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Commissioning Support Fluticasone furoate/vilanterol (Relvar Ellipta®▼) For the treatment of chronic obstructive pulmonary disease Commissioning guidance When making a decision about the use of combination inhaler devices for the treatment of COPD, commissioners may wish to consider the following: At current prices, Relvar Ellipta is one of the more cost-effective long-acting ß2-agonist/inhaled corticosteroid (LABA/ICS) combination inhalers. When a combination inhaler is considered an appropriate option, NICE guidance recommends selection of the least costly device. The availability of a once-daily dose may be beneficial in some patient groups. Q4 rating: The evidence for efficacy of the Relvar Ellipta inhaler was considered to be weak. Only three of six double-blind randomised controlled trials (RCTs) identified, evaluated the licensed dose of Relvar Ellipta (92/22) compared with placebo or a comparator licensed for use in the UK. In these trials, the authors stated that where no statistically significant difference was demonstrated for the primary endpoint, the statistical hierarchy used in the analysis of results mean that no significance could be inferred for secondary endpoints, which limited use of the reported data for the licensed dose in one trial and data for patient oriented outcomes in two trials: St Georges Respiratory Questionnaire and the Chronic Respiratory Questionnaire dyspnoea domain. Place in therapy in primary care Prescribing guidance: Category A (Q4) BNF: 3.2 Relvar Ellipta is suitable for prescribing in primary care for the treatment of COPD, within its licensed indications. Q2 higher place weaker evidence Q1 higher place stronger evidence Q4 lower place weaker evidence Q3 lower place stronger evidence Strength of evidence for efficacy The Q rating relates to the drug’s position on the effectiveness indicator grid. The strength of the evidence is determined by the quality and quantity of studies that show significant efficacy of the drug compared with placebo or alternative therapy. Its place in therapy in primary care takes into account safety and practical aspects of using the drug in primary care, alternative options, relevant NICE guidance, and the need for secondary care input. MTRAC considered the fluticasone furoate/vilanterol dry powder inhaler because it was a new treatment with potential for use in primary care. Description of technology Fluticasone furoate/vilanterol combination dry powder inhaler (Relvar Ellipta®▼) is a once-daily inhaler containing a LABA (vilanterol) and an ICS (fluticasone furoate), both new medications for COPD. Two strengths are provided: one containing 100 µg of fluticasone furoate and 25 µg of vilanterol (delivered doses 92 µg/22 µg), and one containing 200 µg of fluticasone furoate and 25 µg of vilanterol (delivered 1 doses 184 µg/22 µg). Only the lower 92/22 dose combination is licensed for the symptomatic treatment of adults with COPD with a FEV1<70% predicted normal (post-bronchodilator) with an exacerbation history despite regular bronchodilator 1 therapy. The recommended dose is one inhalation per day. Background COPD is an inflammatory disease characterised by pulmonary airflow obstruction that is usually progressive and not fully reversible. COPD is a common cause of long-term disability and death that presents a major burden to healthcare services. There are estimated to be over 3 million people with COPD in 2 the UK. January 2015 Quality and Outcomes Framework (QOF) data for 2012/13 show that the diagnosed prevalence of COPD in the West Midlands is 1.8% (102,588 patients in 3 COPD disease registers). Between April 2012 and March 2013, COPD was the primary diagnosis in 25,639 emergency hospital admissions in the West 4 Midlands. 2 The 2010 NICE clinical guideline on COPD stated that in people with stable COPD who remain breathless or have exacerbations despite using short-acting bronchodilators as needed, the following should be offered as maintenance therapy: • if FEV1 ≥ 50% predicted: a LABA or a long acting muscarinic antagonist (LAMA) • if FEV1 < 50% predicted: a LABA plus ICS combination inhaler, or a LAMA. In people with stable COPD and an FEV1 ≥ 50% predicted who remain breathless or have exacerbations despite maintenance therapy with a LABA: • consider a LABA plus ICS combination inhaler • consider a LAMA in addition to a LABA where an ICS is declined or not tolerated. A LABA plus ICS combination inhaler in addition to a LAMA should be considered in all people with stable Page 1 of 2 COPD who remain breathless or have exacerbations despite maintenance therapy with a LAMA, irrespective 2 of their FEV1. Clinical evidence for efficacy and safety Seven multicentre, double-blind RCTs were identified that evaluated the Relvar Ellipta inhaler in patients with COPD. Two trials were excluded from the review due to 5,6 short duration (28 days) and/or the use of an 6 unlicensed dose (368/22 µg). Five trials evaluated the licensed dose of Relvar (92/22 µg) for the treatment of 7-10 Four of the trials also included comparisons COPD. with other dose combinations of Relvar (46/22, 184/22) 8-10 that will not be further described. Various comparators were used in the trials assessing 8,9 Relvar, including placebo, single component 8,9 8fluticasone furoate