Prescribing information

 

Once-daily mometasone plus indacaterol versus mometasone or twice-daily fluticasone plus salmeterol in patients with inadequately controlled asthma (PALLADIUM): a randomised, double-blind, triple-dummy, controlled phase III study1

  • Overall, this study provides evidence for the additional benefit of indacaterol (IND) with medium- and high-dose inhaled corticosteroid/long-acting beta2-agonist (ICS/LABA) and demonstrates the effectiveness of both doses of IND/mometasone (MF)
  • The study achieved objectives by meeting primary (trough forced expiratory volume in one second [FEV1]) and key secondary (Asthma Control Questionnaire [ACQ-7]) endpoints, which were statistically significant
    • Overall improvements in lung function and asthma control were clinically relevant compared to MF
  • Incidence of adverse events and serious adverse events were generally comparable across treatment arms

 

What was already known?

  • Global Initiative for Asthma (GINA) strategy recommends the combination of a LABA and medium- or high-dose ICS as preferred controller treatment in patients with asthma uncontrolled on ICS alone or LABA/ICS low-dose combination;2 patients stepped-up to receive LABA/ICS reported improved asthma control compared with patients treated with ICS alone3 
  • The fixed-dose combinations (FDCs) of LABA and ICS have been shown to be well-tolerated and effective in the management of asthma;4,5 however, some currently available FDC products (e.g. salmeterol/fluticasone [SAL/FLU], budesonide/formoterol) require twice-daily dosing to achieve their optimum therapeutic effect4,5
  • Once-daily LABA/ICS dosing regimens, compared with twice-daily dosing, have been associated with improved adherence6,7 and lower risk of treatment discontinuation in patients with asthma.6 Moreover, once-daily dosing has been reported to be as effective as twice-daily dosing7

 

Why was PALLADIUM conducted?

  • IND is a LABA with a sustained 24h bronchodilator effect, which has been developed and licensed for use in treatment of chronic obstructive pulmonary disease.8 In early phase development, IND was generally well tolerated in these patients.1,8,9 Both these reasons make IND an ideal choice for the development of a once-daily combination with an ICS for patients with moderate to severe asthma.1
  • MF, a potent ICS approved for asthma via the Twisthaler® device, improved lung function and reduced rescue medication use in patients with asthma, with a comparable safety profile to other ICSs1,10 
  • PALLADIUM was conducted to support the development of a once-daily FDC of IND/MF for use with the Breezhaler® device in patients with inadequately controlled asthma1

 

Trial design1

 

All treatments were administered in the evening.

Adapted from van Zyl-Smit R, et al. 2020.

*e.g. fluticasone propionate 100 µg (twice-daily). Placebo administered by Breezhaler®, Twisthaler®, or Diskus® in the mornings or evenings, as appropriate. Salbutamol/albuterol.
Trial identifier: QVM149B2301. More information can be found at: https://clinicaltrials.gov/ct2/show/NCT02554786

 

Objectives and endpoints1

To evaluate the efficacy and safety of IND/MF high- and medium-doses vs. the two respective MF doses over 52 weeks in patients with inadequately controlled asthma.

Primary endpoint: Superiority of medium- or high-dose IND/MF over corresponding doses of MF in terms of trough FEV1 at Week 26

Key secondary endpoint: Superiority of combined IND/MF doses over combined MF doses in terms of ACQ-7 at Week 26

Other secondary analyses include: 

  • Non-inferiority of IND/MF high-dose vs. SAL/FLU high-dose (in trough FEV1)
  • Comparisons vs. high-dose MF and high-dose SAL/FLU in terms of
    • Morning and evening peak expiratory flow over 26 and 52 weeks of treatment
    • Percentage of patients achieving a minimal clinically important difference (MCID) of ≥0.5 units in ACQ-7 at Week 26 and 52
    • Asthma exacerbations (moderate or severe, severe, all) over 52 weeks
    • Rescue medication use, symptoms, and night-time awakenings

 

Included patients1

  • 2,216 patients (adolescents and adults aged ≥12 and ≤75 years) with a documented diagnosis of asthma (GINA step ≥3) for a period of ≥1 year prior to screening
  • Use of medium- or high-dose ICS or low-dose ICS/LABA required 3 months prior to screening (the dose regimen should be unchanged in the last 1 month)
  • Pre-bronchodilator FEV1 ≥50% and ≤85% of the predicted normal value (at the beginning and at the end of the run-in)
  • Increase in FEV1 of ≥12% and 200 mL within 15–30 minutes after administration of salbutamol 400 µg or albuterol 360 µg at start of run-in period
  • ACQ-7 ≥1.5 (at the beginning and at the end of the run-in)

 

What are the results and why are they relevant?1

Overall, PALLADIUM demonstrated the benefit of combining IND and MF in the newly formulated IND/MF once-daily FDC. IND/MF significantly improved lung function and symptom control vs. MF.

 

Lung function1

The primary endpoint was met: IND/MF significantly improved trough FEV1 by 211 mL (95% CI: 167, 255; p<0.001) and 132 mL (95% CI: 88, 176; p<0.001) vs. MF for medium- and high-doses respectively at Week 26.

 

Trough FEV1 at Week 26: IND/MF vs. MF (primary endpoint)

 

Data are presented as LS mean.
IND/MF medium-dose = IND/MF 150/160 μg (once-daily); IND/MF 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).

 

Asthma control1

The key secondary endpoint was also met: IND/MF combined doses demonstrated a significant improvement in asthma control as measured by ACQ-7 score vs. MF combined doses (treatment difference -0.209 [95% CI: -0.270, -0.149]; p<0.001) at Week 26.

