Evidence Dossier to support COPD formulary decision making and guideline development

Transcription

1 Evidence Dssier t supprt COPD frmulary decisin making and guideline develpment Prescribing and adverse event reprting infrmatin can be fund n the final pages f this dcument. Anr and Ellipta Trademarks are wned by r licensed t the GSK Grup f Cmpanies. 217 GSK Grup f Cmpanies r its licensr. Date f preparatin: August 218

2 Table f Cntents Clinical study infrmatin... 4 Dsing infrmatin... 4 Licensing infrmatin... 4 Interpreting clinical trial results statistical hierarchy... 4 Feldman et al., 217 (active-cmparatr study)... 5 Study design... 5 Patient ppulatin... 5 Endpints... 5 Results... 6 Safety... 8 Maleki-Yazdi et al., 217 (active-cmparatr study)... 1 Study design... 1 Patient ppulatin... 1 Endpints... 1 Results Safety and tlerability Kerwin et al., 217 (active-cmparatr study) Study design Patient ppulatin Endpints Results Safety Decramer et al., 214 (active-cmparatr study) Study design Patient ppulatin Endpints Results Safety Kalberg et al., 216 (active-cmparatr study) Study design Patient ppulatin Endpints Results Dnhue et al., 213 (placeb-cntrlled study) Study design Patient ppulatin Endpints Results Safety Dnhue et al., 214 (safety study) Study design Patient ppulatin Endpints Results Date f preparatin: August 218 2

3 Feldman et al., 212 (safety study) Study design Patient ppulatin Endpints Results Van der Palen et al., 216 (critical errrs) Study design Patient ppulatin Endpints Results References Hw t request additinal infrmatin frm GSK Anr Ellipta (umeclidinium/vilanterl) Prescribing Infrmatin Incruse Ellipta (umeclidinium) Prescribing Infrmatin Date f preparatin: August 218 3

4 Clinical study infrmatin Dsing infrmatin Each single inhalatin f Anr Ellipta prvides a delivered dse (the dse leaving the muthpiece) f 65 mcg umeclidinium brmide equivalent t 55 mcg umeclidinium and 22 mcg vilanterl (as trifenatate). This crrespnds t a pre-dispensed dse f 74.2 mcg umeclidinium brmide equivalent t 62.5 mcg umeclidinium and 25 mcg vilanterl (as trifenatate). 1 Please nte that the licensed dse f umeclidinium/vilanterl (UMEC/VI) is 55/22 mcg. 1 Licensing infrmatin Anr Ellipta (umeclidinium/vilanterl 55/22 mcg) is indicated as a maintenance brnchdilatr treatment t relieve symptms in adult patients with chrnic bstructive pulmnary disease (COPD). 1 The efficacy and safety f Incruse Ellipta (umeclidinium 55 mcg) is als discussed in this Evidence Dssier. Incruse Ellipta is indicated as a maintenance brnchdilatr treatment t relieve symptms in adult patients with COPD. 2 UMEC 113 mcg, VI 22 mcg, UMEC/VI 5/25 mcg and UMEC/VI 113/22 mcg, included in the Dnhue et al., 214 study, Decramer et al., 214 study and Feldman et al., 212 study, are nt licensed fr the treatment f COPD in the UK. The results have nt been included in the efficacy sectin but have been included in the safety sectin fr transparency purpses. Safety studies with an un-licensed dse have als been included fr transparency. Interpreting clinical trial results statistical hierarchy When reviewing the utcmes f clinical trials it is imprtant t understand the relevance f statistical hierarchy and hw that impacts the cnclusins that can be derived frm a study. This cncept is explained belw. Statistical hierarchy sequentially tests the significance f a number f endpints in a study prgramme in a predetermined rder. Fr each endpint, a determinatin f significance can nly be made if all prir endpints were als significant. Treatment cmparisns fr the primary endpints are required t be statistically significant in rder t infer significance fr the secndary endpints. Therefre, if the trial des nt meet its primary endpint, the secndary endpints cannt be statistically analysed; thse results are described as descriptive nly. Date f preparatin: August 218 4

5 Feldman et al., 217 (active-cmparatr study) Cmparative Efficacy f Once-Daily Umeclidinium/Vilanterl and Titrpium/Oldaterl Therapy in Symptmatic Chrnic Obstructive Pulmnary Disease: A Randmized Study 3 Anr Ellipta (UMEC/VI 55/22 mcg OD) demnstrated nn-inferirity and superirity in lung functin imprvement cmpared with Spilt Respimat (TIO/OLO 5/5 mcg OD) Study design A randmised, tw-perid, 8-week, pen-label, crssver study cmparing UMEC/VI 55/22 mcg OD with TIO/OLO 5/5 mcg OD in patients with COPD (n=236). * TIO/OLO was delivered nce daily via tw puffs f 2.5 mcg/2.5 mcg COPD = chrnic bstructive pulmnary disease; FEV 1 = frced expiratry vlume in 1 secnd; FVC = frced vital capacity; mmrc = mdified Medical Research Cuncil; OD = nce daily; R = randmisatin; TIO/OLO = titrpium/ldaterl; UMEC/VI = umeclidinium/vilanterl Patient ppulatin 4 years with a diagnsis f COPD (American Thracic Sciety & Eurpean Respiratry Sciety definitin) Smking histry 1 pack-years Pst-brnchdilatr FEV1/FVC rati <.7 Pst-brnchdilatr FEV1 7% t 5% mmrc dyspnea scre 2 Nt receiving ICS-cntaining therapy at study inclusin Endpints Primary endpint (PP ppulatin) Change frm baseline in trugh FEV1 at Week 8 The margin f nn-inferirity fr the primary endpint was set at 5 ml. If nn-inferirity f UMEC/VI t TIO/OLO was demnstrated, statistical superirity was then investigated; UMEC/VI wuld be cnsidered superir t that f TIO/OLO if the lwer bundary f the estimated treatment difference 95% CI was greater than ml Secndary endpints (ITT ppulatin) Trugh FEV1 superirity assessment at Weeks 4 and 8 Date f preparatin: August 218 5

6 Percentage f FEV1 respnders ( 1 ml change frm baseline) at Weeks 4 and 8 Trugh FVC and inspiratry capacity (IC) at Weeks 4 and 8 CAT scre and percentage respnders (patients with a reductin f 2 units frm baseline CAT scre) at Weeks 4 and 8 Rescue medicatin use and percentage rescue-free days (Weeks 1 8) Weekly mean E-RSCOPD symptm scre and weekly percentage f respnders (patients achieving a reductin frm baseline E-RS scre f 2 units) Inhaler ease f use Safety and tlerability Incidence f AEs and SAEs Incidence f COPD exacerbatins Demgraphics and baseline characteristics (ITT ppulatin) Characteristic Ttal (N=236) Mean age, years ± SD 64.4 ± 8.5 Female gender, n (%) 94 (4) Current smker, n (%) 125 (53) Smking pack-year histry, mean ± SD 5.2 ± 25.5 Pst-brnchdilatr FEV1 (L), % predicted, mean ± SD 59.6 ± 5.6 COPD exacerbatin histry, n (%) Requiring OCS/antibitics 1 Requiring OCS/antibitics 2 Requiring hspitalisatin 1 33 (14) 4 (2) 6 (3) COPD = chrnic bstructive pulmnary disease; FEV 1 = frced expiratry vlume in 1 secnd; ITT = intentin-t-treat; OCS = ral crticsterid; SD = standard deviatin Results Primary endpint Change frm baseline in trugh FEV1 at Week 8 LS mean change frm baseline was significantly greater in the UMEC/VI 55/22 mcg grup (175 ml) cmpared with the TIO/OLO 5/5 mcg grup (122 ml) The difference f 53 ml (95% CI, 26, 8; p<.1) exceeded the nn-inferirity margin f 5 ml, demnstrating nn-inferirity cmpared with TIO/OLO 5/5 mcg Date f preparatin: August 218 6

7 Figure 1: Trugh FEV1 at Week 8 Adapted frm Feldman et al. 217 CI = cnfidence interval; FEV 1 = frced expiratry vlume in 1 secnd; ITT = intentin-t-treat; LS = least squares; PP = per-prtcl; TIO/OLO = titrpium/ldaterl; UMEC/VI = umeclidinium/vilanterl Secndary endpints Trugh FEV1 superirity assessment at Weeks 4 and 8 The UMEC/VI 55/22 mcg grup shwed significantly imprved trugh FEV1 imprvement frm baseline at Weeks 4 (difference: 48 ml; 95% CI 25, 71; p<.1) and 8 (difference: 52 ml; 95% CI 28, 77; p<.1) cmpared with the TIO/OLO 5/5 mcg grup Percentage f FEV1 respnders ( 1 ml change frm baseline) at Weeks 4 and 8 The percentage f trugh FEV1 respnders in each treatment grup was: Week 4: UMEC/VI 55/22 mcg 69%; TIO/OLO 5/5 mcg 51% Week 8: UMEC/VI 55/22 mcg 66%; TIO/OLO 5/5 mcg 48% The likelihd f achieving trugh FEV1 respnse was significantly higher in the UMEC/VI 55/22 mcg grup cmpared with the TIO/OLO 5/5 mcg grup at bth Week 4 (OR 2.9; 95% CI 1.39, 3.14; p<.1) and 8 (OR 2.5; 95% CI 1.34, 3.14; p<.1) Trugh FVC and IC at Weeks 4 and 8 Imprvement in trugh FVC was significantly greater with UMEC/VI 55/22 mcg: Week 4: UMEC/VI 55/22 mcg vs TIO/OLO 5/5 mcg difference: 4 ml; 95% CI 5, 75; p<.5 Week 8: UMEC/VI 55/22 mcg vs TIO/OLO 5/5 mcg difference: 67 ml; 95% CI 34, 1; p<.1 Imprvement in IC was significantly greater with UMEC/VI 55/22 mcg: Week 4: UMEC/VI 55/22 mcg vs TIO/OLO 5/5 mcg difference: 52 ml; 95% CI 16, 88; p<.1 Week 8: UMEC/VI 55/22 mcg vs TIO/OLO 5/5 mcg difference: 47 ml; 95% CI 14, 81; p<.1 CAT scre and percentage respnders (patients with a reductin f 2 units frm baseline CAT scre) at Weeks 4 and 8 Significant imprvements in CAT scre with UMEC/VI 55/22 mcg cmpared with TIO/OLO 5/5 mcg were seen at Week 4 but nt at Week 8: Week 4 difference:.59; 95% CI 1.16,.2; p<.5 Week 8 difference:.11; 95% CI.68,.45 Date f preparatin: August 218 7

8 A similar percentage f patients in the UMEC/VI 55/22 mcg grup were CAT respnders at Weeks 4 and 8: Week 4: OR 1.25; 95% CI.85, 1.82 Week 8: OR 1.5; 95% CI.72, 1.55 Rescue medicatin use and percentage rescue-free days (Weeks 1 8) Patients in the UMEC/VI 55/22 mcg grup used fewer puffs/day f rescue medicatin cmpared with the TIO/OLO 5/5 mcg grup (difference:.25 puffs; 95% CI.37,.41; p<.1) Patients in the UMEC/VI 55/22 mcg grup and TIO/OLO 5/5 mcg grup had a similar number f rescuefree days ver Weeks 1 8 (difference: 1.91; 95% CI.71, 4.53) Weekly mean E-RSCOPD symptm scre and weekly percentage f respnders (patients achieving a reductin frm baseline E-RS scre f 2 units) The change frm baseline in weekly E-RS ttal scres ranged frm 1.79 t 1.61 in the UMEC/VI 55/22 mcg grup and frm 1.72 t 1.31 in the TIO/OLO 5/5 mcg grup during the 8 weeks, with a statistically significant difference in favur f UMEC/VI 55/22 mcg bserved at Week 5 (p =.31) The prprtin f patients shwing a clinically imprtant treatment respnse fr the E-RS ttal scre varied by individual week frm 33% t 41% with the UMEC/VI 55/22 mcg grup and frm 31 t 34% with the TIO/OLO 5/5 mcg grup. The OR fr achieving a treatment respnse with the UMEC/VI 55/22 mcg grup cmpared with the TIO/OLO 5/5 mcg grup varied frm.97 t 1.43, with n statistically significant differences Inhaler ease f use (inhaler-naïve ppulatin; n=75) Safety 96% f patients rated ELLIPTA as very easy r easy t use and 83% f patients rated Respimat as very easy r easy t use Significantly mre patients rated Ellipta higher than Respimat n verall ease f use (4% vs 11%; p=.1), ease f telling the number f dses remaining (53% vs 1%; p<.1); ease f learning t use (43% vs 4%; p<.1); ease f handling (4% vs 4%; p<.1); ease f preparatin (49% vs 3%; p<.1); and ease f hlding while using (32% vs 4%; p<.1) On-treatment AEs were similar acrss treatment grups (UMEC/VI 55/22 mcg 25% and TIO/OLO 5/5 mcg 31%) The mst cmmnly ccurring AEs in bth treatment grups were viral upper respiratry tract infectins (UMEC/VI 55/22 mcg: 5% and TIO/OLO 5/5 mcg: 6%) and upper respiratry tract infectins (UMEC/VI 55/22 mcg: 3% and TIO/OLO 5/5 mcg: 3%) Date f preparatin: August 218 8

