Aclidiniumbromid (2) – Eklira Genuair, Bretaris Genuair®, Bretaris® Genuair®

• Clinical trials
  • The ACLIFORM and AUGMENT trials are two identically designed, conducted in parallel, double-blind, randomised, controlled Phase III trials investigating the efficacy and safety of aclidinium bromide and aclidinium bromide in combination with formoterol, respectively.
  • A total of 3,421 patients were enrolled in the trials (1,729 patients in ACLIFORM, AUGMENT: 1,692 patients) were enrolled and randomised to five treatment arms in each study; for the present benefit assessment, the two study arms in which patients were treated with aclidinium bromide or formoterol, respectively, are relevant.

1a) Adult patients with COPD of moderate severity or greater (50 % ≤ FEV1 < 80 % predicted) – patients with severity grade II (50 % ≤ FEV1 < 80 % predicted)

• The additional benefit is not proven.
• mortality
  • Very few deaths occurred in either study. In the ACLIFORM study, one death occurred in the comparator arm; in the AUGMENT study, two deaths occurred. The difference between the respective study arms is not statistically significant.
  • An additional benefit of aclidinium bromide is not proven for the endpoint category of mortality.
• Morbidity – COPD symptoms (TDI responders, E-RS total score responders)
  • With regard to TDI responders (TDI: transition dyspnoea index) and E-RS total score responders (E-RS: exacerbations of chronic pulmonary disease toll respiratory symptoms), there were no statistically significant differences between the study arms in the ACLIFORM and AUGMENT studies.
  • For both endpoints, it was not possible to perform a meta-analytic evaluation due to the heterogeneous results, each showing a different direction of effect (heterogeneity: p = 0.144 and p = 0.138 respectively). The same applies to the responder analysis of the E-RS ‘chest symptoms’ subscale (heterogeneity: p = 0.055).
  • For the ER-S subscales ‘shortness of breath’ and ‘cough and sputum’, the difference between the interventions was not statistically significant in either the ACLIFORM study, the AUGMENT study or the pooled analysis.
• Morbidity – Health status (EQ-5D VAS)
  • General health status was assessed using the EQ-5D visual analogue scale only in the ACLIFORM study. The mean values of the change measured between the start and end of the study did not differ statistically significantly between the relevant study arms (mean difference (MD): -0.66; 95% CI: [-3.49; 2.17]; p = 0.646).
• Morbidity – Exacerbations
  • The endpoint ‘exacerbations’ is included in the analysis as a composite endpoint comprising moderate and severe exacerbations.
  • In the ACLIFORM study, there was a statistically significant difference in favour of aclidinium bromide for the combined endpoint (odds ratio (OR): 0.29; 95% confidence interval (95% CI): [0.12; 0.71]; p = 0.006). In the AUGMENT study, the difference was not significant (OR: 0.91; 95% CI: [0.52; 1.61]; p-value = 0.750). The meta-analysis of the two studies revealed unexplained heterogeneity without consistent effects, which is why no pooled effect estimate could be calculated.
  • For the patient population with severity grade II, the difference between the treatment arms is statistically significant only in the ACLIFORM study (OR: 0.35; 95% CI: [0.13; 0.95]; p-value = 0.039), but not in the AUGMENT study (OR: 1.45; 95% CI: [0.72; 2.93]; p-value = 0.296). Due to the heterogeneity of the results—which, as in the overall population, show opposing directions of effect—a pooled analysis cannot be carried out.
• Health-related quality of life – St George’s Respiratory Questionnaire (SGRQ)
  • Health-related quality of life was assessed using the SGRQ questionnaire. Patients with a reduction in their total score of at least 4 scale points were classified as responders. The difference between the interventions is not statistically significant in either study (ACLIFORM: OR 0.76; 95% CI: [0.42; 1.36]; p = 0.348; AUGMENT: OR 1.40; 95% CI: [0.77; 2.55]; p = 0.270). A meta-analytic assessment was also not appropriate for this endpoint due to the heterogeneity of the results (p = 0.140).
  • For the quality of life endpoint category, an additional benefit of aclidinium bromide over formoterol is not proven.
• Side effects
  • For the ‘side effects’ endpoint category, there are no statistically significant differences between aclidinium bromide and formoterol.
  • In the ACLIFORM study, 3 patients in the intervention arm and 5 patients in the comparator arm discontinued treatment due to an adverse event. In the AUGMENT study, 7 patients in the aclidinium bromide arm and 6 patients in the formoterol arm discontinued treatment due to an adverse event. These differences, like the difference observed in the pooled analysis of the results (risk ratio (RR): 0.96; 95% CI: [0.41; 2.25]; p = 0.924), are not statistically significant.
  • The available results for the endpoint category ‘side effects’ provide no hints of any additional benefit of aclidinium bromide over formoterol.