 

ACQ-7 at Week 26: IND/MF vs. MF (key secondary endpoint)

 

Data are presented as LS mean.
Combined doses = combined data from both high- and medium-dose; IND/MF medium-dose = IND/MF 150/160 µg (once-daily); IND/MF 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).

 

These secondary analyses were not controlled for multiplicity; inferences based on these data cannot be made due to lack of power.

Treatment differences in ACQ-7 score between IND/MF high- and medium-doses and respective MF doses were seen at Week 26 (–0.171 [95% CI: –0.257, –0.086] and –0.248 [95% CI: –0.334, –0.162]; p<0.001).

Similar results were observed at Week 52, with sustained improvements in ACQ-7 with IND/MF combined-, high- and medium-doses vs respective MF doses.

 

ACQ-7 at Week 26: IND/MF vs. MF and SAL/FLU (secondary analyses)

 

Data are presented as LS mean.
Combined doses = combined data from both high- and medium-dose; IND/MF medium-dose = IND/MF 150/160 µg (once-daily); IND/MF 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).

 

The ACQ-7 responder analysis was not controlled for multiplicity; inferences based on these data cannot be made due to lack of power.

At Week 26, 76.3% of patients achieved improvement from baseline ≥0.5 units (MCID) for IND/MF (combined doses) vs. 69.7% for MF (combined doses).

 

ACQ-7 responder rates at Week 26: IND/MF vs. MF and SAL/FLU (secondary analyses)

 

*Patients with an improvement of ≥0.5 points (MCID) in ACQ-7 score.

Combined doses = combined data from both high- and medium-dose; IND/MF medium-dose = IND/MF 150/160 µg (once-daily); IND/MF 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); SAL/FLU high-dose = SAL/FLU 50/500 µg (twice-daily).

 

The secondary analyses relating to rescue medication and exacerbations were not controlled for multiplicity; inferences based on these data cannot be made due to lack of power.

 

Exacerbations

IND/MF medium- and high-doses both demonstrated a clinically meaningful reduction in the annual rate of moderate or severe exacerbations (secondary endpoint) compared to MF.1,11

 

Rescue medication

The improvements in lung function and asthma symptoms were complemented by a reduction in SABA usage. There was a treatment difference of 0.28 puffs/day in rescue medication (SABA) usage (smaller in the IND/MF group).1,11 In addition, the number of rescue medication-free days improved in all treatment arms, reflecting the importance of treatment adherence for asthma control.

 

Safety2

The incidence of adverse events (AEs) was comparable across all treatment groups (Table 1).

  • The most common AEs were asthma exacerbation, nasopharyngitis, headache, upper respiratory tract infection and bronchitis
  • Serious adverse events (SAEs) included asthma exacerbation, acute myocardial infarction, pneumonia, peritonitis and rib fracture
  • The death of an adolescent patient in the MF medium-dose group was not considered by the investigator to be related to the study drug

 

Table 1. Safety

AE category* IND/MF

medium-dose

(n=437)
IND/MF

high-dose

high-dose
MF

medium-dose

(n=443)
MF

high-dose

(n=440)
SAL/FLU

high-dose

(n=444)
≥1 AE 292 (131.0) 286 (122.7) 320 (166.3) 308 (149.3) 290 (130.6)
≥1 SAE 20 (5.0) 21 (5.2) 31 (8.0) 21 (5.2) 21 (5.1)
Death 0 0 1 (0.2) 0 0

*Data are reported as n (incidence rate [IR]). IR is reported per 100 patient-years (100 x number of patients with at least one event/time at risk for given adverse event in patient-years). The cause of death was status asthmaticus.

Implications for clinical practice1

PALLADIUM provides evidence for the additional benefit of IND added to MF for patients who are at GINA steps 3 and above: 

  • A preferable option over MF for inadequately controlled asthmatic patients ≥12 years
  • Availability of different doses means that treatment can be adjusted as needed
  • Once-daily dosing may improve adherence vs. twice-daily LABA/ICS, thereby potentially leading to improved asthma control
  • Both doses of IND/MF were generally well-tolerated with a similar safety profile to the comparator treatments

 

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.12

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; ICS, inhaled corticosteroid; IND, indacaterol acetate; IR, incidence rate; LABA, long-acting beta2-agonist; LS, least squares; MCID, minimal clinically important difference; MF, mometasone furoate; SABA, short-acting beta2-agonist; SAE, serious adverse event; SAL/FLU, salmeterol/fluticasone propionate.

References

  1. van Zyl-Smit R et al. Lancet Respir Med 2020;8(10):987–999.
  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_-final-_wms.pdf. Date accessed: December 2020.
  3. Bateman E et al. Am J Respir Crit Care Med 2004;170(8):836–844.
  4. Zetterström O et al. Eur Respir J 2001;18(2):262–268.
  5. McKeage K et al. Drugs 2009;69(13):1799–1828.
  6. Averell C et al. J Asthma 2019:1–10. [Epub ahead of print].
  7. Dal Negro R et al. Multidiscip Respir Med 2018;13:18.
  8. LaForce C et al. Allergy 2008;63(1):103–111.
  9. Pearlman D et al. Ann Allergy Asthma Immunol 2008;101(1):90–95.
  10. Tan R & Corren J. Ther Clin Risk Manag 2008;4(6):1201–1208.
  11. van Zyl-Smit R et al. Lancet Respir Med 2020 supplementary appendix 1;8(10):987–999.
  12. ATECTURA BREEZHALER Summary of Product Characteristics.

 

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UK | February 2021 | 103407
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