Stricture
Disease
onset
Diagnosis
Inflammatory activity
(CDAI, CDEIS, CRP)
Stricture
Early
disease
CDAI, Crohn’s Disease Activity Index;
CDEIS, Crohn’s disease endoscopic index of severity
CRP; c-reactive protein
Pariente B et al. Inflamm Bowel Dis. 2011;17(6):1415.
All hospitalization (%)
All-cause hospitalization
through Week 52
20
17
15
10
5
0
0/11
9/53
Deep
remission*
(Week 12)
Non-deep
remission*
(Week 12)
CD-related hospitalization (%)
EXTEND: patients with Crohn’s disease who achieved
deep remission* with adalimumab at Week 12 and
hospitalization rates
CD-related hospitalization
through Week 52
20
15
9
10
5
0
0/11
5/53
Deep
remission*
(Week 12)
Non-deep
remission*
(Week 12)
* Deep remission defined as clinical remission (CDAI <150) and complete mucosal healing in EXTEND
CD: Crohn’s disease; CDAI: Crohn’s disease activity index
Colombel JF, Sandborn WJ, et al. Gut 2010;59(Suppl 3):A80: OP371 at UEGW 2010
Prevention Of Postoperative Recurrence
Crohn’s Disease:
Recurrence After Surgery
100
Patients (%)
80
Survival without
surgery
60
Survival without
laboratory recurrence
40
Survival without
symptoms
20
Survival without
endoscopic lesions
0
0
1
2
3
4
5
6
7
8
Yr
Rutgeerts P, et al. Gastroenterology. 1990;99(4):956
Infliximab for Prevention of
Postoperative Recurrence in Crohn’s Disease
Crohn’s disease patients with surgical resection of the
ileum with an ileocolonic anastomosis
100
Placebo
P=.0006
90
P=.0009
80
80
Infliximab 5 mg/kg
P=.67
67
54
60
(%)
39
40
20
P=.05
15
15
8
0
0
Endoscopic
remission
Absence of CD
on colonoscopy
Clinical
remission
Clinical
recurrence
N=23; within 4 wk of surgery, patients received study drug at 0, 2, 6 wk then Q 8 wk for 1
yr
Regueiro M, et al. Gastroenterology 2009
Anti-TNF Versus Vedolizumab
Infliximab Induction and Maintenance Therapy
in Patients with Ulcerative Colitis:
Clinical Response
ACT 1
Placebo
IFX 5 mg/kg
IFX 10 mg/kg
‡
60
†
‡
52 51
‡
46 44
50
37
30
30
20
20
10
80
‡
70
65
IFX 10 mg/kg
‡
69
‡
60
‡
50
47
40
30
29
60
26
20
0
8 Weeks
‡P<.001
IFX 5 mg/kg
10
0
†P.002
% of Patients
69 ‡
62
70
40
Placebo
‡
80
% of Patients
ACT 2
vs placebo
vs placebo
30 Weeks
54 Weeks
8 Weeks
30 Weeks
Rutgeerts P. N Engl J Med. 2005;353:2462.
Infliximab Induction and Maintenance
Therapy in Patients with Ulcerative Colitis:
Clinical Remission
ACT 1
‡
39
45
% of Patients
40
35
30
IFX 5 mg/kg
‡
34
†
32
‡
37
‡ ‡
35 34
25
20
15
Placebo
IFX 10 mg/kg
16
17
15
10
‡P<.001
vs placebo
vs placebo
36
‡
†
26
20
15
10
0
†P.003
‡
25
0
54 Weeks
IFX 10 mg/kg
28
30
5
30 Weeks
34
35
5
8 Weeks
IFX 5 mg/kg
‡
40
% of Patients
Placebo
ACT 2
11
6
8 Weeks
30 Weeks
Rutgeerts P. N Engl J Med. 2005;353:2462.
Infliximab Induction and Maintenance Therapy
in Patients with Ulcerative Colitis:
Mucosal Healing
ACT 1
‡
70
62
60
% of Patients
IFX 5 mg/kg
Placebo
‡
59
‡
‡
‡
50 49
34
30
25
18
20
60
‡
46 47
‡
62
50
46
40
31
57
30
30
20
0
0
54 Weeks
IFX 10 mg/kg
†
10
30 Weeks
‡
60
10
8 Weeks
IFX 5 mg/kg
‡
70
50
40
IFX 10 mg/kg
% of Patients
Placebo
ACT 2
8 Weeks
30 Weeks
Mucosal healing = endoscopic subscore of 0 or 1
†P.009
‡P<.001
vs placebo
vs placebo
Rutgeerts P. N Engl J Med. 2005;353:2462.
Vedolizumab (Anti-Alpha 4 Beta 7 Integrin) For Moderately-toSeverely Active Ulcerative Colitis: Results at Week 6 in 374
Patients
P<0.001
P=0.0012
P=0.0009
Feagan B. DDW 2012 Late Breaking Abstract
Vedolizumab (Anti- 47 Integrin) For Maintenace of
Response in Moderately-to-Severely Active Ulcerative Colitis:
Results at Week 52 in 373 Patients
Feagan B. ACG 2012 Abstract
Comparative Effectiveness Trials Already
Completed But Results Not Fully
Implemented By Clinicians
 Mesalamine not effective for Crohn’s disease
 SONIC and UC Success – azathioprine < infliximab <
combination therapy
 Early use of azathioprine + steroids not more effective than
a tapering course of steroids
Conclusions
 Comparative effectiveness studies are needed to better
guide future clinical practice