9 Table 1. Summary f n-treatment adverse events UMEC/VI 55/22 mcg (n=235) TIO/OLO 5/5 mcg (n=23) Any AE, n (%) 59 (25) 71 (31) AEs in 3% f patients, n (%) Viral upper respiratry tract infectin Upper respiratry tract infectin Any AE leading t permanent study treatment discntinuatin r withdrawal frm study, n (%) 11 (5) 8 (3) 14 (6) 7 (3) 1 (<1) Any nn-fatal SAE, n (%) 3 (1) 2 (<1) Any fatal SAE, n (%) COPD exacerbatins, n (%) 1 2 AEs f special interest, n (%) Cardivascular Cardiac arrhythmia Cardiac failure Cardiac ischaemia Hypertensin Strke Pneumnia LRTI excluding pneumnia Ocular effects (antimuscarinic) Paradxical brnchspasm Asthma/brnchspasm Urinary retentin 217 (92) 15 (6) 3 (1) 211 (92) AEs with nset during the fllw-up perid are cnsidered n-treatment and have been assigned t the treatment previusly received AE = adverse event; COPD = chrnic bstructive pulmnary disease; LRTI = lwer respiratry tract infectin; SAE = serius adverse event; TIO/OLO = titrpium/ldaterl; UMEC/VI = umeclidinium/vilanterl 4 (2) 1 (<1) 3 (1) 1 (<1) 18 (8) 1 (<1) 4 (2) 1 (<1) 1 (<1) 2 (<1) 1 (<1) 3 (1) 2 (<1) Date f preparatin: August 218 9

10 Maleki-Yazdi et al., 217 (active-cmparatr study) Assessing Shrt-term Deteriratin in Maintenance-naïve Patients with COPD Receiving Umeclidinium/Vilanterl and Titrpium: A Pled Analysis f Three Randmized Trials 4 Early use f Anr Ellipta as a maintenance brnchdilatr has superir efficacy n lung functin and may reduce the risk f shrt-term deteriratin cmpared t titrpium HandiHaler mntherapy in patients with symptmatic COPD Study design A pst-hc pled analysis investigating the efficacy and safety f UMEC/VI 55/22 mcg OD cmpared with TIO 1 mcg OD in a maintenance-naïve (MN) subgrup f patients relative t the ITT ppulatin frm three multicentre, randmised, 24-week, parallel-grup, blinded, active cmparatr studies. Tw f the three studies included ther treatment arms (UMEC/VI 113/22 mcg OD; VI 22 mcg OD and UMEC 113 mcg OD), which are nt licensed in the UK. The results f these treatment arms were included in the pled analysis, althugh were nt presented in the Maleki-Yazdi et al., 217 publicatin. Details f the blinding prcess fr all titrpium cmparatr studies discussed in this Evidence Dssier can be fund n page 474, Decramer M et al., Lancet Respir Med. 214 Jun;2: Di: 1.116/S (14) COPD = chrnic bstructive pulmnary disease; FEV 1 = frced expiratry vlume in 1 secnd; FVC = frced vital capacity; OD = nce daily; R = randmisatin; TIO = titrpium; UMEC/VI = umeclidinium/vilanterl Analysis was perfrmed n a subgrup f MN patients (defined as receiving n maintenance therapy fr 3 days befre screening) and the ITT ppulatin Patient ppulatin 4 years f age A diagnsis f symptmatic COPD Pst-brnchdilatr FEV1 value 7% predicted nrmal FEV1/frced vital capacity (FVC) rati <.7 Mdified Medical Research Cuncil (mmrc) dyspnea scre 2 Endpints Primary endpint Change frm baseline in trugh FEV1 n Day 169 (defined as the mean f the FEV1 values btained 23h and 24h after dsing n Day 168) (MN ppulatin and ITT ppulatin) Date f preparatin: August 218 1

11 Secndary endpints St Gerge s Respiratry Questinnaire (SGRQ) ttal scre and prprtin f respnders (defined as patients experiencing a decrease frm baseline f 4 units) Rescue medicatin use per day (minimal clinically imprtant deteriratin [CID] defined as a treatment benefit f 1 rescue-free mnth per year r 2 rescue-free weeks ut f 24 [crrespnding t a change frm baseline 8.3% in percentage f rescue-free days ver Weeks 1 24]) Deteriratin events Safety and tlerability Time t, and risk f, a shrt-term CID (shrt-term CID is a nvel cmpsite endpint that was assessed and defined as): 1 ml decrease in trugh FEV1; and/r 4-unit increase in SGRQ scre; and/r An n-treatment mderate-t-severe COPD exacerbatin (defined as a wrsening f COPD symptms requiring use f any additinal treatment ther than study drug r rescue salbutaml use and an emergency department visit r hspitalisatin) Sustained CIDs were als assessed and defined as: A mderate-t-severe COPD exacerbatin leading t study withdrawal; r 1 ml FEV1 decrease; r 4-unit increase in SGRQ ttal scre n tw cnsecutive visits r fr 5% f all available subsequent visits Adverse events (AEs) were mnitred Demgraphics and baseline characteristics Characteristic UMEC/VI 55/22mcg (n=878) ITT ppulatin TIO 1 mcg (n=869) UMEC/VI 55/22 mcg (n=275) MN ppulatin TIO 1 mcg (n=258) Mean age, years ± SD 63. ± ± ± ± 8.7 Female gender, n (%) 282 (32) 275 (32) 81 (29) 93 (36) Current smker at screening, a n (%) 457 (52) 439 (51) 18 (65) 155 (6) Smking pack-years, b n (%) 45.1 (25.6) 46.1 (27.) 47.1 (25.6) 49.5 (3.1) Reversible t salbutaml, c,d n (%) 243 (28) 248 (29) 94 (34) 77 (3) Pst-salbutaml % predicted FEV1, mean ± SD 47. ± ± ± ± 12.8 a Patient reclassified as current smker if smked within 6 mnths; b Smking pack-years = (number f cigarettes smked per day/2) x number f years smked; c Reversibility was defined as an increase in FEV 1 12% and 2 ml fllwing administratin f salbutaml; d ITT ppulatin: UMEC/VI 55/22 mcg OD, n=876; TIO 1 mcg OD, n=863 FEV 1 = frced expiratry vlume in 1 secnd; ITT = intent-t-treat; MN = maintenance naïve; OD = nce daily; TIO = titrpium; UMEC/VI = umeclidinium/vilanterl Date f preparatin: August

12 Results Primary endpint Change frm baseline in trugh FEV1 n Day 169 (MN ppulatin and ITT ppulatin) In bth ppulatins, mean imprvements in baseline FEV1 at Day 169 were significantly greater in the UMEC/VI 55/22 mcg grup versus the TIO 1 mcg grup MN ppulatin (LS mean difference 146 ml; 95% CI 12, 189; p<.1) ITT ppulatin (LS mean difference 95 ml; 95% CI 71, 118, p<.1) Figure 2: Trugh FEV1 change ver time in the maintenance-naive and intentin-t-treat ppulatins Adapted frm Maleki-Yazdi et al., 217 CI = cnfidence interval; FEV 1 = frced expiratry vlume in 1 secnd; ITT = intent t treat; LS = least squares; MN = maintenancenaïve; TIO = titrpium; UMEC/VI = umeclidinium/vilanterl Secndary and ther efficacy endpints SGRQ ttal scre and prprtin f respnders UMEC/VI 55/22 mcg and TIO 1 mcg demnstrated mean imprvements ( 4 units) frm baseline in ttal SGRQ scre acrss the MN and ITT ppulatins, with verall imprvements versus baseline shwn t be numerically greater in the MN ppulatin thrughut the study Ttal scres demnstrated significant imprvement with UMEC/VI 55/22 mcg versus TIO 1 mcg in the ITT ppulatin n Days 28 and 84, but nt Day 168 Day 28 ( 2.25 units; 95% CI 3.26, 1.23; p<.1) Day 84 ( 1.63 units; 95% CI 2.76,.49; p=.5) Day 168 (.93 units; 95% CI 2.19,.33; p=.149) UMEC/VI 55/22 mcg patients shwed significantly greater dds f being a SGRQ respnder versus TIO 1 mcg in the ITT ppulatin at Days 28 and 84 (dds rati [OR] 1.3 units at bth time pints; p=.7 at Day 28; p=.9 at Day 84), but nt in the MN ppulatin In either ppulatin at Day 168, the dds f being a respnder versus nn-respnder were nt significantly different between treatment grups Date f preparatin: August

13 Rescue medicatin use per day Deteriratin events A significantly greater percentage f patients achieved a respnse in rescue-free episdes in the UMEC/VI 55/22 mcg grup versus the TIO 1 mcg grup in bth the ITT (46% versus 36% respectively [OR 1.5; 95% CI 1.2, 1.9]) and MN (47% versus 37% respectively [OR 1.5: 95% CI 1., 2.2]) ppulatins An imprvement was seen in the mean number f puffs per day ver Weeks 1 24, favuring UMEC/VI 55/22 mcg cmpared with TIO 1 mcg in bth ppulatins (difference [ITT].5; 95% CI.8,.3; p<.1; difference [MN].5; 95% CI.9,.; p=.66) Time t, and risk f, a shrt-term CID A lwer prprtin f patients displayed a shrt-term CID in the UMEC/VI 55/22 mcg versus TIO 1 mcg treatment grup, in bth ppulatins (MN ppulatin: 41% versus 55%; ITT ppulatin: 41% versus 56%) A reduced risk f first CID was fund in UMEC/VI 55/22 mcg cmpared with TIO 1 mcg in the MN ppulatin, with similar results bserved between treatment grups in the ITT ppulatin (MN ppulatin: hazard rati [HR]=.66; 95% CI.51,.85; p=.1; ITT ppulatin: HR=.66; 95% CI.54,.71: p<.1) Sustained CIDs Safety and tlerability A lwer prprtin f patients demnstrated a sustained CID in the UMEC/VI 55/22 mcg grup cmpared with TIO 1 mcg in bth the MN ppulatin (22% versus 3%) and the ITT ppulatin (21% versus 3%) There was a significantly reduced risk f sustained CID in the UMEC/VI 55/22 mcg treatment grup versus the TIO 1 mcg grup in the MN ppulatin (HR=.69; 95% CI.49,.97; p<.5) and the ITT ppulatin (HR=.64; 95% CI.53,.77; p<.1) Incidence f AEs and serius adverse events (SAEs) was similar fr the tw treatment grups in bth ppulatins Table 2: Summary f adverse events On-treatment nn-fatal SAEs, any event, n (%) UMEC/VI 55/22 mcg (n=878) ITT ppulatin TIO 1 mcg (n=869) UMEC/VI 55/22 mcg (n=275) MN ppulatin TIO 1 mcg (n=258) 42 (5) 35 (4) 8 (3) 11 (4) Fatal AEs, a n (%) 4 (<1) 7 (1) 3 (1) 2 (<1) AEs reprted by 3% f patients n any treatment, n (%) Naspharyngitis Headache Back pain Cugh URTI AEs f special interest, n (%) Cardivascular events (any) Pneumnia 63 (7) 8 (9) 27 (3) 25 (3) 17 (2) 2 (<1) 2 (<1) 62 (7) 55 (6) 28 (3) 26 (3) 26 (3) 2 (<1) 6 (<1) 18 (7) 2 (7) 8 (3) 5 (2) 2 (<1) 15 (6) 15 (6) 4 (2) 8 (3) 1 (4) 1 (<1) 1 (<1) a Deaths were attributable t the fllwing: ITT: cardiac arrest, cardiac failure, COPD and haemrrhagic strke in the UMEC/VI grup; cardiac failure, pulmnary emblism, respiratry arrest, respiratry failure, upper gastrintestinal haemrrhage, sudden death and pancreatic carcinma in the TIO grup. MN: cardiac arrest, haemrrhagic strke and COPD in the UMEC/VI grup; respiratry arrest and respiratry failure in the TIO grup. AE = adverse event; FEV 1 = frced expiratry vlume in 1 secnd; ITT = intentin-t-treat; MN = maintenance-naïve; SAE = serius adverse event; TIO = titrpium; UMEC/VI = umeclidinium/vilanterl; URTI = upper respiratry tract infectin Date f preparatin: August

