Prescribing information

 

   

The 2020 GINA guidelines recommend ICS/LABA as a treatment option for patients at GINA steps 3–5 with a history of exacerbations.1

ATECTURA® BREEZHALER® is indicated as a maintenance treatment of asthma in adults and adolescents 12 years of age and older, not adequately controlled with inhaled corticosteroids and inhaled short-acting beta2-agonists.2

Two phase III trials have assessed the safety and efficacy of ATECTURA® BREEZHALER® – QUARTZ and PALLADIUM – and their results are presented below. 

 

 2–5

The QUARTZ study is a phase III, multicentre, randomised, 12-week treatment, double-blind study to assess the efficacy and safety of ATECTURA® BREEZHALER® (150/80 µg) compared with mometasone furoate (MF) (200 µg) delivered via the Twisthaler®  device in adult and adolescent patients with asthma.

The purpose of the trial was to evaluate efficacy and safety of ATECTURA® BREEZHALER® 150/80 µg once daily delivered via BREEZHALER® compared to MF 200 µg once daily delivered via Twisthaler® in terms of lung function and symptom control in poorly (ie inadequately) controlled asthma patients. This study was to assess contribution of LABA as an add-on therapy to low dose ICS monotherapy.

The primary objective of this study was to demonstrate the superiority of ATECTURA® BREEZHALER® 150/80 microgram once daily (in the evening) delivered via BREEZHALER® compared with MF 200 µg once daily (in the evening) delivered via Twisthaler® in terms of trough FEV1 after 12 weeks of treatment in adults and adolescents. The key secondary objective of this study was to demonstrate the superiority of ATECTURA® BREEZHALER® 150/80 µg to MF 200 µg once daily in terms of ACQ-7 after 12 weeks of treatment. 

 2,6–8

PALLADIUM is a phase III, multicentre, randomised, 52-week treatment, double-blind, triple-dummy, parallel-group study, to assess the efficacy and safety of the indacaterol acetate and mometasone furoate (ATECTURA® BREEZHALER®) combination compared with mometasone furoate (MF) alone in patients with asthma.

The purpose of the trial is to evaluate the efficacy and safety of two different doses of ATECTURA® BREEZHALER®/(ATECTURA® BREEZHALER® 150/160 µg and  ATECTURA® BREEZHALER® 150/320 µg via BREEZHALER®) over two respective MF doses (MF 400 µg and MF 800 µg via Twisthaler® [total daily dose]) in poorly controlled asthmatic participants as determined by pulmonary function testing, and effects on asthma control.

The primary endpoint was to assess lung function improvement and the key secondary endpoint was to assess asthma control improvement.

 

Lung function

In the QUARTZ study, low dose ACTETURA® BREEZHALER® significantly improved lung function over 12 weeks of treatment.

ATECTURA® BREEZHALER® low-dose significantly improved trough FEV1 by +182 mL (95% CI: 148, 217) at Week 12 vs. MF low-dose5

 

Image showing 182 mL significant improvement in trough FEV

Change in trough FEV1 with low dose ATECTURA® BREEZHALER® compared to MF alone, from baseline to Week 125

 

Graph showing 182 ml improvement in trough FEV1 with Atectura Breezhaler versus MF alone at week 12

 

Trough FEV1 improved by by +211 mL (95% CI: 167, 255) and +132 mL (95% CI: 88, 176) for medium- and high-doses respectively at Week 26 vs. medium- and high-doses of MF8

 

Image showing Medium-dose INF vs MF and High-dose IND/MF vs MF

 

Change in trough FEV1 between medium and high dose MF vs medium and high dose ATECTURA® BREEZHALER®, respectively from baseline to Week 268

 

Graph showing 211 ml improvement in trough FEV1 with medium dose Atectura Breezhaler versus medium dose MF, and a 132 ml improvement with high dose Atectura Breezhaler versus high dose MF at week 26

 

Change in trough FEV1 in medium dose ATECTURA® BREEZHALER® vs medium dose MF from baseline to Week 52*8

 

Graph showing 209 ml improvement in trough FEV1 with medium dose Atectura Breezhaler versus medium dose MF at 1 year

 

Change in trough FEV1 in high dose ATECTURA® BREEZHALER® vs high dose MF from baseline to Week 52*8

Graph showing 136 ml improvement in trough FEV1 with high dose Atectura Breezhaler versus high dose MF at 1 year

In the PALLADIUM study, ATECTURA® BREEZHALER® significantly improved lung function through Week 26.8

 

Change in trough FEV1 in high dose ATECTURA® BREEZHALER® vs high dose SAL/FLU from baseline to Week 26*9

Graph showing 43 ml improvement in trough FEV1 with high dose Atectura Breezhaler versus high dose SAL/FLU at 26 weeks

Change in trough FEV1 in high dose ATECTURA® BREEZHALER® vs high dose SAL/FLU from baseline to Week 52*8

 

Graph showing 48 ml improvement trough FEV1 with high dose Atectura Breezhaler versus high dose SAL/FLU at 1 year

Asthma control

In the QUARTZ study, low dose ACTETURA® BREEZHALER® significantly improved asthma control over 12 weeks of treatment.

