Evidence Dossier to support COPD formulary decision making ......UMEC 113 mcg, VI 22 mcg, UMEC/VI 500/25 mcg and UMEC/VI 113/22 mcg, included in the Donohue et al., 2014 study, Decramer

Prescribing and adverse event reporting information can be found on the final pages of this document. Anoro and Ellipta Trademarks are owned by or licensed to the GSK Group of Companies. ©2017 GSK Group of Companies or its licensor.

UK/UCV/0047/17(1) Date of preparation: August 2018

Evidence Dossier to support COPD formulary decision making

and guideline development

UK/UCV/0047/17(1) Date of preparation: August 2018 2

Table of Contents

Clinical study information ..................................................................................................................................................... 4 Dosing information .................................................................................................................................................... 4 Licensing information ................................................................................................................................................ 4 Interpreting clinical trial results – statistical hierarchy ............................................................................................ 4

Feldman et al., 2017 (active-comparator study) ............................................................................................................ 5 Study design ............................................................................................................................................................... 5 Patient population ..................................................................................................................................................... 5 Endpoints ................................................................................................................................................................... 5 Results ........................................................................................................................................................................ 6 Safety .......................................................................................................................................................................... 8

Maleki-Yazdi et al., 2017 (active-comparator study) ................................................................................................... 10 Study design ............................................................................................................................................................. 10 Patient population ................................................................................................................................................... 10 Endpoints ................................................................................................................................................................. 10 Results ...................................................................................................................................................................... 12 Safety and tolerability.............................................................................................................................................. 13

Kerwin et al., 2017 (active-comparator study) ............................................................................................................ 14 Study design ............................................................................................................................................................. 14 Patient population ................................................................................................................................................... 14 Endpoints ................................................................................................................................................................. 14 Results ...................................................................................................................................................................... 15 Safety ........................................................................................................................................................................ 16

Decramer et al., 2014 (active-comparator study)........................................................................................................ 17 Study design ............................................................................................................................................................. 17 Patient population ................................................................................................................................................... 17 Endpoints ................................................................................................................................................................. 18 Results ...................................................................................................................................................................... 19 Safety ........................................................................................................................................................................ 21

Kalberg et al., 2016 (active-comparator study) ........................................................................................................... 23 Study design ............................................................................................................................................................. 23 Patient population ................................................................................................................................................... 23 Endpoints ................................................................................................................................................................. 24 Results ...................................................................................................................................................................... 25

Donohue et al., 2013 (placebo-controlled study) ........................................................................................................ 28 Study design ............................................................................................................................................................. 28 Patient population ................................................................................................................................................... 28 Endpoints ................................................................................................................................................................. 28 Results ...................................................................................................................................................................... 29 Safety ........................................................................................................................................................................ 32

Donohue et al., 2014 (safety study) ............................................................................................................................. 34 Study design ............................................................................................................................................................. 34 Patient population ................................................................................................................................................... 34 Endpoints ................................................................................................................................................................. 34 Results ...................................................................................................................................................................... 35


Feldman et al., 2012 (safety study) .............................................................................................................................. 38 Study design ............................................................................................................................................................. 38 Patient population ................................................................................................................................................... 38 Endpoints ................................................................................................................................................................. 38 Results ...................................................................................................................................................................... 39

Van der Palen et al., 2016 (critical errors) .................................................................................................................... 42 Study design ............................................................................................................................................................. 42 Patient population ................................................................................................................................................... 42 Endpoints ................................................................................................................................................................. 42 Results ...................................................................................................................................................................... 43

References ........................................................................................................................................................................... 46 How to request additional information from GSK ....................................................................................................... 46

Anoro▼Ellipta (umeclidinium/vilanterol) Prescribing Information ................................................................................. 47

Incruse▼Ellipta (umeclidinium) Prescribing Information ................................................................................................. 48


Clinical study information

The efficacy and safety of Incruse Ellipta (umeclidinium 55 mcg) is also discussed in this Evidence Dossier. Incruse Ellipta is indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD.2

UMEC 113 mcg, VI 22 mcg, UMEC/VI 500/25 mcg and UMEC/VI 113/22 mcg, included in the Donohue et al., 2014 study, Decramer et al., 2014 study and Feldman et al., 2012 study, are not licensed for the treatment of COPD in the UK. The results have not been included in the efficacy section but have been included in the safety section for transparency purposes. Safety studies with an un-licensed dose have also been included for transparency.

