Fluticasonfuroat / Vilanterol-Trifenatat (2) – Relvar Ellipta®

• Clinical trials
  • The SLS Asthma trial is a multicentre, randomised, controlled, open-label Phase 3 trial investigating the efficacy and safety of fluticasone furoate/vilanterol (FF/VI) compared with standard therapy in adult patients (N=4233) who had been receiving asthma maintenance therapy with inhaled corticosteroids (ICS) or ICS/long-acting beta-agonists (LABAs) for ≥ 4 weeks and were symptomatic, over a period of 12 months.
  • The Fregate study is a multicentre, randomised, controlled, open-label Phase 3b trial in which the efficacy and safety of FF/VI were investigated in comparison with the existing ICS/LABA fixed-dose combinations FP/SALM and BUD/FOR over 6 months.
  • The 201378 study is a multicentre, randomised, controlled, three-arm, double-blind, double-dummy Phase 3 study in adult and adolescent patients (N=1522) with persistent asthma for whom ICS and LABA have been discontinued twice daily.
  • HZA113091 is a multicentre, randomised, controlled, double-blind, double-dummy Phase 3 trial (N=806) designed to investigate the efficacy and safety of FF/VI 100/25 µg once daily compared with FP/SALM 250/50 µg twice daily over 24 weeks.

Combinations of glucocorticoids with long-acting beta-2 sympathomimetics, Group 1, at Level 3

• On the basis of the documentation submitted by the pharmaceutical manufacturer and following consideration of the comments presented during the written and oral consultation procedures, the G-BA finds that evidence of additional medical benefit as a therapeutic improvement in accordance with Section 35(1b), sentences 1 to 5 of SGB V, in accordance with Section 35a(1), sentence 4, and (3) in conjunction with (4), sentence 1 of SGB V, has not been provided.
• Taking all study results into account, there is no therapeutic improvement within the meaning of Section 35(1b) of the SGB V, as there is no proof that the combination FF/VI offers a clinically relevant greater benefit than other medicinal products in this class of active substances and is therefore to be preferred to the other medicinal products in this class as an appropriate treatment, either on a routine basis or for relevant patient groups or indications.
• Morbidity – Severe asthma exacerbations
  • For key outcome parameters such as severe asthma exacerbations and hospitalisations, none of the studies submitted showed any differences indicating a clinically relevant greater benefit of FF/VI.
• Morbidity – Asthma symptoms (Asthma Control Test, ACT)
  • Only the data from the open-label SLS Asthma study show statistically significant differences in favour of FF/VI for the morbidity endpoint of asthma symptoms as measured by the ACT:
  • In the patient population of patients receiving ICS monotherapy as maintenance treatment prior to the start of the study – a population representative of and relevant to the usual clinical setting – no significant difference was observed in the ACT.
• Morbidity – Health status (EQ-5D-VAS)
  • Although the EQ-5D-VAS revealed a statistically significant difference in health status, the effect is below the clinical relevance threshold of 0.2 (measured using Hedges’ g).
• Health-related quality of life – Asthma Quality of Life Questionnaire (AQLQ)
  • Furthermore, the SLS Asthma trial demonstrated statistically significant and clinically relevant advantages for the quality of life endpoint as measured by the AQLQ.
  • However, the difference between the responder rates in the FF/VI arm and the comparator arm was only 10% (50 versus 40%).
  • In the patient population of patients receiving ICS monotherapy as maintenance treatment prior to the start of the study – a patient population representative of and relevant to the usual clinical setting – no significant difference was observed.
  • When comparing the mean differences, the effect size estimate for the overall result is only 0.29, which generally corresponds to a small effect.
• Side effects
  • Safety endpoints included (serious) adverse events, study discontinuations due to (serious) adverse events, (serious) adverse events of particular interest, pneumonia and hospitalisations.
  • With regard to the comparison of the FF/Vl with other ICS/LABA combinations from the relevant fixed-amount group, no relevant differences were demonstrated in terms of mortality, morbidity and side effects in the blinded studies HZA 201378 and HZA 113091, or in the open-label FREGATE study.
• Overall assessment
  • In summary, no advantages were demonstrated for the key morbidity endpoints of exacerbations and hospitalisation.
  • For the endpoint of asthma symptoms, a statistically significant advantage was demonstrated on the basis of the ACT in only one of the four studies, which also exhibited a high potential for bias due to the lack of blinding.
  • With regard to the quality of life endpoint (AQLQ), the results do not indicate a therapeutically significant extent, regardless of their clinical relevance.
  • The high risk of bias in the SLS Asthma study must also be taken into account for this endpoint.
  • Qualitatively, it cannot be inferred from the study data provided that the advantages have a therapeutic extent, for example in alleviating serious symptoms.

Courtesy translation only, please refer to the German original.