Fluticasonfuroat / Umeclidinium / Vilanterol (Trelegy Ellipta, Elebrato Ellipta, 1) – Trelegy Ellipta, Elebrato Ellipta®, Elebrato 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 dual combination of fluticasone furoate and vilanterol (FF/VI) and the fixed dual combination of umeclidinium and vilanterol (UMEC/VI) in patients with COPD.
  • The randomised, double-blind, controlled FULFIL trial was conducted between January 2015 and April 2016 and investigated the use of the fixed triple combination FF/UMEC/VI versus the dual combination of budesonide and formoterol in patients with COPD.

Adult patients with moderate to severe chronic obstructive pulmonary disease (COPD) who have had their use of a combination of a long-acting beta-2 agonist (LABA) and a long-acting muscarinic receptor antagonist (LAMA) discontinued

• The additional benefit is not proven.
• However, for patients who experience further exacerbations whilst on dual therapy with a LABA and a LAMA, escalation to a triple combination of a LABA, a LAMA and an ICS would be indicated according to current treatment guidelines. It must be assumed that patients in the comparator arm did not receive adequate treatment according to the current state of medical knowledge. For this reason, no conclusions can be drawn regarding the additional benefit of FF/UMEC/VI from the IMPACT and FULFIL studies.
• mortality
  • With regard to all-cause mortality (deaths occurring during treatment with study medication, between the start of study treatment and the end of the follow-up period (7 days after the last dose of study medication)), there were 6 deaths (1.5%) in the FF/UMEC/VI arm and 2 deaths (0.6%) in the FF/VI arm. The difference between the treatment groups is not statistically significant.
  • In the FULFIL trial, deaths were recorded as part of the adverse event monitoring. One death occurred during the trial. There was no statistically significant difference between the treatment groups.
• Morbidity – Exacerbations
  • For the endpoint of exacerbations in both studies, data were available on the ‘annual exacerbation rate’ (‘moderate or severe exacerbations’ and ‘severe exacerbations’, respectively) and, additionally, the ‘proportion of patients with an event’.
  • In the IMPACT study, the annual exacerbation rate for the endpoint ‘moderate or severe exacerbations’ was 0.84 in the FF/UMEC/VI arm and 1.11 in the FF/VI arm (47 per cent and 48 per cent of patients, respectively, experienced an exacerbation within 52 weeks) and, for the endpoint ‘severe exacerbations’, 0.14 in the FF/UMEC/VI arm and 0.13 in the FF/VI arm (11% and 9% 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 [0.62; 0.94], p < 0.001) and is thus statistically significant in favour of FF/UMEC/VI. For “severe exacerbations”, the rate ratio is 1.04; the result is not statistically significant between the treatment groups.
  • In the FULFIL study, the annual exacerbation rate for the endpoint ‘moderate or severe exacerbations’ was 0.38 in the FF/UMEC/VI arm and 0.27 in the control arm (18% and 14% of patients, respectively, experienced an exacerbation within 24 weeks). Two patients in each of the two study arms experienced severe exacerbations. For both endpoints, there was no statistically significant difference between the treatment groups.
• Morbidity – CAT responders
  • The COPD Assessment Test (CAT) assesses COPD symptoms and the associated impairments in patients’ daily lives. For the ‘CAT responder’ endpoint (a reduction in the CAT score of ≥ 2 points), no statistically significant difference was observed between the treatment groups in either study.
• 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 both studies using the PGR and the EQ-5D VAS. In the IMPACT study, there was no statistically significant difference between the treatment arms for either questionnaire.
  • In the FULFIL study, no usable data are available for the EQ-5D VAS. With regard to the PGR, a higher proportion of patients in the FF/UMEC/VI arm reported that the severity of their COPD had improved after 24 weeks of treatment (‘much better’, ‘better’ or ‘slightly better’), whereas patients in the control arm mainly rated the severity of their COPD as unchanged or worsened (OR = 0.42, 95% CI [0.24; 0.72]; p = 0.002).
• Health-related quality of life – SGRQ responders
  • Health-related quality of life was assessed using the St George’s Respiratory Questionnaire (SGRQ). Patients with a reduction in their total score of at least 4 scale points were classified as responders, with a reduction in the score indicating an improvement.
  • In the IMPACT study, a statistically significant advantage in quality of life was observed in favour of FF/UMEC/VI compared with FF/VI, as measured by SGRQ responders at week 52 (37% vs. 29%; RR = 1.27; 95% CI [1.03; 1.57]; p = 0.024).
  • In the FULFIL study, no statistically significant difference in quality of life was observed between the treatment arms at week 24.
• Side effects – severe adverse events (SAEs) and discontinuation due to AEs
  • For SAE (non-fatal, excluding exacerbation events) and for AEs leading to discontinuation of treatment (excluding exacerbation events), there was no statistically significant difference between the treatment groups in the IMPACT study at week 52 or in the FULFIL study at week 24.
• Side effects – Pneumonia
  • In both studies, there were no statistically significant differences between the treatment groups with regard to pneumonia.
• Conclusions from the IMPACT and FULFIL studies
  • In both studies, the enrolled patients exhibited moderate to very severe airway obstruction (GOLD stages 2 to 4) despite having received COPD maintenance therapy for at least three months prior to study enrolment.
  • Taken together, the appropriate comparator therapy was not implemented in either study, and it must be assumed that patients in the comparator arm were not treated in accordance with the current state of medical knowledge. Against this background, neither study can be used to derive the additional benefit of FF/UMEC/VI.
  • Notwithstanding this, the results for the relevant patient population of the IMPACT study show a statistically significant advantage from the administration of FF/UMEC/VI compared with FF/VI in terms of the annual rate of moderate and severe exacerbations, as well as in terms of quality of life (measured using the SGRQ-Responder). In the FULFIL study, the corresponding patient population showed advantages of FF/UMEC/VI compared with BUD/FOR in terms of the severity of COPD (measured using the PGR). For all other endpoints relating to morbidity, mortality and side effects, no statistically significant differences were observed between the treatment groups in either study.

Courtesy translation only, please refer to the German original.