Bezlotoxumab (1) – Zinplava®

• Clinical trials
  • Two randomised, double-blind, placebo-controlled, multicentre trials – MODIFY I and MODIFY II – are available to demonstrate the additional benefit of bezlotoxumab in preventing the recurrence of CDI in adult patients at high risk of CDI recurrence.

Adults at high risk of recurrence of Clostridium difficile infection (CDI)

• In its overall assessment of all results, the G-BA has determined, on the basis of the criteria set out in Section 5(7) of the AM-NutzenV and taking into account the severity of the disease and the therapeutic objective in the present therapeutic indication for the prevention of recurrence of Clostridium difficile infection (CDI) in adults at high risk of CDI recurrence, the G-BA provides an indication that there is evidence of a minor additional benefit.
• Accordingly, despite the existence of two randomised controlled trials, at most an indication of additional benefit can be assumed.
• mortality
  • For the endpoint of overall mortality, the proportion of patients who had died by week 12 was recorded as part of the adverse event survey.
  • The meta-analysis of the studies shows no statistically significant difference in overall mortality between the treatment arms.
  • Based on the available results on mortality, no conclusion can be drawn regarding the additional benefit of bezlotoxumab compared with the appropriate comparator therapy.
• Morbidity – Clinical cure (presented as supplementary data)
  • The first morbidity endpoint, ‘clinical cure’, was defined as an event if the 14-day standard course of antibiotic therapy for the initial CDI episode was successfully completed within 2 days of the end of treatment, i.e. diarrhoea was no longer present (≤ 2 loose stools within 24 hours).
  • Across the treatment groups in both studies, there was no statistically significant difference in ‘clinical cure’ for the patient population considered in the benefit assessment.
  • The endpoint ‘clinical cure’ is presented for supplementary information. The reason for this is that it primarily provides insights into the efficacy of the medicinal products used during the acute treatment of CDI, by reflecting the success of the initial antibacterial therapy for treating the CDI episode.
  • As a standalone endpoint, ‘clinical cure’ is therefore not relevant for determining the additional benefit of bezlotoxumab in preventing the recurrence of CDI.
• Interim conclusion: morbidity
  • In the overall assessment of the results in the morbidity category, the endpoints ‘global cure’ and ‘recurrence of CDI’ show statistically significant effects in favour of bezlotoxumab plus standard antibiotic therapy compared with placebo plus standard antibiotic therapy, which are classified as moderate effects.
  • The ‘global cure’ endpoint has methodological advantages over the ‘recurrence of CDI’ endpoint, as it also takes into account a possible influence of bezlotoxumab on the first endpoint, ‘clinical cure’, in the same direction. For this reason, the ‘global cure’ endpoint is considered to be of particular importance for the interpretation of the results regarding the additional benefit of bezlotoxumab.
  • If bezlotoxumab demonstrates a positive effect that is evident in both ‘recurrence of diarrhoea’ and ‘recurrence of CDI’, this does not constitute an additional advantage of the active ingredient (INN). This is because ‘recurrence of CDI’ builds upon ‘recurrence of diarrhoea’, and the results from both endpoints therefore overlap to some extent.
• quality of life
  • No results on quality of life are available, as no data on quality of life were collected in either the MODIFY I or the MODIFY II study.
• Side effects – severe adverse events (SAEs)
  • When compiling the SAE data in the dossier, events associated with the recurrence of CDI were also taken into account.
  • This means that a valid interpretation of the results is not possible.
  • However, based on the available data, it can be ruled out that bezlotoxumab causes either greater or minor harm with regard to the SAE endpoint (excluding events related to the recurrence of CDI): Even under the assumption, made to the detriment of bezlotoxumab, that all CDI events in the placebo arm are attributable to the recurrence of CDI, whilst all CDI events in the bezlotoxumab arm actually represent SAE, greater harm from bezlotoxumab can be ruled out.
  • In summary, there is no hint that bezlotoxumab causes greater or minor harm with regard to the SAE endpoint compared with the appropriate comparator therapy.
• Overall assessment
  • Data on mortality, morbidity and side effects are available from the MODIFY I and MODIFY II studies for the benefit assessment of bezlotoxumab in the prevention of recurrence of Clostridium difficile infection (CDI) in adults at high risk of CDI recurrence. No data on quality of life were collected.
  • In summary, based on the results from the relevant patient population for the morbidity endpoint category, there are statistically significant differences in favour of bezlotoxumab for the endpoints ‘global cure’ and ‘recurrence of CDI’.
  • In the ‘side effects’ endpoint category, no notable differences were observed between the treatment arms for the endpoints SAE, discontinuation due to AEs and specific AEs. Overall, there is no hint that bezlotoxumab causes greater or minor harm compared with the control group.
  • The majority of patients in the MODIFY trials (around 80 per cent) had mild to moderate CDI, with a Zar score of < 2. It therefore seems questionable whether the results for the morbidity endpoints would be observed to a comparable extent in patients with a severe course of CDI.
  • Furthermore, uncertainties remain regarding the age of the study population, as the average age of onset in Germany is slightly higher than that of the patients included in the study, as well as regarding the operationalisation of the endpoint ‘recurrence of CDI’.

Courtesy translation only, please refer to the German original.