Y-ECCO Literature Review: Aaron S. Bancil

Methods

The SERENE CD trial compared higher versus standard adalimumab induction dosing outcomes as well as CA versus TDM management strategies in patients with moderate to severely active disease.

This phase 3 randomised, double-blind trial, conducted across 93 sites in 19 countries, recruited 514 patients aged 18–75 years, with a CD Activity Index (CDAI) of 220–450, endoscopic evidence of mucosal inflammation (SES-CD ≥6 or ≥4 for isolated ileal disease, excluding the presence of narrowing) and previous failure of standard therapies.

Patients were randomised to receive either the higher induction regimen (HIR) or the standard induction regimen (SIR). The HIR group (n=308) were given 160 mg at weeks 0, 1, 2 and 3; the SIR group (n=206) were given 160 mg at week 0 and 80 mg at week 2, with placebo at weeks 1 and 3, followed by 40 mg every other week.

At week 12, patients were re-randomised, to either CA (n=92) or TDM (n=92) maintenance strategies. CA dose escalation occurred if the CDAI was ≥220 or C-reactive protein (CRP) was ≥10 mg/L; TDM dose escalation occurred if the adalimumab drug level was <5 µg/mL or if it was between ≥5 µg/mL and ≤10 µg/mL with either CRP ≥10 mg/L or CDAI ≥220. The aim in the TDM group was to achieve a minimum adalimumab concentration of 5 μg/mL. This was based on data from the CLASSIC II trial, in which 75% of patients who achieved clinical remission by week 56 had a serum adalimumab level of >5 μg/mL [5]. Once escalation had occurred, dosing remained at 40 mg every week, with all patients receiving weekly injections to maintain blinding (those not escalated were given placebo every other week). 

Key Findings

The co-primary outcomes were the proportion of patients achieving clinical remission (CDAI <150 at week 4) and endoscopic response at week 12, defined as a >50% decrease from baseline in SES-CD (or a ≥2-point reduction in patients with a baseline SES-CD score of 4).

For the induction study, results at week 4 showed that similar numbers in the HIR and SIR groups achieved clinical remission (44% in both, p=0.939) and endoscopic response at week 12 (43% vs 39%, respectively, p=0.462). For the maintenance study, at week 56, 70.7% of patients in the CA group and 66.3% of patients in the TDM group achieved clinical remission (p=0.497), with steroid-free clinical remission in 76.9% and 73.2% in the CA and TDM groups, respectively (p=0.636).

For the induction study, results at week 4 showed that similar numbers in the HIR and SIR groups achieved clinical remission (44% in both, p=0.939) and endoscopic response at week 12 (43% vs 39%, respectively, p=0.462). For the maintenance study, at week 56, 70.7% of patients in the CA group and 66.3% of patients in the TDM group achieved clinical remission (p=0.497), with steroid-free clinical remission in 76.9% and 73.2% in the CA and TDM groups, respectively (p=0.636).

Changes in PROs such as the IBDQ total score and Work Productivity and Activity Impairment questionnaire were similar between the HIR and SIR groups as well as the CA and TDM groups.

Conclusion

These results demonstrate no significant advantage of HIR vs SIR or CA vs TDM management strategies. In the induction study, higher drug levels did not correspond to greater clinical or endoscopic efficacy, thus confirming the appropriateness of the current approved induction dosing regimen. The study did show that long-term treatment of CD with adalimumab was efficacious. Interestingly, the remission rates in SERENE CD were higher than in previous trials [6, 7] despite patients having more severe baseline endoscopic inflammation.

It could be argued that a different minimum serum adalimumab level for dose escalation may have yielded different results, as suggested by the PANTS study, which recommended an optimal drug concentration of 12 μg/mL for adalimumab [4]. This should be addressed in future studies.

Previous studies (TAXIT, TAILORIX) have also failed to demonstrate a benefit of a TDM over a CA approach to dose escalation [8, 9]. Contrastingly, a non-blinded paediatric study (PAILOT) did show a clinical benefit of proactive adalimumab TDM versus reactive TDM [10]. Thus, although TDM has been of interest, there is currently a paucity of data to support its frequent use in practice.

Overall, this is a pivotal study that helps to answer an important component of therapeutic strategy. Future trials may identify that TDM may be beneficial in certain nuanced circumstances or populations, and, of course, this must be studied for each individual drug.

References

1. Shah SC, Colombel JF, Sands BE, Narula N. Systematic review with meta-analysis: mucosal healing is associated with improved long-term outcomes in Crohn's disease. Aliment Pharmacol Ther. 2016;43:317–33.
2. Reinink AR, Lee TC, Higgins PD. Endoscopic mucosal healing predicts favorable clinical outcomes in inflammatory bowel disease: A meta-analysis. Inflamm Bowel Dis. 2016;22:1859–69.
3. Watanabe K, Matsumoto T, Hisamatsu T, et al.; DIAMOND study group. Clinical and pharmacokinetic factors associated with adalimumab-induced mucosal healing in patients with Crohn's disease. Clin Gastroenterol Hepatol. 2018;16:542–549.e1.
4. Kennedy NA, Heap GA, Green HD, et al.; UK Inflammatory Bowel Disease Pharmacogenetics Study Group. Predictors of anti-TNF treatment failure in anti-TNF-naive patients with active luminal Crohn's disease: a prospective, multicentre, cohort study. Lancet Gastroenterol Hepatol. 2019;4:341–53.
5. Chiu YL, Rubin DT, Vermeire S, et al. Serum adalimumab concentration and clinical remission in patients with Crohn's disease. Inflamm Bowel Dis. 2013;19:1112–22.
6. Hanauer SB, Sandborn WJ, Rutgeerts P, et al. Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: the CLASSIC-I trial. Gastroenterology. 2006;130:323–33; quiz 591.
7. Sandborn WJ, Rutgeerts P, Enns R, et al. Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial. Ann Intern Med. 2007;146:829–38.
8. Vande Casteele N, Ferrante M, Van Assche G, et al. Trough concentrations of infliximab guide dosing for patients with inflammatory bowel disease. Gastroenterology. 2015;148:1320–9.e3.
9. D'Haens G, Vermeire S, Lambrecht G, et al.; GETAID. Increasing infliximab dose based on symptoms, biomarkers, and serum drug concentrations does not increase clinical, endoscopic, and corticosteroid-free remission in patients with active luminal Crohn's disease. Gastroenterology. 2018;154:1343–51.e1.
10. Assa A, Matar M, Turner D, et al. Proactive monitoring of adalimumab trough concentration associated with increased clinical remission in children with Crohn's disease compared with reactive monitoring. Gastroenterology. 2019;157:985–96.e2.

Aaron S. Bancil - Short Biography

Aaron S. Bancil is a gastroenterology trainee in South London and a PhD candidate at King’s College London. His research is based on the ADDapt trial, which is a randomised controlled trial looking at the therapeutic effect of a low food additive diet in Crohn’s Disease. He is also a trainee representative for the British Society of Gastroenterology.