14 Kerwin et al., 217 (active-cmparatr study) Efficacy and safety f umeclidinium/vilanterl as step up therapy frm titrpium in patients with mderate COPD 5 Umeclidinium/vilanterl (UMEC/VI) step-up therapy prvided clinical benefit ver titrpium (TIO) HandiHaler mntherapy in patients with mderate COPD wh were symptmatic n TIO alne Study design A Phase III, randmised, multicentre, duble-blind, duble-dummy, parallel-grup, active cntrlled 12-week lung functin study cmparing the efficacy and safety f UMEC/VI 55/22 mcg OD and TIO 1 mcg OD in patients with mderate COPD. Details f the blinding prcess fr all titrpium cmparatr studies discussed in this Evidence Dssier can be fund n page 474 in Decramer M et al., Lancet Respir Med. 214 Jun;2: Di: 1.116/S (14) COPD = chrnic bstructive pulmnary disease; FEV 1 = frced expiratry vlume in 1 secnd; mmrc = mdified Medical Research Cuncil; OD = nce daily; R = randmisatin; TIO = titrpium; UMEC/VI = umeclidinium/vilanterl Patient ppulatin 4 years with clinical diagnsis f mderate COPD Pst salbutaml FEV1 7% and 5% f nrmal predicted mmrc dyspnea scre 1 Prescribed TIO 1 mcg fr 3 mnths Endpints Primary endpint Trugh FEV1 at Day 85 Secndary endpints FEV1 3h pst-dse n Day 84 Trugh FEV1 n Days 2, 28, 56 and 84 Mean serial FEV1 n Days 1, 28, 56 and 84 wmfev1 ver 3h pst-dse n Days 1, 28, 56, 84 and 85 Percentage f rescue-free days and the number f puffs f rescue medicatin during the study Transitin Dyspnea Index (TDI) fcal scre and the prprtin f respnders (defined as patients with a TDI fcal scre f 1 unit) n Days 28, 56 and 84 Date f preparatin: August

15 SGRQ ttal scre and the prprtin f respnders (defined as patients with a reductin frm baseline f 4 units) n Days 28 and 84 CAT scre and the prprtin f respnders (defined as patients with a reductin frm baseline f 2 units) n Days 28 and 84 Safety and tlerability AEs and AEs f special interest Demgraphics and baseline characteristics UMEC/VI 55/22 mcg (n=247) TIO 1 mcg (n=247) Mean age, years ± SD 64.5 ± ±8.7 Female gender, n (%) 84 (44) 87 (45) Mean smking pack-year histry, years ± SD 38.6 ± ± 2.2 Pst-salbutaml % predicted FEV1, mean ± SD 59.8 ± ± 5.3 Pst-salbutaml FEV1/FVC, mean ± SD 53.1 ± ± 8.4 FEV 1 = frced expiratry vlume in 1 secnd; FVC = frced vital capacity; SD = standard deviatin; TIO = titrpium; UMEC/VI = umeclidinium/vilanterl Results Primary endpint Trugh FEV1 at Day 85 Secndary endpints UMEC/VI 55/22 mcg resulted in an 88 ml imprvement ver TIO 1 mcg (95% CI 45, 131; p<.1) FEV1 3 h pst-dse n Day 84 UMEC/VI 55/22 mcg prduced a 73 ml imprvement ver TIO 1 mcg (95% CI 24, 122; p<.1) Trugh FEV1 n Days 2, 28, 56 and 84 Greater imprvements in trugh FEV1 with UMEC/VI 55/22 mcg ver TIO 1 mcg were als bserved at all ther assessments frm Day 2 nward (p<.1) A greater prprtin f patients achieved a 1 ml imprvement in trugh FEV1 at Day 85 with UMEC/VI 55/22 mcg (44%) cmpared with TIO 1 mcg (3%); UMEC/VI 55/22 mcg versus TIO 1 mcg resulted in higher dds f achieving a 1 ml imprvement in trugh FEV1 rati: 1.89 (95% CI 1.27, 2.81; p<.1) at Day 85 Mean serial FEV1 n Days 1, 28, 56 and 84 Imprvements favured UMEC/VI 55/22 mcg ver TIO 1 mcg as early as 5 min pstdse n Day 1 (difference f 5 ml [95% CI 27, 72]; p<.1), which was maintained fr all serial FEV1 time pints up t 3h (p<.5) wmfev1 ver 3h pst-dse n Days 1, 28, 56, 84 and 85 UMEC/VI 55/22 mcg treatment resulted in statistically significant imprvements ver TIO 1 mcg in weighted mean FEV1 3h pstdse and trugh FVC Percentage f rescue-free days and the number f puffs f rescue medicatin ver 12 weeks UMEC/VI 55/22 mcg resulted in a greater imprvement in the number f rescue-free days cmpared with TIO 1 mcg (median estimated difference 2.3 days [95% CI., 4.8; p<.1]) There was a greater reductin in rescue medicatin use, favuring UMEC/VI 55/22 mcg ver TIO 1 mcg (LS mean change difference:.1 puffs/d [95% CI.2,.]; p<.5) Date f preparatin: August

16 TDI fcal scre and the prprtin f respnders (defined as patients with a TDI fcal scre f 1 unit) n Days 28, 56 and 84 TDI fcal scres were imprved with UMEC/VI 55/22 mcg cmpared with TIO 1 mcg at Day 28 (difference.5; 95% CI.,.9; p<.5) but nt at Days 56 and 84 The dds f being a respnder versus a nn-respnder accrding t TDI scre were significantly higher fr patients receiving UMEC/VI 55/22 mcg (63% respnders) cmpared with TIO 1 mcg at Day 84 (49% respnders; OR 1.78; 95% CI 1.21, 2.64; p<.1) SGRQ ttal and CAT scre and the prprtin f respnders n Days 28 and 84 Safety Bth scres and prprtin f respnders were similar between treatment grups On-treatment AEs were similar in bth treatment grups (3 31%) On-treatment drug-related AEs were similar in bth treatment grups (1 3%) On-treatment nn-fatal and fatal SAEs were similar between grups ( 2%) The mst frequent n-treatment AEs were naspharyngitis (bth 7%) and headache (6 7%) AEs f special interest: The incidence f cardivascular AEs f special interest was lw and similar between grups: 2% fr UMEC/VI 55/22 mcg and 1% fr TIO 1 mcg On-treatment COPD exacerbatins were reprted fr tw (<1%) and eight (3%) f patients in the UMEC/VI 55/22 mcg and TIO 1 mcg grups, respectively Table 3. Summary f adverse events UMEC/VI 55/22 mcg (n=247) TIO 1 mcg (n=247) On-treatment AEs, n (%) 75 (3) 77 (31) AEs leading t withdrawal r discntinuatin f medicatin, n (%) 5 (2) 4 (2) On-treatment nn-fatal SAEs, n (%) 6 (2) 6 (2) On-treatment fatal SAEs, a n (%) 1 (<1) On-treatment AEs ccurring in 3% in any grup, n (%) Naspharyngitis Headache AEs f special interest, n (%) Cardivascular Cardiac arrhythmia Cardiac failure Ischaemic heart disease CNS haemrrhages and cerebrvascular cnditins Pneumnia LRTI excluding pneumnia 18 (7) 16 (6) 4 (2) 1 (<1) 2 (<1) 2 (<1) 1 (<1) 2 (<1) 17 (7) 18 (7) 3 (1) 2 (<1) 1 (<1) 1 (<1) On-treatment COPD exacerbatin, n (%) 2 (<1) 8 (3) a One death ccurred during the study due t a cerebrvascular accident in the UMEC/VI grup and was identified as nt related t study treatment by the investigatr AE = adverse event; AESI = adverse event f special interest; CNS = central nervus system; COPD = chrnic bstructive pulmnary disease; CV = cardivascular; SAE = serius adverse event; SD = standard deviatin; TIO = titrpium; UMEC/VI = umeclidinium/vilanterl Date f preparatin: August

17 Decramer et al., 214 (active-cmparatr study) Efficacy and safety f umeclidinium plus vilanterl versus titrpium, vilanterl, r umeclidinium mntherapies ver 24 weeks in patients with chrnic bstructive pulmnary disease: results frm tw multicentre, blinded, randmised cntrlled trials 6 Anr Ellipta (UMEC/VI 55/22 mcg) prvides significant imprvements in lung functin cmpared with titrpium (TIO 1 mcg) in patients with COPD, with a similar safety prfile Study design Tw Phase III, randmised, multicentre, duble-blind, duble-dummy, parallel-grup, active cntrlled 24-week lung functin studies cmparing UMEC/VI 113/22 mcg OD, UMEC/VI 55/22 mcg OD, TIO 1 mcg OD and either VI 22 mcg OD (study 1) r UMEC 113 mcg OD (study 2) in patients with mderate t very severe COPD. UMEC 113 mcg, VI 22 mcg and UMEC/VI 113/22 mcg are nt licensed in the UK and therefre results have nt been included in the efficacy sectin but have been included in the safety sectin. Details f the blinding prcess fr all titrpium cmparatr studies discussed in this Evidence Dssier can be fund n page 474 in Decramer M et al., Lancet Respir Med. 214 Jun;2: Di: 1.116/S (14) COPD = chrnic bstructive pulmnary disease; FEV 1 = frced expiratry vlume in 1 secnd; FVC = frced vital capacity; MRC = Medical Research Cuncil; OD = nce daily; TIO = titrpium; UMEC = umeclidinium; UMEC/VI = umeclidinium/vilanterl; VI = vilanterl The studies used a duble-dummy design fr dsing; patients were given tw inhalers, ne cntaining active drug and the ther placeb Salbutaml was permitted thrughut the study run-ins and treatment perids, but withheld fr 4h befre spirmetry testing Inhaled crticsterids at a stable dse f up t 1 mcg per day f fluticasne prpinate r equivalent were permitted thrughut the study Patient ppulatin 4 years with clinical diagnsis f mderate-t-very severe COPD Smking histry 1 pack-years Pst brnchdilatr FEV1/FVC rati <.7 Date f preparatin: August

