FORTIFYCD · Induction and maintenance
Risankizumab as maintenance therapy for moderately to severely active Crohn's disease: results from the multicentre, randomised, double-blind, placebo-controlled, withdrawal phase 3 FORTIFY maintenance trial
Ferrante M, et al.
Lancet 2022 · PMID 35644155 (PubMed, opens in a new tab) · doi 10.1016/S0140-6736(22)00466-4 (full paper, opens in a new tab)
| Endpoint | 180 mg | 360 mg | Withdrawal | Difference |
|---|---|---|---|---|
| CDAI clinical remission, Week 52 · co-primary in the US protocol (primary endpoint) | 55% (87/157) | 52% (74/141) | 41% (67/164) | Difference vs withdrawal: 180 mg 15% (95% CI 5–24); 360 mg 15% (5–24) |
| Endoscopic response, Week 52 (primary endpoint) | 47% (74/157) | 47% (66/141) | 22% (36/164) | Difference vs withdrawal: 180 mg 26% (95% CI 17–35); 360 mg 28% (19–37) |
| Stool frequency and abdominal pain remission, Week 52 · co-primary outside the US (primary endpoint) | not in this comparison | 52% (73/141) | 40% (65/164) | 360 mg: difference 15% (95% CI 5–25); 180 mg: not significant (P=0.124) |
The withdrawal arm had IV induction, so its 41% remission partly reflects carry-over; endoscopic response separates the arms more clearly.
Source: Ferrante 2022, abstract. Differences are adjusted, each dose vs withdrawal. The abstract gives no 180 mg rate for stool frequency and abdominal pain remission.
Structured abstract
BackgroundIV risankizumab induced remission in ADVANCE and MOTIVATE; whether subcutaneous maintenance, and at which dose, would keep responders well was unknown.
MethodsPhase 3, multicentre, randomised, double-blind, placebo-controlled withdrawal maintenance trial (273 centres, 44 countries). 542 patients. Primary endpoint: Co-primary at week 52: clinical remission (CDAI in the US protocol; stool frequency and abdominal pain score outside the US) and endoscopic response.
ResultsPrimary result. 360 mg vs placebo: CDAI remission 52% (74/141) vs 41% (67/164), adjusted difference 15% (95% CI 5–24); endoscopic response 47% (66/141) vs 22% (36/164), adjusted difference 28% (19–37).
Take-homeSC risankizumab maintains remission and endoscopic response in Crohn's disease, with 360 mg every 8 weeks giving the most consistent benefit.
| Patients | 542 |
|---|---|
| Population | Patients aged 16–80 with moderately to severely active Crohn's disease who had a clinical response to IV risankizumab in ADVANCE or MOTIVATE. |
| Comparison | Risankizumab 360 mg or 180 mg SC every 8 weeks vs withdrawal to SC placebo |
| Drugs | risankizumab |
| Classes | Anti-IL-23 p19 |
| Published | Ferrante M, et al. Lancet 2022;399:2031–46. |
Key points
- Stool frequency and abdominal pain remission with 360 mg: 52% (73/141) vs 40% (65/164), adjusted difference 15% (5–25).
- 180 mg: CDAI remission 55% (87/157), adjusted difference 15% (5–24); endoscopic response 47% (74/157), adjusted difference 26% (17–35); stool frequency and abdominal pain remission not significant (P=0.124).
- More stringent endoscopic and composite endpoints and biomarkers showed a dose–response in favour of 360 mg.
- The placebo arm had received IV risankizumab induction, so its relatively high remission rate partly reflects carry-over.
- Adverse event rates were similar among groups.
Limitations
- Withdrawal design in induction responders only.
- 52-week maintenance; longer-term data come from open-label extension.
- Industry funded (AbbVie).
Commentary
FORTIFY tested two SC maintenance doses after IV risankizumab induction in ADVANCE and MOTIVATE. The 180 mg dose met the CDAI remission and endoscopic co-primary endpoints but not stool frequency and abdominal pain remission, and stringent endoscopic outcomes favoured 360 mg.
Journal club
Design
Phase 3, multicentre, randomised, double-blind, placebo-controlled withdrawal maintenance trial (273 centres, 44 countries). 542 patients.
Primary result. 360 mg vs placebo: CDAI remission 52% (74/141) vs 41% (67/164), adjusted difference 15% (95% CI 5–24); endoscopic response 47% (66/141) vs 22% (36/164), adjusted difference 28% (19–37).
Validity and applicability
- Withdrawal design in induction responders only.
- 52-week maintenance; longer-term data come from open-label extension.
- Industry funded (AbbVie).
Where it sits now
SC risankizumab maintains remission and endoscopic response in Crohn's disease, with 360 mg every 8 weeks giving the most consistent benefit.
- ADVANCE and MOTIVATE (2022): IV risankizumab induction works in both biologic-naive and biologic-experienced Crohn's disease, with endoscopic response rates well above placebo.
- RELIEVE UCCD (CD) (2026): Duvakitug, an anti-TL1A antibody, gave a dose-related endoscopic response signal in Crohn's disease in phase 2b; phase 3 trials will decide whether TL1A becomes a new Crohn's disease target.
- DIVERSITY (2025): Filgotinib failed its week-10 induction endpoints in Crohn's disease, unlike upadacitinib in its own phase 3 trials, so JAK inhibitors should not be assumed to work equally well in Crohn's disease.
- GALAXI-2 and GALAXI-3 (2025): IV guselkumab induction followed by SC maintenance is effective in Crohn's disease and outperformed ustekinumab at week 48 on several endpoints.
Questions for discussion
- The withdrawal arm had 41% CDAI remission at week 52. Why is a withdrawal arm not a true placebo, and how does it shrink the difference?
- Both doses met CDAI remission and endoscopic response, but stringent endoscopic outcomes favoured 360 mg. Which patients would you start on 360 mg?
- Why might the CDAI and the stool frequency and abdominal pain definitions of remission give different answers in the same trial?