Risankizumab for Refractory Perianal Fistulizing Crohn's Disease

PFCD remains a debilitating condition with high morbidity and severely impaired QOL, and an optimal treatment strategy has yet to be established. While combined seton drainage and pharmacotherapy have achieved clinical remission in several studies, the definition of "remission" varies, leading to difficulties in standardizing outcomes. Consequently, there is growing consensus that combining clinical and radiologic (particularly MRI-based) assessments provides a more comprehensive and reliable evaluation of treatment efficacy in PFCD. Ongoing trials of upadacitinib and guselkumab in PFCD are adopting composite endpoints combining clinical and MRI remission. Risankizumab, a selective interleukin-23 (IL-23) inhibitor, has shown favorable anti-inflammatory effects in CD; however, no prospective studies have yet evaluated its efficacy for PFCD using objective imaging modalities such as MRI.

The present study is the first prospective investigation to comprehensively assess the therapeutic efficacy of risankizumab for PFCD through combined clinical and MRI evaluations. This research aims to contribute to establishing new therapeutic strategies and standardizing outcome assessments for PFCD. The findings are expected to clarify the role of IL-23 inhibitors in PFCD management and provide scientific evidence supporting the development of future international treatment guidelines.

• Risankizumab (Drug): Risankizumab (Skyrizi®, AbbVie Inc.) is a humanized IgG1 monoclonal antibody targeting the p19 subunit of interleukin-23 (IL-23). For Crohn's disease, participants receive 600 mg intravenously (IV) at Weeks 0, 4, and 8 as induction therapy, followed by 360 mg subcutaneously (SC) at Week 12 and every 8 weeks thereafter as maintenance therapy. If efficacy diminishes 16 weeks or later after initiating maintenance therapy with the subcutaneous formulation of risankizumab, a single intravenous infusion of 1200 mg may be administered (rescue therapy).

Primary outcomes

• The proportion of participants achieving combined fistula remission at Week 28 [at Week 28]: To confirm the efficacy of risankizumab, a combined evaluation of clinical symptoms and objective MRI findings will be used.

Secondary outcomes

• Proportion of participants achieving combined fistula remission at Week 52 [at Week 52]
• Proportion of participants achieving clinical fistula improvement at Week 28 (Closure of ≥1 draining fistula compared to baseline) [at Week 28]
• Proportion of participants achieving clinical fistula remission at Week 28 (Closure of all draining fistulas compared to baseline) [at Week 28]
• Proportion of participants achieving clinical fistula improvement at Week 52 (Closure of ≥1 draining fistula compared to baseline) [at Week 52]
• Proportion of participants achieving clinical fistula remission at Week 52 (Closure of all draining fistulas compared to baseline) [at Week 52]
• Proportion of participants achieving MRI fistula remission at Week 28 *Defined as the absence of fluid collection exceeding 2 cm in at least two of three dimensions confirmed by central MRI [at Week 28]
• Proportion of participants achieving MRI fistula remission at Week 52 *Defined as the absence of fluid collection exceeding 2 cm in at least two of three dimensions confirmed by central MRI [at Week 52]
• Change from baseline in PDAI score at Week 28 [at Week 28]: Perianal Crohn's Disease Activity Index (PDAI). Minimum score 0, maximum score 20; higher scores mean a worse outcome.
• Change from baseline in PDAI score at Week 52 [at Week 52]: Perianal Crohn's Disease Activity Index (PDAI). Minimum score 0, maximum score 20; higher scores mean a worse outcome.
• Change from baseline in SIBDQ score at Week 28 [at Week 28]: Short Inflammatory Bowel Disease Questionnaire (SIBDQ). Minimum score 10, maximum score 70; higher scores mean a better outcome.
• Change from baseline in SIBDQ score at Week 52 [at Week 52]: Short Inflammatory Bowel Disease Questionnaire (SIBDQ). Minimum score 10, maximum score 70; higher scores mean a better outcome.
• Change from baseline in Van Assche score at Week 28 [at Week 28]: Van Assche score. Minimum score 0, maximum score 22; higher scores mean a worse outcome.
• Change from baseline in Van Assche score at Week 52 [at Week 52]: Van Assche score. Minimum score 0, maximum score 22; higher scores mean a worse outcome.
• Change from baseline in MAGNIFI-CD score at Week 28 [at Week 28]: Magnetic Resonance Novel Index for Fistula Imaging in Crohn's Disease (MAGNIFI-CD). Minimum score 0, maximum score 25; higher scores mean a worse outcome.
• Change from baseline in MAGNIFI-CD score at Week 52 [at Week 52]: Magnetic Resonance Novel Index for Fistula Imaging in Crohn's Disease (MAGNIFI-CD). Minimum score 0, maximum score 25; higher scores mean a worse outcome.
• Change from baseline in CDAI score at Week 28 [at Week 28]: Crohn's Disease Activity Index (CDAI). Minimum score 0, maximum score 600; higher scores mean a worse outcome.
• Change from baseline in CDAI score at Week 52 [at Week 52]: Crohn's Disease Activity Index (CDAI). Minimum score 0, maximum score 600; higher scores mean a worse outcome.
• Proportion of participants achieving combined fistula remission at Week 28 (Investigator assessment at site) [at Week 28]
• Proportion of participants achieving MRI fistula remission at Week 28 (Investigator assessment at site) [at Week 28]

