Bedaquilin (2) – Sirturo®

• Clinical trials
  • The benefit assessment is based on the pivotal Phase IIb registration trial TMC207-C208 (Stage 2). The trial investigated the antibacterial activity, safety and tolerability of bedaquiline and placebo, respectively, as part of a combination therapy ( background regime, BR ) in newly diagnosed patients with pulmonary, multidrug-resistant (MDR) TB with a positive sputum smear.
  • This was a 120-week, randomised, double-blind, multicentre, placebo-controlled trial with a parallel-group design, in which the enrolled patients were treated with bedaquiline or placebo as an ‘add-on’ to their ongoing background therapy for 24 weeks.

Adult patients 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

• For bedaquiline as part of an appropriate combination therapy, there is a substantial added benefit for adult patients with multidrug-resistant pulmonary tuberculosis (multidrug-resistant Mycobacterium tuberculosis; MDR-TB), where an effective treatment regimen cannot be formulated in any other way due to resistance or intolerance, there is a considerable additional benefit.
• On balance, however, the uncertainties regarding mortality do not call into question the significant advantage of bedaquiline in terms of morbidity.
• On the basis of the benefit assessment, the G-BA classifies the extent of the additional benefit of bedaquiline as part of a first-line therapy, in accordance with the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease, the written submissions, the oral hearing and against the backdrop of the current resistance situation, it is considered to be a considerable amount.
• mortality
  • Mortality was recorded in the C208 study 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 disparity in deaths between the treatment groups remains unexplained at present and is the subject of further investigations as part of the conditions of the conditional approval.
• 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, at 57%, compared with 33.3% in the placebo+BR control arm [HR: 1.67 [95% CI: 1.17; 2.38], p = 0.0055].
  • The high proportion of missing values at week 120 in both treatment arms leads to potential bias at the endpoint level (study withdrawal: control group 38.3%; intervention group 36.7%).
  • Notwithstanding the methodological uncertainties described, the significant difference observed in favour of the bedaquiline-containing combination therapy compared with placebo plus standard therapy for the endpoint of cure is considered to have a considerable extent given the current resistance situation.
• Morbidity – time to sputum freedom
  • By week 120, 61% of patients in the bedaquiline+BR arm and 36% of patients in the control arm achieved sputum-free status.
  • There was a statistically significant faster conversion in the bedaquiline arm after 86 days compared with the control arm at 345 days (HR [95% CI]: 2.01 [1.29; 3.14]; p = 0.002).
  • The operationalisation of the endpoint in the study required confirmation of freedom from the pathogen through two consecutive negative microbiological sputum cultures taken at least 28 days apart.
  • As the risk of transmission no longer exists, freedom from the pathogen is a fundamental prerequisite for repealing isolation.
  • The duration of patient isolation has an impact on quality of life and is of relevance to patients.
  • However, the pharmaceutical manufacturer did not collect data on either quality of life or hospitalisation.
  • It should also be noted that there is some overlap in the operationalisation of ‘freedom from the pathogen’ with the endpoint ‘cure’ as described.
• Morbidity – Relapse
  • By week 120, a relapse had been 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.
  • Uncertainties remain due to the operationalisation of the ‘relapse’ endpoint carried out by the pharmaceutical manufacturer, as there is no reference to cure; a relapse was defined not only following a prior cure, but also following a prior conversion.
  • Furthermore, there are overlaps between the operationalisation of the ‘relapse’ endpoint and that of the ‘cure’ endpoint.
• quality of life
  • Data on quality of life were not collected as part of the C208 study.
• Side effects
  • Adverse events were recorded from day 1 until 30 days after the last dose.
  • The median duration of treatment was 92 weeks in the bedaquiline arm and 94 weeks in the placebo arm.
  • At week 120, the incidence of AEs, severe AEs (AEs of grade ≥ 3) and study withdrawals was similar in both treatment groups.
  • Serious adverse events were more common in the bedaquiline+BR arm than in the placebo+BR arm, although this difference was not statistically significant.
  • The most common adverse events at SOC and PT level, defined as an incidence of ≥ 10% in one of the arms and a difference of at least 10 percentage points (rounded) between the arms, were diarrhoea (bedaquiline+BR versus placebo+BR: 6.3% versus 18.5%), dyspepsia (5.1% versus 14.8%), nervous system disorders (50.6% versus 40.7%), arthralgia (36.7% versus 22.9%) and tinnitus (3.8% versus 13.6%).
• Overall assessment
  • For bedaquiline as part of an appropriate combination therapy for the treatment of adult patients 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, data on mortality, morbidity and side effects are available from the pivotal Phase II RCT C208.
  • In summary, there is no statistically significant difference in the endpoint category of mortality.
  • However, based on the available data, uncertainties remain regarding the safety of bedaquiline due to the unexplained imbalance in the number of deaths occurring in the bedaquiline arm compared with the placebo arm.
  • Of the statistically significant differences shown in the morbidity category, the advantage of bedaquiline-containing standard therapy in the endpoint ‘cure according to WHO 2008’ at week 120 is of particular relevance in this assessment.
  • In the morbidity category, a considerable additional benefit is inferred overall, given the current resistance situation.
  • Data on quality of life were not collected as part of the study.
  • With regard to side effects, there were no statistically significant differences between the comparison arms in terms of the overall rates of severe adverse events (CTCAE grade ≥ 3) or SAE.
  • Overall, however, the uncertainties regarding mortality do not call into question the significant advantage of bedaquiline observed in terms of morbidity.

Courtesy translation only, please refer to the German original.