Risankizumab for Refractory Perianal Fistulizing Crohn's Disease

Evaluation of Risankizumab for Refractory Perianal Fistulizing Crohn's Disease Using MRI-Based Remission Criteria: A Prospective, Single-Arm, Multicenter Study

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.

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

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).

Risankizumab 600 mg is administered intravenously over 4 weeks at 3 intervals (initial, 4 weeks, 8 weeks). Starting 4 weeks after completion of the induction therapy with risankizumab intravenous infusion, risankizumab 360 mg is administered subcutaneously at 8-week intervals. If efficacy diminishes 16 weeks or later after initiating maintenance therapy with the subcutaneous formulation of risankizumab (at visit 7, week 28 of this study), a single intravenous infusion of 1200 mg may be administered (rescue therapy). Eight weeks after the single 1200 mg intravenous infusion, administer risankizumab 360 mg subcutaneously.