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 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’.

Dosing information

Each single inhalation of Anoro Ellipta provides a delivered dose (the dose leaving the mouthpiece) of 65 mcg umeclidinium bromide equivalent to 55 mcg umeclidinium and 22 mcg vilanterol (as trifenatate). This corresponds to a pre-dispensed dose of 74.2 mcg umeclidinium bromide equivalent to 62.5 mcg umeclidinium and 25 mcg vilanterol (as trifenatate).1 Please note that the licensed dose of umeclidinium/vilanterol (UMEC/VI) is 55/22 mcg.1

Licensing information

Anoro Ellipta (umeclidinium/vilanterol 55/22 mcg) is indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD).1


Feldman et al., 2017 (active-comparator study)

Comparative Efficacy of Once-Daily Umeclidinium/Vilanterol and Tiotropium/Olodaterol Therapy in Symptomatic Chronic Obstructive Pulmonary Disease: A Randomized Study3

Anoro Ellipta (UMEC/VI 55/22 mcg OD) demonstrated non-inferiority and superiority in lung function improvement compared with Spiolto Respimat (TIO/OLO 5/5 mcg OD)

Study design

A randomised, two-period, 8-week, open-label, crossover study comparing UMEC/VI 55/22 mcg OD with TIO/OLO 5/5 mcg OD in patients with COPD (n=236).

* TIO/OLO was delivered once daily via two puffs of 2.5 mcg/2.5 mcgCOPD = chronic obstructive pulmonary disease; FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity;mMRC = modified Medical Research Council; OD = once daily; R = randomisation; TIO/OLO = tiotropium/olodaterol;UMEC/VI = umeclidinium/vilanterol

Patient population

• ≥40 years with a diagnosis of COPD (American Thoracic Society & European Respiratory Society definition)

• Smoking history ≥10 pack-years

• Post-bronchodilator FEV1/FVC ratio <0.70

• Post-bronchodilator FEV1 ≤70% to ≥50%

• mMRC dyspnoea score ≥2

• Not receiving ICS-containing therapy at study inclusion

Endpoints

Primary endpoint (PP population)

• Change from baseline in trough FEV1 at Week 8

o The margin of non-inferiority for the primary endpoint was set at –50 mL. If non-inferiority of UMEC/VI toTIO/OLO was demonstrated, statistical superiority was then investigated; UMEC/VI would be consideredsuperior to that of TIO/OLO if the lower boundary of the estimated treatment difference 95% CI wasgreater than 0 mL

Secondary endpoints (ITT population)

• Trough FEV1 superiority assessment at Weeks 4 and 8


• Percentage of FEV1 responders (≥100 mL change from baseline) at Weeks 4 and 8

• Trough FVC and inspiratory capacity (IC) at Weeks 4 and 8

• CAT score and percentage responders (patients with a reduction of ≥2 units from baseline CAT score) at Weeks 4and 8

• Rescue medication use and percentage rescue-free days (Weeks 1–8)

• Weekly mean E-RSCOPD symptom score and weekly percentage of responders (patients achieving a reduction frombaseline E-RS score of ≥2 units)

• Inhaler ease of use

Safety and tolerability

• Incidence of AEs and SAEs

• Incidence of COPD exacerbations

Demographics and baseline characteristics (ITT population)

Characteristic Total

(N=236)

Mean age, years ± SD 64.4 ± 8.5

Female gender, n (%) 94 (40)

Current smoker, n (%) 125 (53)

Smoking pack-year history, mean ± SD 50.2 ± 25.5

Post-bronchodilator FEV1 (L), % predicted, mean ± SD 59.6 ± 5.6

COPD exacerbation history, n (%) Requiring OCS/antibiotics ≥1 Requiring OCS/antibiotics ≥2 Requiring hospitalisation ≥1

33 (14) 4 (2) 6 (3)

COPD = chronic obstructive pulmonary disease; FEV1 = forced expiratory volume in 1 second; ITT = intention-to-treat; OCS = oral corticosteroid; SD = standard deviation

