Evidence-Based Medicine Changing Practice
Dr Feagan’s Top 10 Clinical Trials
c/o Dr Brian Feagan
Presented and updated by Barrett Levesque MD,
Director, Academic Research
The RCT at Age 50
0
10
20
30
40
50
60
70
32%
68%
Streptomycin
Placebo
British MRC Working Party. BMJ. 1948;669-782
British MRC Trial 1948 % Improvement at 6 months in
Patients with Pulmonary Tuberculosis
%
0
20
40
60
80
100
120
1948 1960 1970 1980 1990 2000
The Ascending of the RCT 1948-
# of RCTs
1x104
The RCT at Age 50A Gold Standard for Evidence Based Medicine
Reduction of Bias
The RCT A Gold Standard for Evidence Based Medicine
Control of Confounders
TPA
62 (52, 70)
StreptokinaseN=9841 N=10,396
62 (52, 70)
130 (111,144) 130 (113,144)
73 (62, 85) 73 (62, 86)
164 (115, 232) 165 (120, 230)
Age (yr)
Systolic Blood Pressure (mmHg)
Heart Rate (beats/min)
Time to Treatment (min)
#10:Hydrocortisone Therapy for UC
0
5
10
15
20
25
30
35
% R
esp
on
se
Truelove SC, Witts LJ. Br Med J. 1955 Oct 29;(4947):1041-8.
Hydrocortisone Placebo
30.2%
11.1%
p= 0.02
#9 NCCDS: The Trial You Love to Hate
• Circa 1980• Induction
therapy/maintenance of remission
• 4 arms(Placebo, AZA, prednisone, SPS)
• Overwhelming in its’ complexity
• Almost impossible to read!
0
20
40
60
80
% R
esp
on
se
0 10
WeeksPrednisone Placebo SPS
p=0.04
NCCDS Data
Summers et al Gastroenterology 1979
#8 Nobel Prize 20--?
Chu CQ et al. British Journal of Rheumatology
1992;31:653-661
#7 Pentasa Dose -FindingWhat You Don’t Know Can Hurt
(Your Patients!)
5-ASA
0
20
40
60
80
% R
esp
on
se
0 10
WeeksPrednisone Placebo Corticosteroids
p=0.001
NCCDS Data
Corticosteroids: Induction of Remission
5-ASA: Induction of Remission
0
10
20
30
40
50
% R
em
iss
ion 5-ASA vs Placebo
Placebo 1.0 2.0 4.0
mg/kg/daySingleton Gastroenterology 1993
“in contrast to these findings a nearly identical second trial of this same formulation of mesalamine for treatment of active Crohn’s Disease failed to show significant superiority over placebo”
Singleton Letter
Singleton Gastroenterology 1993
5-ASA for Induction of Remission:A Mega Analysis
• 3 RCT’s for induction with a similar design
• Pooled original data
• n= 311 Placebo vs 304 5-ASA
0
10
20
30
40
50
60
70
Placebo 5-ASA 4g/day
p=0.04
Hanauer S, Stromberg U, DDW Abstract 2308; 2001.
63
45
Change in CDAI from
Baseline
#6 NACSG Part I and II (Change is Coming!)
Methotrexate
% R
esp
on
se
Feagan. N Eng J Med. 1995 Feb 2;332 (5):292-7
0
25 19.1%
39.4%p=0.025
Placebo MTX
50
MTX Part I Results: Remission
Results: Time to Relapse%
Rem
issi
on
Weeks Since Randomization
Methotrexate
Placebo
P=0.044
Maini RN et al 1998 Arthritis Rheum. 41:1552
Rationale of Combination Infliximab and MTX
100
75
50
25
0
(% o
f p
atie
nts
)
Infliximab dose (mg/kg)
1 3 10
Antibodies to Infliximab
Infliximab Infliximab + MTX
Weeks
10
Se
rum
infl
ixim
ab
(m
g/m
l)
0
5
1 mg/kg
100
75
50
25
0
0 2 6 1410 18 2622
10 mg/kg
3 mg/kg
20
15
10
5
Pharmacokinetics
#5 Oh Canada! ( eh )
(This Buds for you!)
Corticosteroids in IBD
Toxicity
Budesonide
Budesonide Absorption and Metabolism
Systemic circulation
10% to 20%
Liver
~100%
60% to 70% absorbed in the ileal and ileocecal area
CYP3A4
80% to 90% first-pass metabolism
Metabolites with negligible
glucocorticosteroid affinity
Budesonide for Active Crohn’s Disease
0
10
20
30
40
50
602 wk
4 wk
8 wk
Pa
tie
nts
in R
em
issi
on
(%
)P
ati
en
ts in
Re
mis
sio
n (
%)
n = 66n = 66PlacebPlaceb
oo
3 mg3 mgn = 67n = 67
9 mg9 mgn = 61n = 61
15 mg15 mgn = 64n = 64
Greenberg et al. N Engl J Med. 1994;331:836-841.
