Evaluation of Intratympanic AC102 Versus Oral Prednisolone in Idiopathic Sudden Sensorineural Hearing Loss: A Randomized, Blinded, Phase II Study

The primary objective of this study is to evaluate the **efficacy** of a single intratympanic dose of AC102 compared to oral steroids in patients with moderately-severe to profound **Idiopathic Sudden Sensorineural Hearing Loss** (ISSNHL). This evaluation is based on the improvement of the hearing threshold, specifically the average of the three most affected consecutive frequencies, as tested by pure tone audiometry from baseline to Day 28. This is clinically relevant as it aims to determine a potentially more effective treatment option for ISSNHL, which could lead to better patient outcomes in terms of hearing recovery.

Secondary objectives include:

• Improvement of the hearing threshold over the study duration (up to Day 84) in patients with a baseline hearing threshold of ≥80 dB.
• Improvement of speech recognition in quiet, focusing on the final test at Day 84.
• Incidence of complete, partial, and no recovery.
• Percentage of patients eligible for salvage therapy.
• Improvement of the Hearing Handicap Inventory Score/Quality of Life.
• Assessment of safety and tolerability.
• Incidence of patients qualifying for a hearing aid or a cochlear implant.

The clinical trial involves a total of **55 participants** diagnosed with **Idiopathic Sudden Sensorineural Hearing Loss** (ISSNHL). The study population includes both male and female subjects, aged between 18 and 85 years. Participants were selected based on specific criteria, including the onset of unilateral ISSNHL occurring between 24 to 120 hours prior to randomization and an absolute air conduction hearing threshold of at least 65 dB. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The population includes individuals who are considered vulnerable, and all participants are required to provide informed consent. The trial aims to evaluate the efficacy of a single dose administration of AC102 compared to oral steroids, with the primary outcome being the improvement of the hearing threshold as measured by pure tone audiometry from baseline to Day 28.

The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy, safety, and tolerability of a single intratympanic dose of AC102 compared to oral steroids for the treatment of **Idiopathic Sudden Sensorineural Hearing Loss** (ISSNHL). The trial will involve participants aged 18 to 85 years who meet specific inclusion criteria, such as having unilateral ISSNHL with an onset between 24 to 120 hours prior to randomization and a significant hearing threshold loss. The study will assess the primary endpoint of mean change in absolute hearing thresholds from baseline to Day 28, with secondary endpoints including speech recognition improvement and hearing threshold changes at various intervals up to Day 84.

The trial will commence with a screening visit to confirm eligibility, during which informed consent will be obtained, and baseline audiometric assessments will be conducted. Participants will then be randomized to receive either the investigational product, AC102-Suspension 12 mg/ml, administered intratympanically, or the comparator, Prednisolon 10 mg GALEN® tablets, taken orally. The trial duration is estimated to conclude by December 31, 2025, with recruitment having started on October 13, 2022. Participants will be involved in the study for a maximum treatment period of 24 days, with follow-up visits scheduled on Days 14, 28, 56, and 84 to monitor efficacy and safety outcomes.

The end-of-study visit will occur on Day 84, where final assessments will be conducted to evaluate the long-term effects of the treatment. Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with study procedures, or withdraw consent. The trial aims to provide valuable insights into the comparative effectiveness of AC102 and oral steroids in managing ISSNHL, potentially influencing future therapeutic approaches for this condition.

The clinical trial involves the administration of **AC102-Suspension 12 mg/ml**, an experimental medication formulated as a **gel for injection**. The active substance in this formulation is **6-fluoro-9-methyl-9H-pyrido[3,4-b]-indole**, a chemical compound. The medication is administered via the **intratympanic** route, with a maximum daily and total dose of 0.8 ml. The treatment period is limited to a single day. This investigational product is provided by AUDIOCURE PHARMA GMBH and is designated as an orphan drug under the number EU/3/18/2106.

In addition to the experimental treatment, the study includes a comparator treatment, **Prednisolon 10 mg GALEN®**, which is a standard-of-care therapy. This medication is in the form of a **tablet** and contains **prednisolone** as the active substance. The maximum daily dose is 60 mg, with a total maximum dose of 1140 mg over a treatment period of 24 days. The administration route is **oral use**. This product is manufactured by GALENPHARMA GMBH and has a marketing authorization number of 65255.00.00.

The trial also utilizes a **placebo gel** as a control, which is not specified in terms of pharmaceutical form or active substance. Additionally, a **placebo matching Prednisolone** is used, also lacking specific details regarding its pharmaceutical form or active substance. These placebos serve to maintain the blinding of the study and ensure the validity of the comparative analysis between the experimental and standard treatments.

The efficacy of the clinical trial will be assessed by evaluating the improvement in hearing thresholds in patients with **Idiopathic Sudden Sensorineural Hearing Loss (ISSNHL)**. The primary endpoint is the mean change in absolute hearing thresholds, measured by pure tone audiometry (PTA), from baseline to Day 28. This assessment will focus on the average of the three most affected consecutive frequencies ranging from 0.25 to 8 kHz.

Secondary endpoints include the absolute improvement of speech recognition from baseline to Day 84, and the mean change in absolute hearing thresholds of PTA at various timepoints: Day 14, 56, and 84. Additionally, the trial will evaluate the percentage of patients with complete, partial, or no remission on Day 28, 56, and 84, as well as the percentage of patients qualifying for a hearing aid or cochlear implant at Day 84. Other secondary measures include the improvement of speech recognition in quiet from baseline to Day 14, 28, and 56, the percentage of patients eligible for salvage therapy, and the improvement of scoring in the Hearing Handicap Inventory for Adults (HHIA) from baseline to Day 28 and 84.

The trial will also assess the mean change in absolute hearing thresholds of PTA from baseline to Day 14, 28, 56, and 84 at the three mostly affected consecutive frequencies and the mean change of 4PTA (PTA at the frequencies 0.5, 1, 2, and 4 kHz) in patients with a baseline hearing threshold of ≥80 dB. These efficacy parameters will be collected and analyzed at specified timepoints to determine the effectiveness of a single intratympanic dose of AC102 compared to oral steroids in treating ISSNHL.