Tiotropium / Olodaterol (1) – Spiolto Respimat®

• Clinical trials
  • Two double-blind, multicentre, randomised controlled registration trials (TONADO 1 and TONADO 2), each with a study duration of 52 weeks, were included for the direct comparison of tiotropium/olodaterol with the appropriate comparator therapy.
  • The two 5-arm studies had a randomisation ratio of 1:1:1:1:1 (study arms: tiotropium/olodaterol (5 µg / 5 µg), tiotropium/olodaterol (2.5 µg / 5 µg), tiotropium (5 µg), tiotropium (2.5 µg) and olodaterol (5 µg)) and followed an identical protocol.

a) Adult patients with COPD of moderate severity or greater (50 % ≤ FEV1 < 80 % predicted)

• The likelihood of the finding being valid can, at most, be classified as an indication.
• Based on these considerations, the information in the dossier, the results of the benefit assessment and the addendum, as well as the statements submitted, the G-BA concludes that, for adult patients with COPD of moderate severity or greater (50 % ≤ FEV1 < 80 % predicted) an indication that there is evidence of a minor additional benefit of tiotropium/olodaterol compared with tiotropium.
• mortality
  • For patient population a, the meta-analysis of the included studies showed no statistically significant difference between the treatment groups for the patient-relevant endpoint of all-cause mortality.
  • Consequently, there is no hint of additional benefit from tiotropium/olodaterol compared with tiotropium.
  • An additional benefit in terms of overall survival is therefore not proven.
• Morbidity – COPD symptoms (Transition Dyspnoea Index (TDI) responders)
  • In the meta-analysis of the included studies, no statistically significant difference was observed between the treatment groups for the endpoint ‘COPD symptoms (TDI responders)’ at week 52 in patient population a.
  • Furthermore, there was an indication of an effect modification by the characteristic of sex for patient population a: a statistically significant advantage was observed for women (RR 1.50 [95% CI: 1.17; 1.91]; p = 0.001), whereas the results for men did not differ in a statistically significant manner.
  • The results of these subgroup analyses have no impact on the overall outcome of the treatment groups.
  • An additional benefit is therefore not proven for this endpoint for the entire patient group a.
• Morbidity – moderate and severe exacerbations
  • In the meta-analysis of the included studies, no statistically significant difference was observed between the treatment groups after 52 weeks for the endpoint ‘proportion of patients with moderate and severe exacerbations’.
  • An effect modification was observed for patient population a with regard to the characteristic ‘COPD severity’; however, this did not provide any hint of additional benefit.
  • An additional benefit is therefore not proven for this patient population.
• Morbidity – severe exacerbations
  • For patient population a, the meta-analysis of the included studies revealed significant unexplained heterogeneity at 52 weeks for the endpoint ‘proportion of patients with severe exacerbations’ (Q = 3.12; df = 1; p = 0.077; I = 68%).
  • No additional benefit is therefore proven.
• Morbidity – health status (Patient Global Rating, PGR)
  • Although there was some indication of effect modification with regard to sex, there was no hint of additional benefit for either men or women.
  • There is therefore no proof of additional benefit for this patient population.
• Morbidity – Health status (EQ-5D VAS)
  • In the meta-analysis of the included studies, there was no statistically significant difference between the treatment groups in patient population a for the health status endpoint (EQ-5D VAS) at 52 weeks.
  • There is no hint of additional benefit from tiotropium/olodaterol compared with tiotropium.
  • Consequently, the additional benefit for the health status endpoint (EQ-5D VAS) is not proven.
• Health-related quality of life – St George’s Respiratory Questionnaire (SGRQ) – responders
  • In the meta-analysis of the included studies, there was no statistically significant difference between the treatment groups for the SGRQ responder endpoint at week 52 in either patient population.
  • However, there is an indication of an effect modification with regard to the characteristic of sex: A statistically significant advantage was observed in women (RR 1.38 [95% CI: 1.08; 1.75]; p = 0.009), whereas no statistically significant difference was observed in men.
  • As there is no overall difference between the treatment groups for the SGRQ responder endpoint, the additional benefit of tiotropium/olodaterol compared with tiotropium is not proven for this endpoint in the overall patient group a.
• Side effects – overall rate of serious adverse events (SAEs)
  • For patient population a, the meta-analysis of the included studies revealed significant unexplained heterogeneity for the endpoint ‘overall rate of SAE’ at 52 weeks (Q = 1.70; df = 1; p = 0.192; I = 41.3%).
  • There is no hint of additional benefit.
  • An additional benefit is therefore not proven for this patient population.
• Conclusion on patient population a
  • Taking the results on mortality, morbidity, quality of life and side effects into account as a whole, tiotropium/olodaterol, compared with the appropriate comparator therapy (tiotropium), does not provide a significant improvement in treatment-related benefit that has not previously been achieved in this patient population; in particular, there is no alleviation of serious symptoms, no moderate prolongation of life, no relevant reduction in serious side effects, nor any significant reduction in other side effects.
  • Therefore, classification as a considerable additional benefit is not justified.
  • The G-BA assesses the extent of the minor additional benefit of tiotropium/olodaterol for this patient population as minor, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in the treatment of the disease.
  • In doing so, account is taken of the results for the endpoint ‘therapy discontinuations due to AEs’, which show an advantage for tiotropium/olodaterol compared with tiotropium.
  • In the present assessment, statistically significant differences in favour of the tiotropium/olodaterol combination were observed for the TDI and SGRQ responder endpoints in women.
  • As the significance of this effect modification remains unclear at present and is not reflected in other efficacy endpoints, no conclusions regarding the assessment of additional benefit are drawn from these data.
  • Consequently, no separate assessment is carried out based on the characteristic of sex, meaning that the results of these subgroup analyses have no impact on the overall outcome of the treatment groups.