Budesonide
Budesonide vs Prednisolone: Induction of Remission for Active CD
*p=0.22; †p<0.001; ‡p=0.12.
Rutgeerts et al. N Engl J Med. 1994;331:842-845.
Treatment (weeks)
Prednisolone 40 mg qd tapered q 2 wk to 25 mg (n=88)
Budesonide 9 mg qd x 8 wk tapered to 6 mg (n=88)
2 4 8 10
Pat
ien
ts in
Rem
issi
on
(%
)(C
DA
I 15
0)
100
80
60
40
20
0
*
† ‡‡
Budesonide vs Mesalamine: Induction of Remission
*p=0.001; †p=0.004; ‡p<0.001.
Thomsen et al. N Engl J Med. 1998;339:370-374.
Pat
ien
ts in
Rem
issi
on
(%
)C
DA
I 15
0
Treatment (weeks)
Budesonide 9 mg qd (n=93)
Mesalamine 2 g bid (n=89)100100
8080
6060
4040
2020
002 4 8 12 16
*† ‡
#4 Causing a Traffic Jam in UC !
Endothelial and Leukocyte Adhesion:
4 Integrins
11774• Leukocyte
membrane glycoproteins
1 and 7 subunits• Interact with
endothelial ligands VCAM-1, fibronectin, and MAdCAM-1
• Mediate leukocyte adhesion and trafficking
Springer TA. Cell. 1994;76:301–314. Butcher EC, et al. Science. 1996;272:60-66.
• Ligand for 47 is MAdCAM
• Animal models show that ACT-1 selectively blocks trafficking of 47 positive lymphocytes to the gut
• Raises possibility of gut specific immune modulation
• Striking benefit in cotton top tamarin model
Alpha 4 Beta 7
MAdCAM -1 ACT -1
1. Hesterberg PE. et al. Gastroenterology. 1996 Nov;111(5):1373-80 2. Podolsky. et al JCI,1993;(92):372-80
Background
0
5
10
15
20
25
30
35
Placebo 0.5 mg/kg 2.0 mg/kg
% R
emis
sio
n
Overall p=0.030
15%
34%
33%
p=.021p=.015
Feagan BG. Gastroenterology 2003.
Clinical Remission at Week 6
0
5
10
15
20
25
30
35
Placebo 0.5 mg/kg 2.0 mg/kg
Clinical Remission Week 6
% R
emis
sio
n
Overall P = 0.030
15%
34%
33%
P = .021P = .015
Feagan BG. et al N Engl J Med. 2005;352(24):2499-507.
Vedolizumab Phase III: Study DesignInduction PhaseWeek 0 – Week 6
Maintenance PhaseWeek 6 – Week 52
Cohort 1Blinded
InductionN=374
Cohort 1 complete?
Cohort 2Open-Label
InductionN=521
Screening, Enrollment
PlaceboN=149
VDZN=225
VDZN=521
Week 6: Responder?
PlaceboN=126
VDZ Q8 wksN=122
VDZ Q4 wksN=125
PlaceboN=149
VDZN=373
No
Yes
No
Yes
Week 52 Assess-ments
*Responders began tapering regimen at 6 weeks; others, as soon as a clinical response was achieved.
Corticosteroid Tapering*
Feagan, B.G. et al New Engl J Med 2013
Clinical Response, Clinical Remission, Mucosal Healing at 6 Weeks, ITT Population
25.5
5.4
24.8
47.1
16.9
40.9
0
5
10
15
20
25
30
35
40
45
50
Clinical Response Clinical Remission Mucosal Healing
PlaceboVedolizumab
%
P<0.0001
P=0.0010
21.711.6, 31.7
11.54.7, 18.3
16.16.4, 25.9
P=0.0010
95% CI:
Feagan BG et al New Engl J Med 2013
Primary and Secondary Outcomes Through 52 Weeks, ITT Population
15.9
23.819.8
8.7
13.9
41.8
56.651.6
20.5
31.4
44.8
52.056.0
24.0
45.2
0
10
20
30
40
50
60
Clinical Remission Durable ClinicalResponse
Mucosal Healing Durable ClinicalRemission
CS-Free Remission
PlaceboVDZ Q8WksVDZ Q4Wks
%
26.1 29.1 32.8 28.5 32.0 36.3 11.8 15.3 17.6 31.4
******
****
***
*** ***
***
*
***
*P<0.05. **P<0.01. ***P<0.0001
n: 72 70 73
Feagan BG et al New Engl J Med 2013
#3 Tipping Convention on Its Head!
Early Combined Immunosuppressive Therapy With Infliximab and Azathioprine Versus Conventional Therapy in Active Early Crohn’s Disease
Newly diagnosed Crohn’s disease (n=129)
Step-up (n=64)
Steroids
Top-down (n=65)
IFX (0/2/6) + AZA
+ IFX
+ AZA
MTX
Steroids
Steroids
IFX + AZA
+ (episodic) IFX
Steroids
D’Haens G, et al. Lancet. 2008
The primary endpoints were remission (CDAI <150) and off steroids at months 6 and 12
Early Combined Immunosuppressive Therapy With Infliximab and Azathioprine Versus Conventional Therapy in Active Early Crohn’s Disease (CDAI REMISSION)
D’Haens, Lancet 2008
At week 104, 100% of top-down patients were using azathioprineor methotrexate, compared with 76% of step-up patients.
