Risankizumab for Fibrostenotic Crohn's Disease Treatment

Summary of the plan

Project Name: Prospective, Open-label, Randomized Controlled Study on the Treatment of Fibrostenosing Crohn's Disease with IL-23 Inhibitor Ruxolitinib

Research purpose Main purpose:

Evaluate the effectiveness of full-course (induction + maintenance) treatment with Lentilisinib in participants with fibrosing Crohn's disease who have failed standard therapy

Secondary objectives:

Evaluate the safety and tolerability of participants in the study of fibrosing Crohn's disease who have failed standard treatment after receiving the full course (induction + maintenance) of Lentilimab, and further observe the preliminary efficacy (radiographic remission rate, clinical response rate, surgery-free survival rate, progression-free survival, and reported outcomes, etc.) Study Subjects: The study subjects are research participants aged between 18 and 80 years, of either gender, with endoscopically and histologically confirmed fibrosing Crohn's disease. These participants have either failed standard treatment or have contraindications/intolerances, and plan to receive treatment with lecanicizumab or ustanumab for the first time. During the screening phase, all study participants must confirm through medical history inquiry and medical record review that they have never used lecanicizumab or ustanumab. If they have used other biologics, they must complete a preset washout period (those who have used any TNF-α monoclonal antibody must discontinue for ≥8 weeks) to ensure that the effects of previous medications have been eliminated. Study participants who have already begun treatment with lecanicizumab or ustanumab will not be included to avoid disrupting randomization, confounding baseline assessments, interfering with safety signals, and violating ethical fairness.

Sample size: 130 cases in each group, totaling 260 individuals Inclusion criteria: ① Age range of 18-80 years, with no gender restrictions

• Voluntarily sign the informed consent form ③ Endoscopic and histological confirmation of fibrosclerosing Crohn's disease, and meeting the following criteria:
• Symptoms suggestive of fibrostenosis, such as spasms, dietary restrictions or changes, postprandial vomiting, and abdominal pain;
• Endoscopy or imaging confirms new-onset fibrotic stenosis (not caused by previous dilation/stenting);
• The length of the stenosis is less than 10 cm, and there are a maximum of 2 stenoses in a single intestinal segment;
• Clinical manifestations of intestinal obstruction or sub-obstruction ⑤ Previous insufficient efficacy, intolerance, or contraindications to conventional or biological agents (such as azathioprine, 6-mercaptopurine, methotrexate, TNF-α monoclonal antibody, etc.) ⑥ Plan to receive treatment with lecaniclib or ustunumab for the first time ⑦ Have not previously used risankizumab or ustekinumab; if other biologics have been used, they have been discontinued for ≥ the specified washout period (TNF-α monoclonal antibody ≥ 8 weeks) Exclusion criteria: ① Age <18 or >80 years old
• Refusal or inability to sign the informed consent form
• No symptoms of Crohn's disease such as spasm, dietary restrictions or changes, vomiting after eating, and abdominal pain
• Stenosis has undergone stenting and/or dilation treatment (<1 year)
• Pregnancy, lactation, or preparation for pregnancy
• Endoscopy is not feasible or there are clinical conditions incompatible with endoscopy
• Combined with abscess, fistula, or active complex stenosis (not limited to the stenotic segment) ⑧ The length of the stenosis is ≥10 cm or the number of stenoses is >2 ⑨ Severe coagulation dysfunction (platelet count < 50,000; INR > 1.5) ⑩ Patients with end-organ failure, HIV-positive, uncontrolled infection, or a history of malignancy within the past 5 years ⑪ Has received or started treatment with durvalumab or ustekinumab ⑫ The researcher judges that there are other situations that make the participant unsuitable for participating in this clinical study Trial Design: This study is a multicenter, open-label, randomized, controlled trial. It intends to enroll 260 participants with fibrosing stricturing Crohn's disease who have failed standard treatment. Participants will be randomly assigned in a 1:1 ratio to the ustekinumab group (equivalent intravenous doses at weeks 0 and 8 during the induction phase, and 90 mg subcutaneously every 8 weeks during the maintenance phase) or the lecaniclib group (600 mg intravenously at weeks 0, 4, and 8 during the induction phase, and 360 mg subcutaneously every 8 weeks during the maintenance phase). The treatment duration is 52 weeks, followed by a 24-week follow-up period (approximately 6 months) after the last dose. The primary endpoint is the achievement rate of the clinical-radiological composite endpoint, which includes: 1. No radiological progression of strictures: Changes in the length or diameter of intestinal strictures assessed by MR/CTE compared to baseline are less than 20%; 2. Survival without clinical obstruction events: No intestinal obstruction requiring hospitalization or surgical/endoscopic intervention occurs. Secondary endpoints include safety (TEAEs, SAEs), radiological remission rate, clinical response rate, surgery-free survival rate, progression-free survival period, reported outcomes, etc. Biomarkers such as peripheral blood IL-23 and TIMP-1 will be dynamically monitored to explore predictive factors for efficacy.

