Aclidiniumbromid / Formoterol (1) – Duaklir Genuair, Brimica Genuair®, Brimica® Genuair®

• Clinical trials
  • To directly compare aclidinium bromide/formoterol with the appropriate comparator therapy, three double-blind, multicentre, randomised controlled registration trials (LAC-MD-32, ACLIFORM and AUGMENT with the extension study LAC-MD-36) were included.
  • All three studies compared one morning and one evening inhalation of the fixed-dose combination of 400 μg aclidinium and 12 μg formoterol with 12 μg formoterol.

Patients with COPD of moderate severity: 50 % ≤ FEV1 < 80 % of predicted (corresponding to stage II)

• The G-BA classifies the extent of the additional benefit of aclidinium bromide/formoterol for patient population a) as minor, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic goal in the treatment of the disease.
• The probability of the additional benefit for patient population a) is therefore classified as an indication.
• mortality
  • For the patient-relevant endpoint of overall mortality, the meta-analysis of the included studies revealed no statistically significant difference between the treatment groups in the relevant patient populations.
  • This provides no hint of an additional benefit from aclidinium bromide/formoterol compared with formoterol; an additional benefit for overall survival is therefore not proven.
• Morbidity – COPD symptoms (TDI responders)
  • In the relevant patient population, the meta-analysis of the included studies revealed a statistically significant difference between the treatment groups in favour of aclidinium bromide/formoterol for the endpoint ‘COPD symptoms’ (TDI responders).
  • There was an indication of an interaction with regard to the characteristic of severity.
  • The results of the subgroup analysis showed a statistically significant effect in the meta-analysis exclusively among patients with stage III COPD.
  • Overall, there is no hint of additional benefit from aclidinium bromide/formoterol compared with formoterol, neither for patients with stage II COPD nor for those with stage III COPD experiencing fewer than two exacerbations per year.
• Morbidity – COPD symptoms (E-RS responders)
  • For the endpoint ‘COPD symptoms’, the meta-analysis of the included studies revealed a statistically significant difference between the treatment groups in the relevant patient population, in favour of aclidinium bromide/formoterol in terms of the total score (RR 1.45 [95% CI 1.16; 1.81], p = 0.001).
  • In the subgroup analysis based on the characteristic ‘COPD severity’, a RR of 1.29 (95% CI 0.96; 1.73), p = 0.095, was then observed in patient population a).
  • Although the endpoint is not statistically significant for patient population a), the statistically significant result for the overall population must also be taken into account for patient population a), as there is only an indication of interaction.
  • The results for the endpoint ‘proportion of E-RS responders’ are interpreted as showing minor additional benefit in both patient populations a) and b).
• Morbidity – Moderate exacerbations
  • For the endpoint ‘proportion of patients with moderate exacerbations’, the meta-analysis of the included studies revealed significant unexplained heterogeneity in the relevant patient population, with no clear trend in the results.
  • Overall, no additional benefit of aclidinium bromide/formoterol compared with formoterol can be inferred from this; an additional benefit is therefore not proven for moderate exacerbations.
• Morbidity – Severe exacerbations (HCRU)
  • For the endpoint ‘proportion of patients with severe exacerbations (HCRU)’, the meta-analysis of the included studies revealed no statistically significant difference between the treatment groups.
  • For patient population a), the result was not statistically significant (RR 1.38 [95% CI 0.32; 5.95], p = 0.67). An additional benefit is therefore not proven for patient population a).
• Health-related quality of life – St George’s Respiratory Questionnaire (SGRQ) – responders
  • For the SGRQ responder endpoint, the meta-analysis of the included studies revealed no statistically significant difference between the treatment groups.
  • Consequently, there is no hint of additional benefit from aclidinium bromide/formoterol compared with formoterol; additional benefit is therefore not proven for the SGRQ-responder subgroup.
• Side effects – SAE and discontinuation due to AEs
  • For the endpoints SAE and discontinuation due to AEs, the meta-analysis of the included studies revealed no statistically significant difference between the treatment groups.
  • This provides no hint of greater or minor harm from aclidinium bromide/formoterol compared with formoterol; greater or minor harm is therefore not proven for SAE and discontinuation due to AEs.
• Conclusion
  • Taking the results on mortality, morbidity, quality of life and side effects into account as a whole, there is, for aclidinium bromide/formoterol, compared with the appropriate comparator therapy formoterol in patient population a), there is: a) no significant improvement in treatment-related benefit that has not previously been achieved, in particular no alleviation of serious symptoms, no moderate prolongation of life, no relevant reduction in serious side effects, nor any significant reduction in other side effects.

