Bedaquilin (5) – Sirturo®

• Clinical trials
  • Study C208 investigated the antibacterial activity, safety and tolerability of bedaquiline and placebo, respectively, each as part of a combination therapy (background regime, BR) in newly diagnosed patients with pulmonary, multidrug-resistant (MDR) TB with a positive sputum smear.
  • The C208 trial is a 120-week, randomised, double-blind, multicentre, placebo-controlled study with a parallel-group design, in which enrolled patients received bedaquiline or placebo as an ‘add-on’ to their ongoing background therapy for 24 weeks.
  • The STREAM study is a multicentre, randomised, open-label, parallel-group Phase III study in patients with MDR-TB, including those with rifampicin-resistant and isoniazid-sensitive TB.

Adult patients with multidrug-resistant pulmonary tuberculosis for whom an effective treatment regimen cannot be established other than with bedaquiline (as part of an appropriate combination therapy) due to resistance or intolerance

• For bedaquiline as part of an appropriate combination therapy, there is evidence of substantial added benefit for adult patients with multidrug-resistant pulmonary tuberculosis, for whom an effective treatment regimen cannot be established by any other means due to resistance or intolerance, there is a hint of considerable additional benefit.
• The certainty of the evidence is classified as ‘hint’.
• mortality
  • Mortality was recorded in the C208 trial and during long-term follow-up as part of the safety assessment.
  • By week 120, there had been 10 deaths in the bedaquiline arm (12.7%) and 3 deaths in the placebo arm (3.7%); this result is not statistically significant.
  • The supplementary STREAM (Stage 2) study provides no indications to support the numerically increased overall mortality in the bedaquiline arm of the C208 study; consequently, an increased mortality rate with bedaquiline cannot be assumed overall.
• Morbidity – Cure (according to the 2008 WHO definition)
  • At week 120, the proportion of patients who achieved a cure according to the 2008 WHO definition was significantly higher in the bedaquiline+BR arm.
  • The high proportion of missing values at week 120 in both treatment arms leads to potential bias at the endpoint level (study discontinuation: control group 38.3 per cent; intervention group 36.7 per cent).
  • Furthermore, at the time of the final data cut-off at week 120, not all patients had yet completed the trial.
• Morbidity – time to sputum clearance
  • By week 120, 61% of patients in the bedaquiline+BR arm and 36% of patients in the control arm achieved sputum clearance.
  • There was a statistically significant faster conversion in the bedaquiline arm after 86 days compared with the control arm at 345 days.
• Morbidity – relapse
  • By week 120, relapse was diagnosed in 7.6% of patients in the intervention arm and 13.6% of patients in the control arm; the difference between the treatment arms is not statistically significant.
• quality of life
  • No data on health-related quality of life were collected.
• Side effects
  • At week 120, there was no statistically significant difference in the incidence of severe AEs, SAEs or therapy discontinuations due to AEs between the bedaquiline+BR and placebo+BR arms.
  • Among AEs of any severity, categorised by system organ class and preferred term with an incidence of ≥ 10%, the most common AEs in both groups were ‘nausea’, ‘vomiting’ and ‘arthralgia’.
  • Only for the preferred terms ‘diarrhoea’ and ‘tinnitus’ was there a statistically significant difference in favour of the bedaquiline+BR group.
• Overall assessment
  • In the mortality endpoint category, study C208 showed no statistically significant difference between the treatment arms.
  • In the morbidity category, there was a statistically significant and clinically meaningful advantage for the bedaquiline-containing standard therapy in the endpoint “cure according to WHO 2008” at week 120.
  • Data on quality of life were not collected as part of the C208 study.
  • With regard to side effects, there were no statistically significant differences between the treatment arms in terms of the overall rates of severe adverse events (CTCAE grade ≥ 3) or SAE (serious unspecified events).
  • Overall, there is a significant advantage for bedaquiline in the morbidity endpoint category.
  • The G-BA therefore classifies the extent of the additional benefit of bedaquiline for the treatment of multidrug-resistant tuberculosis in adults as considerable, based on the criteria set out in Section 5(8) in conjunction with § 5(7), first sentence, points 1 to 4 of the AM-NutzenV, as considerable.

Courtesy translation only, please refer to the German original.