Y-ECCO Literature Review: Sasha Fehily

The CALM trial was performed to establish whether a treatment algorithm incorporating biomarkers is more effective in achieving disease control compared with conventional care based on symptoms alone. This multicentre, randomised, open-label, phase 3 trial included 244 patients with at least moderate active ileal, colonic or ileocolonic CD who were naïve to immunomodulators and biologic agents. Key exclusion criteria were disease duration >6 years, fistulising disease and the presence of colonic or ileal fibrotic strictures. Patients were randomly assigned (1:1) to tight control or standard management after 8 weeks of prednisone induction therapy, or earlier if there was active disease.  In the tight control group, treatment was stepped up in the setting of treatment failure defined by FC ≥250 μg/g, CRP ≥5 mg/L, Crohn’s Disease Activity Index (CDAI) ≥150 or prednisone use in the previous week. In the standard management arm, treatment failure was defined by CDAI decrease of <100 points compared with baseline or CDAI ≥200, or prednisone use in the previous week. The treatment model escalated from no treatment to adalimumab induction followed by adalimumab every other week, adalimumab every week, and weekly adalimumab in combination with daily azathioprine. De-escalation was possible for patients receiving weekly adalimumab and azathioprine or weekly adalimumab alone if failure criteria were not met. The primary endpoint was mucosal healing defined by Crohn's Disease Endoscopy Index of Severity (CDEIS) <4 and no deep ulcers on endoscopy at 48 weeks after randomisation.

Key findings

A higher proportion of patients following the tight control algorithm achieved the primary endpoint of mucosal healing at 48 weeks: 56 (46%) versus 37 (30%), p=0.010. Patients in the tight control group were also more likely to achieve deep remission [14.5% (95% CI 2.9–26.0, p=0.014)], biological remission [14.5% (95% CI 4.1–25.0, p=0.006)] and an overall CDEIS <4 [16.1% (95% CI 3.9–28.3, p=0.010)]. No significant difference between groups was observed for overall CDEIS <4 plus a CDEIS <4 in every segment, complete endoscopic remission or endoscopic response. At weeks 11, 35 and 48, a higher proportion of the tight control group achieved steroid-free remission, clinical remission and mean improvement in CDAI from baseline.

Ninety percent of patients in the tight control group versus 78% in the standard management group commenced adalimumab at randomisation, 47% versus 22% were escalated to weekly adalimumab at 12 weeks and by 36 weeks 27% versus 8% were on combination therapy. The higher number of treatment adjustments in the tight control group was associated with improved clinical outcomes and led to rapid optimisation of therapy. The decision to escalate therapy was most frequently due to an increased FC concentration or elevated CRP levels, rather than CDAI or prednisolone use.

Similar rates of study discontinuation occurred in both groups. Twenty-nine (24%) patients in the tight control group versus 32 (26%) in the standard management group discontinued therapy, with a large proportion reporting adverse drug reactions (ADRs) as the primary reason for withdrawal (41% vs 50%, respectively). Overall ADRs were reported by 105 (86%) patients in the tight control group compared with 100 (82%) patients in the standard management group. There was no significant difference in the proportion of patients experiencing serious ADRs, including serious infections, despite intensive immunosuppression in the tight control arm.

Conclusion

The CALM study demonstrated superior outcomes associated with the tight control algorithm, defined as a composite of both clinical and inflammatory biomarker targets. As endoscopic assessment of disease activity [2,3] is limited by accessibility and patient tolerability, non-invasive serum and faecal biomarkers are more suitable for repeated assessment of remission [4,5]. However, this may risk undertreating patients with endoscopically active disease who do not mount a biomarker response. Additionally, the increase in frequency of testing and greater biological exposure will incur additional costs to the health care system.

