Evaluation of Risankizumab-800CW Safety and Optimal Imaging Dose in Inflammatory Bowel Disease Using Fluorescence Molecular Endoscopy

The primary objective of this study is to evaluate the **safety** of risankizumab-800CW in patients with Inflammatory Bowel Disease (IBD). This will be achieved by monitoring vital signs, the injection site, and assessing potential tracer-related severe adverse events (SAEs) and suspected unexpected serious adverse reactions (SUSARs). Additionally, the study aims to investigate the feasibility of using fluorescence molecular endoscopy (FME) and ex vivo fluorescence molecular imaging (FMI) to detect risankizumab-800CW signals and determine the most optimal imaging dose. These objectives are clinically relevant as they aim to ensure the safe application of risankizumab-800CW and optimize its use in visualizing drug targeting in IBD, potentially improving therapeutic outcomes.

Secondary objectives include:

• Investigating a potential correlation between in vivo and ex vivo fluorescence signal intensities and target saturation with clinical response/remission after 14 weeks of risankizumab therapy in IBD patients.
• Quantifying the fluorescence signals of the tracer in vivo using single-fiber reflectance/single-fiber fluorescence (MDSFR/SFF) spectroscopy and correlating these measurements with tracer dose, in vivo fluorescence intensities, and inflammation severity.
• Correlating ex vivo fluorescence signals with inflammation severity and tracer dose based on histopathological examination of obtained biopsies.
• Assessing tracer stability, distribution, and concentration, and identifying the composition of immune cells ex vivo to gain insights into risankizumab mucosal target cells.

The clinical trial involves participants diagnosed with **Inflammatory Bowel Disease (IBD)**, specifically those with either Ulcerative Colitis (UC) or Crohn's Disease (CD). The study population includes both male and female subjects, aged 18 years and older, who are eligible for risankizumab therapy. Participants must have clinically active disease, defined by specific scoring indices or a fecal calprotectin level greater than 60 µg/g. The trial does not include vulnerable populations. Participants are required to provide written informed consent and have a clinical indication for an endoscopic procedure. Female participants of childbearing potential must have a negative pregnancy test. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed to evaluate the **safety** and feasibility of using **risankizumab-800CW** in patients with **Inflammatory Bowel Disease (IBD)**. This is a Phase I/II intervention trial, which is not classified as low intervention. The study employs a randomized, double-blind, controlled design to ensure the reliability and validity of the results. The trial is expected to commence recruitment on October 21, 2024, and conclude by October 20, 2025, with the overall duration spanning approximately one year.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as an established IBD diagnosis, active disease status, and eligibility for risankizumab therapy. The inclusion visit will also involve obtaining written informed consent and conducting a pregnancy test for females of childbearing potential. Following the screening, participants will receive the investigational product, **Skyrizi 600 mg concentrate for solution for infusion**, administered via intravenous infusion.

Subsequent follow-up visits will be scheduled to monitor vital signs, assess the injection site, and evaluate any potential tracer-related severe adverse events (SAEs) or adverse events (AEs). The primary endpoints include monitoring vital signs before and after tracer administration and visual evaluation during fluorescence molecular endoscopy (FME). Secondary endpoints involve the analysis of in vivo fluorescence images and quantification of fluorescence signals, with comparisons to endoscopic and histologic inflammation scores.

The end-of-study visit will mark the conclusion of the participant's involvement, during which final assessments will be conducted to ensure participant safety and gather comprehensive data on the investigational product's effects. The expected length of participant involvement is contingent upon the trial's schedule and individual response to treatment. Conditions that may lead to early termination from the study include the occurrence of severe adverse events or withdrawal of consent by the participant.

The clinical trial involves the administration of **Skyrizi 600 mg concentrate for solution for infusion**, which contains the active substance **risankizumab**. This experimental medication is formulated as a concentrate for solution for infusion and is administered via **intravenous infusion**. The primary objective of the trial is to evaluate the safety and feasibility of risankizumab-800CW in visualizing drug targeting in patients with **Inflammatory Bowel Disease**. The pharmaceutical form is a solution for infusion, and the product is not a pediatric formulation. The trial aims to monitor vital signs, the injection site, and evaluate possible tracer-related severe adverse events (SAEs) and suspected unexpected serious adverse reactions (SUSARs).

Risankizumab, the active substance in Skyrizi, is a protein-based therapeutic agent. It is labeled with IRDye 800CW for the purpose of this study, which involves the use of fluorescence molecular endoscopy (FME) and ex vivo fluorescence molecular imaging (FMI) to detect risankizumab-800CW signals. The trial seeks to determine the most optimal imaging dose for this purpose. The product is manufactured by **ABBVIE DEUTSCHLAND GMBH & CO. KG** and is authorized for use in the European Union under the marketing authorization number EU/1/19/1361/004. The trial does not involve any comparator treatments, placebos, or standard-of-care therapies, focusing solely on the investigational product.

Efficacy in this clinical trial will be assessed through a combination of primary and secondary endpoints. The primary endpoints include monitoring vital signs before and after tracer administration and evaluating possible severe adverse events (SAEs) and adverse events (AEs). Additionally, visual evaluation during fluorescence molecular endoscopy (FME) will be conducted to determine the presence of visible signals, calculate target-to-background ratio (TBR) and contrast-to-noise ratio (CNR), and measure mean fluorescence intensities (MFIs) of biopsies. Measurements such as MDSFR/SFF and fluorescence/light sheet microscopy will also be utilized.

Secondary endpoints involve the analysis of in vivo fluorescence images and the quantification of fluorescence signals in real-time using spectroscopy. These results will be compared to endoscopic and histologic inflammation scores. The fluorescence signal in formalin-fixed paraffin-embedded (FFPE) biopsies of mucosal tissue will be semi-quantified and compared to in vivo results from the same bowel section. For patients undergoing treatment, correlations between in vivo and ex vivo quantified fluorescence and endoscopic/histologic response to **risankizumab** will be explored. Fluorescence signals will be quantified by spectroscopy during endoscopy across all FME-inspected bowel segments, with comparisons made within all dose groups to determine the optimal dose. Spectroscopy measurements will be correlated with fluorescence intensities visualized using the FME camera and compared with inflammation severity to assess **risankizumab** distribution in inflamed versus non-inflamed tissue.

In vivo and ex vivo spectroscopy measurements will be plotted against tracer dose and endoscopic/histopathological inflammation scores. The endoscopic inflammation score will be evaluated by a gastroenterologist during endoscopy, while the histopathological score will be determined by an expert pathologist using H&E staining of FFPE biopsies. A positive correlation is hypothesized between the fluorescence signal and both the tracer dose and inflammation scores. SDS-PAGE with protein extracts of biopsies will be used to confirm that the fluorescence signal originates from the intact tracer. Additionally, 3D ex vivo fluorescence analysis on biopsies will assess the concentration of **risankizumab-800CW** in intact biopsies. Fluorescence microscopy will visualize the tracer signal and perform additional immunofluorescence staining to identify the immune cell type of **risankizumab-800CW** positive cells.