Indacaterol / Glycopyrronium (1) – Ultibro Breezhaler, Xoterna Breezhaler®, Xoterna® Breezhaler®

• Clinical trials
  • In the benefit assessment dossier submitted in accordance with Section 35a of the Fifth Social Security Act (SBG V), the pharmaceutical manufacturer presented the direct comparative, randomised and controlled QUANTIFY (QVA149ADE01) to demonstrate the additional benefit of indacaterol/glycopyrronium compared with tiotropium plus formoterol.

a) Patients with stage II COPD

• For patients with stage II COPD, there is a hint of a minor additional benefit compared with the appropriate comparator therapy.
• The certainty of the evidence (probability of additional benefit) for patients with stage II COPD is classified as ‘hint’.
• As the results of the interaction test in the TDI suggest a potentially minor effect size for patients with Stage II COPD, the probability of additional benefit for the patient population is downgraded from ‘indication’ to ‘hint’.
• Furthermore, there is a lack of data regarding the duration of COPD, smoking status, pack-years and treatment discontinuation among patients with stage II COPD not receiving ICS treatment.
• mortality
  • For the overall population of patients with Stage II and Stage III COPD experiencing no more than one exacerbation per year, there is no statistically significant difference between the treatment groups.
  • The additional benefit of indacaterol/glycopyrronium compared with the appropriate comparator therapy is not proven.
• Morbidity – Transition Dyspnoea Index (TDI)
  • The subgroup analysis by severity shows no significant difference for patients with Stage II COPD.
• Morbidity – COPD Assessment Test (CAT)
  • The responder analysis shows a statistically significant difference between the treatment groups in favour of indacaterol/glycopyrronium for the overall population of patients with stage II and stage III COPD with no more than one exacerbation per year.
  • The change in CAT scores is interpreted as a reduction in relevant symptoms.
  • As there was no indication of interaction, no subgroup analysis was presented.
  • The clinically relevant change in the COPD Assessment Test in the overall population of patients with stage II and stage III COPD experiencing no more than one exacerbation per year is considered relevant for the assessment of additional benefit.
• Morbidity – Moderate and severe exacerbations
  • The results for the endpoint ‘moderate exacerbations’ show no statistically significant difference between the treatment groups in the overall population of patients with stage II and stage III COPD experiencing no more than one exacerbation per year.
  • The subgroup analysis by severity shows no significant difference for patients with Stage II COPD.
  • An additional benefit of indacaterol/glycopyrronium compared with the appropriate comparator therapy has not been demonstrated for the patient population of patients with stage II COPD, nor for the overall population of patients with stage II COPD and patients with stage III COPD experiencing no more than one exacerbation per year, for the endpoints ‘moderate exacerbations’ and ‘severe exacerbations’.
• Quality of life – St George’s Respiratory Questionnaire for COPD patients (SGRQ-C)
  • The responder analysis shows no statistically significant difference between the treatment groups for the overall population of patients with stage II and stage III COPD experiencing no more than one exacerbation per year.
  • An additional benefit of indacaterol/glycopyrronium compared with the appropriate comparator therapy is not proven for the quality of life endpoint.
• Side effects
  • In the QUANTIFY study, there were no statistically significant differences between the treatment groups for the endpoints ‘overall rate of serious adverse events’ and ‘discontinuation due to adverse events’ in the overall population of patients with stage II and stage III COPD with no more than one exacerbation per year.
  • No data are available for the endpoints ‘specific adverse events’ and ‘serious adverse events’ for the overall population of patients with stage II and stage III COPD with no more than one exacerbation per year.
  • There is not enough proof that indacaterol/glycopyrronium causes minor or major side effects compared to the appropriate comparator therapy for the endpoint ‘side effects’.
• Conclusion
  • Taking the results on mortality, morbidity, quality of life and side effects into account as a whole, there is no evidence for indacaterol/glycopyrronium, compared with the appropriate comparator therapy—formoterol in combination with tiotropium—in the overall population of patients with stage II COPD and patients with stage III COPD experiencing no more than one exacerbation per year, there is no previously unachieved significant improvement in treatment-related benefit; in particular, no alleviation of serious symptoms, no moderate prolongation of life, no relevant prevention of serious side effects, and no significant prevention of other side effects.
  • The G-BA assesses the extent of the additional benefit of indacaterol/glycopyrronium for the overall population of patients with stage II COPD and patients with stage III COPD experiencing no more than one exacerbation per year, on the basis of 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 is minor.
  • The results on morbidity – in this case, the results for the endpoints ‘Transition Dyspnoea Index (TDI)’ and ‘COPD Assessment Test (CAT)’, are assessed as a moderate—and not merely minor—improvement in treatment-related benefit compared with the appropriate comparator therapy in accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV, which has not yet been achieved.

