Sodium Thiosulfate + Mannitol for Chemotherapy-Induced Hearing Loss
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Sunnybrook Health Sciences Centre
Must be taking: Cisplatin
Disqualifiers: Severe hearing loss, Meniere's, abnormal renal, others
No Placebo Group
Prior Safety Data
Trial Summary
What is the purpose of this trial?One common side effect of cisplatin chemotherapy is ototoxicity. The drugs sodium thiosulfate and mannitol may protect against cisplatin-induced hearing loss. Specifically, sodium thiosulfate has been found to protect the cells in the inner ear, and may therefore prevent hearing loss. Mannitol can help sodium thiosulfate enter the inner ear, and ponteially increase the effectiveness of sodium thiosulfate. This study aims to assess the efficacy of sodium thiosulfate and mannitol to reduce the hearing impairment caused by cisplatin chemotherapy.
Will I have to stop taking my current medications?
The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.
What evidence supports the effectiveness of the drug sodium thiosulfate for preventing chemotherapy-induced hearing loss?
Research shows that sodium thiosulfate can help prevent hearing loss caused by the chemotherapy drug cisplatin, especially in children with localized cancer. It works by neutralizing harmful effects of cisplatin without affecting its ability to fight cancer.
12345Is Sodium Thiosulfate safe for humans?
Sodium Thiosulfate has been studied for its ability to reduce hearing loss caused by the chemotherapy drug cisplatin. It has been shown to be safe and well-tolerated in both children and adults, with most side effects being mild and related to the method of administration. It has received approval in the USA for use in children to prevent hearing loss from cisplatin.
12467How does the drug sodium thiosulfate differ from other treatments for chemotherapy-induced hearing loss?
Sodium thiosulfate is unique because it acts as an antioxidant that directly interacts with cisplatin, a chemotherapy drug, to form inactive compounds, reducing the risk of hearing loss without affecting the cancer-fighting ability of cisplatin. It is specifically approved for use in children with localized, non-metastatic tumors, making it a targeted option for pediatric patients.
12345Eligibility Criteria
Adults over 18 receiving cisplatin chemotherapy can join this trial if they're willing to consent and use contraception. They must have normal hearing, good overall health (ECOG 0-2), and proper kidney and liver function. Pregnant women or those with severe hearing loss, Meniere's disease, fluctuating or asymmetrical hearing loss are excluded.Inclusion Criteria
Willing to provide informed consent
I am currently receiving cisplatin as part of my cancer treatment.
I can take care of myself and perform daily activities.
+3 more
Exclusion Criteria
I have severe hearing loss confirmed by a hearing test.
My liver tests are much higher than normal, indicating liver issues.
Patient unable to follow the protocol for any reason
+6 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Pilot Feasibility Study
Participants are recruited into a 2-year pilot feasibility study to evaluate treatment outcomes, adverse events, and logistics of treatment delivery.
2 years
Treatment
Participants receive cisplatin-based chemotherapy with or without sodium thiosulfate and mannitol. Experimental drugs are administered 4-8 hours post-chemotherapy.
2 months
Follow-up
Participants undergo follow-up hearing tests and are monitored for renal function, disease-free survival, and overall survival.
12 months
Participant Groups
The trial is testing whether Sodium Thiosulfate plus Mannitol can prevent hearing damage in adults undergoing cisplatin chemotherapy. The study will assess the effectiveness of these drugs in protecting inner ear cells from the ototoxic effects of chemotherapy.
2Treatment groups
Experimental Treatment
Active Control
Group I: Standard Cisplatin-based Chemotherapy + Sodium Thiosulfate + MannitolExperimental Treatment1 Intervention
Participants will receive the standard of care (cisplatin-based chemotherapy) plus the experimental treatment of Sodium Thiosulfate and Mannitol. Both drugs will be administered IV 4 - 8 hours following chemotherapy treatment, as part of post-chemotherapy hydration.
Group II: Standard Cisplatin-based ChemotherapyActive Control1 Intervention
Participants will receive the standard of care (cisplatin-based chemotherapy) only.
Find a Clinic Near You
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Who Is Running the Clinical Trial?
Sunnybrook Health Sciences CentreLead Sponsor
References
Effects of sodium thiosulfate versus observation on development of cisplatin-induced hearing loss in children with cancer (ACCL0431): a multicentre, randomised, controlled, open-label, phase 3 trial. [2022]Sodium thiosulfate is an antioxidant shown in preclinical studies in animals to prevent cisplatin-induced hearing loss with timed administration after cisplatin without compromising the antitumour efficacy of cisplatin. The primary aim of this study was to assess sodium thiosulfate for prevention of cisplatin-induced hearing loss in children and adolescents.
Sodium Thiosulfate: Pediatric First Approval. [2023]Sodium thiosulfate (Pedmark®) is a chemoprotectant/antioxidant developed by Fennec Pharmaceuticals (formerly Adherex Technologies) to reduce to risk of hearing loss associated with cisplatin. Sodium thiosulfate reduces the risk of ototoxicity by interacting directly with cisplatin to produce inactive platinum species, as well as by causing intracellular effects (such as increasing antioxidant glutathione levels and inhibition of oxidative stress) after entering the cells through the sodium sulfate cotransporter 2. In September 2022, sodium thiosulfate received its first approval in the USA for reducing the risk of ototoxicity associated with cisplatin in pediatric patients 1 month of age and older with localized, non-metastatic solid tumours. Sodium thiosulfate is under regulatory review in the EU for the prevention of ototoxicity induced by cisplatin chemotherapy in patients 1 month to < 18 years of age with localised, non-metastatic, solid tumours. This article summarizes the milestones in the development of sodium thiosulfate leading to this pediatric first approval for reducing the risk of ototoxicity associated with cisplatin in pediatric patients.