18 FEV1 7% predicted MRC dyspnea scre 2 Endpints Primary endpint Pre-dse (trugh) FEV1 n Day 169, defined as the mean f FEV1 values btained 23h and 24h after dsing n Day 168 (Week 24 visit) Secndary endpints and ther endpints wmfev1 ver 6h pst-dse n Day 168 Trugh FEV1 and 6h pst-dse wmfev1 at ther timepints Peak FEV1 n Day 168 Trugh FVC n Day 169 Prprtin f patients achieving an increase in FEV1 f 12% and.2 L abve baseline at any time during 6h pst-dse n Day 1 Prprtin f patients achieving an increase f.1 L abve baseline in trugh FEV1 n Day 169 TDI fcal scre and the prprtin f TDI respnders, defined as patients with a TDI fcal scre 1 unit Shrtness f Breath with Daily Activity (SOBDA) diary scre and the prprtin f SOBDA respnders, defined as a decrease f.1 units frm baseline SGRQ scre and the prprtin f SGRQ respnders, defined as a decrease frm baseline in SGRQ ttal scre f 4 units Rescue salbutaml use (percentage f rescue-free days and mean puffs/day) Time t first COPD exacerbatin Device preference (as measured by the COPD device preference questinnaire) Safety and tlerability AEs, vital signs, 12-lead ECG, clinical chemistry and haematlgy Demgraphics and baseline characteristics Study 1 UMEC/VI 55/22 mcg (n=212) TIO 1 mcg (n=28) Age (years), mean ± SD 63. ± ± 9.4 Female gender, n (%) 64 (3) 68 (33) Mean smking pack-year histry, years Pst-salbutaml % predicted FEV1, mean ± SD 48. ± ± 13.4 Pst-salbutaml FEV1/FVC, mean ± SD 47.7 ± ± 11.9 Study 2 UMEC/VI 55/22 mcg (n=217) TIO 1 mcg (n=215) Age (years), mean ± SD 65. ± ± 8.3 Female gender, n (%) 77 (35) 62 (29) Mean smking pack-year histry, years Pst-salbutaml % predicted FEV1, mean ± SD 47.7 ± ± 13.1 Pst-salbutaml FEV1/FVC, mean ± SD 46.2 ± ± 11.6 FEV 1 = frced expiratry vlume in 1 secnd; FVC = frced vital capacity; SD = standard deviatin; TIO = titrpium; UMEC/VI = umeclidinium/vilanterl Date f preparatin: August

19 Results Primary endpint Pre-dse (trugh) FEV1 n Day 169, defined as the mean f FEV1 values btained 23h and 24h after dsing n Day 168 (Week 24 visit) In study 1, trugh FEV1 at Day 169 (least squares mean; LSM) was significantly imprved frm baseline with UMEC/VI 55/22 mcg (9 ml; 95% CI 39, 141; p.1) cmpared with TIO 1 mcg. Significant imprvements were als seen at all ther visits (p<.1) Figure 3: Repeated measures analysis fr change frm baseline in trugh FEV1 ver 24 weeks f treatment (Study 1, ITT ppulatin) Adapted frm Decramer et al., 214 FEV 1 = frced expiratry vlume in 1 secnd; ITT = intentin-t-treat; TIO = titrpium; UMEC/VI = umeclidinium/vilanterl In study 2, trugh FEV1 at Day 169 (LSM) was imprved frm baseline UMEC/VI 55/22 mcg (6 ml; 95% CI 1, 19; p=.182 * ) cmpared with TIO 1 mcg Figure 4: Repeated measures analysis fr change frm baseline in trugh FEV1 ver 24 weeks f treatment (Study 2, ITT ppulatin) Adapted frm Decramer et al., 214 FEV 1 = frced expiratry vlume in 1 secnd; ITT = intentin-t-treat; TIO = titrpium; UMEC/VI = umeclidinium/vilanterl In the pled analysis f trugh FEV1 fr bth studies, there was a significant imprvement n Day 169 fr UMEC/VI 55/22 mcg cmpared with TIO 1 mcg (75 ml; 95% CI 39, 11; p<.1) * This p value (<.5) is nminal nly, because f the restrictins f the predefined statistical testing hierarchy Date f preparatin: August

20 Secndary endpints wmfev1 ver 6h pst-dse n Day 168 In study 1, wmfev1 ver 6h pst-dse n Day 168 was significantly imprved frm baseline with UMEC/VI 55/22 mcg (74 ml; 95% CI 22, 125; p=.52) cmpared with TIO 1 mcg. Significant imprvements were als seen at all ther visits In study 2, wmfev1 ver 6h pst-dse n Day 168 was imprved frm baseline with UMEC/VI 55/22 mcg (96 ml; 95% CI 5, 142; p<.1) cmpared with TIO 1 mcg. Similar imprvements were als seen at all ther visits Peak FEV1 n Day 168 In study 1, peak FEV1 n Day 168 was significantly imprved frm baseline with UMEC/VI 55/22 mcg (72 ml; 95% CI 19, 125; p=.18) cmpared with TIO 1 mcg In study 2, peak FEV1 n Day 168 was imprved frm baseline with UMEC/VI 55/22 mcg (93 ml; 95% CI 44, 142; p=.2) cmpared with TIO 1 mcg Trugh FVC n Day 169 In study 1, trugh FVC n Day 169 was similar with UMEC/VI 55/22 mcg (68 ml; 95% CI 2, 157; p=.13) cmpared with TIO 1 mcg In study 2, trugh FVC n Day 169 was imprved frm baseline with UMEC/VI 55/22 mcg (98 ml; 95% CI 2, 176 ml; p=.143) cmpared with TIO 1 mcg Prprtin f patients achieving an increase in FEV1 f 12% and.2 L abve baseline at any time during 6h pst-dse n Day 1 In study 1, significantly mre patients achieved the defined increase frm baseline with UMEC/VI 55/22 mcg (OR 2.5; 95% CI 1.7, 3.7; p<.1) cmpared with TIO 1 mcg In study 2, mre patients achieved the defined increase frm baseline with UMEC/VI 55/22 mcg (OR 2.1; 95% CI 1.4, 3.1 ml; p=.2) cmpared with TIO 1 mcg Prprtin f patients achieving an increase f.1 L abve baseline in trugh FEV1 n Day 169 In study 1, significantly mre patients achieved the defined increase frm baseline with UMEC/VI 55/22 mcg (OR 2.1; 95% CI 1.4, 3.1; p=.3) cmpared with TIO 1 mcg In study 2, a similar prprtin f patients achieved the defined increase frm baseline with UMEC/VI 55/22 mcg cmpared with TIO 1 mcg (OR 1.4; 95% CI 1., 2.1; p=.6) TDI fcal scre and the prprtin f TDI respnders, defined as patients with a TDI fcal scre 1 unit at Day 168 UMEC/VI 55/22 mcg and TIO 1 mcg prduced clinically meaningful imprvements ( 1 unit) in LSM TDI fcal scre at Day 168 (Study 1 LSM: UMEC/VI 55/22 mcg 2.3, TIO 1 mcg 2.4; Study 2 LSM: UMEC/VI 55/22 mcg 2.3, TIO 1 mcg 2.1) N significant differences were nted in TDI scre r dds f being a TDI respnder n Day 168 between UMEC/VI 55/22 mcg and TIO 1 mcg SOBDA diary scre and the prprtin f SOBDA respnders, defined as a decrease f.1 units frm baseline At Week 24, all treatments were assciated with imprvements in LSM changes frm baseline in SOBDA scre f.1 r greater (Study 1 LSM: UMEC/VI 55/22 mcg.18, TIO 1 mcg.18; Study 2 LSM: UMEC/VI 55/22 mcg.29, TIO 1 mcg.21) SGRQ scre and the prprtin f SGRQ respnders, defined as a decrease frm baseline in SGRQ ttal scre f 4 units All treatments resulted in a decrease in SGRQ f 4 units (Study 1 LSM: UMEC/VI 55/22 mcg 6.87, TIO 1 mcg 7.62; Study 2 LSM: UMEC/VI 55/22 mcg 9.95, TIO 1 mcg 9.78) There were n significant differences between treatments with respect t change frm baseline in SGRQ Date f preparatin: August 218 2

21 Rescue salbutaml use (percentage f rescue-free days and mean puffs/day) In study 1, UMEC/VI 55/22 mcg significantly reduced the use f rescue salbutaml treatment ver 24 weeks cmpared with TIO 1 mcg (treatment difference:.7, 95% CI 1.2,.1, p=.22) In study 2, there was n significant difference in the use f rescue salbutaml treatment ver 24 weeks cmpared with TIO 1 mcg (treatment difference:.6 ( 1.2,.; p=.7) Time t first COPD exacerbatin N differences in risk f a COPD exacerbatin were bserved between the UMEC/VI 55/22 mcg and TIO 1 mcg grups in either study Device preference (as measured by the COPD device preference questinnaire) Safety Ellipta was preferred t HandiHaler acrss the treatment grups, accrding t the results f the COPD device preference questinnaire On-treatment AEs ranged frm 39% t 62% acrss treatment grups Treatment-related AEs ranged frm 3% t 13% acrss treatment grups The mst frequent n-treatment AEs were naspharyngitis (3 1%), headache (4 11%), upper respiratry tract infectin (2 8%), and back pain (1 5%) N ntable differences were reprted fr bld pressure, heart rate, r QT interval in either study, and n treatment-related changes in ECG r clinical labratry parameters were recrded Table 4. Summary f adverse events UMEC/VI 55/22 UMEC/VI 113/22 Study 1 mcg (n=212) mcg (n=214) VI 22 mcg (n=29) TIO 1 mcg (n=28) On-treatment AEs, n (%) 18 (51) 94 (44) 99 (47) 82 (39) Mst cmmn AE type, n (%) Naspharyngitis Headache URTI Back pain 21 (1) 2 (9) 8 (4) 1 (5) 14 (7) 14 (7) 7 (3) 7 (3) 17 (8) 21 (1) 5 (2) 3 (1) Treatment-related AEs, n (%) 11 (5) 9 (4) 12 (6) 7 (3) 16 (8) 9 (4) 8 (4) 4 (2) AEs leading t discntinuatin r study withdrawal, n (%) 1 (5) 15 (7) 1 (5) 9 (4) On-treatment SAEs, n (%) 7 (3) 5 (2) 15 (7) 13 (6) Severe intensity AEs reprted by >1% f patients in any treatment grup, a n (%) Acute exacerbatin f COPD b 4 (2) 1 (<1) 2 (<1) 2 (<1) Fatal AEs, c n (%) 1 (<1) 1 (<1) Anr Ellipta is indicated as a maintenance brnchdilatr treatment t relieve symptms in adult patients with COPD Date f preparatin: August

22 UMEC/VI 55/22 UMEC/VI 113/22 Study 2 mcg (n=217) mcg (n=215) UMEC 113 mcg (n=222) TIO 1 mcg (n=215) On-treatment, n (%) 127 (59) 133 (62) 131 (59) 126 (59) Mst cmmn AE type, n (%) Naspharyngitis 14 (6) 16 (7) 6 (3) 17 (8) Headache 21 (1) 2 (9) 25 (11) 15 (7) URTI 6 (3) 1 (5) 17 (8) 14 (7) Back pain 8 (4) 6 (3) 1 (5) 11 (5) Treatment-related AEs, n (%) 16 (7) 17 (8) 28 (13) 16 (7) AEs leading t discntinuatin r study withdrawal, n (%) 2 (9) 15 (7) 17 (8) 11 (5) On-treatment SAEs, n (%) 22 (1) 15 (7) 15 (7) 9 (4) Severe intensity AEs reprted by >1% f patients in any treatment grup, a n (%) Acute exacerbatin f COPD b 6 (3) 6 (3) 1 (<1) Fatal AEs, a n (%) 1 (<1) 1 (<1) 2 (<1) a Intensity was assessed frm the maximum intensity f the AE thrughut its duratin; b Only acute exacerbatins f COPD that were classified as SAEs were recrded as safety findings; c Includes n-treatment and pst-treatment events. Tw n-treatment deaths ccurred during Study 1 (ne in the UMEC/VI 55/22 mcg grup [cardiac arrest and COPD exacerbatin] and ne in the VI 22 mcg grup [acute heart failure]) and fur deaths ccurred during Study 2 (ne in the UMEC/VI 55/22 mcg grup [haemrrhagic strke], ne in the UMEC/VI 113/22 mcg grup [upper-gastrintestinal haemrrhage] and tw in the TIO 1 mcg grup [uppergastrintestinal haemrrhage and respiratry arrest]). N deaths were cnsidered by the reprting investigatr related t study drug. AE = adverse event; TIO = titrpium; UMEC = umeclidinium; UMEC/VI = umeclidinium/vilanterl; URTI = upper respiratry tract infectin; VI = vilanterl Date f preparatin: August

