Prescribing information

 

Once-daily, single-inhaler mometasone/indacaterol/glycopyrronium versus mometasone/indacaterol or twice-daily fluticasone/salmeterol in patients with inadequately controlled asthma (IRIDIUM): a randomised, double-blind, controlled phase III study1 

  • Primary endpoint (trough forced expiratory volume in one second [FEV1] at Week 26) was met with high level of statistical significance (p<0.001) and confirms added benefit of a long-acting muscarinic antagonist (LAMA)
  • Key secondary endpoint (to demonstrate superiority in change from baseline to Week 26 in Asthma Control Questionnaire [ACQ-7] score) was not met, however all treatment arms demonstrated similarly high and clinically relevant improvements (above the minimal clinically important difference [MCID] of ≥0.5 units) from baseline
  • Additional secondary analyses at Week 52 (inferences based on these data cannot be made due to lack of power):
    • Indacaterol/glycopyrronium/mometasone (IND/GLY/MF) high-dose once-daily demonstrated a reduction in the annual rate of exacerbations compared to indacaterol/mometasone (IND/MF) high-dose once-daily and salmeterol/fluticasone (SAL/FLU) twice-daily
  • IND/GLY/MF was generally well-tolerated and safety was comparable across treatment arm

 

What was already known?

  • 39% of patients with asthma remain uncontrolled, despite current treatment with medium- or high-dose LABA/ICS2
  • Patients require inhaled therapies that maximise efficacy while minimising side effects3,4
  • 30–70% of patients do not adhere to their treatment5
  • 50% of patients are unable to use their inhaler properly, even with training6

 

Why was IRIDIUM conducted?

  • Patients with asthma who are inadequately controlled on LABA/ICS combinations, may benefit from the addition of a LAMA1
  • Use of separate inhalers can complicate asthma management, contribute to non-adherence, and lead to increased morbidity and healthcare expenditure;7 the use of a LABA/LAMA/ICS combination in a single device could be an effective treatment option for patients that remain uncontrolled despite high-dose LABA/ICS, and may simplify asthma management1
  •  IRIDIUM was conducted to show the added benefit of combining GLY (LAMA) with IND (LABA) and MF (ICS) in a single device over IND/MF, and to demonstrate the combined contribution of IND/GLY/MF against standard-of-care SAL/FLU, in adult patients with inadequately controlled asthma1

 

Trial design1

 

All treatments were administered in the evening.

Adapted from Kerstjens H et al. 2020.
*SAL/FLU 50/250 µg (twice-daily). Salbutamol/albuterol.
Trial identifier: QVM149B2302. More information can be found at: https://clinicaltrials.gov/ct2/show/NCT02571777. IND/GLY/MF high-dose = IND/GLY/MF 150/50/160 µg (once-daily); IND/MF medium-dose = IND/MF 150/160 µg (once-daily); IND/MF high-dose = IND/MF 150/320 µg (once-daily); SAL/FLU high-dose = SAL/FLU 50/500 µg (twice-daily).

 

Objectives and endpoints1

To evaluate the efficacy and safety of IND/GLY/MF high-dose vs. IND/MF high-dose over 52 weeks in patients with inadequately controlled asthma; the efficacy and safety of IND/GLY/MF high-dose vs. standard-of-care SAL/FLU high-dose was also assessed.

Primary endpoint: Demonstrate superiority in trough FEV1 of IND/GLY/MF high-dose vs. IND/MF high-dose after 26 weeks.

Key secondary endpoint: Demonstrate superiority in ACQ-7 score with IND/GLY/MF high-dose vs. IND/MF high-dose after 26 weeks.

