PAILOTCD · Biosimilars and dosing
Proactive Monitoring of Adalimumab Trough Concentration Associated With Increased Clinical Remission in Children With Crohn's Disease Compared With Reactive Monitoring
Assa A, et al.
Gastroenterology 2019 · PMID 31194979 (PubMed, opens in a new tab) · doi 10.1053/j.gastro.2019.06.003 (full paper, opens in a new tab)
| Endpoint | Proactive | Reactive | Difference |
|---|---|---|---|
| Sustained steroid-free remission, At every visit, weeks 8–72 (primary endpoint) | 82% (31/38) | 48% (19/40) | P=0.002 |
| Sustained composite remission, Steroid-free remission, CRP ≤0.5 mg/dL and calprotectin ≤150 µg/g | 42% (16/38) | 12% (5/40) | P=0.003 |
| Adalimumab intensified, By week 72 · a process measure, not an outcome | 87% (33/38) | 60% (24/40) | P=0.001 |
The proactive arm was intensified far more often, so the benefit may reflect higher dosing as much as the monitoring itself.
Source: Assa 2019, abstract.
Structured abstract
BackgroundMeasuring adalimumab levels only after loss of response (reactive monitoring) was usual practice. Whether scheduled trough checks with dose adjustment (proactive monitoring) improve outcomes was unproven in children.
MethodsNon-blinded randomised controlled trial (paediatric gastroenterology units in Israel). 78 patients. Primary endpoint: Sustained corticosteroid-free clinical remission at all visits from week 8 to week 72.
ResultsPrimary result. 82% (31/38) with proactive monitoring vs 48% (19/40) with reactive monitoring; P=0.002.
Take-homeIn children on adalimumab, proactive trough monitoring with dose adjustment to 5 µg/mL kept far more patients in steroid-free remission than reactive testing.
| Patients | 78 |
|---|---|
| Population | Children aged 6–18 with Crohn's disease, naive to biologics, who had responded to adalimumab induction. Mean age 14.3 years; 29% female. |
| Comparison | Proactive vs reactive adalimumab trough monitoring (target trough 5 µg/mL) |
| Drugs | adalimumab |
| Classes | Anti-TNF |
| Published | Assa A, et al. Gastroenterology 2019;157:985–96. |
Key points
- Proactive: troughs at weeks 4 and 8, then every 8 weeks to week 72. Reactive: levels given to physicians only after loss of response.
- Composite of sustained steroid-free remission, CRP ≤0.5 mg/dL and faecal calprotectin ≤150 µg/g: 42% vs 12% (P=0.003).
- Adalimumab intensification by week 72: 87% proactive vs 60% reactive (P=0.001).
- Post hoc: combination with an immunomodulator was not more effective than adalimumab monotherapy (sustained steroid-free remission 73% vs 63%; P=0.35) (PMID 31793630).
Limitations
- Small, open-label, single-country paediatric trial.
- Most proactive patients were intensified, so the benefit may reflect higher dosing as much as monitoring.
- Adult trials of proactive monitoring (for example SERENE-CD) have not shown the same benefit.
Commentary
PAILOT is the strongest positive randomised trial of proactive therapeutic drug monitoring in Crohn’s disease. Adult data are less convincing: in SERENE-CD, TDM-guided maintenance was no better than clinically adjusted dosing. Current practice in adults favours reactive drug-level testing at loss of response, with proactive monitoring considered in selected patients.
Later evidence: in adults on maintenance infliximab for IBD and other immune-mediated diseases, NOR-DRUM B found that proactive TDM improved sustained disease control (73.6% vs 55.9%). A Korean paediatric trial (112 biologic-naive children responding to infliximab induction) found more endoscopic healing at week 54 with proactive TDM than with clinically based dosing: 80.0% (40/50) vs 57.1% (28/49); P=0.025 (PMID 40378994).
Journal club
Design
Non-blinded randomised controlled trial (paediatric gastroenterology units in Israel). 78 patients.
Primary result. 82% (31/38) with proactive monitoring vs 48% (19/40) with reactive monitoring; P=0.002.
Validity and applicability
- Small, open-label, single-country paediatric trial.
- Most proactive patients were intensified, so the benefit may reflect higher dosing as much as monitoring.
- Adult trials of proactive monitoring (for example SERENE-CD) have not shown the same benefit.
Where it sits now
In children on adalimumab, proactive trough monitoring with dose adjustment to 5 µg/mL kept far more patients in steroid-free remission than reactive testing.
- SERENE-CD (2022): Extra-intensive adalimumab induction does not beat the standard 160/80 mg regimen, and proactive TDM-guided maintenance was no better than dosing adjusted to symptoms and CRP.
- NOR-DRUM B (2021): In patients on maintenance infliximab, scheduled drug-level monitoring with a dosing algorithm kept more patients in sustained disease control over a year than standard dosing without levels.
- REScUE (2026): After secondary loss of response to ustekinumab, IV reinduction plus every-4-week dosing is no better than reinduction plus every-8-week dosing, and few patients regain remission either way.
- LIBERTY-CD (2024): After IV infliximab induction, subcutaneous infliximab 120 mg every 2 weeks maintains remission and endoscopic response in Crohn's disease, an option for patients who prefer injections to infusions.
Questions for discussion
- Most proactive patients had their dose intensified. Is this a trial of monitoring or a trial of higher dosing?
- Adult trials such as SERENE-CD did not show the same benefit. What differences in population, drug or design might explain that?
- Would you adopt proactive adalimumab monitoring in adults on the strength of this trial? Why or why not?