Interventions for cisplatin-induced hearing loss in children and adolescents with cancer. [2023]The identification of preventive interventions that are safe and effective for cisplatin-induced ototoxicity is important, especially in children because hearing loss can impair speech-language acquisition development. Previous randomised trials assessed systemic drugs such as amifostine, sodium diethyldithiocarbamate or disulfiram, and sodium thiosulfate. Amifostine, sodium diethyldithiocarbamate, and disulfiram did not show hearing preservation. Paediatric trials assessing sodium thiosulfate showed efficacy in terms of hearing protection. The SIOPEL 6 trial consisted solely of patients with localised hepatoblastoma and no effects on survival were shown. In the ACCL0431 trial, which included heterogeneous patients, a post-hoc analysis showed significantly worse overall survival among patients who had disseminated disease receiving sodium thiosulfate than among controls, but not among those with localised disease. Intratympanically administered drugs have mainly been assessed in adults and include N-acetylcysteine and dexamethasone. Inconsistent effects of these drugs were identified but these studies were limited by design, small sample size, and statistical approach. Future studies of systemic drugs will need to consider the measurement of disease outcomes through study design and sample size, and ototoxicity endpoints should be harmonised to enhance comparability between trials.
A randomized controlled trial to test the efficacy of trans-tympanic injections of a sodium thiosulfate gel to prevent cisplatin-induced ototoxicity in patients with head and neck cancer. [2022]Cisplatin-induced hearing loss is frequent and severe. Antioxidants such as sodium thiosulfate (STS) can neutralize the effects of cisplatin. The objective of the trial was to test the efficacy of trans-tympanic injections of a STS gel to prevent cisplatin-induced ototoxicity.
Prevention of cisplatin-induced hearing loss by administration of a thiosulfate-containing gel to the middle ear in a guinea pig model. [2022]Thiosulfate may reduce cisplatin-induced ototoxicity, most likely by relieving oxidative stress and by forming inactive platinum complexes. This study aimed to determine the concentration and protective effect of thiosulfate in the cochlea after application of a thiosulfate-containing high viscosity formulation of sodium hyaluronan (HYA gel) to the middle ear prior to i.v. injection of cisplatin in a guinea pig model.
The comparative effects of sodium thiosulfate, diethyldithiocarbamate, fosfomycin and WR-2721 on ameliorating cisplatin-induced ototoxicity. [2019]The efficacies of four agents in ameliorating cisplatin-induced ototoxicity were investigated. Hamsters were given a series of 5 cisplatin injections (3 mg/kg/injection once every other day, i.p.) either alone or in combination with 1600 mg/kg/injection sodium thiosulfate (STS), 300 mg/kg/injection diethyldithiocarbamate (DDTC), 18 mg/kg/injection WR-2721, or 300 mg/kg/injection fosfomycin (n = 10/group). Ototoxicity was assessed electrophysiologically by auditory brainstem responses (ABRs) and anatomically by cochlear histology. The greatest auditory protection was given by STS, followed by DDTC. WR-2721 and fosfomycin did not provide any protection. All of the animals in the STS and DDTC groups survived, while some fatalities occurred in the fosfomycin, WR-2721, and cisplatin-only groups. Thus, the agents that were protective against ototoxicity were also protective against mortality. The ABRs also provided evidence of cisplatin-induced neuropathy. In summary, STS and DDTC hold promise for ameliorating the ototoxic effects of cisplatin chemotherapy and the hamster proved to be an excellent model of cisplatin ototoxicity.
Phase 1 study to evaluate safety, tolerability and pharmacokinetics of a novel intra-tympanic administered thiosulfate to prevent cisplatin-induced hearing loss in cancer patients. [2021]Cisplatin is a widely used chemotherapy for the treatment of certain solid tumors. Ototoxicity and subsequent permanent hearing loss remain a serious dose-limiting side effect associated with cisplatin treatment. To date, no therapies have been approved to prevent or treat cisplatin-induced hearing loss (CIHL). Sodium thiosulfate effectively inactivates cisplatin through covalent binding and may provide protection against cisplatin-induced ototoxicity. DB-020 is being developed as a novel formulation of sodium thiosulfate pentahydrate in 1% sodium hyaluronate for intratympanic injection (IT), enabling the delivery of high concentrations of thiosulfate into the cochlea prior to cisplatin administration. In the DB-020-002 phase 1a single-ascending dose study, healthy volunteers were enrolled into 5 cohorts to receive different doses of DB-020 via IT injection. Cohorts 1-4 received unilateral injections while Cohort 5 received bilateral injections. Plasma thiosulfate pharmacokinetics was measured, and safety and audiometric data were collected throughout the study. This study has demonstrated that intratympanic administration of DB-020 results in nominal systemic increases in thiosulfate levels, hence it should not compromise cisplatin anti-tumor efficacy. Furthermore, DB-020 was safe and well tolerated with most adverse events reported as transient, of mild-to-moderate severity and related to the IT administration procedure. These results support the design and execution of the ongoing proof-of-concept study, DB-020-002, to assess otoprotection using DB-020 in cancer patients receiving cisplatin without negatively impacting cisplatin anti-tumor efficacy.