LS mean change in ACQ-7 score in low dose ATECTURA® BREEZHALER® vs low dose MF from baseline to Week 125

 

Graph showing 0.218 point LS mean improvement in ACQ-7 score with low dose Atectura Breezhaler compared to low dose MF at week 12

 

ACQ-7 responders in low dose ATECTURA® BREEZHALER® vs low dose MF*5

 

Graph showing 1.69 point improvement in ACQ-7 responders with low dose Atectura Breezhaler compared to low dose MF

 

In the PALLADIUM study, improvement in ACQ-7 score was met.

Change in ACQ-7 SCORE in ATECTURA® BREEZHALER® combined-dose vs MF combined dose from baseline to Week 268

 

Graph showing 0.209 point LS mean improvement in ACQ-7 score with Atectura Breezhaler combined dose compared to MF combined dose at week 26

Exacerbations control

 

ATECTURA® BREEZHALER® medium and high dose once daily both demonstrated a clinically meaningful reduction in the annual rate of moderate or severe exacerbations (secondary endpoint), compared to MF once and twice daily.*2,8

Annualised rate of moderate or severe exacerbations in medium dose ATECTURA® BREEZHALER® vs medium dose MF*10

 

Graphs showing significantly lower annualised rates of moderate to severe exacerbations in medium dose Atectura Breezhaler versus medium dose MF, and high dose Atectura Breezhaler versus high dose MF

Annualised rate of moderate or severe exacerbation in high dose ATECTURA® BREEZHALER® vs high dose SAL/FLU*§9 

 

Graph showing significantly lower annualised rate of moderate to severe exacerbations in high dose Atectura Breezhaler versus high dose SAL/FLU

 

There was a treatment difference in number of patients suffering all exacerbations of 70% between high-dose ATECTURA® BREEZHALER® and high-dose SAL/FLU (smaller in ATECTURA® BREEZHALER® group; rate ratio 0.30 [95% CI: 0.18, 0.50]; p,0.001)9

The PALLADIUM trial showed an increase in the number of rescue medication free days with medium dose ATECTURA® BREEZHALER® (IND/MF) vs medium dose MF and high dose SAL/FLU, respectively.*

Change in rescue medication-free days in medium dose ATECTURA® BREEZHALER® vs medium dose MF from baseline to Week 52*8,10

 

Graph showing significant reduction in rescue drug-free days with medium dose Atectura Breezhaler compared to medium dose MF at one year

Change in rescue medication-free days to high dose ATECTURA® BREEZHALER® vs high dose MF from baseline to Week 5210*

Graph showing significant reduction in rescue drug-free days with high dose Atectura Breezhaler compared to high dose MF at one year

Change in rescue medication-free days in high dose ATECTURA® BREEZHALER® vs high dose SAL/FLU from baseline to Week 52*8

 

Graph showing significant reduction in rescue drug-free days with high dose Atectura Breezhaler compared to high dose SAL/FU at one year

 

In the QUARTZ study, there was a treatment difference in mean daily number of puffs of rescue medication of -0.26 between high dose ATECTURA® BREEZHALER® and high dose SAL/FLU (smaller in ATECTURA® BREEZHALER® group, 95% CI: -0.37, -0.14). There was a treatment difference in rescue medication-free days of 8.1% between high dose ATECTURA® BREEZHALER® and high dose SAL/FLU (greater in ATECTURA® BREEZHALER® group, 95% CI: 4.3, 11.8)5

 

ATECTURA® BREEZHALER® was generally well-tolerated: AEs and SAEs were comparable across treatment arms.5,8

The PLATINUM trial programme

>7,500 patients

still symptomatic on low-dose ICS up to high-dose LABA/ICS treatment were included5,8

Table listing the adverse and serious adverse events across each of the three treatment arms (ATECTURA® BREEZHALER®)5

  • Common AEs included asthma exacerbation, nasopharyngitis, pharyngitis, sinusitis, overdose, cough, dysphonia, allergic rhinitis, headache, upper respiratory tract infection and influenza
  • Angioedema was not observed during the study but is a potential AE of ATECTURA® BREEZHALER®
  • SAEs included asthma exacerbation, prostate cancer, osteoarthritis, incisional hernia, oral abscess, dental cyst

Table listing the adverse and serious adverse events across each of the three treatment arms (ATECTURA® BREEZHALER®)5,8

