Evidence Summary to support COPD formulary decision making and guideline development

Transcription

1 Evidence Summary to support COPD formulary decision making and guideline development Prescribing and adverse event reporting information can be found on the final page of this document. Trelegy and Ellipta Trademarks are owned by or licensed to the GSK Group of Companies GSK Group of Companies or its licensor. Trelegy Ellipta was developed in collaboration with Date of preparation: July 2018

2 Instructions for using this document This document has been designed to allow you to quickly access the information that you require. It may be used in a linear manner by scrolling through the content, or by navigating straight to the section of interest using the links contained within the document. There are six key sections where diverse information has been included these are accessible via the toolbar, which is located at the top of every page. Please see the illustration of the toolbar here: Clicking on the relevant button in the toolbar will take you straight to the first page of that section; from there you will be able to navigate within that section. In certain sections, for example the section, a summary has been provided on the first page of that section and is followed by more detailed information. If at any time you wish to return to your previous page after following a link, you can press Alt + the back arrow key on your keyboard (Alt + ); this will return you to your original place in the document. If in doubt, the button in the toolbar will take you back to the main homepage where all information can be accessed. Trelegy Ellipta is part of the Ellipta range of COPD medicines. The other medicines in the chronic obstructive pulmonary disease (COPD) Ellipta portfolio are: Incruse Ellipta (umeclidinium 55 mcg), indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD 1 Relvar Ellipta (fluticasone furoate/vilanterol 92/22 mcg), indicated for the symptomatic treatment of adults with a FEV1 <70% predicted normal (post-bronchodilator) with an exacerbation history despite regular bronchodilator therapy 2 Anoro Ellipta (umeclidinium/vilanterol 55/22 mcg), indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD 3 For further information please visit Date of preparation: July

3 page The section provides details of Trelegy Ellipta including: Disease area and licensed indication Trade and generic name Drug class and treatment type Strength and dosing Marketing authorisation holder Device The section for Trelegy Ellipta includes: Status of marketing authorisation Health Technology Assessment (HTA) body information The section provides information that may be of use when considering a formulary application, including: Place in therapy as recommended by HTA bodies Place in therapy as recommended by clinical guidelines The section for Trelegy Ellipta includes: Efficacy data for Trelegy and its components Safety data for Trelegy and its components The section for Trelegy Ellipta includes: Ellipta device information Inhaler errors data device preference data The section includes: Cost of Trelegy Ellipta considerations for Trelegy Ellipta Date of preparation: July

4 Disease area Chronic Obstructive Pulmonary Disease (COPD) 4 Trade name Trelegy Ellipta 4 Generic name Drug class Fluticasone furoate (FF; inhaled corticosteroid [ICS]), umeclidinium bromide (UMEC; long-acting muscarinic receptor antagonist [LAMA]) and vilanterol (VI; long-acting β2-agonist [LABA]) combination 4 Respiratory systems; corticosteroids; compound preparations Strength 92/55/22 mcg 4 Dose Marketing authorisation holder One inhalation of Trelegy Ellipta 92/55/22 mcg once daily, at the same time each day 4 GlaxoSmithKline Trading Services Limited 4 Treatment type Long term 4 Licensed indication(s) Trelegy Ellipta is indicated for the maintenance treatment in adult patients with moderate to severe chronic obstructive pulmonary disease (COPD) who are not adequately treated by a combination of an inhaled corticosteroid and a long-acting β2- agonist 4 The Trelegy Ellipta inhaler is a multi-dose dry powder inhaler (DPI). The inhaler consists of a light grey body, a beige mouthpiece cover and a dose counter, packed into a foil laminate tray containing a desiccant packet. The tray is sealed with a peelable foil lid. 4 Device Date of preparation: July

5 Does Trelegy Ellipta have UK/EU marketing authorisation? NICE TA recommendation 92/55/22 mcg 1x30 doses [EU/1/17/1236/002] 4 Consistent with other respiratory medicines prescribed in primary care, Trelegy Ellipta did not undergo a National Institute for Health and Care Excellence (NICE) technology appraisal (TA). SMC number 1301/18 5 AWMSG reference Black triangle The All Wales s Strategy Group (AWMSG) has agreed that Trelegy Ellipta can be granted an exclusion from the HTA process. 6 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 4,7 Date of preparation: July

6 Indication The clinical trial data for fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI; Trelegy Ellipta) has been assessed and approved by the European s Agency (EMA). 8 This is reflected in the license for Trelegy Ellipta. 4 Trelegy Ellipta is indicated for the maintenance treatment in adult patients with moderate to severe chronic obstructive pulmonary disease (COPD) who are not adequately treated by a combination of an inhaled corticosteroid and a longacting β2-agonist 4 Place in therapy recommended by relevant bodies NICE SMC AWMSG In line with other respiratory medicines prescribed in primary care, Trelegy Ellipta did not undergo a NICE technology appraisal. Instead NICE has published an evidence summary for Trelegy Ellipta. 9 The Trelegy Ellipta licence is recommended for use with a restriction for patients with moderate to severe COPD (FEV1 <50% predicted normal) within NHS Scotland. 5 The molecules of FF/UMEC/VI are available in the following medicines: Relvar Ellipta (FF/VI 92/22 mcg) and Incruse Ellipta (UMEC 55 mcg). Trelegy (FF/UMEC/VI) is a combination of established medicines and Incruse and Relvar have previously been assessed and approved by the AWMSG. Trelegy Ellipta has therefore been granted an exclusion from undergoing a technology appraisal by the AWMSG. In these circumstances, it is for Health Boards to consider whether AWMSG-excluded medicines are appropriate for local formulary inclusion. 6 Date of preparation: July

7 Place in therapy recommended by clinical practice guidelines GOLD Strategy 2018 The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2018 categorises patients with COPD into one of four groups on the basis of symptom severity and exacerbation history. 10 s in Group D are those with a COPD Assessment Test (CAT) score 10 and/or modified Medical Research Council (mmrc) dyspnoea score 2 who have experienced 2 exacerbations or 1 severe exacerbation leading to hospital admission in the last year. 10 The GOLD Strategy recommends that patients in Group D receive treatment with a LAMA/LABA, and that patients who require further treatment receive triple therapy. 10 The GOLD 2018 pharmacological treatment algorithm is shown in Figure 1 below. Figure 1: GOLD 2018 pharmacological treatment algorithm 10 GOLD Trelegy Ellipta is indicated as a maintenance treatment in adult patients with COPD who are not adequately treated by a combination of an ICS and LABA (for effects on symptom control see section 5.1 of the SmPC). Relvar Ellipta is indicated for the symptomatic treatment of adults with a FEV 1 <70% predicted normal(postbronchodilator) with an exacerbation history despite regular bronchodilator therapy. LAMAs and LAMA/LABAs are indicated as maintenance bronchodilator treatments to relieve symptoms in adult patients with COPD Global Initiative for Chronic Obstructive Lung Disease, all rights reserved. Use is by express license from the owner. CAT = COPD Assessment Test; FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity; ICS = inhaled corticosteroid; LABA = long-acting beta agonist; LAMA = long-acting muscarinic antagonist; mmrc = modified Medical Research Council breathlessness scale Date of preparation: July

8 NICE 2010 guidelines recommend that ICS + LAMA + LABA be offered to patients with COPD who remain breathless or have exacerbations despite taking ICS/LABA. 11 The NICE 2010 guidelines inhaled pharmacotherapy treatment algorithm is shown in Figure 2 below. Figure 2: NICE COPD guideline algorithm for use of inhaled therapies 11 NICE Trelegy Ellipta is indicated as a maintenance treatment in adult patients with COPD who are not adequately treated by a combination of an ICS and LABA (for effects on symptom control see section 5.1 of the SmPC). Relvar Ellipta is indicated for the symptomatic treatment of adults with a FEV 1 <70% predicted normal(postbronchodilator) with an exacerbation history despite regular bronchodilator therapy. LAMAs and LAMA/LABAs are indicated as maintenance bronchodilator treatments to relieve symptoms in adult patients with COPD. Figure adapted from National Guideline Centre. (2010) Chronic obstructive pulmonary disease: management of chronic obstructive pulmonary disease in adults in primary and secondary care. London: National Guideline Centre. Available from: FEV1 = forced expiratory volume in one second; ICS = inhaled corticosteroid; LABA = long-acting beta-agonist; LAMA = long-acting muscarinic antagonist; SABA = short-acting beta-agonist; SAMA = short-acting muscarinic antagonist Date of preparation: July

