ADMIRE-CDPerianal CD · Other
Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn's disease: a phase 3 randomised, double-blind controlled trial
Panés J, et al.
Lancet 2016 · PMID 27477896 (PubMed, opens in a new tab) · doi 10.1016/S0140-6736(16)31203-X (full paper, opens in a new tab)
| Outcome | Darvadstrocel | Placebo | Estimate (confidence interval) | P |
|---|---|---|---|---|
| Intention to treat, Primary analysis (primary) | 50% (53/107) | 34% (36/105) | +15.2 (97.5% CI 0.2–30.3) | P=0.024 |
| Modified intention to treat | 51% (53/103) | 36% (36/101) | +15.8 (97.5% CI 0.5–31.2) | P=0.021 |
The lower bound sits just above zero, and the larger ADMIRE CD II trial did not reproduce the effect.
Source: Panés 2016, abstract (intention-to-treat and modified intention-to-treat populations).
Structured abstract
BackgroundComplex perianal fistulas in Crohn's disease often persist despite drainage, antibiotics and anti-TNF therapy; allogeneic adipose-derived stem cells offered a new local treatment.
MethodsPhase 3, randomised, double-blind, parallel-group, placebo-controlled trial (49 hospitals, seven European countries and Israel); unmasked surgeon, masked gastroenterologist and radiologist. 212 patients. Primary endpoint: Combined remission at week 24: clinical closure of all treated external openings draining at baseline, plus no collections larger than 2 cm on masked central MRI.
ResultsPrimary result. Intention to treat: 50% (53/107) vs 34% (36/105); difference 15.2% (97.5% CI 0.2–30.3); P=0.024.
Take-homeADMIRE-CD suggested benefit from stem-cell injection for complex perianal fistulas, but the larger ADMIRE CD II was negative and the product has been withdrawn in the EU and was never approved in Canada.
| Patients | 212 |
|---|---|
| Population | Adults with Crohn's disease and treatment-refractory, draining complex perianal fistulas that had not responded to conventional and/or biologic therapy. |
| Comparison | Single intralesional injection of darvadstrocel (120 million allogeneic adipose-derived stem cells) vs 24 mL saline |
| Drugs | darvadstrocel (Cx601) |
| Classes | Cell therapy |
| Published | Panés J, et al. Lancet 2016;388:1281–90. |
Key points
- Modified intention to treat: 51% (53/103) vs 36% (36/101); difference 15.8% (97.5% CI 0.5–31.2); P=0.021.
- Treatment-related adverse events: 17% (18/103) darvadstrocel vs 29% (30/103) placebo; most common were anal abscess (6 vs 9) and proctalgia (5 vs 9).
- The high placebo response (34%) shows how much surgical preparation and concomitant therapy contribute to fistula healing.
- Not confirmed by the larger ADMIRE CD II trial (48.8% vs 46.3%; P=0.571). The EU marketing authorisation was withdrawn on 13 December 2024 at the company's request, and darvadstrocel is not listed in Health Canada's Drug Product Database.
Limitations
- Margin of benefit was small, with a lower 97.5% CI bound close to zero.
- Primary endpoint at 24 weeks only.
- Industry funded (TiGenix).
Commentary
ADMIRE-CD is included for historical context because it is still widely cited. Fellows should know that the confirmatory phase 3 trial, ADMIRE CD II, did not reproduce the result.
For complex perianal Crohn’s disease, standard care remains examination under anaesthesia with drainage and seton placement, an anti-TNF (infliximab has the most evidence), and consideration of surgical closure in suitable patients (PISA-II).
Journal club
Design
Phase 3, randomised, double-blind, parallel-group, placebo-controlled trial (49 hospitals, seven European countries and Israel); unmasked surgeon, masked gastroenterologist and radiologist. 212 patients.
Primary result. Intention to treat: 50% (53/107) vs 34% (36/105); difference 15.2% (97.5% CI 0.2–30.3); P=0.024.
Validity and applicability
- Margin of benefit was small, with a lower 97.5% CI bound close to zero.
- Primary endpoint at 24 weeks only.
- Industry funded (TiGenix).
Where it sits now
ADMIRE-CD suggested benefit from stem-cell injection for complex perianal fistulas, but the larger ADMIRE CD II was negative and the product has been withdrawn in the EU and was never approved in Canada.
- ADMIRE CD II (2026): In the larger confirmatory trial, darvadstrocel was no better than placebo for complex perianal fistulas when both arms had surgical preparation.
- PISA-II (2022): For a high perianal fistula with a single internal opening, surgical closure after seton and short anti-TNF gives more MRI healing and fewer reinterventions than anti-TNF alone, and MRI healing predicts durable closure.
Questions for discussion
- Why might a trial use a 97.5% confidence interval rather than a 95% one, and how does that change how you read a lower bound of 0.2?
- The surgeon was unmasked and placebo was saline. What biases could that introduce in a fistula-closure endpoint?
- The confirmatory trial was negative and the EU authorisation was withdrawn. How much should a single positive phase 3 trial change practice?