Tailorix: A Study on Proactive Treatment Management for Crohn's Disease

1. Journal Club 22/10/2018 Gabriele Giudici

2. Crohn’sDisease Idiopathic, chronic relapsing immune mediated disease that leads to chronic inflammation of one or multiple segments of the bowel (any between mouth and anus – ileum and caecal region more commonly involved)

3. Crohn’sDisease – Clinicalpresentation

4. Crohn’sDisease – Clinicalpresentation Baumgart et al, Lancet 2013

5. Crohn’sDisease – Why so important • Incidence and prevalence of Crohn’s disease is increasing worldwide • Around 25% of patient are age < 20 years • Excess mortality compared with the general population  mortality ratio of 1.38 (95% CI [1.23 - 1.55]) Kalla et al, BMJ 2014

6. Baumgart et al, Lancet 2013

7. Crohn’sDisease – Treatment • Anti-TNFα • Infliximab (IFX) • Adalimumab (ADA) • Anti-Integrin (α4β7) • Vedolizumab (VDZ) • Anti-IL12/23 • Ustekinumab (UST)

8. Crohn’sDisease – Treatment Shah et al, AlimentPharmacolTher. 2016

9. Crohn’sDisease – Treatment GastrointestEndosc 2006;63:433–442

10. Crohn’sDisease – Treatment Am J Gastroenterol 2009;104:760–767

11. Crohn’sDisease – Treatment

12. TAILORIX Randomized controlled trial investigating tailored treatment with infliximab for active luminal Crohn’s disease (TAILORIX) Proof-of-concept randomized double-blind controlled study conducted in 27 centers from Belgium, France, and the Netherlands (06/2012 - 09/2015)

13. TAILORIX – Objective “… if proactive dose increase of IFX based on symptoms, biomarkers, and/or frequently measured trough level (TL) would lead to a better outcome than conventional management in a cohort of biologic-naïve patients with CD …”

14. TAILORIX - Outcomes

15. TAILORIX – InclusionCriteria • Adults with active luminal CD naïve to biologics with an indication to start anti-TNF therapy (IFX 5 mg/kg) • Crohn’s disease activity index (CDAI) >220 with objective signs of active inflammation (CRP >5 mg/L and/or fecal calprotectin >250 mg/g) and visible ulcers at baseline ileo-colonoscopy • Along with immunosuppresant therapy (AZA, 6-MP or MTX)

16. TAILORIX – ExclusionCriteria • Imminent need for surgery • Critical gastrointestinal stricture and obstructive symptoms, • Using corticosteroid therapy at doses >40 mg/d prednisolone orequivalent (if less, patients were enrolled but had to be tapered before week 14 with a fixed schedule) • Active systemic infection • Evidence of TBC • Usual contraindications to anti-TNF or immunosuppressants

17. TAILORIX – Mantainanceregiments Patient were randomized (1:1:1) into 3 maintenance regiments of IFX dose escalation DIS 1 DIS 2 Control group + 2.5 mg/kg (max 2 times) up to 10 mg/kg + 5 mg/kg (max 1 time) up to 10 mg/kg + 5 mg/kg (max 1 time) up to 10 mg/kg

18. TAILORIX – Mantainanceregiment DIS1-DIS2 A single additional IFX infusion at the 4-week interval was administered in case of TL <1 µg/mL in patients in the 2 DIS groups: • 2.5 mg/kg (max 2 times) (DIS 1) • 5 mg/kg (max 1 time) (DIS 2)

19. TAILORIX – Mantainanceregiment Control Group No additionalinfusions in control group

21. TAILORIX – Patientcharacteristicsat baseline

22. TAILORIX – Follow up Induction IFX Maintainance IFX (8w) Studyvisits Every 4 weeks t -3w -1w 0 +2w +4w +6w +12w +14w +54w Colonoscopy • At eachvisit: • CDAI • CRP • FecalCalprotectin • IXL TL • At eachcolonoscopy: • CDEIS (CD endoscopicindex of severity)

23. TAILORIX – Results (1)

24. TAILORIX – Results (2)

25. TAILORIX – Results (3)

26. TAILORIX – Results (4)

27. TAILORIX – Discussion • First prospectiverandomized controlled trial • Proactive dose-intensification schedule (of 43 dose escalation opportunities, 23 were avoided per protocol)

28. TAILORIX – Critics No significantdifferencesbetweengroups... BUT • Verylittlenumbers • Verystrictendpoints • Possiblebias from overreportsymptoms for dose-escalations in the control group (9 out of 15 escalationshadnormal CRP and/or calprotectin) • Notclear IFX pharmacokinetics

29. Conclusion