Phase IIa Randomized, Double-Blind, Placebo-Controlled Study of ACOU085 for Prevention of Cisplatin-Induced Sensorineural Hearing Loss in Testicular Cancer Patients

The primary objective of this Phase IIa randomized, double-blind, placebo-controlled multicenter trial is to investigate the potential of **ACOU085** for the prevention of hearing loss after ototoxic damage induced by cisplatin in patients with testicular cancer. This is achieved through an intraindividual comparison of functional hearing parameters. The clinical relevance of this objective lies in addressing **sensorineural hearing loss (SNHL)**, a common adverse effect of cisplatin treatment, thereby potentially improving the quality of life for these patients.

Secondary objectives include assessing the efficacy, safety, and tolerability profile of **ACOU085** following three administrations via local transtympanic injections in the ears of cisplatin-treated testicular cancer patients. These evaluations are crucial for determining the overall benefit-risk profile of the treatment and its potential for broader clinical application.

The clinical trial involves a study population of **male** adult patients aged between 18 and 45 years, all diagnosed with testicular cancer and scheduled for a cisplatin-containing chemotherapeutic regimen. The trial aims to investigate the potential of ACOU085 in preventing **sensorineural hearing loss** following ototoxic damage induced by cisplatin. Participants are required to have normal hearing at baseline according to WHO and ASHA criteria, with normal otoscopic findings and distortion product oto-acoustic emissions in both ears. The trial excludes female subjects and does not involve a vulnerable population. Participants must be in good general health, with normal heart rate, blood pressure, ECG, and laboratory parameters, including liver and renal function. They must also agree to use two forms of contraception during the trial and be able to communicate effectively in German. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is a **Phase IIa randomized, double-blind, and placebo-controlled** study designed to evaluate the safety, tolerability, and efficacy of ACOU085 in preventing **sensorineural hearing loss** in testicular cancer patients undergoing cisplatin chemotherapy. The trial involves a split-body design, where each participant receives both the investigational medicinal product (IMP) and a placebo, allowing for intraindividual comparison of hearing parameters. The trial is expected to run from September 2023 to June 2026, with participant involvement lasting approximately 9 months.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis, and baseline hearing function. Following successful screening, participants will be randomized to receive either ACOU085 or placebo via **transtympanic injection**. The trial includes multiple follow-up visits to monitor safety and efficacy, with assessments of hearing function, vital signs, and laboratory parameters. The primary endpoint is the proportion of patients showing a significant difference in hearing thresholds between ears at specific frequencies by the end of the third chemotherapy cycle. Secondary endpoints include various audiometric measures and safety assessments.

The end-of-study visit will occur after the completion of the treatment period, where final evaluations will be conducted to assess 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 potential of ACOU085 to mitigate hearing loss in this patient population, with findings expected to contribute to future therapeutic strategies.

The clinical trial involves the administration of **ACOU085**, a small molecule Kv7.4 agonist, formulated as a **thermo-reversible hydrogel**. This investigational medicinal product is designed for **transtympanic injection**. The dosing regimen includes a maximum daily dose of 6 mg, with a total maximum dose of 18 mg over a treatment period of up to 9 days. The primary objective is to assess the safety, tolerability, and efficacy of ACOU085 in preventing hearing loss in testicular cancer patients undergoing cisplatin treatment. The administration of ACOU085 is monitored to ensure participant compliance and to evaluate its potential in mitigating ototoxic damage.

The study also includes a **placebo** group, where the placebo is manufactured to match the characteristics of the investigational medicinal product (IMP) in terms of appearance and size, but without containing the active ingredient. The placebo is used to maintain the double-blind nature of the trial, allowing for an intraindividual comparison of functional hearing parameters. The placebo administration follows the same route and schedule as the active treatment to ensure consistency across the study arms.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints focused on evaluating the prevention of hearing loss in testicular cancer patients receiving cisplatin. The primary endpoint is the proportion of patients showing a difference of ≥10 dB between both ears in at least two frequencies for air conduction in pure tone audiometry (PTA), specifically targeting high (4, 6, 8 kHz) and extended high frequencies (10, 12, 14, 16 kHz). This will be measured between baseline (V1; prior to the first initiation of cisplatin-containing chemotherapy) and the end of the third chemotherapeutic cycle (V4; Day 64).

Secondary endpoints include the efficacy protection for single audiometric variables, such as intra-individual differences between both ears in pure tone and speech audiometry in quiet and noise, as well as otoacoustic emissions (DPOAEs). These will be assessed in terms of the verum- versus placebo-treated ear between various timepoints (V1, V2, V3, V4, V5). Specific measures include the proportion of patients showing a difference of ≥10 dB between both ears for speech reception thresholds (SRT) in quiet, speech discrimination in quiet at 50 and/or 65 dB SPL, and speech discrimination in noise of ≥1.5 dB SNR. Additionally, the proportion of patients showing a difference of ≥10 dB across all frequencies (0.25 to 12 kHz) and high frequencies (4 to 12 kHz) will be calculated as the geometric mean of air conduction hearing thresholds. A difference of ≥5 dB between both ears for otoacoustic emissions will also be evaluated.

Safety and tolerability will be monitored through changes from baseline in facial nerve function, cochlear function, and vestibular function, as well as changes in vital signs, physical examinations, ECGs, and laboratory parameters. The incidence, severity, and relationship of adverse events, including injection site or local reactions at both ears, will be documented throughout the trial.