9 Trelegy Ellipta is the only COPD triple therapy delivered in a single daily inhalation, in one inhaler Trelegy (FF/UMEC/VI) is a combination of an ICS/LAMA/LABA with proven efficacy 12,13 UMEC (Incruse Ellipta) provides superior improvement in lung function vs tiotropium HandiHaler 14 FF/VI (Relvar Ellipta) significantly reduced moderate/severe COPD exacerbations vs twice-daily ICS/LABA, of which a high proportion was FP/SAL 15 Trelegy has a comparable safety profile to that of its components 4,12 The Efficacy studies include: Lipson et al., 2018 (IMPACT) o FF/UMEC/VI vs FF/VI and UMEC/VI Lipson et al., 2017 (FULFIL) o FF/UMEC/VI vs BUD/FOR Bremner et al., 2018 o FF/UMEC/VI vs FF/VI + UMEC Vestbo et al., 2016 (SLS-COPD) o FF/VI vs usual care Feldman et al., 2016 o UMEC vs TIO The Safety summary includes: A summary of Trelegy safety data from the IMPACT and FULFIL studies A pooled analysis of safety data for the component therapies within Trelegy BUD = budesonide; FF = fluticasone furoate; FOR = formoterol; FP = fluticasone propionate; SAL salmeterol; TIO = tiotropium; UMEC = umeclidinium; VI = vilanterol Date of preparation: July

10 Efficacy study summaries Dosing information Each single inhalation of Trelegy Ellipta provides a delivered dose (the dose leaving the mouthpiece) of 92 mcg of fluticasone furoate, 55 mcg of umeclidinium (equivalent to 65 mcg of umeclidinium bromide) and 22 mcg of vilanterol (as trifenatate). This corresponds to a pre-dispensed dose of 100 mcg of fluticasone furoate, 62.5 mcg of umeclidinium (equivalent to 74.2 mcg of umeclidinium bromide) and 25 mcg of vilanterol (as trifenatate). 4 information The components of Trelegy are available as the marketed authorised products, Incruse (UMEC) and Relvar (FF/VI). 1,2,4 We will be discussing the efficacy and safety of Relvar and Incruse in this Evidence Summary. Interpreting clinical trial results statistical hierarchy When reviewing the outcomes of clinical trials, it is important to understand the relevance of statistical hierarchy and how that impacts upon the conclusions that can be derived from a study. This concept is explained below. Statistical hierarchy sequentially tests the significance of a number of endpoints in a study programme in a predetermined order. For each endpoint, a determination of significance can only be made if all prior endpoints were also significant. Treatment comparisons for the primary endpoints are required to be statistically significant in order to infer significance for the secondary endpoints. Therefore, if the trial does not meet its primary endpoint, the secondary endpoints cannot be statistically analysed; those results are described as descriptive only. Date of preparation: July

11 Lipson et al., 2018 (IMPACT [InforMing the Pathway of COPD Treatment]) Please note: Trelegy Ellipta (fluticasone furoate 92 mcg, umeclidinium 55 mcg, vilanterol 22 mcg) is indicated as a maintenance treatment in adult patients with moderate to severe COPD who are not adequately treated by a combination of an ICS and a LABA. 4 Relvar Ellipta is indicated for the symptomatic treatment of adults with COPD with a FEV1 <70% predicted normal (post-bronchodilator) with an exacerbation history despite regular bronchodilator therapy. 2 Anoro Ellipta is indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD. 3 The data from the IMPACT trial are presented in their entirety, including comparisons between Trelegy Ellipta and Anoro Ellipta to provide a complete summary of the data. For more detailed information about this study click here to download the publication via PubMed online. This link will take you to a non-gsk website. GSK does not recommend, endorse or accept liability for sites controlled by third parties. Citation Study objective population Design Treatments Baseline characteristics Lipson et al., Once-Daily Single-Inhaler Triple versus Dual Therapy in s with COPD. NEJM. 2018;378: To demonstrate the efficacy and safety of FF/UMEC/VI 92/55/22 mcg OD against FF/VI 92/22 mcg OD and UMEC/VI 55/22 mcg OD in patients with COPD Inclusion criteria: 40 years of age with a diagnosis of COPD Smoking history 10-pack-year Predicted FEV1 <50% and 1 moderate or severe exacerbation in the previous 12 months, or Predicted FEV % and 2 moderate or 1 severe exacerbations in the previous 12 months Phase III, randomised, multicentre, double-blind, parallel-group, 52-week study 2-week run in period; 52-week treatment period: FF/UMEC/VI 92/55/22 mcg OD FF/VI 92/22 mcg OD UMEC/VI 55/22 mcg OD ITT population FF/UMEC/VI 92/55/22 mcg (n=4,151) FF/VI 92/22 mcg (n=4,134) UMEC/VI 55/22 mcg (n=2,070) Mean age, years ± SD 65.3 ± ± ± 8.3 Female sex, n (%) 1,385 (33) 1,386 (34) 714 (34) Former smoker, n (%) 2,715 (65) 2,711 (66) 1,342 (65) Exacerbation history, n (%) 1 moderate and no severe 1,198 (29) 1,242 (30) 616 (30) 2 moderate or 1 severe 2,953 (71) 2,892 (70) 1,454 (70) 1 severe 1,087 (26) 1,069 (26) 515 (25) Post-bronchodilator FEV1 % predicted, mean ± SD Baseline COPD medications, n (%)* 45.7 ± ± ± 14.7 ICS + LABA + LAMA 1,581 (38) 1,563 (38) 826 (40) ICS + LABA 1,220 (29) 1,177 (28) 576 (28) LABA + LAMA 361 (9) 331 (8) 187 (9) LAMA 288 (7) 346 (8) 146 (7) Date of preparation: July

12 Primary endpoint results Annual rate of moderate or severe** COPD exacerbations during treatment FF/UMEC/VI 92/55/22 mcg: vs FF/VI 92/22 mcg: 0.91 vs 1.07; ratio 0.85 (95% CI 0.80, 0.90; p<0.001); NNT=7 16 vs UMEC/VI 55/22 mcg: 0.91 vs 1.21; ratio 0.75 (95% CI 0.70, 0.81; p<0.001); NNT=4 16 Annual rate of severe (hospitalised) exacerbations FF/UMEC/VI 92/55/22 mcg: 0.13 (95% CI 0.12, 0.14) FF/VI 92/22 mcg: 0.15 (95% CI 0.13, 0.16); vs FF/UMEC/VI 92/55/22 mcg RR 13% (95% CI 1, 24; p=0.064) UMEC/VI 55/22 mcg: 0.19 (95% CI 0.17, 0.22); vs FF/UMEC/VI 92/55/22 mcg RR 34% (95% CI 22, 44; p<0.001) Mean change from baseline in pre-dose (trough) FEV1 FF/UMEC/VI 92/55/22 mcg: 94 ml (95% CI 86, 102): o vs FF/VI 92/22 mcg: 3 ml (95% CI -12, 6); difference between two treatments 97 ml (95% CI 85, 109; p<0.001) o vs UMEC/VI 55/22 mcg: 40 ml (95% CI 28, 52); difference between two treatments 54 ml (95% CI 39, 69; p<0.001) Mean change from baseline in SGRQ total score FF/UMEC/VI 92/55/22 mcg: 5.5 units (95% CI 5.9, 5.0): o vs FF/VI 92/22 mcg: 3.7 units (95% CI 4.2, 3.2); difference between two treatments 1.8 (95% CI 2.4, 1.1; p<0.001) o vs UMEC/VI 55/22 mcg: 3.7 units (95% CI 4.4, 3.0); difference between two treatments 1.8 (95% CI 2.6, 1.0; p<0.001) Secondary and other efficacy endpoint results Proportion of patients with a clinically meaningful improvement from baseline ( 4 units decrease) in SGRQ total score at Week 52 FF/UMEC/VI 92/55/22 mcg 42% (n=1,723): o vs FF/VI 92/22 mcg 34% (n=1,390); OR 1.41 (95% CI 1.29, 1.55; p<0.001) o vs UMEC/VI 55/22 mcg: 34% (n=696); OR 1.41 (95% CI 1.26, 1.57; p<0.001) Annual rate of moderate or severe exacerbations among patients with blood eosinophil count 150 cells/μl at baseline: 17 FF/UMEC/VI 92/55/22 mcg (n=2,296): 0.95 (95% CI 0.9, 1.01) FF/VI 92/22 mcg (n=2,355): 1.08 (95% CI 1.02, 1.14); difference vs FF/UMEC/VI 92/55/22 mcg 12% (95% CI 4, 19; p=0.003) UMEC/VI 55/22 mcg (n=1,195): 1.39 (95% CI 1.29, 1.51); difference vs FF/UMEC/VI 92/55/22 mcg 32% (95% CI 25, 38; p<0.001) Other endpoint FF/UMEC/VI 92/55/22 mcg and FF/VI 92/22 mcg showed a signal towards lower all-cause mortality during treatment than UMEC/VI 55/22 mcg. This was a pre-specified other endpoint but was not adjusted for multiplicity. This should be interpreted in the context of wider clinical evidence. All deaths, including off-treatment FF/UMEC/VI 92/55/22 mcg: 88 patients (2%); FF/VI 92/22 mcg: 92 patients (2%); UMEC/VI 55/22 mcg: 58 patients (3%) Date of preparation: July

