Efficacy and Safety of Risankizumab as Maintenance Therapy in Moderately to Severely Active Ulcerative Colitis: A Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this study is to evaluate the **efficacy** and **safety** of **risankizumab** as a maintenance therapy in subjects with moderately to severely active **ulcerative colitis** who have responded to induction treatment. This is assessed through three sub-studies:

• Sub-study 1 focuses on comparing risankizumab versus placebo.
• Sub-study 2 examines two different dosing regimens for risankizumab, utilizing therapeutic drug monitoring versus clinical assessment for dose escalation.
• Sub-study 3 aims to evaluate the long-term safety of risankizumab in subjects who completed the previous sub-studies or responded to induction treatment but could not undergo final endoscopy due to the Covid-19 pandemic or geopolitical conflicts.

Additionally, the Continued Treatment Extension (CTE) aims to provide continuous treatment for Sub-study 3 completers, ensuring uninterrupted care until the treatment is commercially available or accessible locally. This study is clinically relevant as it seeks to establish the long-term safety and efficacy of risankizumab, potentially offering a sustained therapeutic option for patients with ulcerative colitis.

The clinical trial involves a total of **611 participants** diagnosed with **ulcerative colitis**, focusing on those with moderately to severely active conditions. The study population includes both male and female subjects, with an age range encompassing adolescents, adults, and the elderly. Participants were selected based on their prior involvement in Study M16-067, specifically those who achieved a clinical response to induction treatment. The trial does not include a vulnerable population. Lifestyle factors such as diet, physical activity, or habits are not specified in the available data. The selection criteria emphasize the completion of Study M16-067, including the final endoscopy, unless impacted by the COVID-19 pandemic or geopolitical conflicts, allowing for enrollment in Sub-study 3 if clinical response criteria are met.

The clinical trial is designed to evaluate the efficacy and safety of **risankizumab** in subjects with moderately to severely active **ulcerative colitis**. This is a multicenter, randomized, double-blind, placebo-controlled study with a 52-week maintenance phase followed by an open-label extension. The trial is structured into multiple sub-studies, each with specific objectives. Sub-study 1 aims to assess the efficacy and safety of risankizumab versus placebo as maintenance therapy. Sub-study 2 focuses on comparing two dosing regimens of risankizumab, utilizing therapeutic drug monitoring versus clinical assessment for dose escalation. Sub-study 3 is dedicated to evaluating the long-term safety of risankizumab in subjects who completed the previous sub-studies or responded to induction treatment in a prior study. The trial also includes a Continued Treatment Extension (CTE) to provide ongoing treatment for sub-study 3 completers until risankizumab is commercially available or accessible locally.

The trial duration is estimated to conclude by September 25, 2028, with recruitment having commenced on August 28, 2018. Participants are expected to be involved for the entire duration of the study, which includes the initial 52-week maintenance phase and the subsequent open-label extension. The study visits are sequenced as follows: an inclusion (screening) visit to confirm eligibility based on prior study completion and clinical response, followed by regular follow-up visits to monitor efficacy and safety endpoints, and an end-of-study visit to assess long-term outcomes. The primary endpoints include achieving clinical remission per the Adapted Mayo score at Week 52, while secondary endpoints focus on endoscopic and histologic improvements, as well as quality of life measures.

Participants may be subject to early termination from the study if they do not meet the inclusion criteria, experience adverse events that compromise safety, or withdraw consent. The trial is conducted under strict adherence to ethical guidelines and regulatory requirements, ensuring the integrity and reliability of the data collected. The study employs a rigorous methodology to ensure unbiased results, with the use of placebo controls and blinding to minimize potential biases. The trial's design and procedures are meticulously planned to provide comprehensive insights into the therapeutic potential of risankizumab for ulcerative colitis.

The clinical trial involves the use of **Risankizumab**, a biologic agent of biotechnological origin, administered in various pharmaceutical forms. The primary experimental medication, **ABBV-066 / Risankizumab**, is provided as a **solution for infusion**. This formulation is administered intravenously, with a maximum daily dose of 1200 mg and a total maximum dose of 7200 mg over a treatment period of up to 240 days. The active substance, **Risankizumab**, is a protein of non-chemical origin, developed by AbbVie Deutschland GmbH & Co. KG.

Another formulation of **Risankizumab** is available as a **solution for injection/infusion**, also administered intravenously. This formulation shares the same dosing parameters as the infusion solution, with a maximum daily dose of 1200 mg and a total maximum dose of 7200 mg over 240 days. This product is also developed by AbbVie Deutschland GmbH & Co. KG and contains the same active substance, **Risankizumab**.

Additionally, **Risankizumab** is provided as a **solution for injection in a pre-filled syringe**, intended for subcutaneous use. This formulation allows for a maximum daily dose of 360 mg and a total maximum dose of 13320 mg over the same treatment period of 240 days. This product is manufactured by AbbVie, Inc., and contains the active substance **Risankizumab**, similar to the other formulations.

The study also includes a placebo group, utilizing a **Risankizumab placebo solution for infusion** and a **Risankizumab placebo solution for injection in a pre-filled syringe**. These placebo treatments are designed to match the experimental medications in appearance and administration route but do not contain the active substance. The placebo solutions are used to maintain the double-blind nature of the trial, ensuring unbiased assessment of the efficacy and safety of **Risankizumab** in subjects with moderately to severely active ulcerative colitis.

The efficacy of **risankizumab** in the clinical trial will be assessed through a series of primary and secondary endpoints. The primary efficacy endpoint for Sub-study 1 and 2 is the achievement of clinical remission per the Adapted Mayo score at Week 52. Sub-study 2 will also explore selected efficacy endpoints by comparing the Therapeutic Drug Monitoring (TDM) versus Clinical Assessment (CA) arms. Sub-study 3 focuses on evaluating long-term safety, with no specific efficacy endpoints for the Continued Treatment Extension (CTE).

Secondary endpoints include the achievement of endoscopic improvement, histologic endoscopic improvement of the mucosa, and endoscopic remission at Week 52. Additional secondary endpoints involve achieving clinical remission per the Adapted Mayo score at Week 52 without corticosteroid use for 90 days, and in subjects with clinical remission at Week 0. Other measures include the absence of bowel urgency, abdominal pain, nocturnal bowel movements, and tenesmus at Week 52. Changes from baseline to Week 52 in FACIT-Fatigue and Inflammatory Bowel Disease Questionnaire (IBDQ) total scores will also be evaluated, along with the number of fecal incontinence episodes and days with sleep interrupted due to ulcerative colitis (UC) symptoms. The occurrence of UC-related hospitalizations through Week 52 will be adjusted for exposure.