Bedaquilin (4) – Sirturo®

Children (aged 5 years to under 12 years and weighing at least 15 kg) with multidrug-resistant pulmonary tuberculosis, where an effective treatment regimen cannot be formulated other than with bedaquiline (as part of a suitable combination therapy) due to resistance or intolerance

• For bedaquiline as part of an appropriate combination therapy, in children (aged 5 years to under 12 years and weighing at least 15 kg) with MDR-TB, where an effective treatment regimen cannot be established other than with bedaquiline due to resistance or intolerance, there is a hint of a non-quantifiable additional benefit, as the scientific data do not permit quantification.
• Due to a lack of comparative data, the short study duration and the high potential for bias in the single-arm C211 study, the G-BA classifies the extent of the additional benefit of bedaquiline, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease, the written submissions and the oral hearing.
• Consequently, a quantitative assessment of the extent of the effect and a quantification of the additional benefit into one of the categories ‘minor’, ‘considerable’ or ‘major’ is not possible on the basis of the data submitted.
• mortality
  • No deaths occurred in cohort 2 of the C211 study.
• Morbidity – Resolution of clinical TB symptoms
  • The resolution of TB symptoms was to be assessed by the medical trial staff in accordance with a consensus statement.
  • Although an external assessment of symptoms is not in itself relevant to the patient, the resolution of TB symptoms represents a relevant aspect of recovery.
  • At week 24, this was summarised as ‘completely resolved’, ‘partially resolved’ and ‘not resolved’, although it remains unclear exactly how this categorisation was arrived at.
  • A standardised procedure with predefined criteria for classification was not envisaged for this multicentre study.
  • The systematic recording of individual symptoms in the eCRFs was only introduced retrospectively with Amendment 5 to the study protocol.
  • According to the pharmaceutical manufacturer, the symptoms were recorded prior to this protocol amendment; however, baseline data are not available for all patients.
  • Due to the unclear operationalisation, the endpoint cannot be assessed.
• Morbidity – absence of pathogens in sputum
  • In study C211, only individuals with confirmed MDR-TB and Mycobacteria Growth Indicator Tube (MGIT)-assayable samples were evaluated for the endpoint ‘absence of pathogens in sputum’ during the course of the study.
  • The operationalisation of the endpoint in the study required the demonstration of freedom from the pathogen through two consecutive negative microbiological sputum cultures taken at a minimum interval of 25 days.
  • The German S2k guideline on the treatment of tuberculosis recommends three negative microscopic sputum samples before repealing isolation.
  • The absence of the pathogen is a fundamental prerequisite for the repeal of isolation, as the risk of transmission no longer exists.
  • The duration of patient isolation affects quality of life and is of relevance to patients.
  • However, the pharmaceutical manufacturer has not collected data on either quality of life or hospitalisation.
  • The duration of isolation depends not only on the absence of the pathogen but also on other factors.
  • It is therefore questionable to what extent the endpoint ‘time to pathogen-free status’ alone, as operationalised here, can provide information on the actual duration of patient isolation.
  • In view of the uncertainties regarding patient relevance and the other limitations mentioned, the endpoint of pathogen-free status in sputum cannot be assessed as a whole and is presented for supplementary information only.
• quality of life
  • Data on quality of life were not collected as part of the C211 study.
• Side effects
  • Adverse events (AEs) were recorded both for the 24-week treatment phase with bedaquiline + BR and for the entire study duration (24-week treatment phase (bedaquiline + BR) + follow-up phase (BR only)) up to the data cut-off date of 10 January 2019), with a median observation period of over 61 weeks.
  • Approximately 53% of participants experienced AEs of grade ≥ 3, and approximately 13% experienced serious AEs.
  • AE of particular interest occurred in approximately 53% of participants, including hepatotoxicity in approximately 20% and liver-related coagulation and bleeding disorders (prolonged prothrombin time) in approximately 33%.
  • In approximately 20% of participants, AEs led to discontinuation of bedaquiline therapy, and in approximately 27%, AEs led to discontinuation of at least one drug in the background therapy.
• Overall assessment
  • For bedaquiline as part of an appropriate combination therapy for the treatment of children (aged 5 years to under 12 years and weighing at least 15 kg) with multidrug-resistant pulmonary tuberculosis (MDR-TB), where an effective treatment regimen cannot be formulated without bedaquiline due to resistance or intolerance, results on mortality, morbidity and side effects are available based on Cohort 2 of the C211 study.
  • No deaths occurred in the C211 study.
  • In the morbidity endpoint category, the endpoints ‘absence of the pathogen in sputum’ and ‘resolution of TB symptoms (assessed by medical study staff)’ were recorded.
  • Due to limitations regarding operationalisation, the single-arm study design, the minor number of cases and the short observation period of 24 weeks for this therapeutic indication in the available data set, the endpoints cannot be assessed.
  • In summary, no conclusions regarding the extent of the additional benefit can be drawn from the morbidity data.
  • Furthermore, no data on quality of life were collected.
  • In summary, no conclusions regarding the extent of the additional benefit can be drawn from the data on side effects.

Courtesy translation only, please refer to the German original.