There are several potential biases in the CALM study, including the small cohort and high withdrawal rates. The study was an open-label design, the post-randomisation prednisolone tapering schedule was set at the discretion of the unblinded investigators and endoscopic assessments were performed onsite. Additionally, the CDAI threshold for treatment failure triggering dose intensification differed between the groups, being >150 in the tight control arm versus >200 in the standard management arm. These thresholds were imposed to reflect clinical practice; however, this undoubtedly resulted in more frequent treatment escalation in the tight control group. With regard to the generalisability of these results, the cohort was not reflective of the broad population of CD patients as the study patients were at a very early stage of disease and naïve to most therapy. Rapid optimisation of therapy was achieved with earlier use of anti-TNF monotherapy and overall 90% of patients received adalimumab. However, this escalation schedule was non-conventional as current data support early introduction of combination therapy [6].

In both groups more than 80% of patients reported ADRs, with infections being most frequently reported. Serious infections including perianal abscesses were non-significantly lower in the tight control arm, which may reflect better disease control. The absence of major differences in adverse events observed in the two groups may relate to the short duration of follow-up: several large cohorts have demonstrated increased ADRs with combination therapy [7,8,9].

In summary, the CALM study demonstrates that tight treatment control targeting clinical remission as well as reduction in serum CRP and FC is associated with improved clinical outcomes. However, before clinical decision-making is changed on the basis of these results, long-term studies will be required to evaluate the impact on the natural history of the disease and to confirm the cost-effectiveness of this approach.

References

1. Peyrin-Biroulet L, Sandborn W, Sands BE, et al. Selecting therapeutic 25 targets in inflammatory bowel disease (STRIDE): determining therapeutic goals for treat-to-target. Am J Gastroenterol 2015; 110: 1324–38.
2. Mary JY, Modigliani R. Development and validation of an endoscopic index of the severity for Crohn's disease: a prospective multicentre study. Groupe d'Etudes Therapeutiques des Affections Inflammatoires du Tube Digestif (GETAID). Gut. 1989: 1;30(7):983-9.
3. Schnitzler F, Fidder H, Ferrante M, et al. Mucosal healing predicts long-term outcome of maintenance therapy with infliximab in Crohn's disease. Inflammatory Bowel Diseases. 2009: 1;15(9):1295-301.
4. Heida A, Park KT, van Rheenen PF. Clinical utility of fecal calprotectin monitoring in asymptomatic patients with inflammatory bowel disease: a systematic review and practical guide. Inflamm Bowel Dis 2017; 23: 894–902.
5. Solem CA, Loftus EV Jr, Tremaine WJ, Harmsen WS, Zinsmeister AR, Sandborn WJ. Correlation of C-reactive protein with clinical, endoscopic, histologic, and radiographic activity in inflammatory bowel disease. Inflamm Bowel Dis 2005; 11: 707–12.
6. Colombel JF, Sandborn WJ, Reinisch W, Mantzaris GJ, Kornbluth A, Rachmilewitz D, Lichtiger S, D'haens G, Diamond RH, Broussard DL, Tang KL. Infliximab, azathioprine, or combination therapy for Crohn's disease. New England Journal of Medicine. 2010 Apr 15;362(15):1383-95.
7. Siegel CA, Marden SM, Persing SM, Larson RJ, Sands BE. Risk of lymphoma associated with combination anti-tumor necrosis factor and immunomodulator therapy for the treatment of Crohn's Disease: A meta-analysis. Clin Gastroenterol Hepatol. 2009;7:874–81.
8. Kirchgesner J, Lemaitre M, Carrat F, Zureik M, Carbonnel F, Dray-Spira R. Risk of serious and opportunistic infections associated with treatment of inflammatory bowel diseases. Gastroenterology. 2018;155:337–46.
9. Hagen JW, Pugliano-Mauro MA. Nonmelanoma skin cancer risk in patients with ibd undergoing thiopurine therapy: A systematic review of the literature. Dermatol Surg. 2018;44:469–80.

Sasha Fehily is currently performing her first year of gastroenterology training at St Vincent’s Hospital in Melbourne, Australia. She is particularly interested in the influence of the microbiota on the natural history of Inflammatory Bowel Diseases.

Sasha Fehily  © Sasha Fehily