Future comparative effectiveness studies: unanswered questions

in the care of IBD patients

Jean-Frédéric ColombelIcahn School of Medicine at Mount Sinai

New York, USA

Disclosure

J-F Colombel has served as consultant, advisory board member or speaker for or received research grants from

Abbvie, Amgen, Bristol Meyers Squibb, Celltrion, Ferring, Genentech, Giuliani SPA, Given Imaging, Janssend and Janssen, Merck & Co., Millenium Pharmaceuticals Inc., Nutrition Science Partners Ltd., Pfizer Inc. Prometheus Laboratories, Sanofi, Schering Plough Corporation, Takeda, Teva Pharmaceuticals, UCB Pharma, Vertex, Dr. August Wolff GmbH & Co.

What is comparative effectiveness research (CER) ?

• The generation and synthesis of evidence that compares the benefits andharms of alternative methods to prevent, diagnose, treat, and monitor a clinical condition, or to improve the delivery of care.

• The purpose of CER is to ‘‘assist consumers, clinicians, purchasers, and policy makers to make informed decisions that will improve health care at both the individual and population levels.’’

• Two key elements are 1) the direct comparison of effective interventions2) The application of these interventions in patients who are typical

of day-to-day clinical practice

Ratner R , et al. In: Medicine Io.ed Washington DC 2009; Sox HC, et al. Ann Interm Med 2009.

Why do we need CER in IBD ?

• Defined population

• Prescribed treatment regimen

• Follow-up regimented with schedule

• Uniform primary end-point

• Efficacy

• Heterogeneous population

• Variable treatment regimen with optimization

• Follow-up not fixed

• Variable outcomes

• Effectiveness

Clinical trials Clinical practice

Clinical trial IBD population versus real-world IBD population

31% of patients were not eligible for participationin a clinical trial of biologic therapy*

Ha C, et al. Clin Gastroenterol Hepatol 2012.

*Inclusion criteria based on those published for 9 trials of biologic therapy: ACCENT I, CLASSIC I, CHARM, PRECISE I, ENCORE, ENACT, SONIC, ACT 1, ACT 2

Retrospective study of patients with moderate-severe IBD at a US tertiary referral centre (n=206)

Reasons for exclusion in CD● Strictures or abscesses (62%)● Recent exposure or

nonresponse to anti-TNF (51%)● High-dose steroids (18%)● Comorbidities (26%)

Reasons for exclusion in UC● Current rectal therapy use (57%)● Steroid and immunomodulator

naive (45%)● Newly diagnosed (17%)● Colectomy likely (15%)

Non-eligible CD patients had a significantly lower response rate to biologics than eligible CD patients (60% vs 89%, p=0.03)

Patients with CRP 0.8 mg/dL and Lesions on Baseline Endoscopy*

22.7

41.5

50.0

0

20

40

60

80

100

AZA+ placebo IFX + placebo IFX + AZA

Perc

ent o

f pati

ents

(%)

P=.002

P=.016 P=.354

17/75 27/65 32/64

* Patients who did not enter the study extension were treated as nonresponders

The impact of CE studies: SONIC: Corticosteroid-Free Clinical Remission at Week 50

AZA=azathioprine; IFX=infliximab

Colombel JF, et al. N Engl J Med. 2010

Setting priorities for CER in IBD: results of an international provider survey, expert rand panel, and

patient focus groups

Cheifetz AS , et al. Inflam Bowel Dis 2012.

Unanswered questions…

Take-off

Flying

Landing

Unanswered questions…

Take-off

Which biologic ?

Comparing biologics agents in IBD

IFX CZADA

The anti-TNFs family

Outcomes in CD patients receiving adalimumab or infliximab therapy

Osterman M, et al. Clin Gastroenterol Hepatol 2013

Adalimumab InfliximabPersistence (%) 47 49 OR 0.98, 95% CI 0.81-1.19Surgery 6.9 5.5 HR 0.79, 95% CI 0.60-1.05Hospitalisations 15.4 11.8 HR 0.88, 95% CI 0.72-1.07

Primary outcomes at Week 26

Adalimumab InfliximabSurgery Steroids 7.2 5.6 HR 0.77, 95% CI 0.51-1.14 No steroids 6.5 5.3 HR 0.82, 95% CI 0.55-1.23Hospitalisations Steroids 17.3 13.1 HR 0.86, 95% CI 0.65-1.12 No steroids 13.5 10.7 HR 0.90, 95% CI 0.67-1.20

Primary outcomes according to baseline steroid exposure

Retrospective cohort of US Medicare data (2006–2010) from new users of adalimumab (n=871) and infliximab (n=1,459)

Vedolizumab in UC: 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

D 21.711.6, 31.7

D 11.54.7, 18.3

D 16.16.4, 25.9

P=0.0010

95% CI:

Feagan B et al New Engl J Med 2013

Comparing biologics agents in IBD

IFX CZADA

Anti-Integrins

Anti-TNFs

“The key research topic in the area of IBD from the US Institute of Medicine (IOM) report is to compare the effectiveness of competing

biologic agents”

Biologic vs surgery ?

