Fluticasonfuroat / Umeclidinium / Vilanterol (1) – Trelegy Ellipta®

• Clinical trials
  • The randomised, controlled, double-blind IMPACT trial was conducted between June 2014 and July 2017 and investigated the once-daily inhaled administration of the triple-fixed-dose combination fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) once daily by inhalation, compared with the fixed-dose dual combination of fluticasone furoate/vilanterol (FF/VI) and the fixed-dose dual combination of umeclidinium/vilanterol (UMEC/VI) in patients with COPD.
  • The randomised, double-blind, controlled study 200812 was conducted between June 2016 and May 2017 and investigated the administration of the fixed triple combination FF/UMEC/VI against the free triple combination of FF/VI and UMEC (hereinafter FF/VI + UMEC) in patients with COPD.

Patients with moderate to severe chronic obstructive pulmonary disease (COPD) who have their combination therapy with inhaled corticosteroids (ICS) and long-acting beta-2 agonists (LABA) discontinued

• For this reason, the G-BA concludes that the additional benefit of fluticasone furoate/umeclidinium/vilanterol for the treatment of adult patients with moderate to severe COPD who have had their combination therapy with inhaled corticosteroids (ICS) and long-acting beta-2 agonists (LABA) discontinued is not proven.
• mortality
  • For all-cause mortality, deaths occurring during treatment with the study medication (between the start of study treatment and the end of the follow-up period (7 days after the last dose of the study medication)) were recorded. Sixteen patients (1.3%) died in the FF/UMEC/VI arm and 16 patients (2.8%) in the UMEC/VI arm (HR = 0.43; 95% CI [0.21; 0.85] p = 0.016).
  • In study 200812, deaths were recorded as part of the adverse event monitoring. One death occurred during the study. There was no statistically significant difference between the treatment groups.
• Morbidity – Exacerbations
  • In the IMPACT study, the annual exacerbation rate for the endpoint ‘moderate or severe exacerbations’ was 0.71 in the FF/UMEC/VI arm and 0.93 in the UMEC/VI arm (40% and 45% of patients, respectively, experienced an exacerbation within 52 weeks) and, for the endpoint ‘severe exacerbations’, 0.11 in the FF/UMEC/VI arm and 0.16 in the UMEC/VI arm (9% and 12% of patients, respectively, experienced a severe exacerbation within 52 weeks). The rate ratio of annual exacerbation rates is therefore 0.76 for ‘moderate or severe exacerbations’ (95% CI [0.65; 0.89], p<0.001) and 0.67 (95% CI [0.48; 0.94], p = 0.019) for ‘severe exacerbations’, respectively, and is thus statistically significant in favour of FF/UMEC/VI.
  • In the 200812 study, the annual exacerbation rate for the endpoint ‘moderate or severe exacerbations’ was 0.40 in the FF/UMEC/VI arm and 0.47 in the control arm (20% and 19% of patients, respectively, suffered an exacerbation within 24 weeks). In total, severe exacerbations occurred in only three patients (approximately 1% of patients). For both endpoints, there was no statistically significant difference between the treatment arms.
• Morbidity – CAT responders
  • The ‘CAT responder’ endpoint was assessed exclusively in the IMPACT study and represents patients with a reduction in the CAT score of ≥ 2 points, whereby a reduction in the score indicates an improvement.
  • In the IMPACT study, there was no statistically significant difference between the treatment arms with regard to the ‘CAT responder’ endpoint.
• Morbidity – Transition Dyspnoea Index (TDI-SAC)
  • In both the IMPACT study and the 200812 study, there was no statistically significant difference between the treatment arms for the endpoint ‘mean change in the TDI Focal Score from baseline’ at week 52 (IMPACT) and at week 24 (200812), respectively.
• Morbidity – Patient Global Rating (PGR) and European Quality of Life Questionnaire 5 Dimensions (visual analogue scale, EQ-5D VAS)
  • Patients’ health status was assessed in the IMPACT study using the PGR and the EQ-5D VAS. Overall, however, no statistically significant difference was observed between the treatment arms for either questionnaire.
• Health-related quality of life – SGRQ responders
  • In the IMPACT study, a statistically significant advantage in quality of life was observed in favour of FF/UMEC/VI compared with UMEC/VI, as measured by the SGRQ-Responder at week 52 (48% vs. 39%; RR = 1.22; 95% CI [1.08; 1.37]; p < 0.001).
  • In the 200812 study, there was no statistically significant difference between the treatment arms with regard to the ‘SGRQ responder’ endpoint at week 24.
• Side effects – severe adverse events (SAEs)
  • For non-fatal SAE (excluding exacerbation events), there was no statistically significant difference between the treatment groups, neither in the IMPACT study at week 52 nor in the 200812 study at week 24.
• Side effects – Discontinuation due to AEs
  • In the IMPACT study, a statistically significant lower proportion of patients in the FF/UMEC/VI arm discontinued treatment due to AEs by week 52 (3.3% vs. 5.9%; RR=0.56; 95% CI [0.36; 0.87]; p=0.009).
  • In the 200812 study, there was no statistically significant difference between the treatment groups at week 24 (1.4% vs. 0%).
• Conclusion
  • For the benefit assessment of fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) for the treatment of adult patients with moderate to severe COPD who are not adequately controlled with combination therapy comprising inhaled corticosteroids (ICS) and long-acting beta-2 agonists (LABA), the IMPACT and 200812 studies have been discontinued.
  • In the IMPACT study, at the start of the trial, all patients in the intervention arm underwent a step-up in treatment from the dual combination of ICS/LABA to the triple combination of FF/UMEC/VI, whereas in the control arm, patients were switched to dual therapy consisting of LABA/LAMA (UMEC/VI). In the 200812 study, by contrast, treatment was escalated in both study arms from the dual combination of ICS/LABA to the triple combination of FF, UMEC and VI, with patients in the control arm receiving the ‘loose’ triple combination. Furthermore, no adjustment to treatment was possible during the course of the study. In the case of the two studies, 200812 and IMPACT, it is therefore not possible to assess whether, and to what extent, patients in the relevant patient populations of the studies received adequate treatment for their COPD.
  • In the G-BA’s view, it would have been necessary to allow for a patient-specific assessment of the indication for ICS in line with the appropriate comparator therapy determined by the G-BA. As the appropriate comparator therapy defined by the G-BA – namely, patient-specific treatment optimisation, taking prior therapy into account, with LABA and LAMA and, where appropriate, ICS – what was not implemented, the studies cannot be used to derive the additional benefit of the active ingredient combination FF/UMEC/VI.
  • For this reason, the G-BA concludes that the additional benefit of fluticasone furoate/umeclidinium/vilanterol for the treatment of adult patients with moderate to severe COPD who have their combination therapy with inhaled corticosteroids (ICS) and long-acting beta-2 agonists (LABA) discontinued has not been proven.

Courtesy translation only, please refer to the German original.