23 Kalberg et al., 216 (active-cmparatr study) Dual Brnchdilatr Therapy with Umeclidinium/Vilanterl Versus Titrpium plus Indacaterl in Chrnic Obstructive Pulmnary Disease: A Randmized Cntrlled Trial 7,8 Treatment ver 12 weeks with Anr Ellipta 55/22 mcg OD resulted in imprvements in measures f lung functin, symptms and health status, similar t thse achieved with the free cmbinatin f titrpium HandiHaler (TIO 1 mcg) and IND 15 mcg OD in patients with mderate t very severe COPD, with cmparable safety prfiles Study design A multicentre, randmised, blinded, triple-dummy, parallel-grup, 12-week lung functin study cmparing UMEC/VI 55/22 mcg OD against TIO 1 mcg OD + IND 15 mcg OD, in patients with mderate t very severe COPD. This was a nn-inferirity study t investigate whether treatment with UMEC/VI 55/22 mcg was nn-inferir t TIO 1 mcg OD + IND 15 mcg OD. Details f the blinding prcess fr all titrpium cmparatr studies discussed in this Evidence Dssier can be fund n page 474 in Decramer M et al., Lancet Respir Med. 214 Jun;2: Di: 1.116/S (14) COPD = chrnic bstructive pulmnary disease; FEV 1 = frced expiratry vlume in 1 secnd; FVC = frced vital capacity; IND = indacaterl; OD = nce daily; PBO = placeb; PP = per-prtcl; R = randmisatin; TIO = titrpium; UMEC/VI = umeclidinium/vilanterl After screening, patients entered a 5 7-day run-in perid prir t randmisatin The use f shrt-acting muscarinic antagnists, ICS and salbutaml were permitted during the run-in perid After the run-in perid, patients were randmised (1:1) t receive either UMEC/VI 55/22 mcg OD via an Ellipta inhaler, plus placeb OD via a Handihaler, plus placeb OD via a Breezhaler; r TIO 1 mcg OD via a Handihaler, plus IND 15 mcg OD via a Breezhaler, plus placeb OD via an Ellipta fr 12 weeks Patients were randmised t treatment nly if they had nt experienced a COPD exacerbatin between visits 1 and 2, and if they had nt used any prhibited medicatin during the run-in perid r at visit 2 Clinic visits tk place n Days 2, 14, 28, 56, 84, and 85, with a fllw-up perid f apprximately 7 days Patients were prvided with salbutaml fr use as a rescue medicatin Patient ppulatin 4 years f age An established clinical histry f COPD Date f preparatin: August

24 Current r frmer cigarette smker with 1 pack-years Pre- and pst-brnchdilatr FEV1 values 7% predicted nrmal Pre- and pst-brnchdilatr FEV1/frced vital capacity (FVC) ratis f <.7 Mdified Medical Research Cuncil (mmrc) dyspnea scre 2 Crrected QT interval <45 ms (r <48 ms fr patients with bundle branch blck) Endpints Primary endpint Trugh FEV1 n Day 85 (defined as the mean f the FEV1 values btained 23h and 24h after dsing n Day 84) in the PP ppulatin There was a prespecified nn-inferirity margin f 5 ml in treatment difference, which if met, demnstrated nn-inferirity Secndary and ther efficacy endpints (ITT ppulatin) wmfev1 ver 6h pst-dse n Day 84 wmfev1 ver 6h pst-dse n Day 1 Trugh FEV1 n Days 28 and 56 6h serial FEV1 at Days 1 and 84 Serial and trugh FVC Patient-reprted utcmes (ITT ppulatin) Mean number f puffs f rescue medicatin per day ver Days 1 84 Percentage f rescue-free days ver Days 1 84 Transitin Dyspnea Index (TDI) fcal scre and prprtin f TDI respnders (thse with 1 unit TDI fcal scre) n Days 28, 56 and 84 St Gerge s Respiratry Questinnaire (SGRQ) ttal scre and prprtin f respnders (thse with reductin frm baseline f 4 units ttal SGRQ scre) n Days 28, 56 and 84 Inhaler preference evaluating number f steps t use the inhaler, time required fr use and verall inhaler preference Safety and tlerability (ITT ppulatin) Safety f study treatments was assessed by mnitring the incidence f AEs, vital sign measurements and COPD exacerbatins Demgraphics and baseline characteristics (ITT ppulatin) Characteristic UMEC/VI 55/22 mcg (n=482) TIO 1 mcg + IND 15 mcg (n=479) Age (years), mean ± SD 64 ± ± 8.4 Female gender, n (%) 127 (26) 138 (29) Current smker at screening, n (%) 198 (41) 218 (46) Smking pack-years, a mean ± SD 43.2 ± ± 23.1 Pst-salbutaml FEV1 (L), b mean ± SD ± ±.48 Pst-salbutaml FEV1/FVC, b mean ± SD 45.7 ± ± 11.1 a Smking pack-years = (number f cigarettes smked per day/2) x number f years f smking; b n = 479 in UMEC/VI 55/22 mcg OD, n = 477 in TIO 1 mcg OD + IND 15 mcg OD FEV 1 = frced expiratry vlume in 1 secnd; FVC = frced vital capacity; IND = indacaterl; ITT = intentin-t-treat; SD = standard deviatin; TIO = titrpium; UMEC/VI = umeclidinium/vilanterl Date f preparatin: August

25 Results Primary endpint Trugh FEV1 n Day 85 (PP ppulatin) The LS mean change frm baseline in trugh FEV1 at Day 85 was similar fr bth treatment grups (difference 1 ml; 95% CI 29, 3; p=.964) The lwer limit f the CI was greater than the prespecified nn-inferirity margin f 5 ml, demnstrating UMEC/VI 55/22 mcg is nn-inferir t TIO 1 mcg + IND 15 mcg fr the primary endpint f trugh FEV1 at Day 85 Acrss all time pints, similar imprvements frm baseline in trugh FEV1 were bserved in the tw treatment grups Similar results fr trugh FEV1 at Day 85 were bserved in the ITT ppulatin in UMEC/VI 55/22 mcg versus TIO 1 mcg + IND 15 mcg (difference 7 ml; 95 % CI 22, 35, p=.64) Figure 5: LS mean change frm baseline in trugh FEV1 (PP ppulatin) Adapted frm Kalberg et al., 216 CI = cnfidence interval; FEV 1 = frced expiratry vlume in 1 secnd; IND = indacaterl; LS = least squares; PP = per-prtcl; TIO = titrpium; UMEC/VI = umeclidinium/vilanterl Secndary and ther efficacy endpints (ITT ppulatin) wmfev1 ver 6h pst-dse n Days 1 and 84 The mean change frm baseline between treatments in trugh FEV1 at Day 1 in the 6 hurs pst-dse was 1 ml (95% CI 2, 18, p=.98) Similar imprvements frm baseline were demnstrated at Day 84 in the UMEC/VI 55/22 mcg grup and the TIO 1 mcg + IND 15 mcg grup (difference 23 ml; 95% CI 54, 8, p=.145) Trugh FEV1 n Days 28 and 56 The LS mean change frm baseline in trugh FEV1 at Days 28 and 56 in the ITT ppulatin was similar fr bth treatment grups (Day 28 difference 4 ml; 95% CI 23, 31; p=.774; Day 56 difference 11 ml; 95% CI 17, 4; p=.438) Serial FEV1 at Days 1 and 84 Similar patterns f imprvement were bserved frm baseline in bth treatment grups at Days 1 and 84 (Day 1 difference 7 ml; 95% CI 13, 26; p=.5; Day 84 difference 3 ml; 95% CI 25, 19; p=.784) Date f preparatin: August

26 Serial and trugh FVC Similar mean baseline trugh FVC was bserved between the UMEC/VI 55/22 mcg (2,86 ml) and TIO 1 mcg + IND 15 mcg (2,775 ml) grups. Imprvement frm baseline was bserved fr bth grups at all time pints frm Day 2 thrugh t Day 85 (Day 2 difference 16 ml; 95% CI 25, 57; p=.437; Day 85 difference 2 ml; 95% CI 29, 68; p=.433) Similar patterns f imprvement were bserved in serial FVC at each time pint fr Day 1 and Day 84 between treatment grups Patient reprted utcmes Mean number f puffs f rescue medicatin per day ver Days 1 84 Overall difference in mean puffs per day frm baseline between the UMEC/VI 55/22 mcg and TIO 1 mcg + IND 15 mcg treatment grups was.1 puffs (95% CI.1,.3; p=.215) N difference was detected in percentage f rescue-free days between the UMEC/VI 55/22 mcg and TIO 1 mcg + IND 15 mcg treatment grups (median difference days; 95% CI, 2.6; p=.265) TDI fcal scre and prprtin f TDI respnders n Days 28, 56 and 84 (ITT ppulatin) TDI fcal scres in bth grups were similar acrss all visits. Grups demnstrated a clinically meaningful imprvement in LS mean TDI fcal scre at all visits (at Day 84; 2.32 and 2.62 LS mean change, in patients receiving UMEC/VI 55/22 mcg and TIO 1 mcg + IND 15 mcg, respectively) Day 28 (difference 2.7; 95% CI.29,.39; p=.772) Day 56 (difference 2.8; 95% CI.38,.28; p=.752) Day 84 (difference 2.32; 95% CI.65,.5; p=.96) The prprtin f respnders (TDI fcal scre 1 unit) was similar between treatment grups at Days 28, 56 and 84 Day 28 (OR 1.1; 95% CI.77, 1.33; p=.927) Day 56 (OR.95; 95% CI.73, 1.25; p=.72) Day 84 (OR.88; 95% CI.67, 1.16; p=.364) SGRQ ttal scre and prprtin f respnders n Days 28, 56 and 84 (ITT ppulatin) Bth treatments resulted in similar imprvements frm baseline in SGRQ scre (at Day 84; 4.93 and 5.1 LS mean change, in patients receiving UMEC/VI 55/22 mcg and TIO 1 mcg + IND 15 mcg, respectively) Day 28 (difference 1.12; 95% CI 2.5,.26; p=.112) Day 56 (difference.37; 95% CI 1.86, 1.12; p=.627) Day 84 (difference.8; 95% CI 1.52, 1.67; p=.925) The prprtin f respnders was similar between treatment grups n Days 28, 56 and 84 Inhaler preference Day 28 (OR 1.19; 95% CI.92, 1.55; p=.19) Day 56 (OR 1.4; 95% CI.8, 1.35; p=.764) Day 84 (OR 1.5; 95% CI.81, 1.37; p=.69) A greater number f patients indicated preference fr the Ellipta inhaler acrss the evaluatins fr the number f steps, time t use, and verall preference cmpared with the Breezhaler and Handihaler Overall 65% f users acrss bth treatment grups reprted a preference fr the Ellipta inhaler, stating the reasn as ease f use Date f preparatin: August

27 Safety The verall incidence f AEs during treatment was similar between the treatment grups in the ITT ppulatin (42% in the UMEC/VI 55/22 mcg grup and 39% in the TIO 1 mcg + IND 15 mcg grup), with headache and naspharyngitis reprted mst frequently There were lw incidences f nn-fatal serius adverse events (SAEs) and AEs leading t study withdrawal in bth treatment grups (2% in bth) During the 12-week treatment perid, the mean changes frm baseline in vital signs were similar between treatment grups The incidence f COPD exacerbatins during treatment was lw and the same in bth treatment grups (1% in bth) Table 5. Summary f adverse events UMEC/VI 55/22 mcg (n=482) TIO 1 mcg + IND 15 mcg (n=479) On-treatment AE, n (%) 22 (42) 186 (39) Drug-related AE, n (%) 3 (6) 37 (8) AEs leading t permanent discntinuatin f study drug r withdrawal frm study, n (%) AEs reprted in 3% f patients, n (%) Naspharyngitis Headache Cugh 12 (2) 8 (2) 36 (7) 32 (7) 16 (3) 28 (6) 27 (6) 17 (4) On-treatment nn-fatal SAE, n (%) 17 (4) 15 (3) On-treatment fatal SAE, a n (%) 4 (<1) 1 (<1) Patients experiencing COPD exacerbatin, n (%) 48 (1) 49 (1) AEs f special interest, n (%) Cardivascular effects Cardiac arrhythmia Cardiac failure Ischaemic heart disease CNS haemrrhages and cerebrvascular cnditins Pneumnia LRTI excluding pneumnia a Five n-treatment deaths ccurred during the study (pneumnia and respiratry failure, ventricular fibrillatin, circulatry cllapse and cardiac arrest in the UMEC/VI grup and pneumnia in the TIO + IND grup); the cardiac arrest was reprted by the investigatr as being related t the study medicatin and n ther deaths were identified as being related t the study medicatin. 11 (2) 7 (1) 4 (<1) 2 (<1) 4 (<1) 7 (1) 9 (2) 3 (<1) 3 (<1) 4 (<1) 1 (<1) 2 (<1) AE = adverse event; COPD = chrnic bstructive pulmnary disease; IND = indacaterl; LRTI =lwer respiratry tract infectin; SAE = serius adverse event; TIO = titrpium; UMEC/VI = umeclidinium/vilanterl 9 (2) Date f preparatin: August