Endpoint indicators: Primary endpoint:

Clinical-radiological composite endpoint, meeting all of the following criteria -

1. No progression of stenosis on imaging: The change in the length or diameter of intestinal stenosis as assessed by MR/CTE compared to baseline is less than 20%
2. Survival without clinical obstruction events: No intestinal obstruction requiring hospitalization or surgical/endoscopic intervention

Secondary endpoints:

1. Drug safety

• Incidence of treatment-emergent adverse events (TEAEs) during treatment (including infusion reactions, infections, liver dysfunction, etc.)
• Incidence of serious adverse events (SAEs) and adverse events leading to drug discontinuation (intestinal obstruction, perforation, severe infection, etc.) The incidence of abnormalities in vital signs, electrocardiogram, physical examination, laboratory tests, and changes compared to baseline

1. Drug efficacy 2.1 Objective remission indicators

• Imaging response rate (MR/CTE assessment of intestinal wall thickness reduction ≥25%)
• Clinical response rate (CDAI decrease ≥100 points or clinical remission) 2.2 Disease control indicators
• Surgery-free survival rate (the proportion of patients who are free from intestinal resection or stricture plasty at 1 year/2 years)
• Progression-free survival (PFS) 2.3 Functional improvement indicators Patient-Reported Outcomes (PROs): Improvement in Obstructive Symptom Score (OSS) ≥50%; Increase in IBD-Q Quality of Life Score ≥20 points

Exploratory endpoint:

Dynamic changes of serum/tissue fibrosis markers (TIMP-1, COL3A1, TGF-β)

• Imaging elasticity assessment (ultrasound/MR elastography) of intestinal wall fibrosis degree changes
• Gut microbiota profile and peripheral blood levels of cytokines related to the IL-23/IL-17 pathway Statistical analysis was conducted using SAS 9.4 (or later) software. Continuous variables are described using mean, standard deviation, median, minimum, and maximum values, while count and ordinal data are described using frequency and percentage.

The statistical analysis sets involved in this study are as follows:

Full Analysis Set (FAS): all study participants who were enrolled and received at least one treatment.

Safety Set (SS): individuals who have received at least one treatment and have post-treatment safety indicators The recorded research participants. Distribution of study participants Based on the description of the screened population, the screening and enrollment status of study participants will be summarized. For study participants who failed to be screened, the reasons for their failure will be summarized. Based on the enrolled population, the enrollment status and trial completion status of each dose group will be summarized. For study participants who withdrew from the study, the reasons for their withdrawal will be summarized.

Demographic data and baseline analysis FAS will be used for demographic analysis. The characteristics of study participants include baseline medical history and disease characteristics. Statistical descriptions will be provided for the demographic and baseline characteristics of study participants across different dosage groups, categorized by variable type.

Study on product exposure and analysis of concomitant medication/treatment Conduct analysis based on SS. Descriptive statistics of cell infusion frequency, dosage, and infusion duration.

Previous medications and concomitant medications were encoded using the WHO DRUG dictionary, summarized based on the second-level classification of ATC and PT, and the number of cases and proportions were calculated.

List a detailed inventory of previous medications/treatments and concurrent medications/treatments.

Effectiveness analysis Conduct analysis based on FAS. To calculate the stenosis-free progression rate, the Clopper-Pearson method was used to compute its 95% confidence interval (CI).

For survival rate without surgery, imaging response rate, and clinical response rate, the Kaplan-Meier method was used for analysis. The number of events, number of censored cases, and their percentages were listed, and the median time and its 95% confidence interval (CI) were calculated.

Other continuous indicators (changes in intestinal wall thickness, serum fibrosis marker levels) were analyzed using a mixed linear model.

Safety analysis Analyze based on SS. Adverse events are coded according to the ICH Medical Dictionary for Regulatory Activities (MedDRA).

Calculate the incidence of treatment-emergent adverse events (TEAE)/reactions, serious adverse events/reactions, and adverse events/reactions leading to early withdrawal.

Summarize the number of cases and instances of adverse events/reactions, serious adverse events/reactions, and adverse events/reactions leading to early withdrawal during the treatment period according to SOC, PT, and severity, and calculate the incidence rate.

List a detailed list of cases involving various adverse events/reactions, serious adverse events/reactions, and adverse events/reactions leading to early withdrawal.

List the cross-tabulation of laboratory tests, electrocardiogram, and physical examination before and after medication.

Descriptive statistics of laboratory tests, electrocardiogram, changes in vital signs from baseline, and actual measured values.

List a detailed list of abnormal values from laboratory tests, electrocardiogram, and physical examination.

Research period: October 2025 - October 2028