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

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 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.

Why do we need CER in IBD ?

Clinical trials

• Defined population • Prescribed treatment regimen • Follow-up regimented with schedule • Uniform primary end-point • Efficacy

Clinical practice

• Heterogeneous population • Variable treatment regimen with optimization • Follow-up not fixed • Variable outcomes • Effectiveness

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.

The impact of CE studies: SONIC:

Corticosteroid-Free Clinical Remission at Week 50 100 80

Patients with CRP



0.8 mg/dL and Lesions on Baseline Endoscopy* P=.002

P=.016

P=.354

60 50.0

41.5

40 22.7

20 17/75 27/65 32/64 0 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

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.

Take-off

Unanswered questions…

Flying Landing

Take-off

Unanswered questions…

Which biologic ?

Comparing biologics agents in IBD

The anti-TNFs family

IFX ADA CZ

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

Persistence (%) Surgery Hospitalisations Adalimumab 47 6.9

15.4

Infliximab 49 5.5

11.8

OR 0.98, 95% CI 0.81-1.19

HR 0.79, 95% CI 0.60-1.05

HR 0.88, 95% CI 0.72-1.07

Primary outcomes according to baseline steroid exposure

Adalimumab Infliximab Surgery Steroids No steroids Hospitalisations Steroids No steroids 7.2

6.5

17.3

13.5

5.6

5.3

13.1

10.7

HR 0.77, 95% CI 0.51-1.14

HR 0.82, 95% CI 0.55-1.23

HR 0.86, 95% CI 0.65-1.12

HR 0.90, 95% CI 0.67-1.20

Osterman M, et al. Clin Gastroenterol Hepatol 2013

Vedolizumab in UC: Clinical Response, Clinical Remission, Mucosal Healing at 6 Weeks, ITT Population % 50 45 40 35 30 25 20 15 10 5 0 25.5

47.1

95% CI: Clinical Response  21.7

11.6, 31.7

Feagan B et al New Engl J Med 2013

Placebo Vedolizumab P<0.0001

P=0.0010

16.9

5.4

Clinical Remission  11.5

4.7, 18.3

P=0.0010

40.9

24.8

Mucosal Healing  16.1

6.4, 25.9

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”

Biologic vs surgery ?

The LIRIC -trial

Combo vs mono ?

Steroid-free Remission at Week 26

SONIC

Primary End Point 100 P<0.001

80 60 P=0.009

40 31 20 0 52/170 AZA + Placebo

Steroid-free remission=CDAI <150 points

44 P=0.022

75/169 IFX + Placebo 57 96/169 IFX+ AZA

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

Adalimumab Certolizumab Infliximab

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

Jones J et al. DDW 2013

Methotrexate with IFX vs IFX alone in CD

COMMIT

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

80 70 60 50 40 30 20 10 0

P = 0.83

76.2

77.8

Week 14

MTX Week 14

MTX

P = 0.86

55.6

57.1

Week 50

Week 50 - 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

Feagan B et al. Gastroenterology in press

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

Conventional and evolving treatment strategies in CD

Ordás I et al. Gut 2011

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

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

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

CDAI <150 AND no steroids AND no surgery * * ** Weeks *p<0.01

**p<0.05

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

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

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

Accelerated care therapeutic algorithm for Crohn’s disease

5-ASA Antibiotics

Without fistula

Active luminal CD (HBI >4)

With fistula Yes

Taper steroids Re-evaluate in 12 wks – remission?

Yes No

No maintenance therapy ADA + AZA or MTX (steroids prn) Re-evaluate in 12 wks – remission?

Yes No

Add ADA + AZA or MTX Taper steroids, re-evaluate in 12 wks – remission?

Cont combo maint Rx

Yes

Steroids (budes vs pred based on disease activity and location) Evaluate in 4 wks – remission? (HBI ≤4)

No

Increase ADA to weekly dose Re-evaluate in 12 wks – remission?

No

Complex fistula

Yes No

MRI, US, EUA to rule out abscess Abscess present?

Yes No

Drainage/seton + antibiotics Re-evaluate in 4 wks – improved?

No Yes

Antibiotics/ fistulotomy Surgical reassessment Cont combo maint Rx Switch anti-metabolite

Yes

Cont combo maint Rx

Yes

Re-evaluate in 12 wks – remission?