Patients with COPD with < 2 exacerbations per year, 30 % ≤ FEV1 < 50 % of predicted (corresponding to stage III)

• The G-BA classifies the extent of the additional benefit of aclidinium bromide/formoterol compared with the appropriate comparator therapy, formoterol, in patient population b) as considerable.
• mortality
  • For the patient-relevant endpoint of all-cause mortality, the meta-analysis of the included studies showed no statistically significant difference between the treatment groups in the relevant patient populations.
  • This provides no hint of an additional benefit from aclidinium bromide/formoterol compared with formoterol; an additional benefit for overall survival is therefore not proven.
• Morbidity – COPD symptoms (TDI responders)
  • In the relevant patient population, the meta-analysis of the included studies revealed a statistically significant difference between the treatment groups in favour of aclidinium bromide/formoterol for the endpoint ‘COPD symptoms’ (TDI responders).
  • There was an indication of an interaction with regard to the characteristic of severity.
  • The results of the subgroup analysis showed a statistically significant effect in the meta-analysis exclusively among patients with stage III COPD.
  • Overall, there is no hint of additional benefit from aclidinium bromide/formoterol compared with formoterol, neither for patients with stage II COPD nor for those with stage III COPD experiencing fewer than two exacerbations per year.
• Morbidity – COPD symptoms (E-RS responders)
  • For the endpoint ‘COPD symptoms’, the meta-analysis of the included studies revealed a statistically significant difference between the treatment groups in the relevant patient population, in favour of aclidinium bromide/formoterol in the total score (RR 1.45 [95% CI 1.16; 1.81], p = 0.001).
  • The results for the endpoint ‘proportion of E-RS responders’ are assessed as showing minor additional benefit in both patient populations a) and b).
• Morbidity – Moderate exacerbations
  • For the endpoint ‘proportion of patients with moderate exacerbations’, the meta-analysis of the included studies revealed significant unexplained heterogeneity in the relevant patient population, with no clear trend in the results.
  • Overall, no additional benefit of aclidinium bromide/formoterol compared with formoterol can be inferred from this; an additional benefit is therefore not proven for moderate exacerbations.
• Morbidity – Severe exacerbations (HCRU)
  • For the endpoint ‘proportion of patients with severe exacerbations (HCRU)’, the meta-analysis of the included studies revealed no statistically significant difference between the treatment groups.
  • The results of the subgroup analysis showed a statistically significant effect in the meta-analysis exclusively among patients with stage III COPD.
  • For this patient population, an improvement in severe exacerbations was observed for this treatment group (RR 0.26 [95% CI 0.09; 0.76], p = 0.014).
  • From this advantage in preventing severe exacerbations, a considerable additional benefit can be inferred for patient population b).
• Health-related quality of life – St George’s Respiratory Questionnaire (SGRQ) responders
  • For the SGRQ responder endpoint, the meta-analysis of the included studies showed no statistically significant difference between the treatment groups.
  • This provides no hints of an additional benefit of aclidinium bromide/formoterol compared with formoterol; an additional benefit is therefore not proven for the proportion of SGRQ responders.
• Side effects – SAE and discontinuation due to AEs
  • For the endpoints SAE and discontinuation due to AEs, the meta-analysis of the included studies showed no statistically significant difference between the treatment groups.
  • This provides no hint of greater or lesser harm from aclidinium bromide/formoterol compared with formoterol; greater or minor harm is therefore not proven for SAE and discontinuation due to AEs.
• Conclusion
  • Taking the results on mortality, morbidity, quality of life and side effects into account as a whole, the G-BA considers the extent of the additional benefit of aclidinium bromide/formoterol compared with the appropriate comparator therapy, formoterol, in patient population b) as considerable.
  • The results regarding the endpoints ‘E-RS responder’ and ‘severe exacerbations’ are assessed as a significant improvement in treatment-related benefit, not previously achieved with the appropriate comparator therapy in accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV.

Patients with COPD with < 2 exacerbations per year, FEV1 < 30 % of predicted or respiratory insufficiency (corresponding to stage IV)

• The additional benefit is not proven.
• No evaluable data were available for patients with stage IV COPD.

Patients with COPD of more than moderate severity: 30 % ≤ FEV1 < 50 % of predicted, or FEV1 < 30 %, or respiratory insufficiency (corresponding to stages III and IV) with ≥ 2 exacerbations per year

• An additional benefit is not proven.
• For the patient population with Stage III COPD experiencing at least two exacerbations per year, no statistically significant differences were observed in the individual endpoints; consequently, there are neither positive nor negative effects.

Courtesy translation only, please refer to the German original.