1. Future comparative effectiveness studies: unanswered questions in the care of IBD patients
Jean-Frédéric Colombel
Icahn School of Medicine at Mount Sinai New York, USA

2. 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.

3. What is comparative effectiveness research (CER) ?
The generation and synthesis of evidence that compares the benefits and
harms 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 interventions
2) 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.

4. Why do we need CER in IBD ? Clinical trials Clinical practice
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

5. Clinical trial IBD population versus real-world IBD population
Retrospective study of patients with moderate-severe IBD at a US tertiary referral centre (n=206)
31% of patients were not eligible for participation in a clinical trial of biologic therapy*
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)
*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
Ha C, et al. Clin Gastroenterol Hepatol 2012.

6. Patients with CRP 0.8 mg/dL and Lesions on Baseline Endoscopy*
The impact of CE studies: SONIC: Corticosteroid-Free Clinical Remission at Week 50
Patients with CRP 0.8 mg/dL and Lesions on Baseline Endoscopy*
100
P=.002 80
P=.016
P=.354 60
50.0
Percent of patients (%)
41.5 40
22.7 20
17/75
27/65
32/64
AZA+ placebo
IFX + placebo
IFX + AZA
* Patients who did not enter the study extension were treated as nonresponders
AZA=azathioprine; IFX=infliximab
Colombel JF, et al. N Engl J Med. 2010

7. 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.

8. Unanswered questions…
Flying
Take-off
Landing

9. Unanswered questions…
Take-off

10. Which biologic ?

11. Comparing biologics agents in IBD
IFX CZ
ADA
The anti-TNFs family

12. Outcomes in CD patients receiving adalimumab or infliximab therapy
Retrospective cohort of US Medicare data (2006–2010) from new users of adalimumab (n=871) and infliximab (n=1,459)
Primary outcomes at Week 26
Adalimumab
Infliximab
Persistence (%) 47 49
OR 0.98, 95% CI
Surgery
6.9
5.5
HR 0.79, 95% CI
Hospitalisations
15.4
11.8
HR 0.88, 95% CI
Primary outcomes according to baseline steroid exposure
Adalimumab
Infliximab
Surgery
Steroids
7.2
5.6
HR 0.77, 95% CI
No steroids
6.5
5.3
HR 0.82, 95% CI
Hospitalisations
17.3
13.1
HR 0.86, 95% CI
13.5
10.7
HR 0.90, 95% CI
Osterman M, et al. Clin Gastroenterol Hepatol 2013

13. Vedolizumab in UC: Clinical Response, Clinical Remission, Mucosal Healing at 6 Weeks, ITT Population%
P=0.0010
21.7
11.6, 31.7
11.5
4.7, 18.3
16.1
6.4, 25.9
95% CI:
Feagan B et al New Engl J Med 2013

14. Comparing biologics agents in IBD
Anti-
TNFs
Anti-
Integrins
IFX
ADA CZ
“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”

15. Biologic vs surgery ?

16. The LIRIC -trial

17. Combo vs mono ?

18. Steroid-free Remission at Week 26
SONIC
Primary End Point
100
P<0.001 80
P=0.009
P=0.022 57 60
Proportion of Patients (%) 44 40 31 20
52/170
75/169
96/169
AZA + Placebo
IFX + Placebo
IFX+ AZA
Steroid-free remission=CDAI <150 points
Colombel JF et al. N Engl J Med 2010 18

19. 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
Adalimumab
Certolizumab
Infliximab
OR 0.88 ( )
OR 0.93; ( )
OR 1.79 ( )
Jones J et al. DDW 2013

20. Methotrexate with IFX vs IFX alone in CD
COMMIT
Methotrexate with IFX vs IFX alone in CD
Primary end-point:
Failure to enter steroid-free
remission at week 14 or maintain through week 50
P = 0.83
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
P = 0.86
Steroid-free remission
MTX
Placebo
Week 14
Week 50
Feagan B et al. Gastroenterology in press

21. Step-up vs Accelerated step-up vs Top-down ?

22. Conventional and evolving treatment strategies in CD
Ordás I et al. Gut 2011

23. Early “top-down” therapy with azathioprine is not more effective than placebo or conventional therapy
RAPID
AZTEC
Cosnes J et al. Gastroenterology 2013;145:
Panes J et al. Gastroenterology 2013;145:

24. CDAI <150 AND no steroids AND no surgery
Early top-down biologic therapy vs conventional management of Crohn’s disease
CDAI <150 AND no steroids AND no surgery
Patients (%) ** * *
Weeks
*p<0.01 **p<0.05
D’Haens G, et al. Lancet 2008;371:660-7.