Other secondary analyses: 

IND/GLY/MF high-dose vs. IND/MF high-dose or SAL/FLU high-dose in:

  • Morning and evening peak expiratory flow over 26 and 52 weeks of treatment
  • ACQ-7 change from baseline at Week 52 and percentage of patients achieving the MCID of ≥0.5 units in ACQ-7
  • Asthma exacerbations (moderate or severe, severe and all), symptoms, and nighttime awakenings
  • Rescue medication use
  • Quality of life as assessed by Asthma Quality of Life Questionnaire

 

Included patients1

  • 3,092 patients (men and women aged ≥18 and ≤75 years) with a diagnosis of asthma for a period of ≥1 year prior to screening
  • Treated with medium- or high-dose LABA/ICS for ≥3 months and at a stable dose for ≥1 month prior to screening
  • Pre-bronchodilator FEV1 <80% of predicted normal value prior to randomisation
  • Increase in FEV1 of ≥12% and 200 mL after administration of salbutamol/albuterol
  • ACQ-7 ≥1.5 prior to randomisation
  • ≥1 asthma exacerbation requiring medical care from a physician, emergency room visit or hospitalisation, or requiring systemic corticosteroids, in the 12 months prior to screening

 

What are the results and why are they relevant?1

The IRIDIUM trial is the first to evaluate the once-daily inhaled combination of IND/GLY/MF high-dose from a single device in patients with inadequately controlled asthma. Data highlight the potential benefits of once-daily fixed-dose combination of IND/GLY/MF vs. high-dose IND/MF and the widely used standard-of-care, SAL/FLU high-dose. 

 

Lung function1

The primary endpoint was met – improvement in trough FEV1 at Week 26 with IND/GLY/MF high-dose vs. IND/MF high-dose of (+65mL; p<0.001) was statistically significant in asthma patients who were previously uncontrolled on treatment with a LABA/ICS. This confirms the added benefit of LAMA to LABA/ICS treatment. 

 

Trough FEV1 at Week 26: IND/GLY/MF vs. IND/MF (primary endpoint) and SAL/FLU (secondary analysis 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); IND/MF high-dose = IND/MF 150/320 µg (once-daily); SAL/FLU high-dose = SAL/FLU 50/500 µg (twice-daily).

 

Improvements in trough FEV1 with IND/GLY/MF high-dose, IND/MF high-dose and SAL/FLU high-dose observed at Week 26 were maintained at Week 52.

Lung function at Week 52: IND/GLY/MF vs. IND/MF and SAL/FLU (secondary analyses, not controlled for multiplicity; inferences based on these data cannot be made due to lack of power)2,9

Data are presented as LS mean.
IND/GLY/MF high-dose = IND/GLY/MF 150/50/160 µg (once-daily); IND/MF high-dose = IND/MF 150/320 µg (once-daily); SAL/FLU high-dose = SAL/FLU 50/500 µg (twice-daily). 

 

Onset of action1,8

IND/GLY/MF high-dose, both doses of IND/MF and SAL/FLU high-dose showed improvements in FEV1, observed as early as after 5 minutes on Day 1.

 

FEV1 at 5-60 minutes post-dose on Day 1: IND/GLY/MF vs. IND/MF and SAL/FLU (secondary analyses)

 

Data are presented as LS mean.
IND/GLY/MF high-dose = IND/GLY/MF 150/50/160 µg (once-daily); IND/MF medium-dose = IND/MF 150/160 µg (once-daily); IND/MF high-dose = IND/MF 150/320 µg (once-daily); SAL/FLU high-dose = SAL/FLU 50/500 µg (twice-daily). 

 

Asthma control1

The key secondary endpoint (ACQ-7) was not met; however, all treatment arms  demonstrated similarly high and clinically relevant improvements (above the MCID of ≥0.5 units) from baseline.

 

ACQ-7 at Week 26 vs. IND/MF (key secondary endpoint) and SAL/FLU (secondary analysis, 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); IND/MF high-dose = IND/MF 150/320 µg (once-daily); SAL/FLU high-dose = SAL/FLU 50/500 µg (twice-daily).

 

Percentage of ACQ-7 responders* at Weeks 4, 12, 26 and 52 vs. IND/MF and SAL/FLU (secondary analyses, not controlled for multiplicity; inferences based on these data cannot be made due to lack of power)1,8

*Patients with an improvement of ≥0.5 points (MCID) in ACQ-7 score.
IND/GLY/MF high-dose = IND/GLY/MF 150/50/160 µg (once-daily); IND/MF high-dose = IND/MF 150/320 µg (once-daily); SAL/FLU high-dose = SAL/FLU 50/500 µg (twice-daily).

 

Exacerbations1

Exacerbations were a secondary endpoint (not part of confirmatory testing strategy).10

IND/GLY/MF high-dose once-daily demonstrated a reduction in the annual rate of  exacerbations compared to IND/MF high-dose once-daily and SAL/FLU twice-daily.