13 Safety On-treatment all-cause mortality FF/UMEC/VI 92/55/22 mcg: 50 patients (1%); FF/VI 92/22 mcg: 49 patients (1%); UMEC/VI 55/22 mcg: 39 patients (2%) o FF/UMEC/VI 92/55/22 mcg HR: vs FF/VI 92/22 mcg 0.95 (95% CI, 0.64 to 1.40; 6% difference; unadjusted p=0.780) vs UMEC/VI 55/22 mcg 0.58 (95% CI, 0.38 to 0.88; 42% difference; unadjusted p=0.01) o FF/VI 92/22 mcg HR: vs UMEC/VI 55/22 mcg 0.61 (95% CI, 0.40 to 0.93; 39% difference; unadjusted p=0.02) FF/UMEC/VI 92/55/22 mcg (n=4,151) FF/VI 92/22 mcg (n=4,134) UMEC/VI 55/22 mcg (n=2,070) Any on-treatment AE, n (%) 2,897 (70) 2,800 (68) 1,429 (69) Any AE leading to discontinuation, n (%) 252 (6) 327 (8) 187 (9) Any on-treatment SAE, n (%) 895 (22) 850 (21) 470 (23) Any on-treatment fatal AE, n (%) 68 (2) 76 (2) 49 (2) Most common SAEs occurring in 1% in any group, n (%) COPD worsening 443 (11) 450 (11) 269 (13) Pneumonia 184 (4) 152 (4) 54 (3) Most common AEs of special interest, n (%) Cardiovascular effects 450 (11) 430 (10) 224 (11) Pneumonia 317 (8) 292 (7) 97 (5) Local steroid effects 337 (8) 301 (7) 108 (5) LRTI, excluding pneumonia 200 (5) 199 (5) 95 (5) Hypersensitivity 196 (5) 195 (5) 95 (5) Hyperglycaemia/diabetes 152 (4) 117 (3) 73 (4) Anticholinergic syndrome 184 (4) 140 (3) 70 (3) Decreased bone mineral density 98 (2) 85 (2) 37 (2) Ocular effects 55 (1) 45 (1) 26 (1) Asthma/bronchospasm 27 (<1) 34 (<1) 16 (<1) Effects on potassium 34 (<1) 25 (<1) 8 (<1) Gastrointestinal obstruction 9 (<1) 10 (<1) 2 (<1) Tremor 8 (<1) 4 (<1) 6 (<1) Urinary retention 8 (<1) 12 (<1) 9 (<1) about the safety of Trelegy Ellipta is provided in the Safety summary * These were the most common baseline combinations; treatment combinations may have included PDE4i and/or Xanthine. ** A moderate exacerbation was defined as an exacerbation leading to treatment with antibiotics or systemic glucocorticoids; a severe exacerbation was defined as an exacerbation leading to hospitalisation or death. AE = adverse events; CI = confidence interval; COPD = chronic obstructive pulmonary disease; FEV 1 = forced expiratory volume in 1 second; FF = fluticasone furoate; HR = hazard ratio; ICS = inhaled corticosteroid; ITT = intent-to-treat; LABA = long-acting β2 agonist; LAMA = long acting muscarinic antagonist; NNT = number needed to treat; OD = once daily; OR = odds ratio; RR = relative reduction; SAE = serious adverse event; SD = standard deviation; SGRQ = St George s Respiratory Questionnaire; UMEC = umeclidinium; VI = vilanterol Date of preparation: July

14 Lipson et al., 2017 (FULFIL) For more detailed information about this study, please see the Trelegy Evidence Dossier. You can also request further information by contacting Citation Study objective population Design Treatments Baseline characteristics Co-primary endpoint results Lipson et al., FULFIL Trial: once-daily triple therapy for patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2017;196(4): To assess the benefit of FF/UMEC/VI 92/55/22 mcg OD triple therapy compared with BUD/FOR 320/9 mcg BD dual inhaled corticosteroid/long-acting β2-agonist therapy in patients with COPD Inclusion criteria: 40 years of age with a diagnosis of COPD and: o FEV1 <50% and CAT 10, or o FEV % and CAT 10 and either 2 moderate or 1 severe exacerbations in the past year Regular daily maintenance inhaler for 3 months Phase III, randomised, multicentre, double-blind, double-dummy, parallel-group study 2-week run in period on patient s current COPD treatment; 24-week treatment period; (subset of patients extended to 52 weeks): FF/UMEC/VI 92/55/22 mcg OD BUD/FOR 320/9 mcg BD FF/UMEC/VI 92/55/22 mcg (n=911) ITT population BUD/FOR 320/9 mcg (n=899) FF/UMEC/VI 92/55/22 mcg (n=210) EXT population BUD/FOR 320/9 mcg (n=220) Mean age, years Female sex, n (%) 233 (26) 236 (26) 53 (25) 58 (26) Current smokers, n (%) 400 (44) 394 (44) 95 (45) 97 (44) Smoking pack-years, mean ± SD 39.5 ± ± ± ± 23.1 CV risk factors*, n (%) 599 (66) 602 (67) 144 (69) 152 (69) Moderate/severe COPD exacerbation in previous 12 months, n (%) (34) 317 (35) 62 (30) 72 (33) (28) 253 (28) 77 (37) 79 (36) (38) 329 (37) 71 (34) 69 (31) Mean FEV1, % predicted normal ± SD 45.5 ± ± ± ± 14.9 SGRQ Total score ± SD 51.8 ± ± ± ± 15.5 LS mean difference in clinic visit trough FEV1 ITT population, Week 24: o FF/UMEC/VI 92/55/22 mcg (142 ml) vs BUD/FOR 320/9 mcg ( 29 ml): 171 ml; p<0.001 EXT population, Week 52: o FF/UMEC/VI 92/55/22 mcg (126 ml) vs BUD/FOR 320/9 mcg ( 53 ml): 179 ml; p<0.001 Date of preparation: July

15 Mean difference in SGRQ total score ITT population, Week 24: FF/UMEC/VI 92/55/22 mcg ( 6.6 units) vs BUD/FOR 320/9 mcg ( 4.3 units): 2.2 units; p<0.001 EXT population, Week 52: FF/UMEC/VI 92/55/22 mcg ( 4.6 units) vs BUD/FOR 320/9 mcg ( 1.9 units): not significantly different Mean annualised rate of moderate/severe COPD exacerbations ITT population, Week 24: FF/UMEC/VI 92/55/22 mcg (0.22) vs BUD/FOR 320/9 mcg (0.34) (35%; 95% CI 14, 51; p=0.002) EXT population, Week 52: FF/UMEC/VI 92/55/22 mcg (0.20) vs BUD/FOR 320/9 mcg (0.36) (44%; 95% CI 15, 63; p=0.006) Secondary and other efficacy endpoint results Safety Proportion of patients with a clinically meaningful change ( 100 ml) from baseline in trough FEV1 ITT population, Week 24: FF/UMEC/VI 92/55/22 mcg (n=453; 50%) vs BUD/FOR 320/9 mcg (n=184; 21%; OR 4.03; p<0.001) EXT population, Week 52: FF/UMEC/VI 92/55/22 mcg (n=96; 46%) vs BUD/FOR 320/9 mcg (n=34; 16%; OR 4.79; p<0.001) Proportion of patients with a clinically meaningful improvement from baseline ( 4 unit decrease) in SGRQ total score ITT population, Week 24: FF/UMEC/VI 92/55/22 mcg (n=448; 50%) vs BUD/FOR 320/9 mcg (n=368; 41%; OR 1.41; p<0.001) EXT population, Week 52: FF/UMEC/VI 92/55/22 mcg (n=91; 44%) vs BUD/FOR 320/9 mcg (n=73; 33%; OR 1.50; p=0.046) ITT population, Week 24 EXT population, Week 52 FF/UMEC/VI 92/55/22 mcg BUD/FOR 320/9 mcg FF/UMEC/VI 92/55/22 mcg BUD/FOR 320/9 mcg On treatment AEs, % On treatment SAEs, % Most common on treatment SAE, % COPD exacerbation Pneumonia AESI, CV effects,* n (%) 39 (4.3) 47 (5.2) 18 (8.6) 22 (10.0) AESI, pneumonia, n (%) 20 (2.2) 7 (0.8) 4 (1.9) 4 (1.8) about the safety of Trelegy Ellipta is provided in the Safety summary * CV risk factors included, but were not limited to, hypertension, hypercholesterolemia, coronary heart disease and diabetes mellitus AE = adverse event; AESI = adverse event of special interest; BD = twice daily; BUD/FOR = budesonide/formoterol; CAT = COPD assessment test; COPD = chronic obstructive pulmonary disease; CV = cardiovascular; EXT = extension; FEV 1 = forced expiratory volume in 1 second; FF/UMEC/VI = fluticasone furoate/umeclidinium/vilanterol; ITT = intent-to-treat; LS = least squares; OD = once daily; OR =odds ratio; SAE = serious adverse events; SD = standard deviation; SGRQ = St George s Respiratory Questionnaire Date of preparation: July