Early Combined Immunosuppressive Therapy With Infliximab and Azathioprine Versus Conventional Therapy in Active Early Crohn’s
Disease
Conventional Management
Early Combined Immunosuppression
P=0.0307
Time to Relapse by Treatment Group
D’Haens, Lancet 2008
Pe
rce
nt
Re
lap
se
Fre
e
Early Combined Immunosuppressive Therapy With Infliximab and Azathioprine Versus Conventional Therapy in Active Early Crohn’s Disease
0
20
40
60
80
100
0
20
40
60
80
100
Proportion of Patients Receiving Azathioprine or Methotrexate Over Time by Treatment Group
0 26 52 78 104Weeks Since Randomization
0 26 52 78 104Weeks Since Randomization
Early Combined Immunosuppression Conventional Management
D’Haens, Lancet 2008
Early Combined Immunosuppressive Therapy With Infliximab and Azathioprine Versus Conventional Therapy in Active Early Crohn’s Disease
Po
int
s% o
f P
atie
nts
‡
† Endoscopic healing was scored in 5 ileal and colonic segments as follows: 0=no ulcers, 1= aphthoid ulcers, 2=larger ulcers, 3= ulcerated stenosis. ‡ p<.001
Early Combined Immunosuppression (n=24)
Conventional Management (n=20)
‡
‡
Mucosal Healing
D’Haens, Lancet 2008
#2 SONIC Goes Boom!
SONIC:Clinical Remission Without Corticosteroids at
Week 26
30
45
57
0
20
40
60
80
100
Pro
po
rtio
n o
f P
atie
nts
(%
)
AZA + placebo IFX + placebo IFX+ AZA
p<0.001
p=0.009 p=0.022
52/170 75/169 96/169
Sandborn et al. AJG 2008. 103 Issue: s1 S408-S455 Abstract #1117
Immunogenicity Status at Week 30
Centocor, data on file
1
14
1
15
20
68
94
0
20
40
60
80
100
PBO + AZA IFX + PBO IFX + AZA
Fra
ctio
n o
f p
ts (
%)
Postive Negative Inconclusive
n=89 n=106 n=120
98
#1 The Curious Case of COMMIT
COMMIT :Schematic Overview of Trial Design
MTX
Placebo
Infliximab 5 mg/kg x 8 weekly
Treatment successOff prednisone
CDAI <150
Treatment successSuccess week 14 & maintenance of
remission
Randomization
Week -1 0 1 2 3 4 14 46 50
MTX 10 10 20 20 25 (weekly mg)
Prednisone tapering
0
20
40
60
80
100
0 4 8 12 16 20 24 28 32 36 40 44 48 52
MTX
Placebo
P=0.63
Weeks Since Randomization
Proportion of Patients with Treatment Success
% S
ucc
ess
% Antibody Positive at Endpoint
0
10
20
30
40
50
60
70
80
90
100
MTX
Placebo
%
4.0
20.4
Effect of Methotrexate on Trough Infliximab Concentration
0
10
20
30
40
50
60
70
80
90
100
MTX
Placebo
% Detectable Infliximab
86.0
74.1
Median Trough Concentration of Infliximab at Endpoint
0
1
2
3
4
5
6
7
8
9
10
MTX
Placebo
Micrograms per litre
6.35
3.75
COMMIT :Effect of Infliximab Trough Concentration on Treatment Success
0102030405060708090
100
Detectable Infiximab
Yes
No% Success 72.3
52.4
Top 10!
10)Truelove –Cortisone for UC 1955 9) Summers -NCCDS 1979 8)Vanderventer- Infliximab 7) Singleton - 5 -ASA 1994 6)NACSG I and II- MTX for CD 1995, 2000 5)Greenberg - Bud induction 1994 4) Feagan -MLN-O2 for UC 2005/2013 3 ) D’Haens- Top Down 2007 2) SONIC 1)COMMIT
––––––––––––––––––––––––––
Take Away Messages1) RCTs are gold standard for clinical medicine (Truelove)
2) NCCDS data are a cornerstone for our current therapeutic algorithms in CD (Summers)
3) Case reports can lead to bigger things (Vanderventer)
4) Publication bias does exist and you can be influenced by it (Singleton/Hanauer)
5) MTX has an important role in the management of Crohn’s disease (NACSG)
6) Canada’s IBD Community has changed the world (Greenberg Bud)
7) Selective Inhibition of WBC trafficking is a novel therapeutic strategy in UC (Feagan MLNO2)
8) Early Combined Immunosuppression may be a preferred strategy in CD(D’Haens)
9) SONIC has changed the world (Colombel)
10) Even Evidence- base medicine zealots can be biased (COMMIT)
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