Delamanid (1) – Deltyba®

• Clinical trials
  • The multicentre, randomised, double-blind Phase III trial 213 investigated the safety and efficacy of orally administered delamanid versus placebo, each in combination with OBR, in adult patients with sputum culture-positive pulmonary MDR.
  • Study 242-07-204 (= Study 204) is a multicentre, double-blind, randomised, placebo-controlled Phase II study designed to investigate the safety, efficacy and pharmacokinetics of delamanid in combination with an optimised standard combination regimen (OBR) compared with placebo plus OBR in patients with sputum culture-positive pulmonary MDR-TB.
  • Study 233 is an open-label, uncontrolled study designed to investigate the efficacy, safety and pharmacokinetics of delamanid in children and adolescents from birth up to the age of 17 with a confirmed or suspected diagnosis of MDR-TB.

a) Adults with multidrug-resistant pulmonary tuberculosis, where no other treatment with high efficacy can be formulated due to resistance or for reasons of tolerability

• Hint for a non-quantifiable additional benefit, as the scientific data do not permit quantification.
• Mortality – overall survival
  • Overall mortality was recorded in the 213 study. By week 130, there had been 18 deaths in the delamanid arm (5.3%) and 8 deaths in the placebo arm (4.7%); the result is not statistically significant.
• Morbidity – Sustained sputum culture conversion
  • Sustained sputum culture conversion (SCC) is defined as SCC (two consecutive sputum samples collected at least 25 days apart, which were M. tuberculosis), achieved by month 6 and not followed by any confirmed positive results (≥ 2 positive results) thereafter.
  • In the present study, sustained sputum culture conversion was analysed by number of events and as a time-to-event analysis. Both analyses showed no significant differences between the study arms.
• Morbidity – Cure
  • The endpoint ‘cure’ was operationalised as a secondary endpoint largely in accordance with the WHO 2008 definition of cure.
  • At week 130, there was no statistically significant difference in the proportion of patients who had achieved cure.
• Morbidity – Clinical signs and symptoms
  • In Study 213, changes in the clinical signs and symptoms ‘cough’, ‘haemoptysis’, ‘dyspnoea’, ‘chest/thoracic pain’, ‘night sweats’, ‘weight loss’, ‘loss of appetite’ and ‘feeling feverish’ were recorded over the course of the study.
  • However, no comparative analysis using effect estimators was presented. It is therefore not possible to draw conclusions regarding the extent of the additional benefit for this endpoint.
• quality of life
  • Data on quality of life were not collected as part of Study 213.
• Side effects
  • Despite the uncertainties in operationalisation, no statistically significant differences were observed between the treatment arms in the assessment of serious or severe AEs or AEs leading to discontinuation of the study medication.
  • No AEs of particular interest were defined or analysed.
• Overall assessment / Conclusion
  • For delamanid as part of a suitable combination therapy for multidrug-resistant pulmonary tuberculosis (MDR-TB) in adults, where no other treatment of adequate efficacy can be formulated due to resistance or for reasons of tolerability, the Phase IIIRCT 213, data on mortality, morbidity and side effects are available.
  • In summary, no statistically significant difference was observed in the mortality endpoint category. In the morbidity category, the endpoints ‘cure’ and ‘clinical signs and symptoms’ were identified as patient-relevant and used for the benefit assessment. In each case, there were no statistically significant differences between the treatment arms. Data on quality of life were not collected as part of the study. In the category of side effects, there were also no statistically significant differences between the treatment arms.
  • In summary, no conclusions regarding the extent of the additional benefit can be drawn from the data. A quantitative assessment of the extent of the effect and a quantification of the additional benefit as ‘minor’, ‘considerable’ or ‘major’ is not possible on the basis of the data provided.
  • Taking into account the severity of the disease, the written submissions and the oral hearing, the G-BA classifies the extent of the additional benefit of delamanid for the treatment of adult patients with multidrug-resistant pulmonary tuberculosis (MDR-TB), where an effective treatment regimen cannot otherwise be formulated due to resistance or intolerance, as ‘non-quantifiable’ on the basis of the criteria set out in Section 5(7) of the AM-NutzenV, because the scientific evidence does not permit quantification.

b) Children and adolescents with multidrug-resistant pulmonary tuberculosis and a body weight of at least 10 kg, where no other treatment with high efficacy can be formulated due to resistance or for reasons of tolerability

• Hint for a non-quantifiable additional benefit, as the scientific evidence does not permit quantification.
• Mortality – Overall survival
  • Overall mortality was recorded in study 233. At the end of the study in month 24, one person in the 3–5-year-old age group had died and one person was lost to follow-up.
  • Due to the small sample size, the low number of events and the lack of a comparator, the effect of delamanid on mortality in the paediatric population cannot be conclusively assessed.
• Morbidity – Cure
  • The treatment outcome was recorded by the medical study staff 24 months after administration of the first dose of delamanid. The treatment outcome was assessed in accordance with the WHO outcome definition for the treatment of patients with MDR-TB.
  • Three of the twelve study participants were recorded as cured at the end of the study. However, the description of the operationalisation contains gaps.
  • In particular, the paucibacillary form of TB and the difficulty in obtaining sputum samples can significantly complicate the cultural diagnosis of TB in children and, consequently, the confirmation of cure.
• Morbidity – Clinical signs and symptoms
  • The presence of clinical signs and symptoms of TB was assessed by study staff throughout the course of Study 233. However, the description of the operationalisation contains gaps.
  • On day 182, following completion of delamanid treatment, the clinical sign ‘night sweats’ was recorded once and the sign ‘loss of appetite’ was recorded once for the 12 study participants.
• quality of life
  • Data on quality of life were not collected as part of Study 233.
• Side effects
  • Adverse events (AEs) were recorded in Study 233 from the first administration of delamanid up to Day 365 for each individual patient.
  • By day 365, approximately 8% had experienced serious AEs and 17% had experienced severe AEs. In no patient did AEs lead to discontinuation of delamanid therapy.
• Overall assessment
  • Delamanid is indicated as part of an appropriate combination therapy for multidrug-resistant pulmonary tuberculosis (MDR-TB) in adolescents, children and infants weighing at least 10 kg, where no other effective treatment can be formulated due to resistance or for reasons of tolerability, results on mortality, morbidity and side effects are available from the open-label, uncontrolled Study 233.
  • One death occurred in Study 233.
  • In the morbidity endpoint category, the endpoints ‘cure’ and ‘clinical signs and symptoms’ were recorded. Due to limitations regarding operationalisation, the single-arm study design and the small sample size, no definitive conclusions can be drawn in these endpoint categories. 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, due to the small sample size, the low number of events and the lack of a comparator.
  • Due to the lack of comparative data from the single-arm study 233, the G-BA assesses the extent of the additional benefit of delamanid for the treatment of multidrug-resistant tuberculosis (MDR-TB) in adolescents, children and infants weighing at least 10 kg, where no other treatment of adequate efficacy can be devised due to resistance or for reasons of tolerability, as non-quantifiable on the basis of the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease, the written submissions and the oral hearing, because the scientific evidence does not permit quantification.

Courtesy translation only, please refer to the German original.