Key points from the evidence

The content of this evidence summary was up-to-date in May 2016. See summaries of product characteristics (SPCs), British national formulary (BNF) or the MHRA or NICE websites for up-to-date information.

Summary

Compared with its individual mono-components, a combination of tiotropium/olodaterol (Spiolto Respimat) has shown statistically significant improvements in lung function and health-related quality of life outcomes, although the clinical relevance of these improvements is unclear. There are no published studies which directly compare the efficacy and safety of tiotropium/olodaterol with other long-acting muscarinic antagonist (LAMA) and long-acting beta‑2 agonist (LABA) combination inhalers or with combination treatment with tiotropium plus an individual component LABA inhaler.

Regulatory status: Tiotropium/olodaterol (Spiolto Respimat) was launched in the UK in June 2015 and is the fourth LAMA/LABA combination inhaler to be available in the UK.

Effectiveness

  • Statistically significant improvement in trough FEV1 of 0.071 and 0.050 litres with tiotropium/olodaterol compared with tiotropium in 2 RCTs of 24 weeks' treatment (n=2,624 and 2,539).

  • Statistically significant improvement in trough FEV1 of 0.082 and 0.088 litres with tiotropium/olodaterol compared with olodaterol in 2 RCTs of 24 weeks' treatment (n=2,624 and 2,539).

  • Statistically significant improvement in St George's Respiratory Questionnaire (SGRQ) with tiotropium/olodaterol compared with tiotropium (−1.233 points) and olodaterol (−1.693 points) from a combined analysis (2 RCTs; 24 weeks' treatment; n=5,163).

  • The clinical relevance of all of these differences is unclear.

Safety

  • The risk of cardiovascular side effects should be taken into account when prescribing tiotropium delivered via the Respimat or Handihaler to people with certain cardiac conditions (Drug Safety Update). Olodaterol may also have cardiovascular side effects.

  • The safety profile of the 2 mono-components (tiotropium and olodaterol) is well described. There is no evidence as yet from the clinical trial programme that there are any additive adverse effects when these are combined in 1 inhaler (Dutch Public Assessment Report [PAR]).

Patient factors

  • Spiolto Respimat is provided as an inhaler and a separate cartridge that needs to be inserted into the inhaler before it is first used.

  • Tiotropium/olodaterol is used once daily.

  • Some people may prefer a particular device. Spiolto Respimat is an inhalation solution. Other LAMA/LABA combination inhalers are dry powder inhalers.

Resource implications

  • The annual cost of treatment with Spiolto Respimat is £390 (MIMS; March 2016, excluding VAT), which is the same cost as the 3 other currently available LAMA/LABA combination inhalers.

  • Spiolto Respimat costs less than combination treatment with tiotropium and available LABA individual component inhalers.

Introduction and current guidance

The NICE guideline on chronic obstructive pulmonary disease (COPD; which is being updated, publication date to be confirmed) makes several recommendations about inhaled treatments for managing stable COPD. See the NICE guideline or the NICE pathway on COPD for full details.

Full text of introduction and current guidance.

Product overview

Spiolto Respimat inhalation solution contains tiotropium (a LAMA) and olodaterol (a LABA). It is licensed as a maintenance bronchodilator treatment to relieve symptoms in adults with COPD. Spiolto Respimat contains 2.5 micrograms of tiotropium and 2.5 micrograms of olodaterol per delivered dose (the dose that leaves the mouthpiece of the inhaler). The recommended dose is 5 micrograms of tiotropium and 5 micrograms of olodaterol given as 2 puffs once a day, at the same time of day (summary of product characteristics [SPC]: Spiolto Respimat).

Full text of product overview.

Evidence review

This evidence summary discusses the best available evidence on the efficacy and safety of tiotropium/olodaterol. This consists of 2 replicate 52‑week double-blind, randomised controlled trials (RCTs) comparing tiotropium/olodaterol with the individual mono-components tiotropium and olodaterol in 5,163 people with COPD (Buhl et al. 2015). The main efficacy outcomes in these trials were assessed after 24 weeks' treatment. An additional two 12‑week RCTs comparing tiotropium/olodaterol with tiotropium and placebo in 1,623 people with COPD (Singh et al. 2015) and a 6‑week crossover study (n=229) comparing tiotropium/olodaterol with fluticasone propionate/salmeterol (Beeh et al. 2016) are also briefly discussed.

Buhl et al. (2015) and Singh et al. (2015) included groups randomised to unlicensed doses of tiotropium and tiotropium/olodaterol. This evidence summary only discusses results from the groups given the licensed doses which is tiotropium/olodaterol 5/5 micrograms once daily. For all of the results the clinical relevance of the differences between tiotropium/olodaterol and the individual mono-components is unclear.

  • In the 2 RCTs in Buhl et al. (2015) tiotropium/olodaterol statistically significantly improved trough FEV1 (a measure of the 24‑hour bronchodilation profile) after 24 weeks' treatment compared with the individual components. The mean treatment difference for change from baseline in trough FEV1 with tioptropium/olodaterol compared with tiotropium was 0.071 litres (95% confidence interval [CI] 0.047 to 0.094; p<0.0001) in 1 RCT (n=2,624) and 0.050 litres (95% CI 0.024 to 0.075; p=0.0001) in the other RCT (n=2,539). For tiotropium/olodaterol compared with olodaterol the mean treatment difference for change from baseline in trough FEV1 was 0.082 litres (95% CI 0.059 to 0.106; p<0.0001) and 0.088 litres (95% CI 0.063 to 0.113; p<0.0001).

