Evidence-Based Medicine Changing Practice Dr Feagan’s Top 10 Clinical Trials c/o Dr Brian Feagan...

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!)

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


Pe

rce

nt

Re

lap

se

Fre

e


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



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


#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)

Evidence-Based Medicine Changing Practice Dr Feagan’s Top 10 Clinical Trials c/o Dr Brian Feagan...

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Transcript of Evidence-Based Medicine Changing Practice Dr Feagan’s Top 10 Clinical Trials c/o Dr Brian Feagan...