16 Bremner et al., 2018 (FF/UMEC/VI vs FF/VI + UMEC) For more detailed information about this study click here to download the publication via PubMed online. This link will take you to a non-gsk website. GSK does not recommend, endorse or accept liability for sites controlled by third parties. Citation Study objective population Design Treatments Baseline characteristics Bremner et al., Single-inhaler fluticasone furoate/umeclidinium/vilanterol versus fluticasone furoate/vilanterol plus umeclidinium using two inhalers for chronic obstructive pulmonary disease: a randomized non-inferiority study. Respir Res. 2018;19(1): To demonstrate non-inferiority of the efficacy and safety of FF/UMEC/VI 92/55/22 mcg OD against FF/VI 92/22 mcg +UMEC 55 mcg OD in patients with moderate-to-severe COPD Inclusion criteria: 40 years of age with a diagnosis of COPD Smoking history 10-pack-year CAT 10; FEV1/FVC ratio <0.70; predicted FEV1 <50% and 1 moderate/severe exacerbation in the previous 12 months, OR Predicted FEV1 50 <80% and 2 moderate or 1 severe exacerbations in the previous 12 months Phase III, randomised, multicentre, double-blind, double-dummy, parallel-group, 24-week lung function study 2-week run in period; 24-week treatment period: FF/UMEC/VI 92/55/22 mcg OD FF/VI 92/22 mcg +UMEC 55 mcg OD ITT population FF/UMEC/VI 92/55/22 mcg (n=527) FF/VI 92/22 mcg + UMEC 55 mcg (n=528) Mean age, years ± SD 66.7 ± ± 8.8 Female sex, n (%) 136 (26) 134 (25) Current smoker, n (%) 209 (40) 192 (36) Exacerbation history, n (%) 1 moderate/severe 236 (55) 227 (43) 2 moderate/severe 291 (55) 301 (57) 2 moderate or 1 severe 352 (67) 360 (68) Post-bronchodilator FEV1, % predicted normal, mean ± SD 44.5 ± ± 14.1 FF/UMEC/VI 92/55/22 mcg vs FF/VI 92/22 mcg +UMEC 55 mcg non-inferiority met Primary endpoint results Mean change from baseline in pre-dose (trough) FEV1 (ITT population) FF/UMC/VI 92/55/22 mcg vs FF/VI mcg + UMEC 55mcg: 107 ml vs 81 ml; difference 26 ml (95% CI 2, 53) The lower bound of the 95% CI for the comparison is above the non-inferiority margin of 50 ml Mean change from baseline in the pre-dose (trough) FEV1 (mpp population)* FF/UMEC/VI 92/55/22 mcg vs FF/VI 92/55 mcg + UMEC 55 mcg: 113 ml vs 95 ml; difference 18 ml (95% CI 13, 50, non-inferiority met) The lower bound of the 95% CI for the comparison is above the non-inferiority margin of 50 ml Date of preparation: July

17 Proportion of patients with a clinically meaningful improvement from baseline ( 4 unit decrease) in SGRQ score (ITT population) 50% vs 51%; OR 0.92 (n=243, n=247; 19 95% CI 0.71, 1.20) Change from baseline in SGRQ total score (ITT population) 5.8 units vs 4.9 units; difference 0.9 units (95% CI 2.5, 0.7) Secondary and other efficacy endpoint results Proportion of patients with a clinically meaningful improvement from baseline (>1 unit) in TDI focal score (ITT population) FF/UMEC/VI 92/55/22 mcg 56% (n=268) 19 vs FF/VI 92/22 mcg + UMEC 55 mcg 56% (n=271) 19 Change from baseline in TDI focal score (ITT population) 2.0 units vs 1.9 units; difference 0.1 unit (95% CI 0.2, 0.5) Safety Incidence of and time to first moderate or severe COPD exacerbation (ITT population) 24% vs 27% (n=129, n=142) 166 days vs 150 days; 19 HR: 0.87 FF/UMEC/VI 92/55/22 mcg (95% CI 0.68, 1.12) ITT population FF/UMEC/VI 92/55/22 mcg (n=527) FF/VI 92/22 mcg + UMEC 55 mcg (n=528) On-treatment AEs, n (%) 255 (48) 253 (48) On-treatment SAEs, n (%) 52 (10) 57 (11) Most common AE type, n (%) 19 Viral upper respiratory tract infection Headache COPD 56 (11) 32 (6) 23 (4) 52 (10) 33 (6) 31 (6) AESI, CV effects, n (%) 30 (6) 28 (5) AESI, pneumonia, n (%) 14 (3) 21 (4) about the safety of Trelegy Ellipta is provided in the Safety summary * mpp population included all patients in the ITT population who did not have a protocol deviation affecting efficacy AE = adverse events; AESI = adverse event of special interest; CAT = COPD assessment test; CI = confidence interval; COPD = chronic obstructive pulmonary disease; CV = cardiovascular; FVC = forced vital capacity; FEV 1 = forced expiratory volume in 1 second; FF = fluticasone furoate; ITT = intent-to-treat; mpp = modified per protocol; OD = once daily; SAE = serious adverse event; SD = standard deviation; SGRQ = St George s Respiratory Questionnaire; TDI = Transitional Dyspnea Index; UMEC = umeclidinium; VI = vilanterol Date of preparation: July

18 Vestbo et al., 2016 (SLS-COPD) For more detailed information about this study, please see the Trelegy Evidence Dossier, or click here to download the publication via PubMed online. This link will take you to a non-gsk website. GSK does not recommend, endorse or accept liability for sites controlled by third-parties. Citation Study objective population Design Treatments Vestbo et al., Effectiveness of fluticasone furoate-vilanterol for COPD in clinical practice. N Engl J Med. 2016;375: ,20 To compare the efficacy and safety of once-daily Relvar Ellipta (FF/VI 92/22 mcg) with usual care (GP or investigator s free choice of COPD maintenance treatment) in a large population intended to reflect patients with COPD seen in everyday clinical practice Inclusion criteria: 40 years GP diagnosis of COPD 1 moderate to severe COPD exacerbation in the previous 3 years Regular maintenance inhaler therapy (ICS * and/or LAMA and/or LABA) 12-month, open-label, parallel-group, randomised study 60-day run-in period; 12-month treatment period: FF/VI 92/22 mcg OD ± LAMA Usual care, as determined by the GP o Non-ICS containing treatment: n=391 (14%) o ICS *, ICS/LABA or ICS + LAMA: n=958 (34%) o Triple therapy in multiple inhalers: n=1,450 (52%) Treatment adjustment at GP/investigator discretion (step-up, step-down or switch). Switch to FF/VI not permitted Randomisation stratified by recent exacerbation status and existing COPD maintenance therapy at baseline Entire trial population (n=2,799) mitt FF/VI 92/22 mcg (n=1,396) Usual care (n=1,403) (n=2,269) Mean age, years ± SD 67 ± ± ± 10 Baseline characteristics Female sex, n (%) 698 (50) 671 (48) 1,122 (49) Current smoking, n (%) 623 (45) 666 (47) 1046 (46) Coexisting condition, n (%) 1,069 (77) 1,076 (77) 1758 (77) Mean postbronchodilator FEV1, L ± SD 1.62 ± ± ± 0.64 Mean number of exacerbations during 12 mo before randomisation ± SD 1.98 ± ± ± % (n=2,269) of the ITT population (all patients who underwent randomisation and received a prescription of trial medication) had 1 moderate or severe exacerbations in the year before the trial and made up the mitt population * ICS monotherapy is not indicated in COPD allowed to remain on LAMA in addition to their randomised treatment if already receiving LAMA therapy at randomisation Date of preparation: July