25. Usual care vs accelerated care : REACT 1
20 practices (1,200 pts)
20 practices (1,200 pts)
60 patients
per practice
Accelerated care treatment algorithm
Usual care
Treatment of common diseases such as hypertension and dyslipidemia requires a multidisciplinary approach that includes lifestyle modification in addition to medical therapy. Our challenge as physicians is to identify patients who are at high cardiovascular (CV) risk and prescribe an appropriate treatment program. By performing risk assessment in every patient, we can help to recognize these diseases and treat them effectively to reduce the incidence of heart disease.
Therapeutic noncompliance is a common behavior that leads to ineffective treatment and, subsequently, increased health care costs and decreased cost-effectiveness of interventions.
Primary endpoint: Proportion in remission (HBI 4 and off steroids) at practice level 12 mo following randomization
Patients will be bio-naïve 25 25

26. Accelerated care therapeutic algorithm for Crohn’s disease
5-ASA
Antibiotics
Active luminal CD (HBI >4)
Without fistula
With fistula
Steroids (budes vs pred based on disease activity and location)
Complex fistula
Evaluate in 4 wks – remission? (HBI ≤4)
Yes No
Yes No
MRI, US, EUA
to rule out abscess
Antibiotics/
fistulotomy
Taper steroids
Add ADA + AZA or MTX
Re-evaluate in 12 wks – remission?
Abscess present?
Yes No
Taper steroids, re-evaluate
in 12 wks – remission?
Yes No
No maintenance
therapy
ADA + AZA or MTX
(steroids prn)
Drainage/seton
+ antibiotics
Re-evaluate in 12 wks – remission?
Re-evaluate in 4 wks – improved?
Yes No
Cont combo maint Rx
Increase ADA to weekly dose No
Re-evaluate in 12 wks – remission?
Yes
Surgical reassessment
Yes No
Cont combo maint Rx
Switch anti-metabolite
Follow algorithm for active luminal CD without fistula
Re-evaluate in 12 wks – remission?
Yes No
Cont combo maint Rx
Switch TNF-blocker
Re-evaluate in 12 wks – remission?
Yes No
Cont combo maint Rx
Consider resection

27. Unanswered questions…
Flying

28. Treat to mucosal healing vs treat to symptoms ?

29. Enhanced care treatment algorithm Step care treatment algorithm
Usual care vs enhanced care : REACT 2
15 practices
(600 pts)
15 practices
(600 pts)
40 patients
per practice
Enhanced care treatment algorithm
Step care treatment algorithm
Treatment of common diseases such as hypertension and dyslipidemia requires a multidisciplinary approach that includes lifestyle modification in addition to medical therapy. Our challenge as physicians is to identify patients who are at high cardiovascular (CV) risk and prescribe an appropriate treatment program. By performing risk assessment in every patient, we can help to recognize these diseases and treat them effectively to reduce the incidence of heart disease.
Therapeutic noncompliance is a common behavior that leads to ineffective treatment and, subsequently, increased health care costs and decreased cost-effectiveness of interventions.
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). 29 29

30. Enhanced care algorithm
Active luminal CD (HBI >4, 1 large ulcer)
5-ASA
Antibiotics
Initiate combination therapy (adalimumab + AZA or MTX) +/- GCS as required
Evaluate by ileocolonoscopy in 16 wks – remission? (HBI ≤4, no large ulcers, no GCS)
Yes No
Continue combination maintenance therapy
Increase adalimumab to weekly dose +/- GCS as required
Taper GCS, re-evaluate by ileocolonoscopy in 16 wks – remission? (HBI ≤4, no large ulcers, no GCS)
Yes No
Continue combination maintenance therapy
Switch antimetabolite, +/- GCS as required
Re-evaluate by ileocolonoscopy in 16 wks – remission? (HBI ≤4, no large ulcers, no GCS)
Yes No
Continue combination maintenance therapy
Switch TNF antagonist, +/- GCS as required

31. Treat to biomarkers vs treat to symptoms ?

32. Calprotectin monitoring in CD after IFX withdrawal

33. Usual care vs tight control using biomarkers: CALM
Open-label, multicenter study in Europe and Canada Evaluating two treatment algorithms in CD
Conventional
CDAI, steroid use
Primary endpoint: Mucosal healing 48 weeks after randomisation
Prednisone up to 8 weeks
Patients naïve to immunomodulators and biologic therapy (n=240)
Tight control
CDAI, steroid use, high-sensitivity CRP, faecal calprotectin
Treatment intensification in both arms: 1) No treatment, 2) Adalimumab every other week, 3) Adalimumab weekly, 4) Adalimumab weekly + azathioprine
NCT