Results

Primary endpoint

• Change from baseline in trough FEV1 at Week 8

o LS mean change from baseline was significantly greater in the UMEC/VI 55/22 mcg group (175 mL)compared with the TIO/OLO 5/5 mcg group (122 mL)

o The difference of 53 mL (95% CI, 26, 80; p<0.001) exceeded the non-inferiority margin of –50 mL,demonstrating non-inferiority compared with TIO/OLO 5/5 mcg


Figure 1: Trough FEV1 at Week 8

Adapted from Feldman et al. 2017

CI = confidence interval; FEV1 = forced expiratory volume in 1 second; ITT = intention-to-treat; LS = least squares; PP = per-protocol; TIO/OLO = tiotropium/olodaterol; UMEC/VI = umeclidinium/vilanterol

Secondary endpoints

• Trough FEV1 superiority assessment at Weeks 4 and 8

o The UMEC/VI 55/22 mcg group showed significantly improved trough FEV1 improvement from baseline atWeeks 4 (difference: 48 mL; 95% CI 25, 71; p<0.001) and 8 (difference: 52 mL; 95% CI 28, 77; p<0.001)compared with the TIO/OLO 5/5 mcg group

• Percentage of FEV1 responders (≥100 mL change from baseline) at Weeks 4 and 8

o The percentage of trough FEV1 responders in each treatment group 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%

o The likelihood of achieving trough FEV1 response was significantly higher in the UMEC/VI 55/22 mcg groupcompared with the TIO/OLO 5/5 mcg group at both Week 4 (OR 2.09; 95% CI 1.39, 3.14; p<0.001) and 8(OR 2.05; 95% CI 1.34, 3.14; p<0.001)

• Trough FVC and IC at Weeks 4 and 8

o Improvement in trough FVC was significantly greater with UMEC/VI 55/22 mcg:

▪ Week 4: UMEC/VI 55/22 mcg vs TIO/OLO 5/5 mcg difference: 40 mL; 95% CI 5, 75; p<0.05


o Improvement in IC was significantly greater with UMEC/VI 55/22 mcg:



• CAT score and percentage responders (patients with a reduction of ≥2 units from baseline CAT score) at Weeks 4and 8

o Significant improvements in CAT score with UMEC/VI 55/22 mcg compared with TIO/OLO 5/5 mcg wereseen at Week 4 but not at Week 8:

▪ Week 4 difference: –0.59; 95% CI –1.16, –0.02; p<0.05

▪ Week 8 difference: –0.11; 95% CI –0.68, 0.45


o A similar percentage of patients in the UMEC/VI 55/22 mcg group were CAT responders at Weeks 4 and 8:

▪ Week 4: OR 1.25; 95% CI 0.85, 1.82

▪ Week 8: OR 1.05; 95% CI 0.72, 1.55

• Rescue medication use and percentage rescue-free days (Weeks 1–8)

o Patients in the UMEC/VI 55/22 mcg group used fewer puffs/day of rescue medication compared with theTIO/OLO 5/5 mcg group (difference: –0.25 puffs; 95% CI –0.37, –0.41; p<0.001)

o Patients in the UMEC/VI 55/22 mcg group and TIO/OLO 5/5 mcg group had a similar number of rescue-free days over Weeks 1–8 (difference: 1.91; 95% CI –0.71, 4.53)

• Weekly mean E-RSCOPD symptom score and weekly percentage of responders (patients achieving a reduction frombaseline E-RS score of ≥2 units)

o The change from baseline in weekly E-RS total scores ranged from –1.79 to –1.61 in the UMEC/VI 55/22mcg group and from –1.72 to –1.31 in the TIO/OLO 5/5 mcg group during the 8 weeks, with a statisticallysignificant difference in favour of UMEC/VI 55/22 mcg observed at Week 5 (p = 0.031)

o The proportion of patients showing a clinically important treatment response for the E-RS total scorevaried by individual week from 33% to 41% with the UMEC/VI 55/22 mcg group and from 31 to 34% withthe TIO/OLO 5/5 mcg group. The OR for achieving a treatment response with the UMEC/VI 55/22 mcggroup compared with the TIO/OLO 5/5 mcg group varied from 0.97 to 1.43, with no statistically significantdifferences