19 Primary endpoint results Mean annual rate of moderate or severe exacerbations (mitt population) FF/VI 92/22 mcg ± LAMA: 1.74 per year vs usual care: 1.90 per year o % difference: 8.4% (95% CI 1.1, 15.2; p=0.02) o NNT=6.25 (95% CI 3.47, 46.99; 1 additional moderate/severe exacerbation a year was prevented for every 7 patients treated with FF/VI compared with usual care over 12 months) Mean annual rate of moderate or severe exacerbations in patients who pre-randomisation treatment included ICS/LABA (of which a high proportion were on Seretide [fluticasone propionate/salmeterol]) FF/VI 92/22 mcg ± LAMA: 1.87 per year vs usual case: 2.03 per year o % difference: 8.0% (95% CI 0.11, 15.4; p=0.047) Time to first moderate or severe exacerbation (ITT population) HR (FF/VI 92/22 mcg vs usual care) 0.93 (95% CI 0.85, 1.02; p=0.111) Time to first severe exacerbation (ITT population) HR (FF/VI 92/22 mcg vs usual care) 1.27 (95% CI 0.98, 1.66; p=0.08) Time to first severe exacerbation in patients whose COPD maintenance therapy at baseline included ICS/LABA HR (FF/VI 92/22 mcg vs usual care) 0.92 (95% CI 0.84, 1.02; p=0.108) Secondary endpoint results Rate of severe exacerbations (ITT population) FF/VI 92/22 mcg: 0.09 per year vs usual care: 0.08 per year Percentage change: 9.7% (95% CI 16.9, 44.7; p=0.52) Annual rate of COPD-related primary care contacts (ITT population) The annual rate was 1.7% (95% CI 5.1, 8.0) lower in the FF/VI 92/22 mcg group (2.42) compared with usual care (2.46) (p=0.622) Annual rate of all primary care contacts (ITT population) The annual rate was 12.3% (95% CI 5.4, 19.6; p<0.001) higher in the FF/VI 92/22 mcg group (21.2) compared with usual care group (18.9) -reported outcomes Annual rate of secondary healthcare contacts (ITT population) No significant difference in rates between treatment groups in both COPD related or all cause of contacts CAT score improvement of 2 points (ITT population) FF/VI 92/22 mcg ± LAMA: n=1,317, 45% responders; usual care: n=1,325, 36% responders FF/VI 92/22 mcg vs usual care: OR 1.51 (95% CI 1.28, 1.77; p<0.001) EQ-5D score change from baseline No significant between-group difference More information about -reported outcomes with Trelegy Ellipta is provided in the section Date of preparation: July

20 FF/VI 92/22 mcg (n=1,396) ITT population Usual care (n=1,403) On-treatment AEs, n (%) 211 (15) 97 (7) Most common AE type ( 3% in any group), n (%) Infections and infestations Respiratory, thoracic and mediastinal disorders 74 (5) 78 (6) 51 (4) 20 (1) Safety AEs leading to permanent discontinuation/withdrawal, n (%) 59 (4) 33 (2) On-treatment SAEs, n (%) 404 (29) 383 (27) AEs of special interest, n (%) Cardiovascular event Pneumonia LRTI excluding pneumonia Decreased bone mineral density and associated fracture Effects on glucose level Hypersensitivity Effects on potassium level Glucocorticoid-associated eye disease Local effects from glucocorticoids Incidence ratio 1.1 (95% CI 0.9, 1.5); non-inferiority margin was set at (8) 94 (7) 64 (5) 45 (3) 23 (20) 10 (1) 2 (<1) 2 (<1) (8) 83 (6) 58 (4) 45 (3) 16 (1) 10 (1) 2 (<1) 2 (<1) 1 (<1) All-cause mortality, n (%)* 45 (<1) 30 (<1) Drug-related death from an SAE,** n (%) 1 (<1) 1 (<1) about the safety of Relvar Ellipta is provided in the Safety summary * The most frequent ( 2 subjects within either treatment arm) on-treatment fatal SAEs were infections and infestations (FF/VI: 15 [1%]; usual care: 18 [1%]), cardiac disorders (FF/VI: 12 [<1%]; usual care: 7 [<1%]), respiratory, thoracic and mediastinal disorders (FF/VI: 9 [<1%]; usual care: 8 [<1%]), neoplasms benign, malignant and unspecified (FF/VI: 13 [<1%]; usual care: 3 [<1%]), nervous system disorders (FF/VI: 4 [<1%]; usual care: 3 [<1%]) and renal and urinary disorders (FF/VI: 3 [<1%]; usual care: 2 [<1%]) ** Two subjects experienced fatal SAEs that were considered related to the study treatment in the opinion of the investigator (pneumonia in one patient in the usual care group, and pulmonary embolism and deep-vein thrombosis in one patient in the FF/VI group) AE = adverse event; CAT = COPD Assessment Test; CI = confidence interval; COPD = chronic obstructive pulmonary disease; CV = cardiovascular; EQ-5D = European Quality of Life-5 Dimensions; FEV1 = forced expiratory volume in 1 second; FF/VI = fluticasone furoate/vilanterol; HR = hazard ratio; IR = incidence ratio; ITT = intention-to-treat; LABA = long-acting β2-agonist; LAMA = long-acting muscarinic antagonist; LRTI = lower respiratory tract infection; mitt = modified intention-to-treat; NNT = number needed to treat; NS = not significant; OD = once daily; OR = odds ratio; SAE = serious adverse event; SD = standard deviation Date of preparation: July

21 Feldman et al., 2016 (UMEC vs TIO) For more detailed information about this study, please see the Trelegy Evidence Dossier, or click here to download the publication via PubMed online. This link will take you to a non-gsk website. GSK does not recommend, endorse or accept liability for sites controlled by third-parties. Citation Study objective population Design Treatments Baseline characteristics Primary endpoint results Feldman et al., A randomised, blinded study to evaluate the efficacy and safety of umeclidinium 62.5 mcg compared with tiotropium 18 mcg in patients with COPD. International Journal of Chronic Obstructive Pulmonary Disease 2016;11: ,21,22 To compare the efficacy and safety of Incruse Ellipta (UMEC 55 mcg OD) compared with tiotropium HandiHaler (TIO 10 mcg OD) as assessed by lung function measured using trough FEV1 on treatment Day 85 in patients with moderate to severe COPD Inclusion criteria: 40 years with a diagnosis of COPD Current or former cigarette smoker with 10 pack-years cigarette smoking history Pre- and post- salbutamol FEV1/forced vital capacity (FVC) ratio of <0.70 Post-salbutamol FEV1 of 30% 70% of predicted normal values mmrc dyspnoea score 2 at Visit 1 A 12-week, randomised, blinded, double-dummy, head-to-head, non-inferiority study 7 14 day run-in period; 85-day treatment period UMEC 55 mcg OD Ellipta inhaler + placebo HandiHaler TIO 10 mcg OD HandiHaler + placebo Ellipta inhaler of the blinding process for the tiotropium comparator trial discussed in this document can be found on page 1 of the Supplementary material, Feldman et al., Int J COPD 2016;11: ITT population UMEC 55 mcg (n=509) TIO 10 mcg (n=508) Mean age, years ± SD 64.4 ± ± 8.3 Female sex, n (%) 145 (28) 137 (27) Current smoker at screening, n (%) 259 (51) 260 (51) Smoking pack-years, n (%) 41.2 (21.4) 41.9 (21.9) Post-salbutamol FEV1 (L), mean ± SD 1.49 ± ± 0.44 Post-salbutamol FEV1/FVC (L), mean ± SD 48.9 ± ± 10.1 LS mean change from baseline in trough FEV1 on Day 85 (per-protocol population [PP]) UMEC 55 mcg vs TIO 10 mcg: 154 ml vs 95 ml, respectively; difference 59 ml (95% CI 29, 88; p<0.001; non-inferiority met; superiority demonstrated) ** Smoking pack-years = (number of cigarettes smoked per day/20) x number of years smoked n=508 in UMEC, n=508 in TIO ** Study population mmrc 2: Incruse Ellipta 154 ml improvement vs tiotropium HandiHaler 95 ml improvement at Day 85 Date of preparation: July

