Fidaxomicin (2) – Dificlir®

• Clinical trials
  • To assess the additional benefit, the pharmaceutical manufacturer has submitted the single-blind, parallel, randomised, controlled SUNSHINE trial in the dossier, which compares fidaxomicin with vancomycin.

a) Patients under 18 years of age with mild, treatment-requiring cases of Clostridioides difficile-associated diarrhoea

• For patients under 18 years of age with mild, treatment-requiring cases of Clostridioides difficile-associated diarrhoea, the additional benefit is not proven.
• mortality
  • In the SUNSHINE study, no statistically significant difference was observed between the treatment groups for the endpoint of overall survival.
• morbidity
  • The endpoint ‘global cure’ was defined as a clinical response on or two days after the end of treatment, characterised by the absence of watery diarrhoea (in patients under 2 years of age) or by the consistency of stools, as evidenced by fewer than 3 loose stools (in patients > 2 years) on two consecutive days and a hint of disease recurrence until the end of the study (30 days after the end of treatment), i.e. without evidence of disease recurrence.
  • For the ‘global cure’ endpoint, there is an effect modification by the characteristic of sex. For boys, there is a statistically significant disadvantage of fidaxomicin compared with vancomycin. For girls, there is no difference between the treatment groups.
  • For the endpoints of global cure and cessation of diarrhoea, no clinically relevant differences between the treatment arms were observed in the relevant patient population. Overall, the results show no difference between fidaxomicin and vancomycin in terms of the morbidity endpoint.
• quality of life
  • The SUNSHINE study did not investigate endpoints in the health-related quality of life category.
• Side effects
  • For the endpoints of serious adverse events (SAEs), discontinuation due to adverse events and the overall rates of adverse events, no statistically significant difference was observed between fidaxomicin and vancomycin.
  • A summary of the results shows no difference between fidaxomicin and vancomycin in the side effects category.
• Overall assessment / Conclusion
  • A patient population from the single-blind, parallel, randomised, controlled SUNSHINE trial was presented to assess the extent of the additional benefit of fidaxomicin. Results are available on mortality, morbidity and side effects. Health-related quality of life was not assessed in the study.
  • For the endpoint of overall survival, there was no statistically significant difference between fidaxomicin and vancomycin.
  • In the overall analysis of the morbidity outcomes relating to global cure and cessation of diarrhoea, no statistically significant difference was observed between fidaxomicin and vancomycin.
  • In the overall analysis of the endpoints in the ‘side effects’ category—namely serious adverse events (SAEs), discontinuation due to adverse events, and the overall rates of adverse events—no statistically significant difference was observed between fidaxomicin and vancomycin.
  • In summary, for patients under 18 years of age with mild, treatment-requiring courses of Clostridioides difficile-associated diarrhoea, an overall assessment of the results regarding mortality, morbidity and side effects, fidaxomicin offers no additional benefit over vancomycin.

b) Patients under 18 years of age with severe and/or recurrent cases of Clostridioides difficile-associated diarrhoea

• For patients under 18 years of age with severe and/or recurrent cases of Clostridioides difficile-associated diarrhoea, there is a hint of considerable additional benefit for fidaxomicin.
• Due to uncertainties regarding the stratification of patients by disease severity and the lack of blinding in the Sunshine study, there is a hint of a considerable additional benefit.
• mortality
  • In the SUNSHINE study, no statistically significant difference was observed between the treatment groups for the endpoint of overall survival.
• morbidity
  • The endpoint ‘global cure’ was defined as a clinical response on or two days after the end of treatment, characterised by the absence of watery diarrhoea (in patients < 2 years) or by the consistency of stools, defined as fewer than 3 unformed stools (in patients > 2 years) on two consecutive days and a hint of disease recurrence until the end of the study (30 days after the end of treatment), i.e. without evidence of disease recurrence.
  • For the ‘global cure’ endpoint, a statistically significant difference was observed between the treatment arms in favour of fidaxomicin within the relevant patient population. Here, it is evident that in the fidaxomicin treatment group, 72.5% of patients (37 out of 51) achieved a cure according to the criteria mentioned above, whilst in the vancomycin treatment group this was observed in only 38.7% of patients (12 out of 31). This advantage is classified as considerable.
  • For the endpoint ‘cessation of diarrhoea’, there was no statistically significant difference between the treatment arms.
  • Taking the results for overall cure and cessation of diarrhoea together, there is a considerable additional benefit of fidaxomicin compared with vancomycin for the endpoint of morbidity.
• quality of life
  • The SUNSHINE study did not investigate endpoints in the health-related quality of life category.
• Side effects
  • No statistically significant difference was observed between fidaxomicin and vancomycin for the endpoints of serious adverse events (SAEs), discontinuation due to adverse events, and the overall rates of adverse events.
  • With regard to specific adverse events, a statistically significant disadvantage of fidaxomicin compared with vancomycin was observed at the endpoint category ‘nervous system disorders’ (SOC). All of the events that occurred were non-serious side effects, which are considered irrelevant for the assessment of additional benefit.
  • In the category of side effects, there are no clinically relevant differences between the treatment groups when viewed as a whole.
• Overall assessment / Conclusion
  • A patient population from the single-blind, parallel, randomised, controlled SUNSHINE trial was presented for the assessment of the extent of the additional benefit of fidaxomicin. Results are available on mortality, morbidity and side effects. Health-related quality of life was not assessed in the study.
  • For the endpoint of overall survival, there was no statistically significant difference between fidaxomicin and vancomycin.
  • In the overall analysis of the results in the morbidity category regarding global cure and cessation of diarrhoea, there is a considerable additional benefit of fidaxomicin compared with vancomycin, due to the statistically significant difference in the global cure endpoint.
  • In the ‘Side Effects’ category, for the endpoints of serious adverse events (SAEs), discontinuation due to adverse events and the overall rates of adverse events, there are no clinically relevant differences between the treatment groups when viewed as a whole. At the level of individual specific adverse events (disorders of the nervous system), a statistically significant difference to the detriment of fidaxomicin was observed in each case. All of these side effects were non-serious side effects, which are considered irrelevant for the assessment of additional benefit.
  • Consequently, the additional benefit of fidaxomicin compared with vancomycin for the endpoint of side effects is not proven.
  • In summary, for patients under 18 years of age with severe and/or recurrent courses of Clostridioides difficile-associated diarrhoea, an overall assessment of the results regarding mortality, morbidity and side effects, fidaxomicin offers a considerable additional benefit over vancomycin.

Courtesy translation only, please refer to the German original.