• Inhaler ease of use (inhaler-naïve population; n=75)

o 96% of patients rated ELLIPTA as ‘very easy’ or ‘easy’ to use and 83% of patients rated Respimat as ‘veryeasy’ or ‘easy’ to use

o Significantly more patients rated Ellipta higher than Respimat on overall ease of use (40% vs 11%;p=0.001), ease of telling the number of doses remaining (53% vs 1%; p<0.001); ease of learning to use(43% vs 4%; p<0.001); ease of handling (40% vs 4%; p<0.001); ease of preparation (49% vs 3%; p<0.001);and ease of holding while using (32% vs 4%; p<0.001)

Safety

• On-treatment AEs were similar across treatment groups (UMEC/VI 55/22 mcg 25% and TIO/OLO 5/5 mcg 31%)

• The most commonly occurring AEs in both treatment groups were viral upper respiratory tract infections (UMEC/VI55/22 mcg: 5% and TIO/OLO 5/5 mcg: 6%) and upper respiratory tract infections (UMEC/VI 55/22 mcg: 3% andTIO/OLO 5/5 mcg: 3%)


Table 1. Summary of on-treatment adverse events

UMEC/VI 55/22 mcg (n=235)

TIO/OLO 5/5 mcg (n=230)

Any AE, n (%) 59 (25) 71 (31)

AEs in ≥3% of patients, n (%)

Viral upper respiratory tract infection Upper respiratory tract infection

11 (5) 8 (3)

14 (6) 7 (3)

Any AE leading to permanent study treatment discontinuation or withdrawal from study, n (%)

1 (<1) 0

Any non-fatal SAE, n (%) 3 (1) 2 (<1)

Any fatal SAE, n (%) 0 0

COPD exacerbations, n (%) 0

1

2

217 (92)

15 (6)

3 (1)

211 (92)

18 (8)

1 (<1)

AEs of special interest, n (%) Cardiovascular

Cardiac arrhythmia

Cardiac failure

Cardiac ischaemia Hypertension

Stroke

Pneumonia LRTI excluding pneumonia

Ocular effects (antimuscarinic)

Paradoxical bronchospasm

Asthma/bronchospasm Urinary retention

4 (2)

1 (<1)

0

0 3 (1)

0

0 1 (<1)

0

0

0 0

4 (2)

0

1 (<1)

1 (<1) 2 (<1)

0

1 (<1) 3 (1)

2 (<1)

0

0 0

AEs with onset during the follow-up period are considered on-treatment and have been assigned to the treatment previously received AE = adverse event; COPD = chronic obstructive pulmonary disease; LRTI = lower respiratory tract infection; SAE = serious adverse event; TIO/OLO = tiotropium/olodaterol; UMEC/VI = umeclidinium/vilanterol


Maleki-Yazdi et al., 2017 (active-comparator study)

Assessing Short-term Deterioration in Maintenance-naïve Patients with COPD Receiving Umeclidinium/Vilanterol and Tiotropium: A Pooled Analysis of Three Randomized Trials4

Early use of Anoro Ellipta as a maintenance bronchodilator has superior efficacy on lung function and may reduce the risk of short-term deterioration compared to tiotropium HandiHaler monotherapy in patients with symptomatic COPD

Study design

A post-hoc pooled analysis investigating the efficacy and safety of UMEC/VI 55/22 mcg OD compared with TIO 10 mcg OD in a maintenance-naïve (MN) subgroup of patients relative to the ITT population from three multicentre, randomised, 24-week, parallel-group, blinded, active comparator studies.

Two of the three studies included other treatment arms (UMEC/VI 113/22 mcg OD; VI 22 mcg OD and UMEC 113 mcg OD), which are not licensed in the UK. The results of these treatment arms were included in the pooled analysis, although were not presented in the Maleki-Yazdi et al., 2017 publication.

Details of the blinding process for all tiotropium comparator studies discussed in this Evidence Dossier can be found on page 474, Decramer M et al., Lancet Respir Med. 2014 Jun;2:472-86. Doi: 10.1016/S2213-2600(14)70065-7.