b) Patients with stage III COPD with no more than one exacerbation per year

• For patients with stage III COPD with no more than one exacerbation per year, there is an indication for a minor additional benefit compared with the appropriate comparator therapy.
• The certainty of the finding (probability of additional benefit) for patients with stage III COPD with no more than one exacerbation per year is classified as ‘indication’, as the results were presented from a randomised clinical trial (QUANTIFY), the potential for bias in which was assessed as low both at the study level and for all included endpoints across the entire population.
• The QUANTIFY trial does not meet the criteria for deriving the level of certainty ‘Proof’ from a single study.
• In contrast to patients with Stage II COPD, the interaction tests do not indicate an indication of a potentially lower effect size for patients with Stage III COPD experiencing no more than one exacerbation per year when the subgroup results are considered, compared with the overall population.
• Furthermore, there is a lack of data regarding the duration of COPD, smoking status, pack-years and treatment discontinuation rates for the subpopulation of patients with stage III COPD not receiving ICS treatment.
• mortality
  • For the overall population of patients with Stage II and Stage III COPD experiencing no more than one exacerbation per year, there is no statistically significant difference between the treatment groups.
  • The additional benefit of indacaterol/glycopyrronium compared with the appropriate comparator therapy is not proven.
• Morbidity – Transition Dyspnoea Index (TDI)
  • This result is classified as a reduction in relevant symptoms.
  • The clinically relevant change in the Transition Dyspnoea Index in the overall population of patients with stage II and stage III COPD with no more than one exacerbation per year is considered relevant for the assessment of additional benefit.
• Morbidity – COPD Assessment Test (CAT)
  • The responder analysis shows a statistically significant difference between the treatment groups in favour of indacaterol/glycopyrronium for the overall population of patients with stage II and stage III COPD experiencing no more than one exacerbation per year.
  • The change in CAT scores is classified as a reduction in relevant symptoms.
  • As there was no indication of interaction, no subgroup analysis was presented.
  • The clinically relevant change in the COPD Assessment Test scores in the overall population of patients with stage II and stage III COPD experiencing no more than one exacerbation per year is considered relevant for the assessment of additional benefit.
• Quality of life – St George’s Respiratory Questionnaire for COPD patients (SGRQ-C)
  • The responder analysis shows no statistically significant difference between the treatment groups for the overall population of patients with stage II and stage III COPD with no more than one exacerbation per year.
  • No additional benefit of indacaterol/glycopyrronium compared with the appropriate comparator therapy is proven for the quality of life endpoint.
• Side effects
  • In the QUANTIFY study, there were no statistically significant differences between the treatment groups for the endpoints ‘overall rate of serious adverse events’ and ‘discontinuation due to adverse events’ in the overall population of patients with stage II and stage III COPD experiencing no more than one exacerbation per year.
  • No data are available for the endpoints ‘specific adverse events’ and ‘serious adverse events’ for the overall population of patients with stage II and stage III COPD with no more than one exacerbation per year.
  • There is not enough proof that indacaterol/glycopyrronium causes minor or major side effects compared to the appropriate comparator therapy for the endpoint ‘side effects’.
• Conclusion
  • Taking the results on mortality, morbidity, quality of life and side effects into account as a whole, there is no evidence for indacaterol/glycopyrronium, compared with the appropriate comparator therapy—formoterol in combination with tiotropium—in the overall population of patients with stage II COPD and patients with stage III COPD experiencing no more than one exacerbation per year, does not provide a previously unattained significant improvement in treatment-related benefit; in particular, no alleviation of serious symptoms, no moderate prolongation of life, no relevant reduction in serious side effects, or no significant reduction in other side effects.
  • Therefore, classification as having considerable additional benefit is not justified.
  • The G-BA classifies the extent of the additional benefit of indacaterol/glycopyrronium for the overall population of patients with stage II COPD and patients with stage III COPD with no more than one exacerbation per year as ‘low’ on the basis of 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 is minor.
  • The results regarding morbidity – in this case, the results for the endpoints ‘Transition Dyspnoea Index (TDI)’ and ‘COPD Assessment Test (CAT)’, are assessed as a moderate—and not merely minor—improvement in treatment-related benefit that has not yet been achieved compared with the appropriate comparator therapy in accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV.

c) Patients with stage IV COPD with no more than one exacerbation per year

• For patients with stage IV COPD with no more than one exacerbation per year, the additional benefit is not proven.
• The study submitted by the pharmaceutical manufacturer for the active substance combination indacaterol/glycopyrronium under assessment is not suitable for demonstrating additional benefit, as the number of patients included with stage IV COPD and no more than one exacerbation per year is too minor.
• No additional benefit can be inferred for this patient population.

d) Patients with stage III and stage IV COPD with ≥ 2 exacerbations per year

• For patients with stage III and stage IV COPD with at least two exacerbations per year, the additional benefit is not proven.
• The study submitted by the pharmaceutical manufacturer for the active substance combination indacaterol/glycopyrronium is not suitable for demonstrating additional benefit, as the number of patients included with COPD Stage III and Stage IV and at least two exacerbations per year is too minor.
• No additional benefit can be inferred for this patient population.

Courtesy translation only, please refer to the German original.