28 Dnhue et al., 213 (placeb-cntrlled study) Efficacy and safety f nce-daily umeclidinium/vilanterl 55/22 mcg in COPD 9,1 Anr Ellipta significantly imprved lung functin and symptms in patients with COPD cmpared with placeb and was well tlerated Study design A Phase III, randmised, multicentre, duble-blind, placeb-cntrlled, parallel-grup 24-week lung functin study cmparing UMEC/VI 55/22 mcg OD against its cnstituents, UMEC 55 mcg OD and VI 22 mcg OD, and placeb in patients with COPD. VI 22 mcg is nt licensed fr the treatment f COPD in the UK and therefre the results have nt been included in the efficacy sectin but have been included in the safety sectin COPD = chrnic bstructive pulmnary disease; FEV 1 = frced expiratry vlume in 1 secnd; FVC = frced vital capacity; OD = nce daily; R = randmisatin; UMEC = umeclidinium; UMEC/VI = umeclidinium/vilanterl; VI = vilanterl Inhaled crticsterids (ICS) were allwed at a stable dse f 1 mcg/day f fluticasne prpinate r equivalent Cncmitant use f inhaled salbutaml as rescue medicatin was allwed Patient ppulatin 4 years with clinical histry f COPD with airflw limitatin that is nt fully reversible Smking histry 1 pack-years Pst-salbutaml FEV1/FVC rati <.7 Pst-salbutaml FEV1 7% mmrc dyspnea scre 2 Endpints Primary endpint Pre-dse (trugh) FEV1 n Day 169, defined as the mean f FEV1 values btained 23h and 24h after dsing n Day 168 (Week 24 visit) Date f preparatin: August

29 Secndary and ther endpints Weighted mean (wm) FEV1 ver 6h pst-dse n Day 168 Serial FEV1 assessments Time t nset during 6h pst-dse n Day 1 Prprtin f patients achieving an increase in FEV1 f 12% and.2 L abve baseline at any time during 6h pst-dse n Day 1 Prprtin f patients achieving an increase f.1 L abve baseline in trugh FEV1 Peak FEV1 and serial and trugh FVC Transitin Dyspnea Index (TDI) fcal scre Mean SOBDA scre Rescue salbutaml use COPD exacerbatins SGRQ Safety and tlerability AEs, vital signs, 12-lead ECG and 24h Hlter mnitring, clinical chemistry and haematlgy Demgraphics and baseline characteristics Characteristic UMEC/VI 55/22 mcg (n=413) UMEC 55 mcg (n=418) Placeb (n=28) Age (years), mean ± SD 63.1 ± ± ± 9. Female gender, n (%) 18 (26) 12 (29) 85 (3) Smking pack-year histry, years ± SD 46.5 ± ± ± 27.1 Pst-salbutaml % predicted FEV1, mean ± SD 47.8 ± ± ± 12.7 Pst-salbutaml FEV1/FVC, mean ± SD 48. ± ± ± 11.5 FEV 1 = frced expiratry vlume in 1 secnd; FVC = frced vital capacity; UMEC = umeclidinium; UMEC/VI = umeclidinium/vilanterl Results Primary endpint Pre-dse (trugh) FEV1 n Day 169 Trugh FEV1 at Day 169 (LSM) was significantly imprved frm baseline with UMEC/VI 55/22 mcg (167 ml; 95% CI 128, 27) and UMEC 55 mcg (115mL; 95% CI 76, 155) cmpared with placeb (all p<.1) A statistically significant imprvement frm baseline in trugh FEV1 was demnstrated fr UMEC/VI 55/22 mcg cmpared with UMEC 55 mcg (52 ml; p=.4) Date f preparatin: August

30 Figure 6: Change frm baseline in trugh FEV1 (ITT ppulatin) Adapted frm Dnhue et al., 213 CI = cnfidence interval; FEV 1 = frced expiratry vlume in 1 secnd; ITT = intentin-t-treat; LS = least squares; UMEC = umeclidinium; UMEC/VI = umeclidinium/vilanterl; VI = vilanterl Secndary and ther endpints wmfev1 ver 6h pst-dse n Day 168 wmfev1 at Day 168 (LSM) was significantly imprved frm baseline with UMEC/VI 55/22 mcg (242 ml; 95% CI 22, 282) and UMEC 55 mcg (15mL; 95% CI 11, 19) cmpared with placeb (bth p<.1) Statistically significant imprvements in wmfev1 ver 6h were als demnstrated fr UMEC/VI 55/22 mcg cmpared with UMEC 55 mcg (92 ml; p<.1) Serial FEV1 assessments In the subset f patients with serial spirmetry ver 24h, significant imprvements in serial FEV1 values were btained with UMEC/VI 55/22 mcg and UMEC 55 mcg cmpared with placeb fr the majrity f timepints ver 24h n Day 168 Imprvements in serial FEV1 values ver 24h with UMEC/VI 55/22 mcg were greater cmpared with UMEC 55 mcg fr the majrity f timepints Time t nset during 6h pst-dse n Day 1 The median time t nset, defined as a pst-dse FEV1 1 ml abve baseline, during 6h pst-dse Day 1 was 27 minutes with UMEC/VI 55/22 mcg and 56 minutes with UMEC 55 mcg Subjects in the UMEC/VI 55/22 mcg treatment grup had a higher likelihd f achieving an increase in FEV1 1 ml abve baseline n Day 1 than subjects in the UMEC 55 mcg treatment grups (p<.1) Prprtin f patients achieving an increase in FEV1 f 12% and.2 L abve baseline at any time during 6h pst-dse n Day 1 The dds f achieving the defined increase in FEV1 was higher fr UMEC/VI 55/22 mcg and UMEC 55 mcg cmpared with placeb (OR 9., 95% CI 6.1, 13.2; and OR 5.9, 95% CI 4., 8.6 respectively; bth p<.1) The dds f achieving the defined increase in FEV1 was higher fr UMEC/VI 55/22 mcg versus UMEC 55 mcg (OR 1.5, 95% CI 1.2, 2., p=.3) Date f preparatin: August 218 3

31 Prprtin f patients achieving an increase f.1 L abve baseline in trugh FEV1 Peak FEV1 Trugh FVC TDI fcal scre Mean SOBDA scre The dds f achieving.1 L increase in FEV1 abve baseline was higher fr UMEC 55 mcg and UMEC/VI 55/22 mcg cmpared with placeb (OR 3.2, 95% CI 2.2, 4.5 and OR 4.1, 95% CI 2.9, 5.9, respectively; bth p<.1) There was n statistically significant difference in the dds f achieving.1 L increase in FEV1 abve baseline was higher fr UMEC/VI 55/22 mcg cmpared with UMEC 55 mcg (OR 1.3, 95% CI 1., 1.7, p=.55) Peak FEV1 increases frm baseline (LSM) at Day 168 were significantly greater with UMEC/VI 55/22 mcg (224 ml, 95% CI 182, 267) and UMEC 55 mcg (13 ml, 95% CI 88, 172) cmpared with placeb (bth p<.1) Peak FEV1 increases frm baseline (LSM) at Day 168 were significantly greater with UMEC/VI 55/22 mcg cmpared with UMEC 55 mcg (94 ml, 95% CI 57, 132; p<.1) Imprvements in trugh FVC change frm baseline (LSM) at Day 169 were significantly greater with UMEC/VI 55/22 mcg (248 ml, 95% CI 184, 313, p.1) and UMEC 55 mcg (175 ml, 95% CI 11, 239, p=.2) cmpared with placeb Imprvements in trugh FVC change frm baseline (LSM) at Day 169 were significantly greater with UMEC/VI 55/22 mcg cmpared with UMEC 55 mcg (74 ml, 95% CI 16, 131, p=.12) Clinically meaningful imprvements in mean TDI scres frm baseline (>1 demnstrating an imprvement in dyspnea) were bserved with UMEC/VI 55/22 mcg (2.4 units) and UMEC 55 mcg (2.2 units) at Day 168 Statistically significantly greater LSM TDI fcal scres were demnstrated fr the UMEC/VI 55/22 mcg and UMEC 55 mcg treatment grups cmpared with placeb at Day 168 (1.2 and 1. units, respectively, bth p<.1) Differences in LSM TDI fcal scres between UMEC/VI 55/22 mcg and UMEC 55 mcg were nt statistically significant At Week 24, UMEC/VI 55/22 mcg and UMEC 55 mcg were assciated with significant imprvements in SOBDA scre cmpared with placeb (UMEC/VI 55/22 mcg.17, p<.1 and UMEC 55 mcg.1, p=.43) Differences in SOBDA scres between UMEC/VI 55/22 mcg and UMEC 55 mcg were nt statistically significant Rescue salbutaml use Over the 24-week study perid, bth active treatments resulted in less rescue salbutaml use cmpared with placeb (UMEC/VI 55/22 mcg.8 puffs/day, p=.1 and UMEC 55 mcg.3 puffs/day, p=.276) Rescue medicatin use was significantly lwer with UMEC/VI 55/22 mcg cmpared with UMEC 55 mcg (.6 puffs/day, p=.14) Date f preparatin: August

32 COPD exacerbatins SGRQ Safety On-treatment COPD exacerbatins were reprted in 13% f patients in the placeb grup, 8.4% f patients in the UMEC 55 mcg grup and 7.% f patients in the UMEC/VI 55/22 mcg grup The analysis f time t first COPD exacerbatin indicated that UMEC/VI 55/22 mcg and UMEC 55 mcg resulted in a lwer risk f COPD exacerbatin cmpared with placeb (HR.5, p=.4 fr UMEC/VI 55/22 mcg and HR.6, p=.35 fr UMEC 55 mcg) The analysis f time t first COPD exacerbatin indicated that the risk f COPD exacerbatin was nt statistically significantly different between UMEC/VI 55/22 mcg and UMEC 55 mcg Bth the UMEC/VI and UMEC treatments resulted in an imprvement (i.e. a reductin) in SGRQ scre at Day 168 (UMEC/VI 55/22 mcg 5.51; UMEC 55 mcg 4.69; bth p<.1) Differences in SGRQ scres between UMEC/VI 55/22 mcg and UMEC 55 mcg were nt statistically significant On-treatment AEs were similar acrss treatment grups (46 52%) Treatment-related AEs ccurred in 8%, 6%, 6% and 7% f patients in the UMEC 55 mcg, UMEC/VI 55/22 mcg, VI 22 mcg, and placeb grups, respectively The mst frequent n-treatment AEs were headache (6 9%), naspharyngitis (6 9%), and upper respiratry tract infectins (3 5%) N clinically meaningful changes were bserved in vital signs, 12-lead ECG and 24h Hlter ECG parameters, r clinical labratry tests fr UMEC/VI 55/22 mcg, UMEC 55 mcg and VI 22 mcg, cmpared with placeb Fatal AEs ccurred in nine patients: three in the UMEC 55 mcg grup (COPD/acute respiratry failure, sudden death, chlecystitis and peritnitis); three in the UMEC/VI 55/22 mcg grup (COPD exacerbatin/respiratry failure, mycardial infarctin, unknwn cause); and three in the VI 22 mcg grup (sudden death, COPD exacerbatin, COPD exacerbatin/renal failure) Anr Ellipta is indicated as a maintenance brnchdilatr treatment t relieve symptms in adult patients with COPD and Incruse Ellipta is indicated as a maintenance brnchdilatr treatment t relieve symptms in adult patients with COPD. This study was nt specifically designed t evaluate the effect f treatments n COPD exacerbatins and in rder t minimise the impact f acute wrsening f disease and related treatments n the lung functin assessments, subjects were t be withdrawn if an exacerbatin ccurred. Date f preparatin: August

