Umeclidinium / Vilanterol (1) – Anoro, Laventair®, Laventair®

• Clinical trials
  • To demonstrate the additional benefit, the pharmaceutical manufacturer submitted three directly comparative, randomised controlled trials (DB2113360, DB2113374 and ZEP117115) comparing umeclidinium/vilanterol with tiotropium.

a) Patients with chronic obstructive pulmonary disease (COPD) of moderate severity or greater (50 % ≤ FEV1 < 80 % predicted)

• The additional benefit is not proven.
• In this case, the subgroup analysis of patients not receiving concomitant ICS therapy is regarded as an approximation of the patient population under consideration and is used for the benefit assessment, as precise information on the history of exacerbations for the year prior to study inclusion is not available for patients not receiving concomitant ICS therapy.
• Nevertheless, it can be assumed that a significant proportion of patients not receiving concomitant ICS therapy (≥ 80 %) had fewer than 2 exacerbations in the year prior to the start of the study.
• mortality
  • The results on overall survival are based on data for the ‘overall mortality’ endpoint derived from information on deaths recorded as part of the documentation of (serious) adverse events (AEs) collected in studies DB2113360, DB2113374 and ZEP117115.
  • There is no statistically significant difference in overall survival between umeclidinium/vilanterol and tiotropium.
  • An additional benefit of umeclidinium/vilanterol compared with the appropriate comparator therapy is not proven for overall survival.
  • Consequently, the data for the relevant patient population (patients not taking ICS) do not allow for the conclusion that there is either an additional benefit or greater harm compared with tiotropium bromide.
• morbidity
  • In the dossier, the pharmaceutical manufacturer also cites the endpoints of rescue medication use, days without rescue medication use, FEV1 (trough level), weighted mean FEV1 and FEV1 responders to demonstrate its additional benefit.
  • The use of reliever medication (as rescue treatment) is regarded as a surrogate endpoint for COPD symptoms and is not, in itself, relevant to patients.
  • No proof has been provided to demonstrate the validity of rescue treatment as a surrogate endpoint for COPD symptoms.
  • FEV1 is assessed as a surrogate parameter and is not, in itself, patient-relevant.
  • The analyses submitted by the pharmaceutical manufacturer to validate FEV1 failed to provide proof that the effect of the treatment on the patient-relevant endpoints (exacerbations, COPD symptoms (TDI) and health-related quality of life (SGRQ)) is explained by the effect of the treatment on the surrogate endpoint FEV1.
• Morbidity – Transition Dyspnoea Index (TDI)
  • The Transition Dyspnoea Index (TDI) was used in studies DB2113360 and DB2113374 to measure shortness of breath.
  • A Focal Score of ≥ 1 is used as a valid response criterion, as this represents a clinically relevant improvement in breathlessness; in other words, the patient is now able to undertake an activity requiring significantly greater physical exertion without becoming breathless.
  • The responder analysis showed no statistically significant difference between the treatment groups.
• Morbidity – COPD Assessment Test (CAT)
  • The COPD Assessment Test (CAT) was used in studies DB2113360 and DB2113374 to measure COPD symptoms and the associated impairment of daily life.
  • The change in the total score compared with baseline and the number of CAT responders (patients with a change of at least two points in the total score) were examined.
  • The responder analysis shows no statistically significant difference between the treatment groups.
• Morbidity – SOBDA
  • The SOBDA questionnaire was used in studies DB2113360 and DB2113374 as a further validated instrument for measuring COPD symptoms.
  • Patients answered 13 questions on their perception of breathlessness whilst performing various activities every evening before going to bed, using a 5-point response scale.
  • The total score ranges from 1 to 4. A change of 0.2 is considered a relevant difference.
  • The responder analysis regarding the measurement of COPD symptoms using the SOBDA questionnaire shows no statistically significant difference between umeclidinium/vilanterol and tiotropium.
• Quality of life – St George’s Respiratory Questionnaire for COPD patients (SGRQ-C)
  • To assess health-related quality of life, the validated disease-specific questionnaire SGRQ-C was used in studies DB2113360, DB2113374 and ZEP117115.
  • The SGRQ-C covers the domains of symptoms, activity and impact in relation to social, functional and psychological impairments caused by the disease.
  • The change in the total score from baseline and the proportion of patients with a clinically relevant reduction of at least four points in the total score were analysed.
  • The responder analysis shows no statistically significant difference between the treatment groups for the population not receiving concomitant ICS therapy.
  • No additional benefit of umeclidinium/vilanterol compared with the appropriate comparator therapy is proven for the quality of life endpoint.
• Side effects
  • For the endpoint ‘discontinuation due to AEs’, the meta-analysis revealed no statistically significant difference between the treatment arms; for the endpoint ‘SAE’, there is significant heterogeneity without consistent results.
  • No notable differences were identified with regard to the results on specific side effects submitted by the pharmaceutical manufacturer as part of the commenting procedure.
  • Consequently, it is not proven that umeclidinium/vilanterol causes greater or minor harm compared with the appropriate comparator therapy, tiotropium, for these endpoints.
• Overall assessment
  • When the results on mortality, morbidity, quality of life and side effects are considered as a whole, no additional benefit or greater harm can be identified for umeclidinium/vilanterol compared with the appropriate comparator therapy, tiotropium, for the patient population of those with chronic obstructive pulmonary disease (COPD) of moderate severity or greater (50 % ≤ FEV1 < 80 % predicted).
  • The additional benefit is not proven.
  • For none of the patient-relevant endpoints was there a statistically significant advantage in favour of umeclidinium/vilanterol compared with the appropriate comparator therapy.
  • Furthermore, for the endpoints ‘moderate and severe exacerbations’ and ‘discontinuation due to AEs’, the results were heterogeneous and did not show consistent effects.

b) Patients with COPD of greater severity (30 % ≤ FEV1 < 50 % of predicted or FEV1 < 30 % or respiratory failure) with ≥ 2 exacerbations per year

• The additional benefit of umeclidinium/vilanterol compared with the appropriate comparator therapy (inhaled corticosteroids in addition to long-acting beta-2-agonists (formoterol or salmeterol) or long-acting anticholinergics (tiotropium bromide) or a combination of both classes of active substances) is deemed not proven.
• The pharmaceutical manufacturer has not provided any data to demonstrate additional benefit for this patient group, as too few patients meeting the criteria for this patient population were included in the three direct comparative studies considered.
• Due to the lack of data, no additional benefit can be inferred for this patient population.

Courtesy translation only, please refer to the German original.