1b) Adult patients with COPD of moderate severity or greater (50 % ≤ FEV1 < 80 % predicted) – patients with severity grade III (30 % ≤ FEV1 < 50 % predicted) and < 2 exacerbations per year

• Indication of a considerable additional benefit.
• mortality
  • Very few deaths occurred in either study. In the ACLIFORM study, one death occurred in the comparator arm; in the AUGMENT study, two deaths occurred. The difference between the respective study arms is not statistically significant.
  • An additional benefit of aclidinium bromide is not proven for the endpoint category of mortality.
• Morbidity – COPD symptoms (TDI responders, E-RS total score responders)
  • With regard to TDI responders (TDI: transition dyspnoea index) and E-RS total score responders (E-RS: exacerbations of chronic pulmonary disease toll respiratory symptoms), there were no statistically significant differences between the study arms in the ACLIFORM and AUGMENT studies.
  • For both endpoints, it was not possible to perform a meta-analytic evaluation due to the heterogeneous results, each showing a different direction of effect (heterogeneity: p = 0.144 and p = 0.138, respectively). The same applies to the responder analysis of the E-RS ‘chest symptoms’ subscale (heterogeneity: p = 0.055).
  • For the ER-S subscales ‘shortness of breath’ and ‘cough and sputum’, the difference between the interventions was not statistically significant in either the ACLIFORM study, the AUGMENT study or the pooled analysis.
• Morbidity – Health status (EQ-5D VAS)
  • General health status was assessed using the EQ-5D visual analogue scale only in the ACLIFORM study. The mean values of the change measured between the start and end of the study did not differ statistically significantly between the relevant study arms (mean difference (MD): -0.66; 95% CI: [-3.49; 2.17]; p = 0.646).
• Morbidity – Exacerbations
  • The endpoint ‘exacerbations’ is included in the analysis as a composite endpoint comprising moderate and severe exacerbations.
  • For the endpoint ‘exacerbations’, the patient population analysis also identified proof of an effect modification by the characteristic ‘COPD severity’ (interaction: 0.028).
  • For severity grade III, the results from the relevant treatment arms in the individual studies do not differ significantly. However, a pooled analysis is appropriate for the patient population. In the meta-analytic evaluation, the difference between aclidinium bromide and formoterol is statistically significant (OR: 0.27; 95% CI: [0.11; 0.71]; p-value = 0.008) in favour of aclidinium bromide.
  • With regard to severe exacerbations, which were reported individually in addition to the composite endpoint, no statistically significant difference was found either in the individual studies or in the meta-analytical analysis (OR: 0.90; 95% CI: [0.19; 4.31]; p-value = 0.893).
  • For the morbidity endpoint category, there is a considerable additional benefit for aclidinium bromide in patients with severity grade III and fewer than two exacerbations per year. This additional benefit is based on the difference in favour of aclidinium bromide with regard to the endpoint of exacerbations. For the other morbidity endpoints assessed, no statistically significant difference was found, or the results could not be used due to heterogeneity.
• Health-related quality of life – St George’s Respiratory Questionnaire (SGRQ)
  • Health-related quality of life was assessed using the SGRQ questionnaire. Patients with a reduction in their total score of at least 4 scale points were classified as responders. The difference between the interventions was not statistically significant in either study (ACLIFORM: OR 0.76; 95% CI: [0.42; 1.36]; p = 0.348; AUGMENT: OR 1.40; 95% CI: [0.77; 2.55]; p = 0.270). A meta-analytic assessment was also not appropriate for this endpoint due to the heterogeneity of the results (p = 0.140).
  • For the quality of life endpoint category, the additional benefit of aclidinium bromide over formoterol is not proven.
• Side effects
  • For the ‘side effects’ endpoint category, there are no statistically significant differences between aclidinium bromide and formoterol.
  • In the ACLIFORM study, 3 patients in the intervention arm and 5 patients in the comparator arm discontinued treatment due to an adverse event. In the AUGMENT study, 7 patients in the aclidinium bromide arm and 6 patients in the formoterol arm discontinued treatment due to an adverse event. These differences, like the difference observed in the pooled analysis of the results (risk ratio (RR): 0.96; 95% CI: [0.41; 2.25]; p = 0.924), are not statistically significant.
  • The available results for the endpoint category ‘side effects’ provide no hints of any additional benefit of aclidinium bromide over formoterol.
• Overall assessment
  • The G-BA classifies the extent of the additional benefit of aclidinium bromide for patients with severity grade III and fewer than two exacerbations per year as ‘considerable’, based on 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 the treatment of the disease, which is considered considerable.
  • Compared with the appropriate comparator therapy, this represents, in accordance with Section 5(7) in conjunction with § 2(3) of the AM-NutzenV, this represents a significant improvement in treatment-related benefit that has not previously been achieved, as it results in a noticeable alleviation of the condition for patients in the form of a reduced risk of exacerbations.

1c) Adult patients with COPD of moderate severity or greater (50 % ≤ FEV1 < 80 % predicted) – patients with stage IV disease (FEV1 < 30 % predicted or respiratory failure) and < 2 exacerbations per year

• Any additional benefit is deemed not proven.
• As the required proof has not been provided, the additional benefit in relation to the appropriate comparator therapy is deemed not proven.

2) For more severe stages (30 % ≤ FEV1 < 50 % of predicted or FEV1 < 30 % of predicted or respiratory failure) with ≥ 2 exacerbations per year

• Any additional benefit is deemed not proven.
• As the necessary evidence has not been provided, the additional benefit in relation to the appropriate comparator therapy is deemed not proven. The pharmaceutical manufacturer has not provided any data for the patient population in question.

Courtesy translation only, please refer to the German original.