Key points from the evidence

The content of this evidence summary was up-to-date in February 2014. See summaries of product characteristics (SPCs), British national formulary (BNF) or the MHRA or NICE websites for up-to-date information.

Summary

Indacaterol/glycopyrronium (Ultibro Breezhaler 85/43 micrograms) is the first long-acting beta2 agonist (LABA)/long-acting muscarinic antagonist (LAMA) combination inhaler to be approved for chronic obstructive pulmonary disease (COPD). It is licensed as a maintenance bronchodilator treatment to relieve symptoms in adults with COPD and is expected to be launched in the UK in quarter 2, 2014. Although some small statistically significant improvements in lung function, dyspnoea (breathlessness), health status and use of rescue medication were seen with indacaterol/glycopyrronium compared with active comparators, the clinical importance of these differences is unclear and indacaterol/glycopyrronium's place in therapy is currently difficult to assess.

Effectiveness

  • Indacaterol/glycopyrronium statistically significantly reduced the rate of moderate or severe exacerbations compared with glycopyrronium alone in people with severe or very severe COPD. However, the European Medicines Agency considered that the reduction was insufficient to support an indication for reducing exacerbations.

  • Overall, indacaterol/glycopyrronium showed a small but statistically significant improvement in lung function (forced expired volume in 1 second [FEV1]) compared with active comparators in people with moderate to very severe COPD.

  • Indacaterol/glycopyrronium also showed small statistically significant improvements in dyspnoea, health status and use of rescue medication compared with active comparators, which were of uncertain clinical benefit.

  • The European Medicines Agency noted that, although the differences between treatments were often not large enough to be clinically relevant in the total population, responder analyses have shown that differences can be important to individual patients.

Safety

  • The summary of product characteristics reports that up to 15 months' treatment with indacaterol/glycopyrronium showed similar adverse reactions to those observed when people were treated with each drug individually.

  • In a 52-week safety study, the overall incidence of adverse events was similar between placebo and indacaterol/glycopyrronium (p value not reported).

  • Compared with established drugs such as formoterol, salmeterol and tiotropium, the long-term safety of indacaterol and glycopyrronium (alone or in combination) is unclear.

  • A 52-week study that is currently in progress may provide better evidence on the comparative safety and efficacy of LABA/LAMA and inhaled corticosteroid (ICS)/LABA.

  • Although the combination inhaler delivers the same clinically effective dose of indacaterol as the single-component inhaler, the stated doses are different which may confuse prescribers and patients.

Patient factors

  • People who are prescribed a LABA and a LAMA may find it easier to use a combination inhaler, rather than 2 single-component inhalers.

  • Indacaterol/glycopyrronium and the single-component inhalers are administered once daily using the Breezhaler dry powder inhalation device. Other LABAs, LAMAs and ICS/LABA inhalers are administered using different devices and many are taken twice daily.

  • NICE advises that treatment and care should take into account a person's needs and preferences.

Resource implications

  • The indacaterol/glycopyrronium combination inhaler is expected to be less expensive than the combined cost of the single-component inhalers (indacaterol £29.26, glycopyrronium £27.50 for 30-days' treatment).

Key points

Indacaterol/glycopyrronium (Ultibro Breezhaler 85/43 micrograms) is a once-daily, inhaled LABA/LAMA combination inhaler. It is the first LABA/LAMA combination inhaler to receive marketing authorisation in Europe and is indicated as a maintenance bronchodilator treatment to relieve symptoms in adults with COPD (summary of product characteristics for Ultibro Breezhaler). The manufacturer (Novartis) declined to share the UK launch date.

This evidence summary focuses on 2 published studies (SPARK [Wedzicha et al. 2013]) and BLAZE [Mahler et al. 2013]) that reported exacerbations and dyspnoea respectively, as their primary outcomes. Additional studies that reported lung function outcomes and longer-term assessments of safety are also discussed.

In SPARK (n=2224), indacaterol/glycopyrronium statistically significantly reduced the annualised rate of moderate to severe exacerbations in people with severe or very severe COPD by 12% compared with glycopyrronium alone (relative risk [RR] 0.88, 95% confidence interval [CI] 0.77 to 0.99, p=0.038). A non-significant reduction of 10% was seen in this outcome between indacaterol/glycopyrronium and open-label tiotropium (RR 0.90, 95% CI 0.79 to 1.02, p=0.096). In the European public assessment report for indacaterol/glycopyrronium, the 12% reduction was considered to be 'very small' and not supportive of the manufacturer's requested indication of 'exacerbation reduction'. The full NICE guideline on COPD considers a relative reduction in the risk of exacerbations of 20% or more to be clinically important.

BLAZE (n=247) found that indacaterol/glycopyrronium statistically significantly improved dyspnoea scores in people with moderate or severe COPD compared with placebo. The mean difference exceeded the 1 point improvement considered to be clinically important (least squares mean [LSM] difference 1.37, 95% CI 0.95 to 1.79; p<0.001). The dyspnoea score for indacaterol/glycopyrronium was also statistically significantly higher than for tiotropium (LSM difference 0.49, 95% CI 0.07 to 0.91; p=0.021). However, this difference is unlikely to be clinically important.

