CALM: Superior outcomes with tight Crohn’s disease control using adjunctive biomarkers
In patients with Crohn’s disease, tight control of inflammatory activity based on clinical symptoms and biomarkers, such as C-reactive protein (CRP) and faecal calprotectin (FC), results in more favourable clinical and endoscopic outcomes compared with a treatment algorithm based on symptom-driven decisions alone, as reported in the phase III CALM study.
CALM included 244 active Crohn’s disease patients who were randomly assigned to either the tight control group (n=122; mean age 32.1 years; 59 percent female) or the clinical management group (n=122; mean age 31.1 years; 57 percent female). All patients had their treatment escalated in a stepwise manner: no treatment, adalimumab induction, increasing doses of adalimumab and the addition of azathioprine.
Escalation was guided by a stringent treatment failure criteria including FC ≥250 μg/g, CRP ≥5 mg/L, Crohn's Disease Activity Index (CDAI) ≥150 or prednisone use in the previous week in the tight control group; and a CDAI decrease of <100 points from baseline or CDAI ≥200, or prednisone use in the previous week in the clinical management group.
At 48 weeks following randomization, mucosal healing (Crohn's Disease Endoscopic Index of Severity [CDEIS] <4) with absence of deep ulcers—the primary endpoint—occurred with greater frequency in the tight control group (46 vs 30 percent; p=0.010). [Lancet 2017;390:2779-2789]
Likewise, significantly more patients in the tight control vs the clinical management group met the secondary endpoints of deep remission (36.9 vs 23.0 percent; p=0.014) and remission based on FC and serum CRP levels (29.5 vs 15.6 percent; p=0.006).
“Early treatment escalation to adalimumab was well tolerated, and proactive biomarker monitoring reduced the use of corticosteroids,” the investigators noted.
Treatment-emergent adverse events (AEs) were similar between the two treatment groups (86 and 82 percent). The most common AEs were nausea, nasopharyngitis and headache in the tight control group, and worsening Crohn's disease, arthralgia and nasopharyngitis in the clinical management group. No treatment-related deaths were reported.
“This study reinforces the evidence supporting the efficacy of early biologic therapy and the use of objective markers of inflammation in making therapeutic decisions in Crohn’s disease,” the investigators said. [Lancet 2015;386:1825-1834; Am J Gastroenterol 2015;110:1324-1338]
“No new safety signals were identified with treatment escalation [and] the safety profile of study treatments was similar to the known safety of adalimumab monotherapy and combination therapy and adalimumab dosing schedules in Crohn’s disease,” they added.
The study had several limitations, including its open-label design, the assessment of endoscopies by site readers, and the tapering and continuation of prednisone treatment at the discretion of the investigators.
Additional studies are needed to evaluate the effects of timely escalation with an antitumour necrosis factor therapy on the basis of clinical symptoms combined with biomarkers on long-term outcomes such as bowel damage, surgeries, hospital admissions and disability, the investigators said.