  • In the combined analysis of the 2 RCTs in Buhl et al. (2015), tiotropium/olodaterol statistically significantly improved SGRQ total score (a health-related quality of life measure ranging from 0 to 100 points) compared with the individual components. The mean treatment difference for the SGRQ total score after 24 weeks' treatment with tiotropium/olodaterol was −1.233 (95% CI −2.313 to −0.153; p=0.0252) compared with tiotropium and −1.693 (95% CI −2.778 to −0.608; p=0.0022) compared with olodaterol. For the same outcome, in the combined analysis of both RCTs reported by Singh et al. (2015), the mean treatment difference after 12 weeks' treatment with tiotropium/olodaterol compared with tiotropium was −2.10 (95% CI −3.47 to −0.72; p<0.01).

  • In the combined analysis of the 2 RCTs in Buhl et al. (2015) the mean treatment difference for transition dyspnoea index (TDI) focal score (a measure of dyspnoea which ranges from −9 to +9) after 24 weeks' treatment with tiotropium/olodaterol was 0.356 (95% CI 0.092 to 0.619; p<0.05) compared with tiotropium and 0.420 (95% CI 0.155 to 0.684; p<0.005) compared with olodaterol. Although statistical analysis is provided for this outcome, it is not strictly inferential due to the hierarchical testing method used in the study. For the same outcome, in the combined analysis of both RCTs reported by Singh et al. (2015), the mean treatment difference after 12 weeks' treatment with tiotropium/olodaterol compared with tiotropium was 0.59 (95% CI 0.22 to 0.97; p<0.01).

  • In Buhl et al. (2015) and Singh et al. (2015) the treatment difference between tiotropium/olodaterol and the individual mono-components for trough FEV1, SGRQ total score and TDI focal score was less than what is generally considered to be the minimum clinically important difference for these outcomes (which is: 0.100 litres for FEV1, −4 points for SGRQ total score and 1 unit for TDI focal score) [see the full NICE guideline on COPD]. However, it is unclear if these minimum clinical important differences are appropriate as a benchmark for clinical significance for comparisons between a combination of 2 bronchodilators (LAMA/LABA) and 1 bronchodilator (either a LAMA or a LABA).

  • Limited data on exacerbations were reported in Buhl et al. (2015), see the full text section of this evidence review for details. However, the study was not designed to assess the effect of tiotropium/olodaterol on exacerbation rates. In all of the studies discussed in this evidence summary participants were allowed to have concomitant treatment with an inhaled corticosteroid.

  • In Beeh et al. (2016) tiotropium/olodaterol 5/5 microgram once daily statistically significantly improved FEV1 area under the curve from 0 to 12 hours (AUC0-12) compared with fluticasone propionate/salmeterol 500/50 micrograms twice daily; adjusted mean treatment difference for change from baseline 0.129 litres (95% CI 0.107 to 0.150, p<0.0001). For the same comparison, there was also a statistically significant improvement in trough FEV1 (a secondary outcome measure); adjusted mean treatment difference for the change from baseline 0.058 litres (95% CI 0.032 to 0.082, p<0.0001).

  • In Buhl et al. (2015), 16.4% (169/1029) of people in the tiotropium/olodaterol group, 16.7% (172/1033) of people in the tiotropium group and 17.4% (181/1038) of people in the olodaterol group reported serious adverse events. The Dutch PAR for Spiolto Respimat inhalation solution concludes that, as yet, there is no evidence from the clinical trial programme that there is an additive effect in terms of the safety profile when the individual drugs (tiotropium and olodaterol) are combined in 1 inhaler. Both tiotropium and olodaterol may have cardiovascular side effects. The February 2015 Drug Safety Update issued advice to take the risk of cardiovascular side effects into account when prescribing tiotropium delivered via the Respimat or Handihaler for the treatment of COPD to people with certain cardiac conditions. See the SPC for further information on contraindications, warnings and precautions for use, potential interactions and adverse effects of tiotropium/olodaterol.

Full text of evidence review.

Context

Tiotropium/olodaterol is the fourth LAMA/LABA combination inhaler to be launched in the UK for treating COPD, following umeclidinium/vilanterol (Anoro Ellipta: see the evidence summary on chronic obstructive pulmonary disease: umeclidinium/vilanterol), indacaterol/glycopyrronium (Ultibro Breezhaler: see the evidence summary on chronic obstructive pulmonary disease: indacaterol/glycopyrronium) and aclidinium/formoterol (Duaklir Genuair: see the evidence summary on chronic obstructive pulmonary disease: aclidinium/formoterol). The annual cost of Spiolto Respimat is £390 (excluding VAT; costs taken from MIMS, March 2016), which is the same cost as the 3 other currently available LAMA/LABA combination inhalers. It costs less than combination treatment with tiotropium and available LABA individual component inhalers.

Full text of context.

Estimated impact for the NHS

The NICE guideline on COPD (which is currently being updated, publication date to be confirmed) 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, its side effects and its costs. Tiotropium/olodaterol is an inhalation solution delivered by the Respimat soft mist inhaler. 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. Tiotropium/olodaterol is used once daily. Two of the other currently available LAMA/LABA combination inhalers are also used once daily. Costs for the 4 currently available LAMA/LABA inhalers are the same. However there are no published RCTs which directly compare their efficacy and safety.

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.