22 UMEC 55 mcg vs TIO 10 mcg LS mean change from baseline in trough FEV1 on Day 85 (Intent-to-treat [ITT] population) 147 ml vs 94 ml: difference 53 ml (95% CI 25, 81; p<0.001) LS mean change from baseline in trough FEV1 on Days 2, 28, 56 and 84 (PP population) Day 2: 103 ml vs 91 ml: difference 13 ml (95% CI 9, 35; p=0.254) Day 28: 144 ml vs 102 ml; difference 42 ml (95% CI 14, 69; p=0.003) Day 56: 136 ml vs 89 ml; difference 46 ml (95% CI 17, 76; p=0.002) Day 84: 142 ml vs 86 ml; difference 56 ml (95% CI 26, 85; p<0.001) Secondary and other efficacy endpoint results LS mean change from baseline in trough FVC on: (ITT population) Day 2: 152 ml vs 131 ml: difference 21 ml (95% CI 17, 60; p=0.274) Day 28: 194 ml vs 138 ml; difference 56 ml (95% CI 13, 99; p=0.011) Day 56: 174 ml vs 118 ml; difference 56 ml (95% CI 11, 102; p=0.016) Day 84: 187 ml vs 108 ml; difference 79 ml (95% CI 34, 125; p<0.001) Day 85: 192 ml vs 112 ml; difference 80 ml (95% CI 34, 127; p<0.001) wmfev1 on Day 84 (24 hour population ) 0 12 hours post-dose: 152 ml vs 113 ml; difference 39 ml (95% CI 24, 101; p=0.222) hours post-dose: 55 ml vs 15 ml; difference 70 ml (95% CI 14, 127; p=0.015) 0 24 hours post-dose: 104 ml vs 49 ml; difference 55 ml (95% CI 2, 113; p=0.058) -reported outcomes LS mean change from baseline in serial FEV1 on Day 84, statistical difference at: (24 hour population ) Pre-dose: 167 ml vs 80 ml; difference 87 ml (95% CI 26, 148; p=0.005) 21 hours post-dose: 1 ml vs 75 ml; difference 76 ml (95% CI 11, 141, p=0.022) 24 hours post-dose: 165 ml vs 98 ml; difference 67 ml (95% CI 8, 126; p=0.026) Similar improvements in TDI, SGRQ and CAT scores in both UMEC 55 mcg and TIO 10 mcg treatment groups at Day 84 (ITT population) TDI focal scores: 1.96 vs 1.90 (95% CI ; p=0.746) MCID SGRQ total score: 6.03 vs 5.57 (95% CI 2.04, 1.13; p=0.571) TDI, SGRQ and CAT responders (responder definitions: 1 unit TDI focal score; reduction from baseline 4 units SGRQ total score; or reduction from baseline 2 units in CAT score): o TDI: 55% in both treatments (n=277, n=279; 95% CI 0.76, 1.25; p=0.816) o SGRQ: 48% vs 47% (n=241, n=237; 95% CI 0.81, 1.35; p=0.727) o CAT: 50% vs 45% (n=253, n=228; 95% CI 0.96, 1.60; p=0.104) LS mean change from baseline in daily rescue medication use over Weeks 1 12 (ITT population) No differences between treatment groups (0.0 puffs/day; 95% CI 0.2, 0.1; p=0.557) Median percentage of rescue-free days (ITT population) No differences between treatment groups (0.0 puffs/day; 95% CI 0.00, 0.18) 24-hour population comprised all patients in the ITT population for whom 24-hour spirometry was performed Date of preparation: July

23 preference for inhaler device and ease of use assessed on Day 84 (ITT population) Overall device preference for the Ellipta inhaler compared with the HandiHaler (57% [n=570] and 19% [n=189], respectively) The Ellipta inhaler was rated very easy or easy to use by 95% of patients (n=902) while the HandiHaler was rated very easy or easy to use by 78% of patients (n=736) Inhaler errors at Days 1, 28 and 84 (Inhaler Error population; n=168) s with at least one error: ranged from 8 13%, similar between groups s with critical errors: ranged from 1 4%, similar between groups More information about -reported outcomes with Trelegy Ellipta is provided in the section ITT population UMEC 55 mcg (n=509) TIO 10 mcg (n=508) On-treatment AEs, n (%) 165 (32) 153 (30) Safety Most common AE type, n (%) Headache Nasopharyngitis 30 (6) 27 (5) 32 (6) 23 (5) On-treatment non-fatal SAE, n (%) 17 (3) 14 (3) On-treatment fatal SAE, n (%) None were considered related to the study drug 0 2 (<1) Alcohol poisoning; seizure On-treatment COPD exacerbation, ** n (%) 58 (11) 48 (9) about the safety of Trelegy Ellipta is provided in the Safety summary * Smoking pack-years = (number of cigarettes smoked per day/20) x number of years smoked; n=508 in UMEC, n=508 in TIO; 24-hour population comprised all patients in the ITT population for whom 24-hour spirometry was performed; Study population mmrc 2: Incruse Ellipta 154 ml improvement vs tiotropium HandiHaler 95 ml improvement at Day 85. UMEC n=489, TIO n=487. ** Incruse Ellipta is indicated for the maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD) 22 AE = adverse event; CAT = COPD Assessment Test; CI = confidence interval; COPD = chronic obstructive pulmonary disease; FEV 1 = forced expiratory volume in 1 second; FVC = forced vital capacity; ITT = intent-to-treat; LS = least squares; MCID = minimal clinically important difference; mmrc = modified Medical Research Council; OD = once daily; PP = per-protocol; SAE = serious adverse event; SD = standard deviation; SGRQ = St George s Respiratory Questionnaire; TDI = Transition Dyspnoea Index; TFH = 24-hour population; TIO = tiotropium; UMEC = umeclidinium Date of preparation: July

24 Safety summary Please consult the full Summary of Product Characteristics (SPC) for Trelegy Ellipta before prescribing. In the IMPACT study, the safety of FF/UMEC/VI 92/55/22 mcg has been studied in a total of 4,151 patients with COPD for up to 52 weeks. 13 Table 1 shows a summary of the adverse events detected during the IMPACT study. Table 1: Summary of adverse reactions detected during the IMPACT study 13 FF/UMEC/VI 92/55/22 mcg (n=4,151) FF/VI 92/22 mcg (n=4,134) UMEC/VI 55/22 mcg (n=2,070) Any on-treatment AE, n (%) 2,897 (70) 2,800 (68) 1,429 (69) Any on-treatment drug-related AE, n (%) 478 (12) 492 (12) 214 (10) Any AE leading to discontinuation, n (%) 252 (6) 327 (8) 187 (9) Any on-treatment SAE, n (%) 895 (22) 850 (21) 470 (23) Any on-treatment drug-related SAE, n (%) 64 (2) 57 (1) 27 (1) Any on-treatment fatal AE, n (%) 68 (2) 76 (2) 49 (2) AEs occurring in 2% of patients, n (%) Viral URTI 521 (13) 479 (12) 223 (11) URTI 299 (7) 283 (7) 117 (6) Pneumonia 298 (7) 264 (6) 93 (4) Bronchitis 152 (4) 130 (3) 73 (4) Oral candidiasis 161 (4) 146 (4) 41 (2) Influenza 117 (3) 102 (2) 50 (2) Sinusitis 104 (3) 98 (2) 45 (2) Urinary tract infection 92 (2) 86 (2) 35 (2) Pharyngitis 82 (2) 81 (2) 48 (2) Rhinitis 89 (2) 69 (2) 33 (2) COPD 455 (11) 472 (11) 279 (13) Cough 145 (3) 117 (3) 58 (3) Dyspnea 82 (2) 95 (2) 52 (3) Oropharyngeal pain 99 (2) 71 (2) 39 (2) Back pain 148 (4) 140 (3) 83 (4) Arthralgia 122 (3) 86 (2) 46 (2) Diarrhoea 88 (2) 72 (2) 46 (2) Constipation 65 (2) 63 (2) 16 (<1) Nausea 37 (<1) 46 (1) 32 (2) Headache 233 (6) 198 (5) 103 (5) Hypertension 91 (2) 79 (2) 41 (2) AEs of special interest, n (%) Cardiovascular effects 450 (11) 430 (10) 224 (11) Cardiac arrhythmia 153 (4) 161 (4) 81 (4) Cardiac failure 138 (3) 126 (3) 68 (3) Central nervous system haemorrhages and cerebrovascular conditions 41 (<1) 28 (<1) 11 (<1) Hypertension 113 (3) 115 (3) 54 (3) Ischaemic heart disease 80 (2) 57 (1) 47 (2) Date of preparation: July

25 Pneumonia 317 (8) 292 (7) 97 (5) Local steroid effects 337 (8) 301 (7) 108 (5) LRTI, excluding pneumonia 200 (5) 199 (5) 95 (5) Hypersensitivity 196 (5) 195 (5) 95 (5) Hyperglycaemia/diabetes 152 (4) 117 (3) 73 (4) Anticholinergic syndrome 184 (4) 140 (3) 70 (3) Decreased bone mineral density 98 (2) 85 (2) 37 (2) Ocular effects 55 (1) 45 (1) 26 (1) Asthma/bronchospasm 27 (<1) 34 (<1) 16 (<1) Effects on potassium 34 (<1) 25 (<1) 8 (<1) Gastrointestinal obstruction 9 (<1) 10 (<1) 2 (<1) Tremor 8 (<1) 4 (<1) 6 (<1) Urinary retention 8 (<1) 12 (<1) 9 (<1) AE = adverse event; COPD = chronic obstructive pulmonary disease; FF = fluticasone furoate; LRTI = lower respiratory tract infection; SAE = serious adverse event; UMEC = umeclidinium; URTI = upper respiratory tract infection; VI = vilanterol In the FULFIL study, the safety of FF/UMEC/VI 92/55/22 mcg has been studied in a total of 911 patients with COPD for up to 24 weeks. 12 Of these, 210 patients continued treatment for up to 52 weeks during the FULFIL study. 12 Table 2 shows a summary of the adverse reactions detected during the FULFIL study. In the 1,810 patients with advanced COPD and mean FEV1 ~45% of predicted normal (65% of whom had experienced a moderate or severe exacerbation in the year prior to study entry), there was a higher incidence of pneumonia at 24 weeks in the FF/UMEC/VI 92/55/22 mcg group (n=20; 2.2%) compared with the BUD/FOR 320/9 mcg group (n=7; 0.8%). 12 Date of preparation: July

