Prescribing information

 

Fixed-dose combination (FDC) of indacaterol/glycopyrronium/mometasone furoate (IND/GLY/MF) once-daily versus salmeterol/fluticasone (SAL/FLU) twice-daily plus tiotropium (TIO) once-daily in patients with uncontrolled asthma: A randomised, Phase IIIb, non-inferiority study (ARGON)1

  • Primary endpoint was met: Change from baseline in Asthma Quality of Life Questionnaire (AQLQ) total score with IND/GLY/MF high-dose was non-inferior vs. SAL/FLU high-dose + TIO at Week 24 (p<0.001)
  • Secondary and exploratory analyses assessed quality of life, lung function, asthma control, health status, and rate of moderate exacerbations with IND/GLY/MF high-dose vs. SAL/FLU high-dose + TIO
  • IND/GLY/MF was generally well-tolerated with a safety profile comparable to that of SAL/FLU high-dose + TIO

 

What was already known?

  • A stepwise treatment approach with a long-acting beta2-agonist (LABA) and ICS is currently the mainstay for asthma treatment2
  • In patients with inadequately controlled asthma despite LABA/ICS, adding TIO, a long-acting muscarinic antagonist (LAMA), improved lung function and decreased asthma exacerbations3–8
  • The availability of LABA/LAMA/ICS once-daily FDC in a single device may offer advantages of improved patient adherence and convenience over the use of multiple, and often different, inhalers9–11

 

Why was ARGON conducted?1

The ARGON study is the first to evaluate the efficacy and safety of once-daily fixed dose LABA/LAMA/ICS combination of IND/GLY/MF high-dose ICS vs. the concurrent administration of SAL/FLU high-dose + TIO in patients with uncontrolled asthma

 

Study design1

Adapted from Gessner C et al. 2020.

*Salbutamol/albuterol.
Trial identifier: QVM149B2306. More information can be found at: https://clinicaltrials.gov/ct2/show/NCT03158311.
IND/GLY/MF high-dose = IND/GLY/MF 150/50/160 μg (once-daily); SAL/FLU high-dose = SAL/FLU 50/500 μg (twice-daily); TIO = TIO 5 μg (once-daily).

 

Objectives and endpoints1

Demonstrate non-inferiority of high-dose IND/GLY/MF (once-daily) vs. concurrent administration of high-dose SAL/FLU (twice-daily) + TIO (once-daily) in terms of AQLQ score.

Primary endpoint: Change from baseline in AQLQ total score after 24 weeks.

Secondary analyses:

  • Change from baseline in AQLQ and Asthma Control Questionnaire (ACQ-7) total scores
  • Proportion of patients achieving the minimal clinically important difference (MCID) in AQLQ of ≥0.5 and ACQ-7 of ≥0.5 (responders) over 24 weeks
  • Change from baseline in trough forced expiratory volume in 1 second (FEV1) after 24 weeks
  • Change from baseline in forced vital capacity (FVC) and forced expiratory flow at 25–75% of FVC over 24 weeks

Exploratory analyses:

  • Health status (St. George’s Respiratory Questionnaire [SGRQ]), peak expiratory flow and rate of asthma exacerbations over 24 weeks

 

​​Included patients1

  • 1,426 patients (men and women aged ≥18 years) with asthma for ≥6 months prior to screening treated with LABA/ICS medium- or high-dose
  • Pre-bronchodilator FEV1 <85% of the predicted normal value (after withholding bronchodilators) prior to spirometry at both run-in and randomisation visits
  • Reversibility in FEV1 of ≥12% and 200 mL or historical evidence within the past 5 years of reversibility or positive bronchial provocation test
  • Symptomatic (ACQ-7 ≥1.5) despite treatment with stable medium- or high-dose ICS/LABA during the run-in period
  • History of ≥1 severe asthma exacerbation that required medical care from a physician, emergency room visit or hospitalisation and systemic corticosteroid treatment for at least 3 days in the past 12 months

 

What are the results and why are they relevant?1

Single inhaler FDC of IND/GLY/MF high-dose was non-inferior to SAL/FLU high-dose + TIO in terms of AQLQ at Week 24.