COPD = chronic obstructive pulmonary disease; FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity; OD = once daily; R = randomisation; TIO = tiotropium; UMEC/VI = umeclidinium/vilanterol

• Analysis was performed on a subgroup of MN patients (defined as receiving no maintenance therapy for ≥30 daysbefore screening) and the ITT population

Patient population

• ≥40 years of age

• A diagnosis of symptomatic COPD

• Post-bronchodilator FEV1 value ≤70% predicted normal

• FEV1/forced vital capacity (FVC) ratio <0.70

• Modified Medical Research Council (mMRC) dyspnoea score ≥2

Endpoints

Primary endpoint

• Change from baseline in trough FEV1 on Day 169 (defined as the mean of the FEV1 values obtained 23h and 24hafter dosing on Day 168) (MN population and ITT population)


Secondary endpoints

• St George’s Respiratory Questionnaire (SGRQ) total score and proportion of responders (defined as patientsexperiencing a decrease from baseline of ≥4 units)

• Rescue medication use per day (minimal clinically important deterioration [CID] defined as a treatment benefit of 1rescue-free month per year or 2 rescue-free weeks out of 24 [corresponding to a change from baseline ≥8.3% inpercentage of rescue-free days over Weeks 1–24])

• Deterioration events

o Time to, and risk of, a short-term CID (short-term CID is a novel composite endpoint that was assessed anddefined as):

▪ ≥100 mL decrease in trough FEV1; and/or

▪ ≥4-unit increase in SGRQ score; and/or

▪ An on-treatment moderate-to-severe COPD exacerbation (defined as a worsening of COPDsymptoms requiring use of any additional treatment other than study drug or rescue salbutamoluse and an emergency department visit or hospitalisation)

o Sustained CIDs were also assessed and defined as:

▪ A moderate-to-severe COPD exacerbation leading to study withdrawal; or

▪ ≥100 ml FEV1 decrease; or

▪ ≥4-unit increase in SGRQ total score on two consecutive visits or for ≥50% of all availablesubsequent visits


• Adverse events (AEs) were monitored

Demographics and baseline characteristics

Characteristic

ITT population MN population UMEC/VI 55/22mcg

(n=878)

TIO 10 mcg (n=869)


TIO 10 mcg (n=258)

Mean age, years ± SD 63.0 ± 8.6 63.4 ±8.7 61.7 ± 8.6 62.3 ± 8.7

Female gender, n (%) 282 (32) 275 (32) 81 (29) 93 (36)

Current smoker at screening,a n (%) 457 (52) 439 (51) 180 (65) 155 (60)

Smoking pack-years,b n (%) 45.1 (25.6) 46.1 (27.0) 47.1 (25.6) 49.5 (30.1)

Reversible to salbutamol,c,d n (%) 243 (28) 248 (29) 94 (34) 77 (30) Post-salbutamol % predicted FEV1, mean ± SD

47.0 ± 13.1 47.0 ± 13.0 50.9 ± 12.3 50.1 ± 12.8

a Patient reclassified as current smoker if smoked within 6 months; b Smoking pack-years = (number of cigarettes smoked per day/20) x number of years smoked; c Reversibility was defined as an increase in FEV1 ≥12% and ≥200 mL following administration of salbutamol; d ITT population: UMEC/VI 55/22 mcg OD, n=876; TIO 10 mcg OD, n=863 FEV1 = forced expiratory volume in 1 second; ITT = intent-to-treat; MN = maintenance naïve; OD = once daily; TIO = tiotropium; UMEC/VI = umeclidinium/vilanterol


Results

Primary endpoint

• Change from baseline in trough FEV1 on Day 169 (MN population and ITT population)

o In both populations, mean improvements in baseline FEV1 at Day 169 were significantly greater in theUMEC/VI 55/22 mcg group versus the TIO 10 mcg group

▪ MN population (LS mean difference 146 mL; 95% CI 102, 189; p<0.001)

▪ ITT population (LS mean difference 95 mL; 95% CI 71, 118, p<0.001)

Figure 2: Trough FEV1 change over time in the maintenance-naive and intention-to-treat populations

Adapted from Maleki-Yazdi et al., 2017 CI = confidence interval; FEV1 = forced expiratory volume in 1 second; ITT = intent to treat; LS = least squares; MN = maintenance-naïve; TIO = tiotropium; UMEC/VI = umeclidinium/vilanterol