  • Very common AEs** during the trial included asthma exacerbation and nasopharyngitis
  • Common AEs** included upper respiratory tract infection, hypersensitivity, headache, oropharyngeal pain, dysphonia and musculoskeletal pain
  • Angioedema was not observed during the study but is a potential AE of ATECTURA® BREEZHALER®
  • SAEs included asthma exacerbation, acute myocardial infarction, pneumonia, peritonitis and rib fracture

 

*None of these secondary analyses were controlled for multiplicity;5,8 inferences based on these data cannot be made due to lack of power.
Responders included patients with an improvement of 0.5 points (MCID) in ACQ-7 score.
A moderate asthma exacerbation was defined as the occurrence of two or more of the following: 1. Progressive increase of at least one asthma symptom like shortness of breath, cough, wheezing, or chest tightness. The symptoms were outside the patient’s usual range of day-to-day asthma and were to last at least two consecutive days. 2. Increased use of “rescue” inhaled bronchodilators defined by: >50% increase in SABA use and >8 puffs on two out of any three consecutive days compared to baseline captured or night-time awakenings requiring SABA use on at least two out of any three consecutive nights. 3. Deterioration in lung function, which lasted for two days or more but usually not severe enough to warrant systemic corticosteroids for more than two days or hospitalisation. A severe exacerbation is defined as an aggravation of asthma symptoms (such as shortness of breath, cough, wheezing, or chest tightness) that required systemic corticosteroids for at least 3 consecutive days and/or a need for an emergency room visit, hospitalisation due to asthma, or death due to asthma.
§From a pre-specified pooled analysis across PALLADIUM and IRIDIUM to evaluate benefit of ATECTURA® BREEZHALER® high-dose vs. SAL/FLU high-dose in patients with uncontrolled asthma.5,8
**Common AEs affect between ≥1/100 to <1/10.
Very common AEs affect ≥1/10.

IND/MF (ATECTURA® BREEZHALER®) low-dose = IND/MF 150/80 μg (once-daily); MF low-dose = MF 200 μg (once-daily). IND/MF (ATECTURA® BREEZHALER®) medium-dose = IND/MF 150/160 μg (once-daily); MF medium-dose = MF 400 μg (once-daily). IND/MF (ATECTURA® BREEZHALER®) high-dose = IND/MF 150/320 μg (once-daily); SAL/FLU high-dose = SAL/FLU 50/500 μg (twice-daily). Combined doses = combined data from both high- and medium-dose; IND/MF (ATECTURA® BREEZHALER®) medium-dose = IND/MF 150/160 μg (once-daily); IND/MF (ATECTURA® BREEZHALER®) high-dose = IND/MF 150/320 μg (once-daily); MF medium-dose = MF 400 μg (once-daily); MF high-dose = MF 800 μg (400 μg twice-daily).

Indication: ATECTURA® BREEZHALER® is indicated as a maintenance treatment of asthma in adults and adolescents 12 years of age and older not adequately controlled with inhaled corticosteroids and inhaled short-acting beta2-agonists.2

ACQ-7, Asthma Control Questionnaire-7; AE, adverse event; CI, confidence interval; FEV1, forced expiratory volume in 1 second; FLU, fluticasone propionate; GINA, Global Initiative for Asthma; ICS, inhaled corticosteroid; IND, indacaterol; LABA, long acting beta agonist; LS, least squares; MCID, minimal clinically important difference; MF, mometasone furoate; SAE, serious adverse event; SAL, salmeterol xinafoate.

References

  1. GINA 2020 Guidelines. Available at: https://ginasthma.org/gina-reports/. Date accessed: January 2021.
  2. ATECTURA® BREEZHALER®. Summary of Product Characteristics. June 2020.
  3. Novartis Press Release. Available at: https://www.novartis.com/news/media-releases/novartis-phase-iii-quartz-s.... Date accessed: January 2021.
  4. Clinical Trials NCT002892344. Available at: https://clinicaltrials.gov/ct2/show/NCT02892344?term=NCT02892344. Date accessed: January 2021.
  5. Kornmann O et al. Respiratory Medicine 2020;161:105809 [Epub ahead of print].
  6. Novartis Press Release. Available at: https://www.novartis.com/news/media-releases/novartis-phase-iii-data-new.... Date accessed: January 2021.
  7. Clinical Trials NCT02554786. Available at: https://clinicaltrials.gov/ct2/show/NCT02554786?term=NCT02554786&rank=1. Date accessed: January 2021.
  8. van Zyl-Smit R et al. Lancet Respir Med 2020;8(10):987–999.
  9. Chapman K et al. Poster A3004. ATS, Philadelphia; 15–20 May, 2020 [abstract].
  10. van Zyl-Smit R et al. Lancet Respir Med 2020 Supplementary Appendix 1;8(10):987–999.
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UK | April 2021 | 114847
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Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard. Adverse events should also be reported to Novartis via [email protected] or online through the pharmacovigilance intake (PVI) tool at www.report.novartis.com
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