b) Adult patients with COPD of more severe severity (30 % ≤ FEV1 < 50 % predicted or FEV1 < 30 % or respiratory failure) with ≥ 2 exacerbations per year

• For this patient population, the health status endpoint was assessed using the PGR and EQ-5D VAS; however, the pharmaceutical manufacturer presented only the PGR results.
• Against this background, the health status endpoint (PGR) is classified as potentially highly biased.
• Furthermore, the dossier did not take into account, for patient population b, the adequate application of the ITT principle for the health status endpoint (PGR) in the TONADO 1 study and the quality of life (SGRQ-Responder) in both studies was not taken into account; for this reason, both endpoints are classified as potentially highly biased in this patient population.
• Furthermore, country-specific differences in access to hospitals give rise to considerable uncertainty regarding the validity of the ‘severe exacerbations’ endpoint.
• Given that, in particular, statistical significance for one of the endpoints was achieved only through the meta-analysis but could not be demonstrated by the individual studies, the combined effect is an increased potential for bias in the validity of the results, meaning that the probability of the finding being true can be regarded as a hint.
• Based on these considerations, the information in the dossier, the results of the benefit assessment and the expert opinions, the G-BA concludes that, for adult patients with COPD of higher severity (30 % ≤ FEV1 < 50 % of predicted or FEV1 < 30% or respiratory insufficiency) experiencing ≥ 2 exacerbations per year, the G-BA identifies a hint of less benefit for tiotropium/olodaterol + ICS compared with the appropriate comparator therapy, tiotropium + ICS.
• Morbidity – severe exacerbations
  • For the endpoint ‘proportion of patients with severe exacerbations’ in the morbidity category, the meta-analysis of the studies revealed a statistically significant difference to the detriment of tiotropium/olodaterol + ICS compared with tiotropium + ICS (RR 3.32 [95% CI: 1.02; 10.84]; p = 0.047).
  • The proportion of patients treated with tiotropium/olodaterol + ICS who experienced severe exacerbations was 17.8% (TONADO 1) and 19.4% (TONADO 2).
  • In contrast, the proportion of patients treated with the appropriate comparator therapy, tiotropium + ICS, who experienced severe exacerbations was significantly lower: In the TONADO 1 study, no patients experienced severe exacerbations, whilst in the TONADO 2 study, 7.5% of patients experienced severe exacerbations.
  • These results indicate that, for patient population b, tiotropium/olodaterol + ICS offers less benefit than the appropriate comparator therapy, tiotropium + ICS, with regard to the endpoint of severe exacerbations.
• Conclusion on patient population b
  • When the results on mortality, morbidity, quality of life and side effects are considered as a whole, there are no positive findings for tiotropium/olodaterol + ICS compared with the appropriate comparator therapy, tiotropium + ICS, in this patient population; in particular, there was no prolongation of life, no significant reduction in serious side effects, and no significant reduction in other side effects.
  • In summary, there were statistically significantly more severe exacerbations during treatment with tiotropium/olodaterol + ICS than during treatment with tiotropium + ICS alone, indicating an increase in serious symptoms for tiotropium/olodaterol + ICS.
  • On the basis of the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in treating the disease, the G-BA assesses the benefit of tiotropium/olodaterol + ICS to be minor compared to the appropriate comparator therapy, tiotropium + ICS, for patient population b.
  • Compared with the appropriate comparator therapy, tiotropium + ICS, there is less benefit in accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV, as an increase in serious symptoms (endpoint: severe exacerbations) has been observed.

Courtesy translation only, please refer to the German original.