Evaluation of Transtympanic Sodium Thiosulfate for Prevention of Cisplatin-Induced Ototoxicity in Patients with Head and Neck Squamous Cell Carcinoma

The primary objective of this study is to assess the efficacy of **transtympanic sodium thiosulfate** (STS) 0.1M/0.5 HYA in preventing platinum-related ototoxicity in patients with head and neck squamous cell carcinoma. This is clinically relevant as cisplatin, a common chemotherapeutic agent, is known to cause significant hearing loss, impacting the quality of life and communication abilities of affected patients.

Secondary objectives include evaluating the superiority of STS compared to an untreated ear in terms of hearing capacity based on audiometry, and hearing loss according to the American Speech-Language-Hearing Association (ASHA) criteria, TUNE criteria, and the Common Terminology Criteria for Adverse Events (CTCAE). Additionally, the study aims to determine the median 1- and 2-year survival rates and assess quality of life through patient-related outcome measures (PROM), focusing on subjective hearing loss following platinum treatment.

The clinical trial involves participants diagnosed with **head and neck squamous cell carcinoma**. The study population includes both male and female subjects, aged 18 years and older, with a **WHO performance status** of 0, 1, or 2, indicating they are ambulatory and capable of self-care. Participants are required to have a histological or cytological confirmation of solid head and neck malignancies and must be scheduled for treatment with high-dose cisplatin, with a cumulative dose of at least 200 mg/m². The trial does not include vulnerable populations. The sponsor has not provided information regarding the total number of participants. Participants must be able and willing to provide written informed consent. Lifestyle factors such as diet, physical activity, or habits are not specified as part of the selection criteria. The trial population was selected based on specific medical and treatment-related criteria, ensuring a focus on individuals who are undergoing or are scheduled to undergo cisplatin treatment for their condition.

The clinical trial is designed to evaluate the efficacy of **sodium thiosulfate** administered via transtympanic injection in preventing cisplatin-related hearing loss in patients with head and neck squamous cell carcinoma. This is a randomized, controlled, multicenter phase III trial. The trial will commence with an estimated recruitment start date in March 2025 and is expected to conclude by March 2030. Participants will be randomly assigned to receive either the investigational treatment or a control, with both participants and investigators blinded to the treatment allocation to ensure unbiased results.

The trial will involve several study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histological proof of solid head and neck malignancies, a WHO performance status of 0, 1, or 2, and age over 18 years. Participants must also provide written informed consent. Following the screening, participants will undergo baseline assessments before the initiation of treatment. The treatment phase will consist of a maximum of 7 cycles of high-dose cisplatin, with the investigational product administered as a transtympanic injection.

Follow-up visits will be scheduled to monitor the primary endpoint, which is the percentage of patients experiencing a clinically relevant benefit in hearing threshold changes between baseline and three months post-treatment. Secondary endpoints include differences in sensorineural hearing loss between treated and untreated ears, assessed using various criteria, and quality of life measures. The end-of-study visit will occur after the final follow-up assessments, marking the completion of the participant's involvement in the trial.

Participant involvement is expected to last for the duration of the treatment cycles and follow-up period, with the possibility of early termination if adverse events occur or if the participant withdraws consent. The trial aims to provide valuable insights into the potential protective effects of sodium thiosulfate against platinum-related ototoxicity, contributing to improved management strategies for patients undergoing cisplatin treatment.

The clinical trial involves the administration of **sodium thiosulfate** as the experimental medication. Sodium thiosulfate is provided in the form of a **solution for injection**. The pharmaceutical preparation consists of sodium thiosulfate compounded with hyaluronate gel, resulting in a concentration of 0.1M sodium thiosulfate in 0.5% hyaluronate, delivered in a volume of 1 mL. The route of administration is via **transtympanic injection**, specifically targeting the prevention of cisplatin-related hearing loss. The maximum daily dose is 2 mL, with a total maximum dose of 14 mL over the course of the treatment period, which spans up to 7 days. Sodium thiosulfate is classified as an antineoplastic detoxifying agent, and its role in the trial is to assess its efficacy against platinum-related ototoxicity.

In addition to the experimental treatment, the study may include non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments, although specific details are not provided in the source data. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the treatment protocol. The trial is designed to evaluate the clinically relevant benefits of the experimental medication in a controlled setting, with the primary objective being the assessment of its efficacy in preventing hearing loss associated with cisplatin therapy.

The efficacy of transtympanic sodium thiosulfate (STS) in preventing cisplatin-induced hearing loss will be assessed in a randomized controlled multicenter phase III trial. The primary endpoint for evaluating efficacy is the percentage of patients experiencing a clinically relevant benefit from the STS injection, defined as a change in hearing threshold of ≥10 dB at any three adjacent frequencies from 0.5 to 16 kHz, measured between baseline and three months post-treatment, favoring the STS-treated ear.

Secondary endpoints include the mean difference in threshold shift between STS-treated and untreated ears at sensorineural pure tone averages (PTA) of 1-2-4 kHz and 8-10-12.5 kHz, assessed in decibels. Additional assessments will be based on the American Speech-Language-Hearing Association (ASHA) criteria, TUNE criteria, and Common Terminology Criteria for Adverse Events (CTCAE) for sensorineural hearing loss. Disease-specific survival, recurrence-free survival, and overall survival will be evaluated at median intervals of one and two years post-treatment initiation. Quality of life and patient-reported outcomes will be measured using the Speech, Spatial and Qualities of Hearing scale (SSQ) and the Tinnitus Handicap Inventory (THI)-12 to assess subjective hearing loss following platinum treatment.