26 Table 2: Summary of adverse reactions detected during the FULFIL study 12 Adverse reaction, n (%) Nasopharyngitis Upper respiratory tract infection Pneumonia Pharyngitis Rhinitis Influenza Frequency* as per SPC FF/UMEC/VI 92/55/22 mcg (n=911) 64 (7) 20 (2) 19 (2) 15 (2) 10 (1) 10 (1) Up to 24 weeks BUD/FOR 320/9 mcg (n=899) 43 (5) 19 (2) 7 (<1) 9 (1) 11 (1) 8 (<1) FF/UMEC/VI 92/55/22 mcg (n=210) 23 (11) 6 (3) 4 (2) 5 (2) 3 (1) 2 (1) Up to 52 weeks BUD/FOR 320/9 mcg (n=220) 22 (10) 10 (5) 4 (2) 1 (<1) 5 (2) 0 Cough 10 (1) 10 (1) 3 (1) 3 (1) Headache 44 (5) 53 (6) 17 (8) 22 (10) Arthralgia Back pain Candidiasis of mouth and throat Viral respiratory tract infection Supraventricular tachyarrhythmia Tachycardia Atrial fibrillation 17 (2) 19 (2) 2 (<1) 2 (<1) 0 1 (<1) 2 (<1) 13 (1) 18 (2) 3 (<1) 4 (<1) 2 (<1) 1 (<1) 2 (<1) 5 (2) 4 (2) 0 3 (1) 2 (1) 0 2 (<1) 6 (3) 5 (2) 2 (<1) 3 (1) 4 (2) 1 (<1) 2 (<1) Oropharyngeal pain 9 (<1) 10 (1) 6 (3) 1 (<1) Fractures 3 (<1) 2 (<1) 1 (<1) 1 (<1) * 1/100 to <1/10; uncommon 1/1,000 to <1/100 BUD/FOR = budesonide/formoterol; FF/UMEC/VI = fluticasone furoate/umeclidinium/vilanterol; SPC = Summary of Product Characteristics Adverse events of special interest Pneumonia requiring hospitalisation occurred in 1% (n=9) of patients receiving FF/UMEC/VI 92/55/22 mcg and 0.3% (n=3) of patients receiving BUD/FOR 320/9 mcg. One fatal case of pneumonia was reported in a patient who received FF/UMEC/VI; however, this was not considered by the investigator to be related to the study treatment. In the subset of 430 patients treated for up to 52 weeks, the incidence of pneumonia was 1.9% (n=4) in the FF/UMEC/VI 92/55/22 mcg group and 1.8% (n=4) in the BUD/FOR 320/9 mcg group. The incidence of pneumonia with FF/UMEC/VI 92/55/22 mcg is comparable with that observed with FF/VI and other ICS/LABAs used to treat patients with COPD. An increase in the incidence of pneumonia, including pneumonia requiring hospitalisation, has been observed in patients with COPD receiving inhaled corticosteroids. There is some evidence of an increased risk of pneumonia with increasing steroid dose but this has not been demonstrated conclusively across all studies. There is no conclusive clinical evidence for intra-class differences in the magnitude of the pneumonia risk among inhaled corticosteroid products. 2,4 Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of such infections overlap with the symptoms of COPD exacerbations. Risk factors for pneumonia in patients with COPD include current smoking, older age, low body mass index (BMI) and severe COPD. 2,4 Date of preparation: July

27 Adverse events associated with component medicines Safety has been assessed in 14,775 patients across the clinical development programmes for the components of FF/UMEC/VI. This has included 6,237 patients for FF/VI 92/22 mcg, 6,855 patients for UMEC/VI 55/22 mcg and 1,663 patients for UMEC 55 mcg (Table 3). The safety profiles of FF/VI, UMEC/VI and UMEC are similar to that of FF/UMEC/VI. 1-3,12 Table 3: Adverse events listed in the SPCs of the molecular components of FF/UMEC/VI 92/55/22 mcg Adverse events from FF/VI 92/22 mcg SPC 2 Headache Nasopharyngitis Abdominal pain Arthralgia Back pain Bronchitis Candidiasis of the mouth and throat Cough Dysphonia Fractures Influenza Muscle spasms Oropharyngeal pain Pharyngitis Pneumonia Pyrexia Rhinitis Sinusitis Upper respiratory tract infection Extrasystoles Vision blurred Anxiety Hypersensitivity reactions including anaphylaxis, angioedema, rash, and urticaria Palpitations Paradoxical bronchospasm Tachycardia Tremor Frequency* as per SPC Very common Very common Rare Rare Rare Rare Rare Rare * Very common 1/10; common 1/100 to <1/10 FF/VI = fluticasone furoate/vilanterol; SPC = Summary of Product Characteristics; UMEC = umeclidinium; UMEC/VI = umeclidinium/vilanterol Date of preparation: July

28 Adverse events from UMEC/VI 55/22 mcg SPC 3 Constipation Cough Dry mouth Headache Nasopharyngitis Oropharyngeal pain Pharyngitis Sinusitis Upper respiratory tract infection Urinary tract infection Atrial fibrillation Dysgeusia Dysphonia Hypersensitivity reactions including: Rash Palpitations Rash Rhythm idioventricular Supraventricular extrasystoles Supraventricular tachycardia Tachycardia Tremor Hypersensitivity reactions including: Anaphylaxis, angioedema and urticaria Bladder outlet obstruction Dysuria Glaucoma Intraocular pressure increased Paradoxical bronchospasm Urinary retention Vision blurred Frequency* as per SPC Rare Rare Rare Rare Rare Rare Rare Rare * Very common 1/10; common 1/100 to <1/10 FF/VI = fluticasone furoate/vilanterol; SPC = Summary of Product Characteristics; UMEC = umeclidinium; UMEC/VI = umeclidinium/vilanterol Date of preparation: July

29 Adverse events from UMEC 55 mcg SPC 1 Cough Headache Nasopharyngitis Sinusitis Tachycardia Upper respiratory tract infection Urinary tract infection Atrial fibrillation Constipation Dry mouth Dysgeusia Hypersensitivity reactions including: Rash, urticaria and pruritus Pharyngitis Rash Rhythm idioventricular Supraventricular extrasystoles Supraventricular tachycardia Frequency* as per SPC * Very common 1/10; common 1/100 to <1/10 FF/VI = fluticasone furoate/vilanterol; SPC = Summary of Product Characteristics; UMEC = umeclidinium; UMEC/VI = umeclidinium/vilanterol Date of preparation: July

30 However efficacious an inhaled medication is, if it is not delivered optimally it will not work as effectively. 23 Incorrect inhaler device use is associated with increased risk of hospitalisation and emergency visits, and inhaler handling errors impact the effectiveness of clinical control. 24 When patients are prescribed an inhaler, the choice should in part be based on how easy an inhaler is to use, and training to minimise errors in the use of the device is essential to achieve the desired drug effect. 25 The GOLD Strategy indicates that when a treatment is given via an inhaled device, the importance of education and training in inhaler device technique cannot be overemphasized. 10 How to use Trelegy Ellipta 95% of patients with COPD used Ellipta correctly first time after initial demonstration. 26 With just three steps, patients simply: Open, inhale, close. 4 The Ellipta portfolio for COPD Ellipta is the only inhaler that enables device continuity for patients with COPD requiring a maintenance therapy. 4 With Ellipta, significantly fewer patients with COPD made critical errors compared to other commonly used inhalers after reading the patient information leaflet. 27 Critical error defined as an error that is most likely to result in no, minimal or significantly reduced medication being delivered to the lungs. Proportion of participants who made at least one critical error after reading the patient information leaflet: Ellipta 13%; MDI 60%; p<0.001 (n=80). 25 Date of preparation: July

