Key points from the evidence

The content of this evidence summary was up-to-date in April 2015. See summaries of product characteristics (SPCs), British national formulary (BNF) or the MHRA or NICE websites for up-to-date information.

Summary

Aclidinium/formoterol (Duaklir Genuair) is a combination inhaler containing a long‑acting muscarinic antagonist (LAMA) and long‑acting beta‑2 agonist (LABA). It is licensed for treating chronic obstructive pulmonary disease (COPD).

Two randomised controlled trials (RCTs) found that aclidinium/formoterol statistically significantly improved lung function and breathlessness over 24 weeks compared with placebo and aclidinium and formoterol monotherapies. Not all of the improvements compared with aclidinium or formoterol monotherapy were considered to be clinically important using conventional criteria. Improvements in lung function and breathlessness were similar to those seen with the other recently licenced LAMA/LABA combinations, umeclidinium/vilanterol and indacaterol/glycopyrronium.

Regulatory status: Duaklir Genuair (aclidinium/formoterol) received a European marketing authorisation for maintenance bronchodilator treatment to relieve symptoms in adults with COPD in December 2014.

Effectiveness

In a pooled analysis of 2 RCTs (n=1729 and n=1692) aclidinium/formoterol statistically significantly improved:

  • 1 hour post‑dose FEV1 more than aclidinium monotherapy (difference 118 ml, p<0.0001) and placebo (difference 293 ml, p<0.0001)

  • trough FEV1 more than formoterol monotherapy (difference 68 ml, p<0.0001: not clinically important) and placebo (difference 138 ml, p<0.0001)

  • breathlessness compared with placebo (difference 1.43 units, p<0.0001) and aclidinium (difference 0.44 units, p=0.016: not clinically important) and formoterol monotherapy (difference 0.47 units, p=0.009: not clinically important)

  • exacerbations of any severity compared with placebo (difference 0.33 exacerbations per patient/year, p=0.01: clinical importance unclear).

There are no published studies comparing the efficacy and safety of aclidinium/formoterol with other single or combination treatments for COPD.

Safety

Patient factors

  • Aclidinium/formoterol is used twice daily. Other LAMA/LABA combination inhalers are available which are used once daily.

  • Aclidinium/formoterol and umeclidinium/vilanterol are both multi‑dose breath‑activated dry powder inhalers (Genuair and Ellipta respectively). Indacaterol/glycopyrronium is a single dose breath‑activated dry powder inhaler (Breezhaler). Some people may prefer a particular device.

  • Some people with COPD like to use a spacer. None of the LAMA/LABA combination inhalers can be used with a spacer.

Resource implications

  • The aclidinium/formoterol combination inhaler costs less than the combined cost of the single‑component inhalers.

  • Aclidinium/formoterol and umeclidinium/vilanterol inhalers cost £32.50 for 30 days of treatment. An indacaterol/glycopyrronium inhaler costs £36.88 (MIMS, March 2015).

Introduction and current guidance

The NICE clinical guideline on chronic obstructive pulmonary disease (COPD) makes several recommendations about inhaled treatments for managing stable COPD that are relevant to the likely place in therapy of aclidinium/formoterol. The use of dual therapy with a LAMA and LABA may be considered if an inhaled corticosteroid (ICS; as part of combination therapy with a LABA) is declined or not tolerated. See the NICE guideline or the NICE pathway on COPD for full details.

Full text of introduction and current guidance.

Product overview

Duaklir Genuair (aclidinium/formoterol) is a breath‑activated dry powder inhaler containing aclidinium bromide (a LAMA) and formoterol fumarate dihydrate (a LABA). It received a European marketing authorisation for maintenance bronchodilator treatment to relieve symptoms in adults with COPD in December 2014.

Full text of product overview.

Evidence review

  • This evidence summary is based on 2 RCTs (ACLIFORM-COPD and AUGMENT-COPD), which evaluated the efficacy of aclidinium/formoterol compared with placebo and aclidinium and formoterol monotherapies in people with moderate or severe stable COPD over 24 weeks. It includes pooled analyses of data from ACLIFORM and AUGMENT, taken from the European Public Assessment Report for aclidinium/formoterol.

  • In the pooled population at week 24, aclidinium/formoterol improved 1 hour post‑dose forced expired volume in 1 second (FEV1) statistically significantly more than aclidinium monotherapy (primary outcome 1: difference 118 ml, p<0.0001) and placebo (difference 293 ml, p<0.0001). These results are clinically important because they are above the 100 ml level generally considered to be a minimum clinically important difference in FEV1 (see the full NICE guideline on COPD).

  • Aclidinium/formoterol also improved trough FEV1 statistically significantly more than formoterol monotherapy (primary outcome 2: difference 68 ml, p<0.0001) and placebo (difference 138 ml, p<0.0001). The difference between the combination and formoterol is below the 100 ml level generally thought to be clinically important (see the full NICE guideline on COPD). According to the European Public Assessment Report for aclidinium/formoterol, this difference is similar to that seen with other recently licensed LAMA/LABA combinations. The European Public Assessment Report also notes that it has been argued that an additional improvement in FEV1 of 100 ml cannot be achieved by adding a second bronchodilator to the first because people with moderate to severe COPD generally have limited airways reversibility.

  • In the pooled population, aclidinium/formoterol improved breathlessness (Transition Dyspnoea Index [TDI] focal scores) statistically significantly more than placebo (difference 1.43 units, p<0.0001), aclidinium monotherapy (difference 0.44 units, p=0.016) and formoterol monotherapy (difference 0.47 units, p=0.009). Only the comparison with placebo is above the 1 unit improvement generally considered to be clinically important for this outcome (see the full NICE guideline on COPD).