These data support the potential clinical benefit of single inhaler IND/GLY/MF over the current standard of care for uncontrolled asthma.

 

Quality of life1

The primary endpoint was met – change from baseline in AQLQ total score with IND/GLY/MF high-dose was non-inferior vs. SAL/FLU high-dose + TIO at Week 24 (p<0.001).*

 

AQLQ total score at Week 24: IND/GLY/MF vs. SAL/FLU + TIO (primary endpoint)

 

*Primary analysis was to demonstrate non-inferiority with a 0.25 point change in AQLQ score. Data are presented as LS mean.
Data are presented as LS mean.
IND/GLY/MF high-dose = IND/GLY/MF 150/50/160 μg (once-daily); SAL/FLU high-dose = SAL/FLU 50/500 μg (twice-daily); TIO = TIO 5 μg (once-daily).

 

Over 24 weeks, the percentage of AQLQ responders with IND/GLY/MF high-dose and SAL/FLU high-dose + TIO was 73.3% and 67.8%, respectively.

AQLQ responder rates at Week 24: IND/GLY/MF vs. SAL/FLU + TIO (secondary analyses not controlled for multiplicity; inferences based on these data cannot be made due to lack of power)

 

*Patients with an improvement of ≥0.5 units (MCID) in AQLQ score.
IND/GLY/MF high-dose = IND/GLY/MF 150/50/160 μg (once-daily); SAL/FLU high-dose = SAL/FLU 50/500 μg (twice-daily); TIO = TIO 5 μg (once-daily).

 

Asthma control1

Change from baseline in ACQ-7 total score at Week 24 for IND/GLY/MF high-dose and SAL/FLU high-dose + TIO was -1.172 and -1.048, respectively.

No difference in the proportion of ACQ-7 responders was seen between IND/GLY/MF high-dose and SAL/FLU high-dose + TIO (85.2% and 83.9%, respectively).

 

ACQ-7 at Week 24: IND/GLY/MF vs. SAL/FLU + TIO (secondary analyses not controlled for multiplicity; inferences based on these data cannot be made due to lack of power)

 

Data are presented as LS mean.
IND/GLY/MF high-dose = IND/GLY/MF 150/50/160 μg (once-daily); SAL/FLU high-dose = SAL/FLU 50/500 μg (twice-daily); TIO = TIO 5 μg (once-daily).

 

Health status1

Improvements in SGRQ total score were observed for IND/GLY/MF high-dose and SAL/FLU high-dose + TIO.

 

SGRQ total score at Week 24: IND/GLY/MF vs. SAL/FLU + TIO (exploratory analyses not controlled for multiplicity; inferences based on these data cannot be made due to lack of power)

 

Data are presented as LS mean.
IND/GLY/MF high-dose = IND/GLY/MF 150/50/160 μg (once-daily); SAL/FLU high-dose = SAL/FLU 50/500 μg (twice-daily); TIO = TIO 5 μg (once-daily).

 

Lung function1

In terms of lung function, IND/GLY/MF high-dose and SAL/FLU high-dose + TIO showed improvements in trough FEV1; these improvements were observed as early as Week 8 and were sustained until Week 24.

 

Trough FEV1 at Week 24: IND/GLY/MF vs. SAL/FLU + TIO (secondary analyses not controlled for multiplicity; inferences based on these data cannot be made due to lack of power)

 

Data are presented as LS mean.
IND/GLY/MF high-dose = IND/GLY/MF 150/50/160 μg (once-daily); SAL/FLU high-dose = SAL/FLU 50/500 μg (twice-daily); TIO = TIO 5 μg (once-daily).