The LIRIC -trial

Combo vs mono ?

Steroid-free Remission at Week 26

Primary End Point

31

44

57

0

20

40

60

80

100

Prop

ortio

n of

Pati

ents

(%)

AZA + Placebo IFX + Placebo IFX+ AZA

P<0.001

P=0.009 P=0.022

52/170 75/169 96/169

SONIC

Steroid-free remission=CDAI <150 points

Colombel JF et al. N Engl J Med 2010

Impact of concomitant immunomodulator treatment on efficacy and safety of anti-TNF therapy in Crohn’s disease: a meta-

analysis of placebo-controlled trials using patient-level data

Results: 6 Month Clinical Remission Stratified by anti-TNF agent

CertolizumabAdalimumab

OR 0.93; (0.65-1.34) OR 0.88 (0.58-1.35) OR 1.79 (1.06-3.01)

Infliximab

Jones J et al. DDW 2013

Methotrexate with IFX vs IFX alone in CD

- Highest success rate ever observed

- At week 14 and 50 there was between the IFX group vs IFX+MTX group

- All patients on prednisone 15 to 40mg/d

55.6

76.2

57.1

77.8

01020304050607080

Week 14 Week 50

% s

ucce

ss

MTX Placebo

P = 0.83

P = 0.86

COMMIT

MTX PlaceboWeek 14 Week 50

Ster

oid-

free

rem

issio

n

Primary end-point:Failure to enter steroid-free remission at week 14 or maintain through week 50

Feagan B et al. Gastroenterology in press

Step-up vsAccelerated step-up vs

Top-down ?

Ordás I et al. Gut 2011

Conventional and evolving treatment strategies in CD

Early “top-down” therapy with azathioprine is not more effective than placebo or conventional therapy

RAPIDAZTEC

Cosnes J et al. Gastroenterology 2013;145: 758-65 Panes J et al. Gastroenterology 2013;145: 766-74

CDAI <150 AND no steroids AND no surgery

Weeks

Patie

nts (

%)

*

**

*p<0.01**p<0.05

D’Haens G, et al. Lancet 2008;371:660-7.

*

Early top-down biologic therapy vs conventional management of Crohn’s disease

Usual care vs accelerated care : REACT 1

20 practices

(1,200 pts)

20 practices

(1,200 pts)60 patientsper practice

Accelerated care

treatmentalgorithm

Usual care

Patients will be bio-naïvePrimary endpoint: Proportion in remission (HBI 4 and off steroids) at practice level 12 mo following randomization

YesEvaluate in 4 wks – remission? (HBI ≤4)

5-ASAAntibiotics

Re-evaluate in 12 wks – remission?Yes No

NoYes

Cont combo maint Rx Consider resection

Taper steroids, re-evaluate in 12 wks – remission?

Re-evaluate in 12 wks – remission?

No

Re-evaluate in 12 wks – remission?Yes No

Re-evaluate in 12 wks – remission?NoYes

Re-evaluate in 12 wks – remission?

With fistulaWithout fistula

Complex fistula

Yes

MRI, US, EUAto rule out abscess

Antibiotics/fistulotomy

Abscess present?

Yes NoDrainage/seton

+ antibioticsRe-evaluate in 4 wks – improved?

No

Yes

NoSurgical

reassessment

Yes No

Follow algorithm for activeluminal CD without fistula

Switch TNF-blockerCont combo maint Rx

Switch anti-metaboliteCont combo maint Rx

Cont combo maint Rx Increase ADA to weekly dose

ADA + AZA or MTX (steroids prn)

No maintenancetherapy

Taper steroids Add ADA + AZA or MTX

Steroids (budes vs pred based ondisease activity and location)

Active luminal CD (HBI >4)

Accelerated care therapeutic algorithm for Crohn’s disease

Unanswered questions…

Flying

Treat to mucosal healing vstreat to symptoms ?

40 patientsper practice

Step caretreatmentalgorithm

Primary endpt: risk of CD-related complications at one-year, measured at the practice level. CD-related complications include (1) CD-related hospitalizations for CD-related surgeries and non-surgical CD events (such as disease flare, bowel obstruction, excluding hospitalization for side effects of study medication), and (2) Bowel damage events not requiring hospitalization (such as symptomatic bowel obstruction, cutaneous fistula, abscess).

