CALMMust knowCD · Treatment strategy
Effect of tight control management on Crohn's disease (CALM): a multicentre, randomised, controlled phase 3 trial
Colombel JF, et al.
Lancet 2017 · PMID 29096949 (PubMed, opens in a new tab) · doi 10.1016/S0140-6736(17)32641-7 (full paper, opens in a new tab)
| Endpoint | Tight control | Clinical management | Difference |
|---|---|---|---|
| Mucosal healing, no deep ulcers, Week 48 (primary endpoint) | 46% (56/122) | 30% (37/122) | Adjusted risk difference 16.1% (95% CI 3.9–28.3); P=0.010 |
Tight control escalated on calprotectin ≥250 µg/g or CRP ≥5 mg/L as well as symptoms; clinical management escalated on symptoms alone.
Source: Colombel 2017, abstract (intention to treat).
Structured abstract
BackgroundFaecal calprotectin and CRP were recommended for monitoring Crohn's disease, but whether using them to make treatment decisions improves outcomes was unknown.
MethodsOpen-label, randomised, controlled phase 3 trial (74 centres, 22 countries). 244 patients. Primary endpoint: Mucosal healing (CDEIS below 4) with no deep ulcers, 48 weeks after randomisation.
ResultsPrimary result. 46% (56/122) with tight control vs 30% (37/122) with clinical management; adjusted risk difference 16.1% (95% CI 3.9–28.3); P=0.010.
Take-homeEscalating therapy on biomarkers plus symptoms, rather than symptoms alone, gives more mucosal healing in early Crohn's disease.
| Patients | 244 |
|---|---|
| Population | Adults aged 18–75 with active endoscopic Crohn's disease (CDEIS above 6 with ulcers), CDAI 150–450 depending on prednisone dose, and no previous immunomodulator or biologic. Mean disease duration about 1 year. |
| Comparison | Tight control (symptoms plus faecal calprotectin and CRP) vs clinical management (symptoms only) |
| Drugs | adalimumab, azathioprine |
| Classes | Anti-TNF, Thiopurine |
| Published | Colombel JF, et al. Lancet 2017;390:2779–89. |
Key points
- Both arms escalated in the same steps: no treatment, adalimumab every other week, weekly adalimumab, then weekly adalimumab plus daily azathioprine.
- Tight-control escalation triggers: faecal calprotectin ≥250 µg/g, CRP ≥5 mg/L, CDAI ≥150, or prednisone use in the previous week.
- Clinical-management triggers after randomisation: CDAI decrease of less than 100 points from baseline or CDAI ≥200, or prednisone use in the previous week.
- Treatment-emergent adverse events: 86% (105/122) with tight control vs 82% (100/122) with clinical management; no treatment-related deaths.
- Discontinuation was similar (26% vs 24%), mostly because of adverse events.
- In CALM follow-up (median 3 years, 122 patients), deep remission at the end of the trial was associated with fewer major adverse outcomes (adjusted HR 0.19, 95% CI 0.07–0.31) regardless of study arm (PMID 32224129).
Limitations
- Open-label; a single drug pathway (adalimumab, then azathioprine).
- Early, biologic-naive disease; applicability to long-standing or biologic-experienced disease is uncertain.
- Primary endpoint at 48 weeks; the long-term benefit comes from observational follow-up, not a randomised comparison.
- Industry funded (AbbVie).
Commentary
CALM is the trial behind treat-to-target in Crohn’s disease. It showed that acting on calprotectin and CRP, even when symptoms look acceptable, leads to more mucosal healing. It underpins the STRIDE-II targets and the routine use of calprotectin to decide when to escalate.
Not every treat-to-target design has worked: STARDUST found no benefit from an endoscopy-driven algorithm with ustekinumab. The common lesson is that the benefit comes from timely escalation to an effective therapy in early disease.
Journal club
Design
Open-label, randomised, controlled phase 3 trial (74 centres, 22 countries). 244 patients.
Primary result. 46% (56/122) with tight control vs 30% (37/122) with clinical management; adjusted risk difference 16.1% (95% CI 3.9–28.3); P=0.010.
Validity and applicability
- Open-label; a single drug pathway (adalimumab, then azathioprine).
- Early, biologic-naive disease; applicability to long-standing or biologic-experienced disease is uncertain.
- Primary endpoint at 48 weeks; the long-term benefit comes from observational follow-up, not a randomised comparison.
- Industry funded (AbbVie).
Where it sits now
Escalating therapy on biomarkers plus symptoms, rather than symptoms alone, gives more mucosal healing in early Crohn's disease.
- STARDUST (2022): With ustekinumab, an endoscopy-driven treat-to-target algorithm did not improve 48-week endoscopic response over clinically driven care; treat-to-target only helps if escalation has something to add.
- PROFILE (2024): In newly diagnosed active Crohn's disease, starting infliximab plus an immunomodulator straight away gives far better 1-year and 5-year outcomes than step-up care.
- STRIDENT (2022): Symptomatic Crohn's strictures with active inflammation often respond to adalimumab; intensifying therapy did not significantly improve symptoms; secondary results on treatment failure and MRI stricture appearance favoured it but are hypothesis-generating.
- REACT (2015): Early combined immunosuppression did not improve 1-year symptom remission but lowered 2-year surgery, admissions and complications, supporting early effective therapy.
Questions for discussion
- Both arms used the same drugs; only the trigger for escalation differed. What exactly did CALM test?
- Patients had early, biologic-naive disease. Would tight control help as much in long-standing or biologic-experienced disease?
- How would you build calprotectin and CRP triggers into follow-up in your own clinic?