33 Table 6. Summary f adverse events Placeb (n=28) UMEC 55 mcg (n=418) VI 22 mcg (n=421) UMEC/VI 55/22 mcg (n=413) On-treatment AE, n (%) 13 (46) 216 (52) 24 (48) 212 (51) Treatment-related AE, n (%) 19 (7) 34 (8) 26 (6) 25 (6) AEs leading t permanent discntinuatin f study drug r withdrawal frm study, a n (%) 9 (3) 34 (8) 24 (6) 23 (6) On-treatment SAE, n (%) 9 (3) 27 (6) 24 (6) 21 (5) Fatal SAE, b n (%) 3 (<1) 3 (<1) 3 (<1) Mst frequent n-treatment AEs ccurring in 5% in any grup, n (%) Headache Naspharyngitis URTI AEs f special interest, n (%) Cardivascular Acquired lng QT Cardiac arrhythmias Cardiac failure Cardiac ischaemia Hypertensin Sudden death Strke Effects n glucse Effects n ptassium Tremr Urinary retentin Ocular effects Gallbladder disrders Pneumnia Intestinal bstructin Antichlinergic syndrme 26 (9) 16 (6) 14 (5) 26 (9) 12 (4) 5 (2) 3 (1) 6 (2) 2 (<1) 1 (<1) 1 (<1) 1 (<1) 2 (<1) 1 (<1) 2 (<1) 8 (3) 32 (8) 29 (7) 21 (5) 41 (1) 1 (<1) 2 (5) 7 (2) 7 (2) 12 (3) 1 (<1) 7 (2) 3 (<1) 3 (<1) 3 (<1) 6 (1) 18 (4) 25 (6) 26 (6) 18 (4) 31 (7) 18 (4) 3 (<1) 3 (<1) 7 (2) 1 (<1) 2 (<1) 7 (2) 2 (<1) 2 (<1) 4 (<1) 14 (3) 35 (8) 39 (9) 13 (3) 33 (8) 18 (2) 3 (<1) 7 (2) 15 (4) 6 (1) 4 (<1) 8 (2) 1 (<1) 1 (2) a Includes bth n-treatment and pst-treatment AEs; b Fatal AEs ccurred in nine patients: three in the VI 22 mcg grup (sudden death, COPD exacerbatin, COPD exacerbatin/renal failure), three in the UMEC/VI 55/22 mcg grup (COPD exacerbatin/respiratry failure, mycardial infarctin, unknwn cause) and three in the UMEC 55 mcg grup (COPD/acute respiratry failure, sudden death, chlecystitis and peritnitis). AE = adverse event; OD = nce daily; SAE = serius adverse event; UMEC = umeclidinium; UMEC/VI = umeclidinium/vilanterl; URTI = upper respiratry tract infectin; VI = vilanterl Date f preparatin: August

34 Dnhue et al., 214 (safety study) Safety and tlerability f nce-daily umeclidinium/vilanterl 125/25 mcg and umeclidinium 125 mcg in patients with chrnic bstructive pulmnary disease: results frm a 52-week, randmised, duble-blind, placeb-cntrlled study 11 This safety study was dne with unlicensed dses but has been included in the Evidence Dssier fr safety transparency purpses. UMEC/VI 113/22 mcg and UMEC 113 mcg were well tlerated ver 12 mnths f treatment in patients with COPD Study design A Phase III, randmised, multicentre, duble-blind, placeb-cntrlled, parallel-grup, 52-week study t assess the safety and tlerability f UMEC/VI 113/22 mcg OD and UMEC 113 mcg OD in patients with COPD. UMEC 113 mcg and UMEC/VI 113/22 mcg are nt licensed in the UK COPD = chrnic bstructive pulmnary disease; FEV1 = frced expiratry vlume in 1 secnd; FVC = frced vital capacity; OD = nce daily; R = randmisatin; UMEC = umeclidinium; UMEC/VI = umeclidinium/vilanterl; VI = vilanterl Patients wh experienced a COPD exacerbatin r lwer respiratry tract infectin (LRTI) during the run-in perid r at Visit 2 were allwed t re-screen and repeat the run-in perid All treatments were administered in the mrning via the Ellipta dry pwder inhaler Rescue medicatins permitted thrughut the run-in and treatment perids included salbutaml and/r ipratrpium brmide, administered via metered dse inhaler r nebules Patient ppulatin Current r frmer smkers with a smking histry f 1 pack-years 4 years f age Clinical histry f COPD Pst-salbutaml FEV1/FVC rati <.7 Pst-salbutaml FEV1 35% and 8% f predicted values Endpints Incidence f AEs, SAEs, drug-related AEs and AEs f special interest thrughut the curse f the study Clinical labratry assessments and vital sign evaluatins 12-lead ECG and 24h Hlter ECG assessment Date f preparatin: August

35 Trugh FEV1 and trugh FVC mean change (ml) frm baseline COPD exacerbatins (incidence and time t first COPD exacerbatin) and rescue medicatin use All endpints were assessed in the ITT ppulatin Baseline demgraphics and clinical characteristics UMEC 113 mg UMEC/VI 113/22 mg Placeb Characteristic (n=227) (n=226) (n=19) Mean age, years ± SD 61.7 ± ± ± 8.3 Female gender, n (%) 82 (36) 7 (31) 36 (33) Smking pack-years, mean ± SD 39.2 ± ± ± 24.7 Current medical cnditin, n (%) 196 (86) 19 (84) 88 (81) Pre-brnchdilatr FEV1 (L), mean ± SD ±.5 n= ±.5 n= ±.6 n=18 Pst-salbutaml % predicted FEV1 (ml), mean ± SD 54.2 ± 11.8 n= ± 12.1 n= ± 11.7 n=19 FEV 1 = frced expiratry vlume in 1 secnd; SD = standard deviatin; UMEC = umeclidinium; UMEC/VI = umeclidinium/vilanterl Results Incidence f AEs, serius AEs, drug-related AEs and AEs f special interest thrughut the curse f the study The incidence f n-treatment AEs, SAEs and drug-related AEs was similar acrss treatment grups and placeb (AEs: 52 58%; SAEs: 6 7%; drug-related AEs: 12 13%) Headache (8 11%), naspharyngitis (5 9%) and ventricular extrasystles (5% in each treatment grup) were the mst frequently reprted AEs Patients in the UMEC 113 mcg grup reprted 2% higher incidences f headache and naspharyngitis cmpared with placeb. Patients in the UMEC/VI 113/22 mcg grup reprted similar ( 1% difference) r fewer incidences f the mst cmmn AEs when cmpared with placeb The incidence f AEs resulting in permanent discntinuatin r withdrawal was less in the UMEC 113 mcg grup and the UMEC/VI 113/22 mcg grup cmpared with placeb (9% and 8% f patients respectively, cmpared with 12% fr placeb) The nly n-treatment SAEs reprted by 1% f patients in any treatment grup were COPD and pneumnia (all incidences 3%) The incidence f predefined AEs f special interest (pneumnia and glucse effect) and further special interest grups was lw and generally similar acrss treatment grups, with n individual n-treatment AE reprted by >5% f patients In the pneumnia special interest grup, a higher verall incidence f AEs was reprted with UMEC 113 mcg (5%) cmpared with UMEC/VI 113/22 mcg r placeb (bth 2%) In the glucse effect special interest grup, a higher verall incidence f AEs was reprted with UMEC/VI 113/22 mcg (4%) cmpared with UMEC 113 mcg (<1%) r placeb (%) In the cardivascular special interest grup, a lwer verall incidence f AEs was reprted with UMEC 113/22 mcg (15%) cmpared with the UMEC 113 mcg grup (22%) r placeb (23%) Date f preparatin: August

36 Table 7: Summary f AEs UMEC 113 mg (n=227) UMEC/VI 113/22 mg (n=226) Placeb (n=19) On-treatment AE, n (%) 132 (58) 12 (53) 57 (52) On-treatment SAE, n (%) 17 (7) 14 (6) 7 (6) On-treatment deaths, a n (%) Nne were cnsidered related t the study treatment 4 (2) 1 (<1) Mst cmmn AEs reprted by 4% patients, n (%) Headache Naspharyngitis Ventricular extrasystles Extrasystles Back pain Hypertensin Sinusitis Influenza Upper respiratry tract infectin Ventricular tachycardia Mst cmmn SAEs reprted by 1% patients, n (%) COPD Pneumnia AESI reprted by 2% patients, n (%) Cardivascular Pneumnia Antichlinergic syndrme Effects n glucse Prprtin f patients with ne r mre abnrmal, clinically significant ECG interpretatin 25 (11) 2 (9) 12 (5) 1 (4) 9 (4) 4 (2) 6 (3) 5 (2) 8 (4) 3 (1) 4 (2) 34 (15) 5 (2) 5 (2) 8 (4) 2 (9) 11 (5) 11 (5) 1 (4) 1 (4) 8 (4) 8 (4) 6 (3) 2 (<1) 4 (2) 2 (<1) 3 (1) 49 (22) 11 (5) 5 (2) 1 (<1) 9 (8) 5 (5) 5 (5) 4 (4) 3 (3) 5 (5) 3 (3) 5 (5) 3 (3) 4 (4) 3 (3) 25 (23) 2 (2) 2 (2) At any time pst baseline 26% 24% 23% Prprtin f patients with ne r mre abnrmal, clinically significant 24-hur Hlter ECG interpretatin At any time pst baseline 55% 55% 52% COPD exacerbatins, b n (%) Prprtin f patients reprting Prprtin resulting in hspitalisatin 15% 7% 13% 6% 24% 12% HR vs placeb (time t first.4; 95% CI:.3,.8;.6; 95% CI:.3, 1.; exacerbatin) RR = 6% RR = 4% - a On-treatment deaths ccurred in five patients: fur patients in the UMEC 113 mcg grup (spine metastases; liver metastases; pneumnia; cardiac failure) and ne patient in the placeb grup (crnary artery insufficiency). Nne were cnsidered related t the study treatment. b Anr Ellipta is indicated as a maintenance brnchdilatr treatment t relieve symptms in adult patients with COPD and Incruse Ellipta is indicated as a maintenance brnchdilatr treatment t relieve symptms in adult patients with COPD AE = adverse event; AESI = adverse event f special interest; ECG = electrcardigram; SAE = serius adverse event; UMEC = umeclidinium; UMEC/VI = umeclidinium/vilanterl Date f preparatin: August

37 Clinical labratry assessments and vital sign evaluatins Clinical labratry assessments and vital sign evaluatins shwed n clinically significant change frm baseline r treatment-related effect in any parameter acrss treatments 12-lead ECG and 24h Hlter ECG assessment A similar prprtin f patients measured n 12-lead ECG at any time pst-baseline reprted ne r mre abnrmal clinically significant interpretatin acrss treatment grups (23 26%) A similar prprtin f patients with ne r mre abnrmal, clinically significant Hlter ECG interpretatin at any-time pst-baseline was reprted acrss treatment grups (52 55%) COPD exacerbatins (incidence and time t first COPD exacerbatin) COPD exacerbatins were reprted less frequently with UMEC 113 mcg (15%) and UMEC/VI 113/22 mcg (13%) cmpared with placeb (24%). COPD exacerbatins resulting in hspitalisatin were als fewer with UMEC 113 mcg (7%) and UMEC/VI 113/22 mcg (6%) cmpared with placeb (12%). UMEC 113 mcg and UMEC/VI 113/22 mcg were assciated with a lwer risk f COPD exacerbatin cmpared with placeb, based n analysis f time t first exacerbatin (hazard rati [HR] =.4, 95% CI.3,.8; risk reductin 6%; HR =.6, 95% CI.3, 1., risk reductin 4%, respectively) Anr Ellipta is indicated as a maintenance brnchdilatr treatment t relieve symptms in adult patients with COPD Date f preparatin: August