31 Device study summaries van der Palen et al., 2016 (CRITICAL ERRORS) For more detailed information about this study, please see the Trelegy Evidence Dossier, or click here to download the publication via PubMed online. This link will take you to a non-gsk website. GSK does not recommend, endorse or accept liability for sites controlled by third-parties. Citation Study objective population Design Treatments Baseline characteristics Primary endpoints/results Secondary endpoints/results van der Palen et al., A randomised open-label cross-over study of inhaler errors, preference and time to achieve correct inhaler use in patients with COPD or asthma: comparison of Ellipta with other inhaler devices. NPJ Prim Care Respir Med. 2016;26: ,28 To compare the Ellipta inhaler with other devices The information below focuses only on COPD studies; asthma results are not presented Inclusion criteria: 18 years with a physician diagnosis of COPD and currently receiving treatment for COPD Naïve to Ellipta and other inhaler Multicentre, single-visit, randomised, open-label, cross-over study s with COPD were assigned to one of five groups: Ellipta vs Accuhaler Ellipta vs MDI Ellipta vs Turbohaler Ellipta vs HandiHaler Ellipta vs Breezhaler Total (N=567) Ellipta vs Accuhaler (n=171) Ellipta vs MDI (n=80) Ellipta vs Turbohaler (n=100) Ellipta vs HandiHaler (n=118) Ellipta vs Breezhaler (n=98) Mean age, years Female sex, n (%) 225 (40) 68 (40) 27 (34) 33 (33) 46 (39) 51 (52) COPD history, n (%) 6 m 10 years years 25 years 422 (74) 123 (22) 22 (4) 135 (79) 29 (17) 7 (4) 59 (74) 18 (22) 3 (4) 62 (62) 32 (32) 6 (6) 92 (78) 23 (19) 3 (3) 74 (76) 21 (21) 3 (3) Number of patients with at least one critical error* after reading the patient information leaflet (PIL), n (%): Ellipta vs Accuhaler: 9 (5) vs 75 (44); p<0.001 Ellipta vs MDI: 10 (13) vs 48 (60); p<0.001 Ellipta vs Turbohaler: 8 (8) vs 44 (44); p<0.001 Ellipta vs HandiHaler: 17 (14) vs 57 (48); p<0.001 Ellipta vs Breezhaler: 13 (13) vs 45 (46); p<0.001 Number of patients with at least one overall error after reading the PIL, n (%): Ellipta vs Accuhaler: 52 (30) vs 112 (65); p<0.001 Ellipta vs MDI: 25 (31) vs 68 (85); p<0.001 Ellipta vs Turbohaler: 31 (31) vs 71 (71); p<0.001 Ellipta vs HandiHaler: 51 (43) vs 73 (62); p<0.001 Ellipta vs Breezhaler: 30 (31) vs 55 (56); p<0.001 Date of preparation: July

32 Percentage of patients making no errors after reading the PIL and thus not requiring instruction from trained respiratory nurse: Ellipta vs Accuhaler: 70% (n=119) vs 35% (n=59) Ellipta vs MDI: 69% (n=55) vs 15% (n=12) Ellipta vs Turbohaler: 69% (n=69) vs 29% (n=29) Ellipta vs HandiHaler: 57% (n=67) vs 38% (n=45) Ellipta vs Breezhaler: 69% (n=68) vs 44% (n=43) Percentage of patients requiring instruction from trained respiratory nurse after reading PIL: Ellipta vs Accuhaler: 30% (n=52) vs 65% (n=68) Ellipta vs MDI: 31% (n=25) vs 85% (n=68) Ellipta vs Turbohaler: 31% (n=31) vs 71% (n=80) Ellipta vs HandiHaler: 43% (n=51) vs 62% (n=73) Ellipta vs Breezhaler: 31% (n=30) vs 56% (n=56) Percentage of patients who rated the ease of use of the device as very easy or easy: Ellipta vs Accuhaler: 97% (n=165) vs 60% (n=104) Ellipta vs MDI: 92% (n=73) vs 44% (n=35) Ellipta vs Turbohaler: 96% (n=96) vs 55% (n=55) Ellipta vs HandiHaler: 98% (n=115) vs 38% (n=38) Ellipta vs Breezhaler: 94% (n=92) vs 55% (n=54) preference - the majority of patients preferred Ellipta overall compared with: Ellipta vs Accuhaler: 74% (n=126) vs 11% (n=19); p<0.001 Ellipta vs MDI: 75% (n=60) vs 19% (n=15); p<0.001 Ellipta vs Turbohaler: 86% (n=86) vs 6% (n=6); p<0.001 Ellipta vs HandiHaler: 87% (n=103) vs 11% (n=13); p<0.001 Ellipta vs Breezhaler: 72% (n=71) vs 19% (n=19); p<0.001 s preferred the Ellipta inhaler for most individual criteria: Number of steps for correct use, time taken to use, size of device, dose counter, comfort of mouthpiece and ease of opening (p<0.001) with some exceptions where there was no difference (listed below) Criteria for which there was no difference in patient preference between devices: Size of the inhaler, % patients preferring: o Ellipta: 39% or MDI: 33% o Ellipta: 44% or Turbohaler: 38% o Ellipta: 41% or Breezhaler: 44% Comfort of mouthpiece, % patients preferring: o Ellipta: 33% or HandiHaler: 31% o Ellipta: 40% or Breezhaler: 37% Safety No adverse events were reported throughout the study Critical error was defined as an error that is most likely to results in no, minimal or significantly reduced medication being delivered to the lungs 27 COPD = chronic obstructive pulmonary disease; m = months; MDI = metered-dose inhaler; PIL = patient information leaflet; SD = standard deviation Date of preparation: July

33 Financial Impact The 30-day cost for Trelegy Ellipta is Trelegy Ellipta is the only COPD triple therapy (ICS/LAMA/LABA) delivered in a single daily inhalation, in one inhaler. 4 At 44.50, Trelegy Ellipta costs less than commonly prescribed multiple inhaler triple therapy. 29,30 Figure 3 shows the 30-day list price for some branded maintenance therapy combinations for the treatment of COPD. Figure 3: Cost of Trelegy Ellipta compared with other branded multiple inhaler triple therapy combinations in COPD * Spiriva HandiHaler Data taken from (last updated in June 2018). Doses stated are delivered doses. All formoterol preparations are assumed to be dosed at 12 mcg twice daily. Prescribing decisions should not be based on cost alone. You should refer to the Summary of Product Characteristics of each medicine for further information such as indications, contraindications, precautions and adverse events. BDP/FOR = beclomethasone dipropionate/formoterol; BUD/FOR = budesonide/formoterol; FF/UMEC/VI = fluticasone furoate/umeclidinium/vilanterol; FP/SAL = fluticasone propionate/salmeterol; ICS/LABA = inhaled corticosteroid/long-acting β agonist; MITT = multiple inhaler triple therapy; SITT = single inhaler triple therapy; TIO = tiotropium GOLD recommends that training in the use of the device should be provided when prescribing a device to ensure that inhaler technique is adequate. 10 Additionally, it has been suggested that clinical review should be conducted at least annually or at least twice annually in very severe COPD patients. Demonstrate potential cost-savings A GSK Health Outcomes Consultant can demonstrate potential cost savings that Trelegy Ellipta and the wider Ellipta range of medicines can offer your local health economy or health care system. To arrange an appointment with a Health Outcomes Consultant to discuss, please either: uk.hoc-on-demand@gsk.com Live Chat: An appointment may be arranged to suit your preference - either in person, telephone or video call. Date of preparation: July

34 Impact When considering respiratory medicine optimisation, in addition to the clinical, patient and financial impact, it is also important to consider the environmental sustainability of inhalers. GSK and the NHS are bound by the targets set out in the Climate Change Act (2008). A key milestone within the 2008 act is for companies bound by this act, such as GSK and the NHS, to achieve a 25% reduction in their entire CO2 footprint by Healthcare procurement, which accounts for 61% of the NHS total carbon footprint, offers several significant opportunities for carbon footprint reduction. 32 Within healthcare procurement, 35% of emissions are attributed to pharmaceuticals, from which carbon footprint is calculated from aspects such as manufacturing, distribution and use phase. 32 Each year around 73 million inhalers are prescribed for asthma and COPD in the UK. 33 Approximately 70% of these inhalers are pmdis (pressurised Metered Dose Inhalers) containing greenhouse gases, such as HFA (hydrofluoroalkane) propellants, that are either discharged into the local environment during use by patients or put into household waste. 34 UK emissions of HFAs from inhalers is equivalent to 8% of the NHS entire carbon footprint. 34 Dry Powder Inhalers (DPIs) that do not contain greenhouse gases are available as an alternative to pmdis. Devices used for the delivery of bronchodilators and steroids can be equally efficacious and may be equally appropriate For example, the Ellipta inhaler (DPI), has a carbon footprint 24 times smaller than Evohaler (Figure 4; NB. Evohaler is not licensed in COPD). 37 The British Thoracic Society (BTS) are now advocating change: 38 Complete elimination of pmdis may not be possible due to patient preference and the need to generate sufficient inspiratory flow to activate the DPIs. However, BTS encourages all prescribers and patients to consider switching pmdis to DPIs whenever they are likely to be equally effective. Figure 4: Carbon footprint associated with Evohaler MDI and Ellipta DPI 37 Figure for illustrative purposes only; Evohaler MDI is not indicated for the treatment of COPD. KgCO2e values include all emissions for the full life cycle of each product (from raw material production to consumer use and disposal) and are reflective of values for maintenance inhalers only. GSK have an inhaler recycling and recovery scheme for all respiratory inhalers. By working together with patients, pharmacies and healthcare professionals, we aim to reduce waste and greenhouse gas emissions, moving towards a more environmentally sustainable treatment of respiratory disease. For further information follow the link here. To find out more information about how decreasing your reliance on MDIs may help your local health economy to meet their carbon emission reduction target by 2020, contact uk.hoc-on-demand@gsk.com. Date of preparation: July