  • Aclidinium/formoterol improved health‑related quality of life (St. George's Respiratory Questionnaire [SGRQ]) total scores statistically significantly more than placebo in AUGMENT (difference 4.36 units, p≤0.01: 4 units is generally considered to be clinically important; see the full NICE guideline on COPD). No statistically significant differences were found when the combination was compared with aclidinium or formoterol monotherapy. In ACLIFORM, a high and clinically important placebo response was seen (6.51 units compared with 2.21 units in AUGMENT). Post‑hoc analyses failed to identify a single reason for this unexpected result and suggest that the cause is likely to have been multi‑factorial.

  • The percentages of people in the pooled aclidinium/formoterol group who achieved 1 unit for TDI focal score (62%) and 4 units for SGRQ total score (57%) were similar to those achieved by the 2 other recently approved LAMA/LABA combinations (umeclidinium/vilanterol, 58% and 49% respectively; and indacaterol/glycopyrronium, 68% and 64% respectively; European Public Assessment Report for aclidinium/formoterol).

  • In the pooled population, rates of moderate or severe exacerbations using the Healthcare Resource Utilisation definition (an increase of COPD symptoms for 2 days or more that needed a change in COPD treatment), but not exacerbations of any severity, were statistically significantly lower with aclidinium/formoterol compared with placebo (difference 0.13 per patient/year, p=0.036). A statistically significant difference was seen in the rate of exacerbations of any severity using the EXAcerbations of Chronic pulmonary disease Tool (EXACT) definition (a persistent increase from baseline in total EXACT score of at least 9 points for at 3 days or more, or at least 12 points for 2 days or more; difference between aclidinium/formoterol and placebo 0.33 per patient/year, p=0.01). The European Public Assessment Report for aclidinium/formoterol notes that a reduction of at least 1 exacerbation/year is currently the best estimate of a minimum clinically important difference in exacerbations and it is debatable whether a reduction of 0.33 exacerbations per year is clinically meaningful. However, the RCTs were too short to assess exacerbations satisfactorily.

  • The incidences of adverse events that led to discontinuation in AUGMENT were the same between aclidinium/formoterol (6.3%) and placebo (6.3%), and slightly lower in the aclidinium (4.7%) and formoterol (4.2%) groups (p values not reported). In ACLIFORM, the number of adverse events that led to discontinuation was similar across the groups (placebo 4.1%, aclidinium/formoterol 4.2%, aclidinium 4.4% and formoterol 3.6%; p values not reported).

  • The most commonly reported treatment‑emergent adverse events were cough, nasopharyngitis and headache in AUGMENT and exacerbations of COPD, headache and nasopharyngitis in ACLIFORM. According to the European Public Assessment Report for aclidinium/formoterol, the number of drug‑related adverse events seen with the combination was generally low and the reported events did not give rise to any major safety concerns. Many people with COPD have significant cardiovascular risk or cardiovascular co‑morbidities and warnings about the potential cardiovascular risks of aclidinium/formoterol were included in the summary of product characteristics. This is consistent with the warnings for other LABA/LAMA combination inhalers.

  • The study participants had moderate to severe COPD and it is unclear how effective aclidinium/formoterol is in people with mild or very severe COPD. The length of follow up in ACLIFORM and AUGMENT was 24 weeks only; therefore, the long‑term effects of aclidinium/formoterol are currently uncertain. An extension study to AUGMENT (NCT01572792) and another long‑term safety study (NCT01437540) have been undertaken but not yet published.

Full text of evidence review.

Context

The aclidinium/formoterol combination inhaler costs less than the combined cost of the single‑component inhalers. The cost of an aclidinium/formoterol inhaler is the same as an umeclidinium/vilanterol inhaler (£32.50) and less than an indacaterol/glycopyrronium inhaler (£36.88) (MIMS, January 2015).

Full text of context.

Estimated impact for the NHS

The NICE guideline on COPD recommends that the choice of drug treatment for COPD should take into account the person's symptomatic response and preference, and the drug's potential to reduce exacerbations, its side effects and its costs. Dual therapy with a LAMA and a LABA may be considered if an ICS/LABA is declined or not tolerated.

According to the European Public Assessment Report for aclidinium/formoterol, improvements in lung function and breathlessness were similar to those seen with the other recently licenced LAMA/LABA combinations, umeclidinium/vilanterol and indacaterol/glycopyrronium. However, it is unclear whether the combination has clinically important benefits over aclidinium or formoterol monotherapy, or whether it reduces exacerbations by a clinically important amount. Also, there are no published studies which directly compare the efficacy and safety of aclidinium/formoterol with other combination LAMA/LABAs or other single or combination treatments for COPD. A study comparing aclidinium/formoterol with salmeterol/fluticasone has been completed but not yet published (NCT01908140).

Aclidinium/formoterol is administered twice daily, whereas umeclidinium/vilanterol and indacaterol/glycopyrronium, the other LAMA/LABA combination inhalers available, are administered once daily.

Aclidinium/formoterol and umeclidinium/vilanterol are both multi‑dose breath‑activated dry powder inhalers (Genuair and Ellipta devices respectively). Indacaterol/glycopyrronium is a single dose breath‑activated dry powder inhaler (Breezhaler device). Some people may prefer a particular device or be able to use one device better than another. Some people with COPD are unable to use a spacer, others are; none of these combination inhalers can be used with a spacer.

Local decision makers will need to take safety, efficacy, cost and patient factors into account when considering the likely place in therapy of aclidinium/formoterol.

Full text of estimated impact for the NHS.

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.