Bedaquilin (3) – Sirturo®

• Clinical trials
  • Study C211 is a single-arm, open-label, multicentre Phase II study designed to investigate the pharmacokinetics, safety, tolerability and anti-mycobacterial efficacy of bedaquiline as part of a combination therapy (background regime, BR) in adolescent patients with confirmed or probable MDR-TB.

Adolescent patients (aged 12 years to under 18 years and weighing at least 30 kg) with multidrug-resistant pulmonary tuberculosis (multidrug-resistant Mycobacterium tuberculosis; MDR-TB), where an effective treatment regimen cannot be established other than with bedaquiline (as part of an appropriate combination therapy) due to resistance or intolerance.

• mortality
  • No deaths occurred in the C211 study.
• Morbidity – Resolution of clinical TB symptoms
  • The resolution of TB symptoms should 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 cure.
  • 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 a priori defined criteria for classification was not envisaged in this multicentre study.
  • Due to the unclear operationalisation, the endpoint cannot be assessed.
• 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 14 November 2017 (median follow-up period approx. 40 weeks).
  • The number of participants experiencing AEs was very similar across both observation periods, although the total study duration was approximately 16 weeks longer than the 24-week treatment phase with bedaquiline + BR.
  • Adverse events (AEs) occurred in 93.3% of participants; approximately 26.7% experienced AEs of severity grade ≥ 3, 13.3% experienced serious AEs, and 33.3% experienced AEs of particular interest.
  • No AEs led to discontinuation of bedaquiline therapy; however, 33.3% of participants had to discontinue their background therapy.
  • Results for a longer observation period were not presented; consequently, a comprehensive assessment of the long-term effects of the treatment is not currently possible.
  • In summary, no conclusions regarding the extent of the additional benefit can be drawn from the data on side effects.
• Overall assessment / Conclusion
  • For bedaquiline as part of a suitable combination therapy for the treatment of adolescent patients (aged 12 years to under 18 years and weighing at least 30 kg) with multidrug-resistant pulmonary tuberculosis (multidrug-resistant Mycobacterium tuberculosis; MDR-TB), where an effective treatment regimen cannot otherwise be established due to resistance or intolerance, results on mortality, morbidity and side effects are available from the C211 study.
  • No deaths occurred in the C211 study.
  • In the morbidity endpoint category, the endpoints ‘absence of the pathogen in sputum’, ‘resolution of TB symptoms – assessed by medical trial staff’ and ‘relapses’ were recorded.
  • Due to limitations regarding operationalisation, the single-arm study design, the minor sample size and the short observation period of 24 weeks for this therapeutic indication, the endpoints cannot be evaluated.
  • 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.
  • The evidence transfer sought by the pharmaceutical manufacturer has not been achieved, partly due to the unclear comparability of the patient populations and disease symptoms between studies C208 and C211, and the significantly shorter observation period of 24 weeks in study C211 compared with study C208 (120 weeks), the evidence transfer sought by the pharmaceutical company is not accepted for the early benefit assessment.
  • Due to the lack of comparative data, the short study duration and the high potential for bias in the single-arm study C211, the G-BA classifies the extent of the additional benefit for bedaquiline as non-quantifiable.
  • In summary, for bedaquiline as part of a combination therapy for multidrug-resistant pulmonary tuberculosis in adolescents, a hint of non-quantifiable additional benefit is derived.
• Overall assessment / Conclusion
  • For bedaquiline as part of a suitable combination therapy for the treatment of adolescent patients (aged 12 years to under 18 years and with a body weight of at least 30 kg) with multidrug-resistant pulmonary tuberculosis (multidrug-resistant Mycobacterium tuberculosis; MDR-TB), where an effective treatment regimen cannot otherwise be established due to resistance or intolerance, results on mortality, morbidity and side effects are available based on the C211 study.
  • No deaths occurred in the C211 study.
  • In the morbidity endpoint category, the endpoints ‘absence of the pathogen in sputum’, ‘resolution of TB symptoms – assessed by medical study staff’ and ‘relapses’ were recorded.
  • Due to limitations regarding operationalisation, the single-arm study design, the minor sample size and the short observation period of 24 weeks for this therapeutic indication, the endpoints cannot be evaluated.
  • 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.
  • The evidence transfer sought by the pharmaceutical manufacturer has not been achieved, partly due to the unclear comparability of the patient populations and disease symptoms between studies C208 and C211, and the significantly shorter observation period of 24 weeks in study C211 compared with study C208 (120 weeks), the evidence transfer sought by the pharmaceutical company is not accepted for the early benefit assessment.
  • Due to the lack of comparative data, the short study duration and the high potential for bias in the single-arm study C211, the G-BA classifies the extent of the additional benefit for bedaquiline as non-quantifiable.
  • In summary, for bedaquiline as part of a combination therapy for multidrug-resistant pulmonary tuberculosis in adolescents, a hint of non-quantifiable additional benefit is derived.

Courtesy translation only, please refer to the German original.