Two studies have reported lung function measures as primary outcomes: SHINE (Bateman et al. 2013; n=2144) and ILLUMINATE (Vogelmeier et al. 2012; n=523). In SHINE, indacaterol/glycopyrronium statistically significantly improved trough FEV1 compared with indacaterol, glycopyrronium, open-label tiotropium and placebo (LSM differences 70 ml, 90 ml, 80 ml and 200 ml respectively; p<0.001 in all comparisons). For comparisons with active comparators, these changes in FEV1 are less than the 100 ml or more that the full NICE guideline on COPD considers to be clinically important. In the other study, ILLUMINATE, FEV1 standardised area under the curve from 0 to 12 hours (FEV1 AUC0-12h) at week 26 was significantly higher with indacaterol/glycopyrronium compared with salmeterol/fluticasone (LSM difference 138 ml, 95% CI 100 ml to 176 ml; p<0.0001).

A 52-week safety study (ENLIGHTEN; n=339) found that the incidence of adverse events was similar in the indacaterol/glycopyrronium and placebo groups (57.8% and 56.6% respectively; p value not reported). Thirteen people receiving indacaterol/glycopyrronium (5.8%) had an adverse event leading to discontinuation of the study drug compared with 7 people receiving placebo (6.2%; p value not reported).

The summary of product characteristics for Ultibro Breezhaler reports that up to 15 months' treatment with indacaterol/glycopyrronium showed similar adverse reactions to those observed when people were treated with each drug individually. The safety profile of indacaterol/glycopyrronium is characterised by typical anticholinergic and beta-adrenergic symptoms.

Overall, indacaterol/glycopyrronium showed a statistically significant improvement in lung function compared with active comparators (indacaterol, glycopyrronium, tiotropium and fluticasone/salmeterol) in people with moderate to very severe COPD for up to 52 weeks. Indacaterol/glycopyrronium also showed small statistically significant improvements in dyspnoea, health status and use of rescue medication compared with active comparators. These improvements are of uncertain clinical benefit. Nevertheless, the European Medicines Agency states that, although the differences between treatments were often not large enough to be clinically relevant in the total population, responder analyses have shown that differences can be important to individual patients.

The NICE clinical guideline Chronic obstructive pulmonary disease (NICE clinical guideline 101) recommends that the choice of drug treatment should take into account the person's symptomatic response and preference, and the drug's potential to reduce exacerbations, side effects and costs. Use of dual therapy with a LAMA and LABA may be considered if an ICS (as part of combination therapy with a LABA) is declined or not tolerated.

The indacaterol/glycopyrronium combination inhaler is expected to be less expensive than the combined cost of the single-component inhalers and may be more convenient for people. However, compared with established drugs such as formoterol, salmeterol and tiotropium, the comparative efficacy and long-term safety of indacaterol and glycopyrronium (alone and in combination) is unclear, particularly in terms of reducing exacerbations. In addition, although the combination inhaler delivers the same clinically effective dose of indacaterol as the single-component inhaler, the stated doses are different which may confuse prescribers and patients.

Patients are currently being recruited for a 52-week study comparing the effects of indacaterol/glycopyrronium and fluticasone/salmeterol on exacerbations in people with moderate to very severe COPD (ClinicalTrials.gov NCT01782326). In addition to important patient-oriented outcome data, this study is likely to provide better longer-term comparative safety data for the 2 treatments.

Key evidence

Mahler DA, Decramer M, D'Urzo A et al. (2013) Dual bronchodilation with QVA149 reduces patient-reported dyspnoea in COPD: BLAZE study. European Respiratory Journal October 31. doi: 10.1183/09031936.00124013

Wedzicha JA, Decramer M, Ficker JH et al. (2013) Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind, parallel-group study. The Lancet Respiratory Medicine 1:199−209

Update

The following information has become available since this ESNM was produced.

December 2014: Availability of indacaterol/glycopyrronium (Ultibro Breezhaler)

Indacaterol/glycopyrronium has been launched in the UK as Ultibro Breezhaler. The cost of Ultibro Breezhaler (excluding VAT) is £14.30 for 12 capsules plus an inhaler or £35.75 for 30 capsules plus an inhaler. Costs taken from MIMS, December 2014.

May 2015: Medicines Evidence Commentary

Chronic obstructive pulmonary disease (COPD): indacaterol/glycopyrronium combination inhaler compared with tiotropium and formoterol in a randomised, non-inferiority study

This article discusses the implications of a 26-week double-blind randomised controlled trial in people with moderate to severe COPD which found that indacaterol/glycopyrronium was non-inferior to tiotropium plus formoterol in terms of health-related quality of life.

Medicines Evidence Commentaries form part of NICE's Medicines Awareness Service and help to contextualise important new evidence, highlighting areas that could signal a change in clinical practice. They do not constitute formal NICE guidance. See the article above for more information.

About this evidence summary

'Evidence summaries: new medicines' provide summaries of key evidence for selected new medicines, or for existing medicines with new indications or formulations, that are considered to be of significance to the NHS. The strengths and weaknesses of the relevant evidence are critically reviewed within this summary to provide useful information for those working on the managed entry of new medicines for the NHS, but this summary is not NICE guidance.