Natriumthiosulfat (1) – Pedmarqsi®

• Clinical trials
  • The ACCL0431 trial is an open-label, randomised, multicentre Phase III trial comparing sodium thiosulphate with no administration of sodium thiosulphate.
  • The SIOPEL 6 trial is an open-label, randomised, multicentre Phase III trial comparing sodium thiosulphate with no administration of sodium thiosulphate.

a) Patients aged 1 month to < 18 years with localised, non-metastatic hepatoblastoma, for whom there is an indication to prevent cisplatin-induced ototoxicity

• Indication of a non-quantifiable additional benefit.
• Consequently, a non-quantifiable added benefit has been identified for sodium thiosulphate in the treatment of patients aged 1 month to < 18 years with localised, non-metastatic hepatoblastoma, where the indication is the prevention of cisplatinchemotherapy has been established as providing a non-quantifiable additional benefit.
• An indication is therefore included regarding the certainty of the established additional benefit.
• mortality
  • In the SIOPEL 6 study, overall survival was defined as the time from randomisation to death from any cause.
  • No statistically significant difference was observed between the treatment groups for the endpoint of overall survival.
• Morbidity – Failure of curative treatment (event-free survival, EFS)
  • No suitable data are available for the endpoint ‘failure of curative treatment’ (event-free survival, EFS).
• Morbidity – hearing loss (BROCK grade ≥ 1)
  • The primary endpoint of the SIOPEL 6 study was defined as the proportion of patients with hearing loss – defined as BROCK grade ≥ 1 (measured using pure-tone audiometry [PTA], PTA]) – whereby the hearing threshold was to be assessed at baseline (before the start of treatment) and after completion of the study treatment or at an age of at least 3.5 years, whichever occurred later.
  • The results on hearing loss submitted for the benefit assessment are based on single measurements taken 6 to 12 weeks after completion of the study treatment or at an age of at least 3.5 years (whichever occurred later).
  • There is a clear advantage for sodium thiosulphate when imputed as a hearing loss responder and a moderate advantage when imputed as a non-responder.
  • With regard to the results for the hearing loss endpoint (BROCK grade ≥ 1), it should be noted that only single measurements were carried out in each case to assess hearing loss based on the BROCK scale.
  • Furthermore, no data are available on the speech development of the affected children.
  • Against this background, and given that the results of the underlying sensitivity analyses differ in terms of the extent of the respective effect, the extent of the overall advantage cannot be quantified with certainty.
• Health-related quality of life
  • In the SIOPEL 6 study, no endpoints relating to health-related quality of life were assessed.
  • At the time of study inclusion, the patients were, on a median basis, 13 months old.
• Side effects – Adverse events (AE)
  • An adverse event (AE) occurred in 96.2% of patients in the intervention arm and in 87.5% of patients in the control arm.
  • The results are presented here for supplementary information only.
• Side effects – Serious adverse events (SAEs)
  • In summary, no suitable data are available for serious adverse events (SAEs) in the SIOPEL 6 study.
  • On the one hand, AEs were recorded as SAEs that are potentially not SAEs at all according to the standard definition of SAEs (unexpected Grade 3 and 4 AEs).
  • On the other hand, expected AEs were defined which, per se, should not be documented as SAEs, although they could potentially be SAEs according to the standard definition of SAEs (for example, expected toxicities associated with hospitalisation).
  • Furthermore, the AE ‘transient hypernatraemia’ (Grade 3 or 4) was recorded as a SAE only in the control arm, but not in the intervention arm.
• Side effects – discontinuation due to AEs
  • In the SIOPEL 6 study, discontinuations due to AEs were documented only for SAE.
  • Consequently, no suitable data are available for the endpoint ‘withdrawal due to AEs’.
  • Overall, only one discontinuation (due to hypersensitivity [PT]) was documented in the intervention arm in the SIOPEL 6 study.
  • Furthermore, it is unclear whether discontinuations due to AEs relate solely to the discontinuation of sodium thiosulphate and were therefore documented only in the intervention arm.
• Side effects – severe AE
  • For the endpoint ‘severe AEs’, there is no statistically significant difference between the treatment arms.
• Side effects – Specific AEs
  • In detail, for the specific AE of vomiting (AE) as well as hypokalaemia and hypophosphataemia (both severe AEs), a statistically significant disadvantage was observed in relation to sodium thiosulphate in each case.
• Overall assessment
  • Overall, there is an advantage for the endpoint of hearing loss, although this cannot be reliably quantified.

b) Patients aged 1 month to < 18 years with localised, non-metastatic solid tumours other than hepatoblastoma, for whom there is an indication for cisplatin-based chemotherapy to prevent cisplatin-induced ototoxicity

• The additional benefit is not proven.
• The ACCL0431 study is not suitable for benefit assessment, as a significant proportion of the patients do not represent the population relevant to the benefit assessment, namely patients with localised, non-metastatic disease.
• There are therefore no suitable data available for an assessment of additional benefit.

Courtesy translation only, please refer to the German original.