 

Safety1

IND/GLY/MF was generally well-tolerated, with a comparable safety profile to that of SAL/FLU high-dose + TIO (Table 1).

  • Common adverse events (AEs) included asthma exacerbation, nasopharyngitis, bronchitis, pharyngitis, headache and upper respiratory tract infection
  • The most common serious adverse events (SAEs) were pneumonia and asthma exacerbation
  • The death during the study was not asthma-related or considered by the investigator to be related to the study drug

 

Table 1. Safety 

AE category* IND/GLY/MF high-dose

(n=476)
ISAL/FLU high-dose + TIO

(n=475)
≥1 AE 249 (52.3) 245 (51.6)
≥1 SAE 18 (3.8) 19 (4.0)
≥1 AE suspected to be related to the study drug 26 (5.5) 19 (4.0)
≥1 AE leading to treatment discontinuation 3 (0.6) 3 (0.6)
Death 0 1 (0.2)

*Data are reported as n (%). Cause of death in one patient was due to a fatal stroke (haemorrhagic). 

 

Implications for clinical practice1

ARGON data support the potential clinical benefits of single inhaler IND/GLY/MF over the current standard of care for uncontrolled asthma:

  • IND/GLY/MF high-dose was non-inferior to SAL/FLU high-dose + TIO delivered concurrently via two inhalers in terms of AQLQ at Week 24
  • Once-daily dosing regimen via a single device offers comparable benefits in quality of life to SAL/FLU + TIO
  • IND/GLY/MF was generally well-tolerated with a similar safety profile to the comparator treatment

 

Data relating to ENERZAIR® BREEZHALER® medium-dose have been excluded as this dosing regimen is not licensed for use in the UK. Full information on these endpoints can be obtained from Novartis Medical Information. 

Indication: ENERZAIR® BREEZHALER® (indacaterol acetate/glycopyrronium bromide/mometasone furoate inhalation powder) is indicated as a maintenance treatment for asthma in adult patients not adequately controlled with a maintenance combination of a long-acting beta2-agonist and a high dose of an inhaled corticosteroid, who experienced one or more asthma exacerbations in the previous year.12

ACQ-7, Asthma Control Questionnaire-7; AE, adverse event; AQLQ, Asthma Quality of Life Questionnaire; CI, confidence interval; FDC, fixed-dose combination; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; GLY, glycopyrronium; ICS, inhaled corticosteroid; IND, indacaterol acetate; LABA, long-acting beta2-agonist; LAMA, long-acting muscarinic antagonist; LS, least squares; MCID, minimal clinically important difference; MF, mometasone furoate; SAE, serious adverse event; SAL/FLU, salmeterol/fluticasone propionate; SGRQ, St. George’s Respiratory Questionnaire; TIO, tiotropium.

References

  1. Gessner C et al. Respir Med 2020;106021.
  2. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2020. Available at: https://ginasthma.org/wp-content/uploads/2020/04/GINA-2020-full-report_-.... Date accessed: December 2020.
  3. Fardon T et al. Respir Med 2007;101(6):1218–1228.
  4. Kerstjens H et al. J Allergy Clin Immunol 2011;128(2):308–314.
  5. Kerstjens H et al. N Engl J Med 2012;367(13):1198–1207.
  6. Kerstjens H et al. Lancet Respir Med 2015;3(5):367–376.
  7. Befekadu E et al. J Asthma Allergy 2014;7:11–21.
  8. Kew K & Dahri K, Cochrane Database Syst Rev 2016;CD011721.
  9. Marceau C et al. J Allergy Clin Immunol 2006;118:574–581.
  10. Virchow J et al. Lancet 2019;394(10210):1737–1749.
  11. Stoloff S et al. J Allergy Clin Immunol 2004;113(2):245–251.
  12. ENERZAIR BREEZHALER Summary of Product Characteristics.
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UK | February 2021 | 103407
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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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