Enhanced care

treatmentalgorithm

15 practices(600 pts)

15 practices(600 pts)

Usual care vs enhanced care : REACT 2

Yes No

Yes

Taper GCS, re-evaluate by ileocolonoscopy in 16 wks– remission? (HBI ≤4, no large ulcers, no GCS)

No

Enhanced care algorithm

Active luminal CD (HBI >4, 1 large ulcer)

Yes

Initiate combination therapy (adalimumab + AZA or MTX) +/- GCS as required

Evaluate by ileocolonoscopy in 16 wks – remission?(HBI ≤4, no large ulcers, no GCS)

Continue combinationmaintenance therapy

Increase adalimumab to weekly dose +/- GCS as required

No

Continue combinationmaintenance therapy

Switch antimetabolite, +/- GCS as required

Re-evaluate by ileocolonoscopy in 16 wks– remission? (HBI ≤4, no large ulcers, no GCS)

Continue combinationmaintenance therapy

Switch TNF antagonist, +/- GCS as required

5-ASAAntibiotics

Treat to biomarkers vstreat to symptoms ?

Calprotectin monitoring in CD after IFX withdrawal

Prednisoneup to 8 weeks

ConventionalCDAI, steroid use

Tight controlCDAI, steroid use, high-sensitivity CRP, faecal calprotectin

Primary endpoint:Mucosal healing 48 weeks

after randomisation

Usual care vs tight control using biomarkers: CALM

Open-label, multicenter study in Europe and Canada

Evaluating two treatment algorithms in CD

Treatment intensification in both arms:1) No treatment, 2) Adalimumab every other week, 3) Adalimumab weekly, 4) Adalimumab weekly + azathioprine

Patients naïve toimmunomodulatorsand biologic therapy(n=240)

www.clinicaltrial.gov: NCT01235689

R w9 w21 w33 w45

Treatment may change at weeks 9, 21, 33 and 45 based on success criteria at weeks 8, 20, 32 and 44

At week 9, 21, 33 and 45, did subject meet all objective criteria?:– CDAI <150– HS-CRP <5mg/L– Calprotectin <250 μg/g– Off steroids starting wk 9

Flare = CDAI↑ ≥70 from BL and ≥220, pt continues as non-responder

* Flare between wks 9 + 21, ADA started

** Flare between evaluation wks, then next option

N = ADA wkly**

N = 120Prednisone8 wks

Y = No change**

Y = No change**

N = ADA EOW**

N = ADA

Y = No change*

Y = No change**

N = ADA EOW**

Y = No change**N = ADA wkly

Y = No change**N = ADA wkly

Y = ADA EOW**

N = ADA wkly + AZA

Y = No change**N = ADA EOW**

Y = No change**N = ADA wkly**

Y = No change**N = ADA wkly**

Y = No change**N = ADA wkly**

Y = ADA EOW**

Y = ADA EOW**

Y = No change**N = ADA wkly**

N = ADA wkly AZA**

Y = ADA EOW AZA**N = ADA wkly AZA**

w56

N = ADA wkly AZA**

Tight control arm

Treat to trough levels vstreat to symptoms ?

Pk of biologics: What we know already

• Drug levels of IFX and ADA are associated with outcome in Crohn’s disease

• Antibody status is not directly associated with outcome but is important in understanding reasons for loss of response (LOR) to anti-TNF

• Dose escalation can increase drug levels

• Immunomodulation can decrease antibody production

Colombel JF, et al. Inflamm Bowel Dis 2012

Date of preparation September 2013 AXHUG130882am

Randomised, single-blind, multicentre Danish study in CD (n=69)

Individualised therapy vs dose intensification in patients with CD who lose response to anti-TNF

Steenholdt C , et al. Gut 2013; gutjnl-2013-305279 [ePub ahead of print]

Co-primary clinical endpoint in intention-to-treat and per protocolpopulations. Dashed lines illustrate the predefined non-inferiority margin

0%-25%-50% 25% 50%

True difference

IFX intensificationbetter

Algorithmbetter

Per protocol

Intention-to-treat

Patients with secondary IFX failure were randomised to IFX dose intensification (5 mg/kg every 4 weeks) or interventions based on serum IFX and IFX antibody levels

Co-primary economic endpoint in per protocol populations.Data are average treatment per patient

IFXintensification

0 4 8 12

Study week

0

2

4

6

8

10

Cost

per

pati

ent,

€ m

ean

Algorithm

*

**p<0.001

Biologic Naïve Subjects with active luminal CD (N=120)