No

Switch TNF-blocker Follow algorithm for active luminal CD without fistula Re-evaluate in 12 wks – remission?

No

Cont combo maint Rx Consider resection

Unanswered questions…

Flying

Treat to mucosal healing vs treat to symptoms ?

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

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 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

Continue combination maintenance therapy

Yes No

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)

No

Continue combination maintenance therapy Switch antimetabolite, +/- GCS as required

Yes

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

No

Switch TNF antagonist, +/- GCS as required

Treat to biomarkers vs treat to symptoms ?

Calprotectin monitoring in CD after IFX withdrawal

Usual care vs tight control using biomarkers: CALM

Open-label, multicenter study in Europe and Canada Evaluating two treatment algorithms in CD

Patients naïve to immunomodulators and biologic therapy

(n=240)

Prednisone up to 8 weeks Conventional CDAI, steroid use Primary endpoint: Mucosal healing 48 weeks after randomisation 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 www.clinicaltrial.gov

: NCT01235689

Tight control arm

R N = 120 Prednisone 8 wks w9 N = ADA Y = No change** N = ADA EOW** Y = No change** Y = No change** N = ADA EOW** Y = No change** N = ADA wkly Y = No change** N = ADA wkly 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 wkly** Y = ADA EOW** N = ADA wkly AZA** 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

N = ADA wkly** w21 w33 Y = ADA EOW** N = ADA wkly + AZA w45 Y = No change** N = ADA wkly** Y = ADA EOW AZA** N = ADA wkly AZA** w56 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

Treat to trough levels vs treat 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

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

Intention-to-treat Per protocol -50% -25% 0% 25% True difference IFX intensification better Algorithm better 50% 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-2013-305279 [ePub ahead of print]

10 4 2 8 6 *p<0.001

* * IFX intensification Algorithm 0 0 4 8 Study week 12 Co-primary economic endpoint in per protocol populations.

Data are average treatment per patient

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

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

Visits

Week 0 * Cohort 1 n=40 Cohort 2 n=40 Cohort 3 (control) n=40 IFX 5 mg/kg (0,2,6 then every 8 wks) + AZA 2-2.5 mg/kg (if tolerated) Week 2 Week 6 * * Week 12 Ileocolonoscopy/TL Week 14 *

18

Week 22 *

26

Week 30

34

Week 38

42

* *

Upon Clinical Relapse and/or TL

↓

: † -1 st time: IFX 7.5 mg/kg -2 nd time: IFX 10mg/kg Upon Clinical Relapse and/or TL

↓

: † -IFX 10 mg/kg Only upon Elevated CDAI: -IFX 10 mg/kg

Week 46 *

50

Week 54 Ileocolonoscopy * Primary endpoint:

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

Unanswered questions…

Landing

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 p<0.005

0.8

0.6

Log Rank (Cox): 0.735; Breslow: 0.906

10 0.4

0.2

Continued Discontinued 1 0.0

0 0 20 40 60 Time (weeks) 80 100 Continued Discontinued



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

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.

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 >6x10 9 /L, hsCRP ≥5 mg/L, Fecal calprotectin ≥300 µg/g, CDEIS>0 infliximab trough ≥2 mg/L

1.0

0.8

0.6

0.4

0.2

0.0

0 Proportion Without Relapse 6 12 18 24 No. deleterious factors Months since infliximab withdrawal 30 <4 4 5-6 >6

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

A pro S pective randomized controlled trial com P aring inflixim A b-antimetabolites combination therapy to anti metabolites monothe R apy and infliximab monoth E rapy in patients with Crohn’s disease in sustained steroid-free remission on combination therapy SPARE

Nycibdc CCFA

Screening Randomisation

Continuing the combination therapy at the same dosage

Relapse No remission

Intensification of infliximab at 10 mg/Kg/8 weeks

Study end

Judged as failure per protocol. Managment at the discretion of the investigator 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 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 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

Colonoscopy Small bowel MRI * Timeline (weeks) * Scheduled visits

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

Comparative effectiveness research in IBD

A huge opportunity

• • • •

Formidable challenges

design recruitment funding

…