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

Abstract

SUMMARY Background Sodium thiosulfate (STS) is an antioxidant shown in preclinical studies to prevent cisplatin-induced hearing loss (CIHL) but not compromise anti-tumour efficacy with timed administration post-cisplatin. The primary study aim was to evaluate STS for prevention of CIHL. Methods ACCL0431 was an open-label, phase 3 randomised cooperative group trial. Eligible participants 1–18 years old with newly diagnosed cancer and normal audiometry were randomly allocated (1:1) to receive STS or not in addition to their planned cisplatin-containing chemotherapy regimen using permuted blocks of 4. Randomisation was initially stratified by age (< or ≥ 5 years) and duration of cisplatin infusion (< or ≥ 2 hours). Stratification by prior cranial irradiation was added later. Sequence was computer-generated centrally and concealed to all personnel. If allocated to STS, participants received STS 16 grams/m2 intravenously 6 hours after each cisplatin dose. Hearing was measured using standard audiometry and reviewed centrally by audiologists masked to allocation using American Speech-Language-Hearing Association criteria. The primary endpoint was incidence of hearing loss 4 weeks post final cisplatin dose. Analysis was by intention to treat and restricted to evaluable participants. Enrollment is complete and this report represents the final analysis. This trial is registered with ClinicalTrials.gov, number NCT00716976. Findings Between June 23, 2008 and September 28, 2012, 125 eligible participants were enrolled from 38 sites in the United States (US) and Canada. Of these, 104 were evaluable for the primary aim. The proportion with hearing loss for STS versus control (%, 95% confidence interval) was 14/49 (28.6%, 16.6, 43.3) and 31/55 (56.4%, 42.3, 69.7), respectively (p=0.00022). Adjusted for stratification variables, the likelihood of hearing loss was significantly lower in the STS group compared with control group (odds ratio 0.31, 95% confidence interval 0.13, 0.73; p=0.0036). The most common grade 3–4 haematological adverse events (AE) reported in STS and control participants, irrespective of attribution, were neutropaenia in 117/177 (66.1%) and 145/223 (65.0%) participant-cycles, while the most common non-haematological AE was hypokalaemia in 25/147 (17.0%) and 22/187 (11.8%) participant-cycles, respectively. Of 194 serious AEs reported in STS recipients, none were considered probably or definitely related to STS; the most common was neutrophil count decreased in 26/194 (13.4%). Interpretation STS protects against CIHL in children and is not associated with serious adverse events attributed to its use. Further research is needed to define the appropriate role for STS among emerging otoprotection strategies. Funding United States NCI; STS was provided at no cost by Fennec Pharmaceuticals.