Colombel JF, et al. - Researchers performed CALM study to compare endoscopic and clinical outcomes in patients with moderate to severe Crohn's disease who were managed with a tight control algorithm, using clinical symptoms and biomarkers, vs patients managed with a clinical management algorithm. In this study, they for the first time demonstrated that timely escalation with an anti-tumour necrosis factor therapy on the basis of clinical symptoms combined with biomarkers in patients with early Crohn's disease results in better clinical and endoscopic outcomes than symptom-driven decisions alone. They recommended assessing the effects of such a strategy on long-term outcomes such as bowel damage, surgeries, hospital admissions, and disability in the future studies.

Methods

• CALM was an open-label, randomised, controlled phase 3 study.
• It was performed in 22 countries at 74 hospitals and outpatient centres.
• CALM evaluated adult patients (aged 18–75 years) with active endoscopic Crohn's disease (Crohn's Disease Endoscopic Index of Severity [CDEIS] >6; sum of CDEIS subscores of >6 in one or more segments with ulcers), a Crohn's Disease Activity Index (CDAI) of 150–450 depending on dose of prednisone at baseline, and no previous use of immunomodulators or biologics.
• Researchers randomly assigned patients at a 1:1 ratio to tight control or clinical management groups, stratified by smoking status (yes or no), weight (<70 kg or ≥70 kg), and disease duration (≤2 years or >2 years) after 8 weeks of prednisone induction therapy, or earlier if they had active disease.
• In both groups, they escalated treatment in a stepwise manner, from no treatment, to adalimumab induction followed by adalimumab every other week, adalimumab every week, and lastly to both weekly adalimumab and daily azathioprine.
• This escalation was based on meeting treatment failure criteria, which differed between groups.
• If failure criteria were not met, de-escalation was possible for patients receiving weekly adalimumab and azathioprine or weekly adalimumab alone.
• For this study, the primary endpoint was mucosal healing (CDEIS <4) with absence of deep ulcers 48 weeks after randomisation. In the intention-to-treat population, they performed primary and safety analyses.

Results

• From Feb 11, 2011, to Nov 3, 2016, researchers randomly assigned 244 patients (mean disease duration: clinical management group, 0·9 years [SD 1·7]; tight control group, 1·0 year [2·3]) to monitoring groups (n=122 per group).
• Mostly because of adverse events, 29 (24%) patients in the clinical management group and 32 (26%) patients in the tight control group discontinued the study.
• They observed a significantly higher proportion of patients in the tight control group who achieved the primary endpoint at week 48 (56 [46%] of 122 patients) than in the clinical management group (37 [30%] of 122 patients), with a Cochran–Mantel–Haenszel test-adjusted risk difference of 16·1% (95% CI 3·9–28·3; p=0·010).
• In the tight control group, 105 (86%) of 122 patients and in the clinical management group, 100 (82%) of 122 patients reported treatment-emergent adverse events; there appeared no treatment-related deaths.
• In this study, the most common adverse events were nausea (21 [17%] of 122 patients), nasopharyngitis (18 [15%]), and headache (18 [15%]) in the tight control group, and worsening Crohn's disease (35 [29%] of 122 patients), arthralgia (19 [16%]), and nasopharyngitis (18 [15%]) in the clinical management group.