34. Tight control arm R w9 w21 w33 w45 w56
Treatment may change at weeks 9, 21, 33 and 45 based on success criteria at weeks 8, 20, 32 and 44
Y = No change**
Y = No change**
N = ADA EOW**
N = ADA EOW**
Y = No change**
Y = No change**
N = ADA wkly**
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
Y = No change**
Y = No change*
N = ADA wkly**
N = ADA EOW**
Y = No change**
N = ADA wkly
Y = ADA EOW**
N = ADA wkly AZA**
Y = No change**
N = ADA wkly**
Y = No change**
N = 120
Prednisone 8 wks
N = ADA wkly
Y = No change**
Y = ADA EOW**
N = ADA
N = ADA wkly AZA**
Y = No change**
Flare = CDAI↑ ≥70 from BL and ≥220, pt continues as non-responder
* Flare between wks , ADA started
** Flare between evaluation wks, then next option
N = ADA wkly**
N = ADA wkly**
Y = ADA EOW**
N = ADA wkly + AZA
Y = ADA EOW AZA**
N = ADA wkly AZA** R w9
w21
w33
w45
w56

35. Treat to trough levels vs treat to symptoms ?

36. 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

37. Individualised therapy vs dose intensification in patients with CD who lose response to anti-TNF
Randomised, single-blind, multicentre Danish study in CD (n=69)
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
IFX intensification 4 8 12
Study week 2 6 10
Cost per patient, € mean
Algorithm *
*p<0.001
Intention-to-treat
Per protocol
-50%
-25% 0%
25%
50%
True difference
IFX intensification better
Algorithm better
Co-primary clinical endpoint in intention-to-treat and per protocol populations. Dashed lines illustrate the predefined non-inferiority margin
Steenholdt C , et al. Gut 2013; gutjnl [ePub ahead of print]

38. Biologic Naïve Subjects with active luminal CD (N=120)
Optimizing anti-TNF based on trough levels vs clinical symptoms: TAILORIX
Biologic Naïve Subjects with active luminal CD (N=120)
Ileocolonoscopy at screening
Cohort 1
n=40
Cohort 2
n=40
Cohort 3 (control)
n=40
Visits
Week 0 *
IFX 5 mg/kg (0,2,6 then every 8 wks)
+ AZA mg/kg (if tolerated)
Week 2 *
Week 6 *
Week 12
Ileocolonoscopy/TL
Week 14 * 18
Week 22 *
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 26
Week 30 * 34
Week 38 * 42
Week 46 * 50
Week 54
Ileocolonoscopy *
Primary endpoint: steroid-free remission between wk22 and wk54 (CDAI < 150) and endoscopic healing at wk54

39. Unanswered questions…
Landing

40. Discontinuation of Immunomodulator in Stable Remission on Combination Therapy (Infliximab Maintained)
No need for early ‘rescue’ IFX: primary endpoint
Median IFX levels, Week 8 to Week 104 combined
1.0
100
Cumulative survival
p<0.005
IFX trough levels (μg)
0.8
Log Rank (Cox): 0.735; Breslow: 0.906
0.6 10
0.4
Continued
Discontinued
0.2 1
0.0 20 40 60 80
100
Continued
Discontinued
Time (weeks)
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)
Van Asche et al, Gastroenterology 2008

41. 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.

42. Predictive Model for Time to Relapse After Stopping IFX and Continuing AZA
Kaplan Meier time-to-relapse curves according to multivariate models and scores generated through Cox model using multiple imputations method
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 6 12 18 24 30
Months since infliximab withdrawal
No. deleterious factors
<4 4
5-6
>6
Proportion Without Relapse
Louis E et al. Gastroenterology. 2012;142:63-70.

43. 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
CCFA
Nycibdc

44. Screening Randomisation Relapse No remission Study end Scheduled
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/Kg
If 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
Discontinuing anti-metabolites and continuing infliximab at the same dosage
Infliximab intensification like in first arm. If no remission, anti-metabolite is restarted
Colonoscopy
Small bowel MRI * *
Scheduled
visits
Timeline (weeks)

45. Comparative effectiveness research in IBD
A huge opportunity
Formidable challenges
design
recruitment
funding …