VisitsCohort 1

n=40Cohort 2

n=40Cohort 3 (control)

n=40

IFX 5 mg/kg (0,2,6 then every 8 wks) + AZA 2-2.5 mg/kg (if tolerated)

Upon Clinical Relapse and/or TL ↓: †

-1st time: IFX 7.5 mg/kg -2nd time: IFX 10mg/kg

Upon Clinical Relapse and/or TL ↓: †

-IFX 10 mg/kg

Only upon Elevated CDAI: -IFX 10 mg/kg

***

Primary endpoint: steroid-free remission between wk22 and wk54 (CDAI < 150) and endoscopic healing at wk54

Week 22

Week 14

Week 30

Week 38

Week 46

Week 54Ileocolonoscopy

Week 6Week 2Week 0

*

*

*

*

*

*

Week 12 Ileocolonoscopy/TL

18

26

34

42

50

Ileocolonoscopy at screening

Optimizing anti-TNF based on trough levels vs clinical symptoms: TAILORIX

Unanswered questions…

Landing

Median IFX levels, Week 8 to Week 104 combined

No need for early ‘rescue’ IFX: primary endpoint

p<0.005

0

1

10

100

Continued DiscontinuedIF

X tr

ough

leve

ls

(μg)Cum

ulat

ive

surv

ival

0 20 40 60 80 100

0.0

0.2

0.4

0.6

0.8

1.0

Time (weeks)

Log Rank (Cox): 0.735; Breslow: 0.906

ContinuedDiscontinued

Van Asche et al, Gastroenterology 2008

80 patients randomized to continue (+CON , n=40) or to interrupt (++DIS, n=40) immunomodulators (azathioprine or methotrexate) 6 months after the start of infliximab (5 mg/kg IV)

Discontinuation of Immunomodulator in Stable Remission on Combination Therapy (Infliximab Maintained)

Discontinuation of Infliximab in Stable Remission on Combination Therapy (azathioprine maintained)

STORI

• n=52 relapses/115 patients• Median follow-up 28+/- 2 months

• Median time to relapse: 16.4 months

Louis E et al. Gastroenterology. 2012;142:63-70.

Louis E et al. Gastroenterology. 2012;142:63-70.

Deleterious factors: • No previous surgery• Steroids within 12-6 months

before infliximab withdrawal• Male gender• Hemoglobin ≤14.5 g/dL, • Leukocyte count >6x109/L, • hsCRP ≥5 mg/L, • Fecal calprotectin ≥300 µg/g, • CDEIS>0• infliximab trough

≥2 mg/L

0.0

0.4

0.6

0.2

0.8

1.0

0 6 12 18 24 30

Months since infliximab withdrawal

No. deleteriousfactors

<4

4

5-6

>6

Proportion Without Relapse

Kaplan Meier time-to-relapse curves according to multivariate models and scores generated through Cox model using multiple imputations method

Predictive Model for Time to Relapse After Stopping IFX and Continuing AZA

A proSpective randomized controlled trial comParing infliximAb-antimetabolites combination therapy to anti-

metabolites monotheRapy and infliximab monothErapy in patients with Crohn’s disease in sustained steroid-free

remission on combination therapy

SPARE

CCFANycibdc

Crohn’s disease patients in steroid-free remission for 6

months and treated with infliximab and anti-

metabolites combination therapy for at least 1 year, infliximab being given at 5

mg/Kg /8 weeks for at least 6 months

Continuing the combination therapy at the same dosage

Intensification of infliximab at 10 mg/Kg/8 weeks

Judged as failure per protocol. Managment at the discretion

of the investigator

Discontinuing infliximab and continuing the anti-metabolite

at the same dosage

infliximab 5 mg/Kg infusion. If no remission at 4 weeks,

reinfusion at 10 mg/KgIf further relapse beyond one

year, the same treatment regimen is applied

If further relapse within 1 year, the same retreatment

regimen is applied and a scheduled treatment with 5

mg/Kg or 10 mg/Kg depending how the remission was recovered, is applied like

in group one

Judged as failure per protocol. Managment at the discretion

of the investigator

Discontinuing anti-metabolites and continuing infliximab at

the same dosage

Infliximab intensification like in first arm. If no remission, anti-

metabolite is restarted

Judged as failure per protocol. Managment at the discretion

of the investigator

Randomisation Relapse No remission

Timeline (weeks)

-3 0 8 16 24 32 40 48 56 64 72 80 88 96 104

Screening

Scheduled visits

Colonoscopy Small bowel MRI * *

Study end

Comparative effectiveness research in IBD

A huge opportunity

Formidable challenges• design• recruitment• funding• …