Other outcomes

• Change from baseline in fecal calprotectin (up to Week 52) [up to Week 52]: Fecal calprotectin concentration (unit of measure: micrograms per gram of stool, µg/g), measured by central laboratory assay. This outcome measure reports a laboratory analyte concentration rather than a score on a scale; a defined scale minimum/maximum therefore does not apply. Higher concentrations indicate greater disease activity (a worse outcome).
• Change from baseline in LRG (leucine-rich alpha-2 glycoprotein) (up to Week 52) [up to Week 52]: Serum leucine-rich alpha-2 glycoprotein (LRG) concentration (unit of measure: micrograms per milliliter, µg/mL), measured by central laboratory assay. This outcome measure reports a laboratory analyte concentration rather than a score on a scale; a defined scale minimum/maximum therefore does not apply. Higher concentrations indicate greater disease activity (a worse outcome).
• Incidence proportion of serious adverse events / adverse reactions (up to Week 52) [up to Week 52]
• Incidence proportion of adverse events / adverse reactions (up to Week 52) [up to Week 52]

Sex: All, ages: 15 Years to any

Inclusion Criteria:

1. 15 years of age or older
2. Patients with an MRI-confirmed perianal fistula due to Crohn's disease
3. Patients with a draining anal fistula (maximum of 2 internal openings and maximum of 3 external openings) persisting for at least 2 weeks
4. Patients who have experienced inadequate response, diminished response, or intolerance to one or more of the following treatments in the past:

   ① Antibiotics (ciprofloxacin or metronidazole): Treatment lasting one month or longer.

   ② Immunomodulators (azathioprine, 6-mercaptopurine, or methotrexate): Treatment for 3 months or longer.

   ③ Advanced therapies (infliximab, adalimumab, vedolizumab, ustekinumab, and upadacitinib): Standard therapy administered for 14 weeks or longer as induction or maintenance therapy.
5. Patients who can agree to removal of the perianal seton by week 20 (week 20 ± 1 week) of administration, if patients already have setons inserted.
6. Patients with draining fistulas that were drained at least 6 weeks prior to enrollment.
7. Patients who have received a sufficient explanation regarding participation in this study, understood it fully, and provided their voluntary written consent, or patients whose legal representative received a sufficient explanation regarding participation in this study, understood it fully, and provided their voluntary written assent, if participating hospital/clinic requires.

Exclusion Criteria:

1. Patients with a rectovaginal fistula at baseline (excluding past rectovaginal fistulas)
2. Patients with severe rectal and/or anal stricture and/or severe proctitis (defined as the presence of large ulcers exceeding 0.5 cm in the rectum)
3. Patients with abscesses or fluid collections exceeding 2 cm
4. Patients for whom MRI is contraindicated
5. Patients with a history of risankizumab, mirikizumab, or guselkumab administration
6. Patients who are refractory to three or more prior lines of advanced therapy
7. Patients who are intolerant to two or more prior lines of advanced therapy
8. Patients previously treated with darvadstrocel
9. Patients with a colostomy or ileostomy
10. Patients with disease activity (CDAI) > 400
11. Patients receiving systemic steroids
12. Patients requiring new treatment with immunomodulators or advanced therapies during the screening period
13. Patients undergoing cytapheresis
14. Patients with a history of malignancy (excluding carcinoma in situ)
15. Patients with concomitant uncontrolled liver disease, hematologic disease, gastrointestinal disease (excluding Crohn's disease), endocrine disease, pulmonary disease, cardiac disease, neurological disease, psychiatric disease, brain disease, or active infection
16. Patients who underwent major surgery or suffered severe trauma within the past 6 months
17. Patients who are breastfeeding, pregnant, or may be pregnant, or who plan to become pregnant during the study period
18. Patients who showed persistent positivity for HBsAg and HBV-PCR, or seropositivity for HCV and quantitative HCV-PCR within 6 months prior to the start of the screening period
19. Patients who received a live vaccine within 4 weeks prior to the start of risankizumab administration
20. Patients with active tuberculosis
21. Other patients deemed inappropriate for trial participation by the principal/ sub-investigator responsible

• Yuki Horio, MD, PhD, Principal investigator, Hyogo Medical University