38 Feldman et al., 212 (safety study) Safety and tlerability, pharmacdynamics (PD) and pharmackinetics (PK) f umeclidinium/vilanterl in patients with mderate t very severe COPD 12 This safety study was dne with unlicensed dses but has been included in the Evidence Dssier fr safety transparency purpses. Once-daily dsing with UMEC 5 mcg in cmbinatin with VI 25 mcg in patients with mderate t very severe COPD was well tlerated ver 28 days Study design A multicentre, duble-blind, placeb-cntrlled, parallel grup study f UMEC/VI 5/25 mcg ** in patients with mderate t very severe COPD. UMEC/VI 5/25 mcg is nt licensed in the UK COPD = chrnic bstructive pulmnary disease; FEV 1 = frced expiratry vlume in 1 secnd; FVC = frced vital capacity; OD = nce daily; R = randmisatin; UMEC/VI = umeclidinium/vilanterl; wm = weighted mean Patient ppulatin 4 years f age Clinical histry f COPD Smking histry f 1 pack-years Pst-salbutaml FEV1/FVC rati <.7 Pst-salbutaml FEV1 8% f predicted values Endpints Primary endpint Change frm baseline in wm pulse rate during 6h pst-dse n Day 28 Secndary and ther endpints wm pulse rate during 6h pst-dse n Days 1 and 14 Maximum and minimum pulse rate during 6h pst-dse n Days 1, 14 and 28 wm systlic and diastlic bld pressure 6h pst-dse n Days 1, 14 and 28 ** UMEC/VI 5/25 mcg is nt licensed in the UK Date f preparatin: August

39 Maximum systlic and minimum diastlic bld pressure n Days 1, 14 and 28 24h Hlter ECG parameters at screening and Day 28 Maximum QTc with interval crrected by Fridericia s methd (QTcF) (during 6h pst-dse) n Days 1, 14, and 28 (measured using 12-lead ECG) Changes in haematlgical and clinical chemistry parameters frm baseline n Days 14 and 29 Incidence f AEs and SAEs thrughut the 28-day treatment perid and fllw-up Incidence f COPD exacerbatins Plasma cncentratins and derived PK (maximum plasma cncentratin (Cmax), time t maximum plasma cncentratin (tmax), area under the curve (AUC) fr UMEC and VI parameters) Demgraphics and baseline characteristics UMEC/VI 5/25 mcg (n=42) Placeb (n=9) Age (years), mean ± SD 59.2 ± ± 9.8 Female gender, n (%) 18 (43) 2 (22) Smking pack-years, mean ± SD 58.4 ± ± 44.7 Pre-brnchdilatr FEV1 (L), mean ± SD ± ±.46 Pst-brnchdilatr % predicted FEV1 (ml), mean ± SD 48.4 ± ± 15.6 FEV 1 = frced expiratry vlume in 1 secnd; FVC = frced vital capacity; SD = standard deviatin; UMEC/VI = umeclidinium/vilanterl Results Primary endpint Change frm baseline in wm pulse rate during 6h pst-dse n Day 28 UMEC/VI 5/25 mcg was nn-inferir t placeb in wm pulse rate ver 6h at Day 28 (difference f.5 bpm; 95% CI 5.5, 4.5) Secndary and ther endpints wm pulse rate during 6h pst-dse n Days 1 and 14 On Day 1 the adjusted mean changes frm baseline in wm pulse rate ( 6h) were similar fr UMEC/VI 5/25 mcg (.6 bpm) and placeb ( 1.2 bpm) On Day 14 the adjusted change frm baseline fr UMEC/VI 5/25 mcg was 3.1 bpm and fr placeb was 1.7 bpm The adjusted mean treatment differences between UMEC/VI 5/25 mcg, and placeb fr wm pulse rate ( 6h) was.6 bpm (95% CI 3.9, 5.2) n Day 1 and 4.8 bpm (95% CI 1.2, 1.9) n Day 14 Maximum and minimum pulse rate during 6h pst-dse n Days 1, 14 and 28 The adjusted mean treatment differences between UMEC/VI 5/25 mcg and placeb during 6h maximum pulse rate were 2. bpm (95% CI 3.7, 7.6) n Day 1; 4.8 bpm (95% CI 1.8, 11.3) n Day 14, and 1.3 bpm (95% CI 6.9, 4.3) n Day 28 The adjusted mean treatment differences between UMEC/VI 5/25 mcg, and placeb fr 6h minimum pulse rate were.3 bpm (95% CI 4.3, 5.) n Day 1; 4. bpm (95% CI 2.3, 1.2) n Day 14, and 1.7 bpm (95% CI 3.6, 7.1) n Day 28 wm systlic and diastlic bld pressure 6h pst-dse n Days 1, 14 and 28 The adjusted mean changes in 6h weighted mean systlic/diastlic bld pressure frm baseline n Days 1, 14, and 28 were 13.8/79.2 mmhg, 131./79.3 mmhg and 134.6/81.3 mmhg fr placeb and 134./8.1 mmhg, 131.1/78.7 mmhg and 13.9/77.8 mmhg fr UMEC/VI 5/25 mcg, respectively Maximum systlic and minimum diastlic bld pressure n Days 1, 14 and 28 Date f preparatin: August

40 The adjusted mean changes in maximum systlic bld pressure frm baseline n Days 1, 14, and 28 fr placeb and UMEC/VI 5/25 mcg were and mmhg, and mmhg and and 14.6 mmhg, respectively The adjusted mean changes in minimum diastlic bld pressure frm baseline n Days 1, 14, and 28 fr placeb and UMEC/VI 5/25 mcg were 73.7 and 73.7 mmhg, 73.2 and 71.4 mmhg and 75.7 and 7.6 mmhg, respectively 24h Hlter ECG parameters at screening and Day 28 86% f patients n UMEC/VI and 89% f patients n placeb had n change r insignificant changes, and 11% f patients in each grup had clinically significant unfavurable changes The prprtin f patients wh had a clinically significant unfavurable change frm baseline in the 12- lead ECG at any time pst-baseline was similar between UMEC/VI 5/25 mcg (29%) and placeb (22%) Maximum QTc with interval crrected by Fridericia s methd (QTcF) (during 6h pst-dse) n Days 1, 14, and 28 (measured using 12-lead ECG) Analysis f change frm baseline in 6h maximum QTcF shwed n evidence f a difference between UMEC/VI 5/25 mcg cmpared with placeb: Day 1, 3. ms (95% CI 5.2, 11.2); Day 14, 1.4 ms (95% CI 9.9, 2.8); Day 28, 2.6 ms (95% CI 8.9, 14.2) Changes in haematlgical and clinical chemistry parameters frm baseline n Days 14 and 29 There were n clinically relevant treatment changes in haematlgy, clinical chemistry r urinalysis assessments Incidence f AEs and SAEs thrughut the 28-day treatment perid and fllw-up On-treatment AEs were higher with UMEC/VI than with placeb (26% vs 11%) N deaths r SAEs were reprted Table 8. Adverse events reprted by at least ne patient Placeb UMEC/VI 5/25 mcg On-treatment AE, n (%) 1 (11) 11 (26) Sinusitis 1 (11) 1 (2) Gastrenteritis 1 (2) Upper abdminal pain 1 (2) Dry muth 1 (2) Nausea 1 (2) Swllen tngue 1 (2) Cugh 1 (2) Dyspnea 1 (2) Pleurisy 1 (2) Allergic rhinitis 1 (2) Gut 1 (2) Hypkalemia 1 (2) Abnrmal dreams 1 (2) Anxiety 1 (2) Chlelithiasis 1 (2) Muscle strain 1 (2) Rash 1 (2) AE = adverse event; UMEC/VI = umeclidinium/vilanterl Date f preparatin: August 218 4

41 Incidence f COPD exacerbatins Three patients (UMEC/VI 5/25 mcg) had a COPD exacerbatin; the primary causes reprted by the investigatr were lack f efficacy (treatment) (n=2) and upper respiratry infectin ther than the cmmn cld (n=1) Plasma cncentratins and derived PK (maximum plasma cncentratin (Cmax), time t maximum plasma cncentratin (tmax), area under the curve (AUC) fr UMEC and VI parameters) Fllwing single and repeat dsing f UMEC in cmbinatin with VI, bth UMEC and VI were rapidly absrbed (median tmax ~6 min fr bth drugs) with a higher Cmax n Day 14 cmpared with Day 1 The bserved mean accumulatin f Cmax fr Day 14 vs. Day 1 was 38% (9% CI 6, 8) fr UMEC and 31% (9% CI 5, 63) fr VI. N further accumulatin was seen n Day 28 There were n differences in AUC fr either drug n Day 1, 14 and 28, with ratis ranging between.8 and.9 fr bth cmparisns (Day 14/Day 1 and Day 28/Day1). PK data n bth days shwed high variability with a large percent cefficient f variance Evaluatin f individual steady-state Cmax and change frm baseline in pulse rate n Day 28 shwed n bvius trends fr either UMEC r VI, and the changes frm baseline were similar t that bserved with placeb Anr Ellipta is indicated as a maintenance brnchdilatr treatment t relieve symptms in adult patients with COPD Date f preparatin: August

42 Van der Palen et al., 216 (critical errrs) A randmised pen-label crss-ver study f inhaler errrs, preference and time t achieve crrect inhaler use in patients with COPD r asthma: cmparisn f Ellipta with ther cmmnly used inhaler devices 13 The Ellipta inhaler is easy t use and significantly fewer patients made critical errrs cmpared with ther cmmnly used devices after reading the patient infrmatin leaflet Study design A randmised, multicentre, single visit, pen-label, crss ver study cmparing the Ellipta inhaler device against ther devices in patients with asthma and patients with COPD. The results belw fcus nly n COPD studies; asthma results are nt presented here. COPD = chrnic bstructive pulmnary disease; MDI = metered-dse inhaler; R = randmisatin Patients entering the study were naïve t Ellipta and at least ne ther device Each substudy was individually pwered Critical errrs were assessed by trained respiratry nurses after patients had read the patient infrmatin leaflet (PIL). A critical errr is defined as an errr that is likely t result in the inhalatin f significantly reduced, minimal r n medicatin If the patient made errrs, the investigatr demnstrated the crrect use f the inhaler, and the patient demnstrated inhaler use again Patient ppulatin 18 years with a physician diagnsis f COPD and currently receiving treatment fr COPD Naïve t Ellipta inhaler use Endpints Primary endpint Critical errrs using the devices after reading the PIL nly Secndary endpints Overall errrs using the devices after reading the PIL nly Instructin frm trained respiratry nurse n use f the devices Time t crrect inhaler use Ease f use f the devices Patient preference fr devices Date f preparatin: August

43 Demgraphics and baseline characteristics Characteristic Ttal (N=567) Ellipta vs Accuhaler (n=171) Ellipta vs MDI (n=8) Ellipta vs Turbhaler (n=1) Ellipta vs HandiHaler (n=118) Ellipta vs Breezhaler (n=98) Mean age, years ± SD 67.3 ± ± ± ± ± ± 8.2 Female gender, n (%) 225 (4) 68 (4) 27 (34) 33 (33) 46 (39) 51 (52) COPD histry, n (%) 6 mnths 1 years 1 25 years 25 years 422 (74) 123 (22) 22 (4) 135 (79) 29 (17) 7 (4) 59 (74) 18 (22) 3 (4) COPD = chrnic bstructive pulmnary disease; MDI = metered-dse inhaler Results Primary endpint Critical errrs using the devices after reading the PIL nly 62 (62) 32 (32) 6 (6) 92 (78) 23 (19) After reading the PIL, the prprtin f patients with COPD wh made at least ne critical errr was significantly lwer with the Ellipta device cmpared with all thers (all p<.1) 3 (3) 74 (76) 21 (21) Fr the Ellipta inhaler, the mst cmmn critical errr was exhaling directly int the muthpiece (31/567 [5%] patients with COPD) Fr the Accuhaler device, the lever was nt pushed back prperly by 33% f patients with COPD (56/171) Fr the MDI device, pr press-and-breathe crdinatin was bserved in 43% (34/8) f patients with COPD Fr the Turbhaler device, 29% (29/1) patients with COPD did nt twist the base prperly and hear the click Fr bth the HandiHaler and the Breezhaler, the capsule did nt rattle with 36% (42/118) and 43% (42/98) f patients with COPD, respectively Figure 7: Percentage f patients with COPD with at least ne critical errr after reading the PIL 3 (3) Adapted frm van der Palen et al., 216 MDI = metered-dse inhaler; PIL = patient infrmatin leaflet Date f preparatin: August