 

Annualised rate of exacerbations vs. IND/MF and SAL/FLU (secondary analyses, not controlled for multiplicity; inferences based on these data cannot be made  due to lack of power)

 

*A severe exacerbation was defined as an aggravation of asthma symptoms (such as shortness of breath, cough, wheezing, or chest tightness) that requires systemic corticosteroids for at least 3 consecutive days or a need for an emergency room visit, hospitalisation owing to asthma, or death due to asthma.1

IND/GLY/MF high-dose = IND/GLY/MF 150/50/160 µg (once-daily); IND/MF high-dose = IND/MF 150/320 µg (once-daily); SAL/FLU high-dose = SAL/FLU 50/500 µg (twice-daily).

 

Safety1

IND/GLY/MF was generally well-tolerated and safety was comparable across treatment arms (Table 1).

  • Adverse events (AEs) included asthma exacerbation, nasopharyngitis, bronchitis, headache and respiratory tract infections
  • Serious AEs (SAEs) included asthma exacerbation, pneumonia, respiratory tract infection, cholelithiasis and pulmonary embolism
  • Asthma exacerbation was the most common AE leading to permanent treatment discontinuation
  • None of the deaths during the study were considered by the investigator to be related to the study drugs

 

Table 1. Safety

AE category* ND/GLY/MF

high-dose

(n=616)
IND/MF

medium-dose

(n=608)
IND/MF

high-dose

(n=613)
SAL/FLU

high-dose

(n=618)
≥1 AE 458 (163.3) 453 (163.8) 454 (169.0) 487 (193.9)
≥1 SAE 46 (8.2) 38 (6.8) 52 (9.3) 39 (7.0)
≥1 AE suspected to be related to the study drug 51 (9.2) 42 (7.6) 38 (6.9) 51 (9.3)
≥1 AE leading to treatment discontinuation 13 (2.2) 19 (3.3) 18 (3.1) 21 (3.7)
Death 2 (0.3) 0 4 (0.7) 0

*Data are reported as n (incidence rate [IR]). IR is reported per 100 patient-years (100 × number of patients with at least one event/time at risk for given adverse event in patient-years).1
Reasons for death during the study include one case of cancer, five cases of cardiovascular events and one accident.1

 

Implications for clinical practice1

IRIDIUM demonstrated that IND/GLY/MF has the potential to become established for patients with asthma at GINA step 5:

  • IND/GLY/MF high-dose significantly improved lung function (trough FEV1) vs. IND/MF high-dose at Week 26 (p<0.001)
  • Once-daily dosing regimen and administration via a single device may improve adherence9 and asthma control11
  • Use of a single inhaler device facilitates step-up from LABA/ICS therapy in the same device, if required
  •  IND/GLY/MF was generally well-tolerated with a similar safety profile to the comparator treatments
     

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 is indicated as a maintenance treatment of 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.10

ACQ-7, Asthma Control Questionnaire-7; AE, adverse event; CI, confidence interval; FDC, fixed-dose combination; FEV1, forced expiratory volume in 1 second; GINA, Global Initiative for Asthma; GLY, glycopyrronium; ICS, inhaled corticosteroid; IND, indacaterol acetate; IR, incidence rate; 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.

References:

  1. Kerstjens H et al. Lancet Respir Med 2020;8(10):1000–1012.
  2. Buhl R et al. Respir Med 2019;162:105859 [Epub ahead of print].
  3. 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_-.... Accessed: December 2020.
  4. Dahl R. Respir Med 2006;100:1307–1317.
  5. Lindsay J & Heaney L. Patient Prefer Adherence 2013;7:329–336.
  6. Azzi E et al. NPJ Prim Care Respir Med 2017;27:29.
  7. Stoloff S et al. J Allergy Clin Immunol 2004;113:245–251.
  8. Kerstjens H et al. Lancet Respir Med 2020 supplementary appendix 1;8(10):1000–1012.
  9. Saini S et al. Am J Manag Care 2009;15:e22–e33.
  10. ENERZAIR BREEZHALER Summary of Product Characteristics.
  11. Woodcock A et al. Lancet 2017;390: 2247–2255
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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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