Phase III Randomized Controlled Trial of ICEF15 in Fecal Incontinence Due to External Anal Sphincter Dysfunction

The primary objective of this study is to conduct a final assessment of the **clinical efficacy** and **clinical safety** of ICEF15 therapy in patients with **fecal incontinence** due to external anal sphincter dysfunction caused by its disruption and/or weakness. This evaluation is clinically relevant as it aims to address the underlying causes of fecal incontinence, potentially offering a therapeutic option that could improve patient outcomes and quality of life.

Secondary objectives include:

• The assessment of treatment efficacy during the observation period.
• The evaluation of improvement in the condition of fecal incontinence.
• The assessment of improvement in patients' quality of life.

The clinical trial involves a total of **60 participants** diagnosed with **fecal incontinence** due to external anal sphincter dysfunction. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on their ability to comply with study procedures and their mental competence to understand study requirements. The trial includes individuals who have experienced symptoms of urge fecal incontinence for a duration of at least 6 months but not exceeding 10 years, with insufficient improvement from prior conservative treatment. Both genders are represented, and the study does not exclude vulnerable populations. Participants are required to have a maximal incremental voluntary squeeze pressure on anal manometry of 100 mmHg or less in women and 150 mmHg or less in men. Additionally, an ultrasound of the anal canal must show an intact external anal sphincter or a maximal overall extent of external anal sphincter injury and tear of 180 degrees. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the **clinical efficacy** and safety of ICEF15 therapy for patients with **fecal incontinence** due to external anal sphincter dysfunction. This is a phase III, randomized, controlled, double-blind, two-armed study. The trial will involve the administration of ICEF15, an autologous skeletal muscle-derived cell therapy, and a placebo, both delivered via intramuscular injection. The study is expected to run from May 2022 to December 2025, with a maximum treatment period of 57 days for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, mental competence, and specific symptoms of fecal incontinence. Following successful screening, participants will be randomized to receive either the active treatment or placebo. The primary endpoint is the change in frequency of incontinence episodes, measured by bowel diary records, from baseline to the end of the study. Secondary endpoints include the frequency of response, defined as a reduction in incontinence episodes by at least 50%.

Study visits will include follow-up assessments to monitor safety and efficacy, with the final visit occurring on target day 457. Participants are expected to be involved in the study for approximately 15 months, from screening to the end-of-study visit. Conditions that may lead to early termination from the study include non-compliance with study procedures or the occurrence of adverse events that compromise participant safety. The trial aims to provide robust data on the potential benefits of ICEF15 therapy for individuals suffering from fecal incontinence.

The clinical trial involves the administration of **ICEF15**, an investigational product, which is an **injection** containing **autologous skeletal muscle-derived cells (aSMDC)**. The active substance, **ICEF15**, is classified as a structurally diverse substance used in **cell therapy**. The product is manufactured by INNOVACELL AG and is administered via **intramuscular use**. The maximum daily dose is 6,000,000 units, with a total maximum dose of 60,000,000 units over a treatment period of 57 days. The primary objective of the study is to evaluate the clinical efficacy and safety of ICEF15 in patients with fecal incontinence due to external anal sphincter dysfunction.

The study also includes a **placebo** control, which is a **solution for injection**. The placebo is chemically inert and is administered via **intramuscular use**. The maximum daily dose for the placebo is 60,000,000 units, with a total maximum dose of 6,000,000 units over the same treatment period of 57 days. The placebo serves as a comparator to assess the efficacy and safety of the experimental treatment, ICEF15. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol.

The efficacy of the ICEF15 therapy for the treatment of **fecal incontinence** will be assessed through a phase III, randomized, controlled, double-blind, two-armed clinical study. The primary endpoint for evaluating efficacy is the change in the frequency of incontinence episodes. This will be measured by comparing bowel diary records prior to Visit 8 (target day 457) with the baseline period from diary records prior to implantation Visit 3 (target day 92) in both treatment groups. Secondary endpoints include the frequency of response, defined as a reduction of the frequency of incontinence episodes by ≥ 50% under treatment, derived from diary records prior to Visit 8 compared to the baseline period from diary records prior to implantation Visit 3.