and single component vilanterol, 10 neither of which is licensed as an individual treatment for COPD. Relvar was also compared with twice daily use of the licensed active comparator fluticasone propionate (500 µg)/salmeterol (50 µg) via the 7 Accuhaler device (Seretide). For the purposes of this summary, only comparisons with placebo and the licensed active comparator are presented. The trials ranged in duration from 12 to 24 weeks, following a 2 to 4 week run-in period. The active comparator trial evaluated the change in lung function (FEV1: change in forced expiratory volume in one second) from the pre-dose FEV1 at baseline compared with the weighted mean 24-hour FEV1 after 7 12 weeks’ treatment (primary outcome). Two further trials evaluated changes from baseline to the end of the study in the weighted mean FEV1 at 0 to 4 hours postdose (peak), and at 23 to 24 hours post-dose 8,9 (trough). Secondary outcomes included measures of dyspnoea (domain of the Chronic Respiratory 8,9 Questionnaire; CRQ-SAS) and change in health 7 status from baseline to trial end (St George’s Respiratory Questionnaire score; SGRQ). Results are reported for comparisons of the licensed dose (92/22) of Relvar with a licensed active comparator or placebo. Compared with fluticasone propionate/salmeterol 7 500/50 in a 12-week trial (n=528), the change in FEV1 from baseline (pre-dose, day 1) to the end of the trial (24-hour weighted mean FEV1 on day 84) was not significantly different in patients using Relvar 92/22. Mean ± SD changes in FEV1 for Relvar vs. Seretide were 130 ± 222 mL vs. 108 ± 221 mL. Due to the design of the trial, statistical significance could not be inferred for the comparison of scores for improvement of health status using the SGRQ. According to the authors, the minimal clinically important difference for improvement from baseline in SGRQ was achieved in the Relvar group (mean ± SD 7 -4.3 ± 11.8) but not in the Seretide group (-3.0 ± 11.8). 9 Compared with placebo in a 24-week trial (n=1,030), Relvar 92/22 was associated with significantly greater increases in peak and trough FEV1 at the end of the study than placebo; the differences between the groups were +173 mL [95% CI 123 to 224] for peak FEV1 and +115 mL [60 to 169] for trough FEV1 (p<0.001 for both 8 comparisons). In another 24 week trial (n=1,224), the difference between Relvar 92/22 and placebo for peak FEV1 was +214 mL [161 to 266] and for trough FEV1 the difference was +144 mL [91 to 197], but statistical significance could not be inferred in this trial. Dyspnoea scores were measured in both trials using the CRQ-SAS. Both trials reported that there was no clinically meaningful difference seen for Relvar vs. 8,9 placebo using this outcome measure. Adverse events For the comparison of Relvar with Seretide, the overall incidence of adverse events (AEs) was similar, but there were more AEs leading to withdrawal with Relvar than Seretide (6 patients vs. 3) and more serious 7 adverse events (6 vs. 3). The most frequently reported 7 drug-related AE in the trial was oral candidiasis. Exacerbations occurred in 2-3% of patients in the 7 comparative trial and 7-9% of Relvar-treated patients 8,9 in the placebo-controlled trials (10% with placebo). Pneumonia was reported in one patient receiving Relvar and in two patients receiving Seretide in the 7 comparative trial. There was one case of pneumonia 8 with Relvar treatment in one 24-week trial, and 5 cases reported in the second 24-week trial vs. 3 cases in 9 placebo-treated patients. Considerations for cost impact Based on QOF data for 2012/13, in the West Midlands the average prevalence of diagnosed COPD is 1.8% and there are 102,588 patients in COPD disease registers. At current prices, the Relvar Ellipta inhaler (92/22, one inhalation/day) costs £338 per patient per year. [Price taken from MIMS, March 2015] References 1. GlaxoSmithKline UK. Relvar Ellipta 92 micrograms/22 2. 3. 4. 5. 6. 7. 8. 9. 10. micrograms inhalation powder. EMC 2014 http://www.medicines.org.uk/emc CG101 Chronic obstructive pulmonary disease: Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update). NICE 2010 http://publications.nice.org.uk/chronicobstructive-pulmonary-disease-cg101/guidance Quality and Outcomes Framework - 2012-13. HSIC http://www.hscic.gov.uk/catalogue/PUB12262 Hospital Episode Statistics Data (HES). HSIC 2014 http://www.hscic.gov.uk/hes Boscia JA et al. Clin Ther 2012; 34(8):1655-1666. Lotvall J et al. BMJ Open 2012; 2(1):e000370. Agusti A et al. Eur Respir J 2014; 43(3):763-772. Martinez FJ et al. Respir Med 2013; 107(4):550-559. Kerwin EM et al. Respir Med 2013; 107(4):560-569. Dransfield MT et al. Lancet Respir Med 2013; 1(3):210223. Launch date: January 2014 Manufacturer: GSK WARNING: This sheet should be read in conjunction with the Summary of Product Characteristics This guidance is based upon the published information available in English at the time the drug was considered. It remains open to review in the event of significant new evidence emerging. NICE TECHNOLOGY APPRAISAL GUIDANCE ON THE RELVAR ELLIPTA INHALER WAS NOT AVAILABLE AT TIME OF PUBLICATION OF THIS GUIDANCE School of Pharmacy, Keele University, Keele, Staffordshire ST5 5BG ©Midlands Therapeutics Review & Advisory Committee Tel: 01782 734131 Email: [email protected] Web: www.mtrac.co.uk Date: January 2015