Secondary and other efficacy endpoints

• SGRQ total score and proportion of responders

o UMEC/VI 55/22 mcg and TIO 10 mcg demonstrated mean improvements (≥4 units) from baseline in totalSGRQ score across the MN and ITT populations, with overall improvements versus baseline shown to benumerically greater in the MN population throughout the study

o Total scores demonstrated significant improvement with UMEC/VI 55/22 mcg versus TIO 10 mcg in the ITTpopulation on Days 28 and 84, but not Day 168

▪ Day 28 (–2.25 units; 95% CI –3.26, –1.23; p<0.001)

▪ Day 84 (–1.63 units; 95% CI –2.76, –0.49; p=0.005)

▪ Day 168 (–0.93 units; 95% CI –2.19, 0.33; p=0.149)

o UMEC/VI 55/22 mcg patients showed significantly greater odds of being a SGRQ responder versus TIO 10mcg in the ITT population at Days 28 and 84 (odds ratio [OR] 1.3 units at both time points; p=0.007 at Day28; p=0.009 at Day 84), but not in the MN population

▪ In either population at Day 168, the odds of being a responder versus non-responder were notsignificantly different between treatment groups


• Rescue medication use per day

o A significantly greater percentage of patients achieved a response in rescue-free episodes in the UMEC/VI55/22 mcg group versus the TIO 10 mcg group in both 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 1.0, 2.2]) populations

o An improvement was seen in the mean number of puffs per day over Weeks 1–24, favouring UMEC/VI55/22 mcg compared with TIO 10 mcg in both populations (difference [ITT] –0.5; 95% CI –0.8, –0.3;p<0.001; difference [MN] –0.5; 95% CI –0.9, 0.0; p=0.066)

• Deterioration events

o Time to, and risk of, a short-term CID

▪ A lower proportion of patients displayed a short-term CID in the UMEC/VI 55/22 mcg versus TIO10 mcg treatment group, in both populations (MN population: 41% versus 55%; ITT population:41% versus 56%)

▪ A reduced risk of first CID was found in UMEC/VI 55/22 mcg compared with TIO 10 mcg in theMN population, with similar results observed between treatment groups in the ITT population(MN population: hazard ratio [HR]=0.66; 95% CI 0.51, 0.85; p=0.001; ITT population: HR=0.66;95% CI 0.54, 0.71: p<0.001)

o Sustained CIDs

▪ A lower proportion of patients demonstrated a sustained CID in the UMEC/VI 55/22 mcg groupcompared with TIO 10 mcg in both the MN population (22% versus 30%) and the ITT population(21% versus 30%)

▪ There was a significantly reduced risk of sustained CID in the UMEC/VI 55/22 mcg treatmentgroup versus the TIO 10 mcg group in the MN population (HR=0.69; 95% CI 0.49, 0.97; p<0.05)and the ITT population (HR=0.64; 95% CI 0.53, 0.77; p<0.001)


• Incidence of AEs and serious adverse events (SAEs) was similar for the two treatment groups in both populations

Table 2: Summary of adverse events

ITT population MN population UMEC/VI 55/22

mcg (n=878) TIO 10 mcg

(n=869) UMEC/VI 55/22

mcg (n=275) TIO 10 mcg

(n=258) On-treatment non-fatal SAEs, any event, n (%)

42 (5) 35 (4) 8 (3) 11 (4)

Fatal AEs,a n (%) 4 (<1) 7 (1) 3 (1) 2 (<1) AEs reported by ≥3% of patients on any treatment, n (%)

Nasopharyngitis Headache Back pain Cough URTI

63 (7) 80 (9) 27 (3) 25 (3) 17 (2)

62 (7) 55 (6) 28 (3) 26 (3) 26 (3)

18 (7) 20 (7) 8 (3) 5 (2)

2 (<1)

15 (6) 15 (6) 4 (2) 8 (3)

10 (4) AEs of special interest, n (%)

Cardiovascular events (any) Pneumonia

2 (<1) 2 (<1)

2 (<1) 6 (<1)

0 0

1 (<1) 1 (<1)

a Deaths were attributable to the following: ITT: cardiac arrest, cardiac failure, COPD and haemorrhagic stroke in the UMEC/VI group; cardiac failure, pulmonary embolism, respiratory arrest, respiratory failure, upper gastrointestinal haemorrhage, sudden death and pancreatic carcinoma in the TIO group. MN: cardiac arrest, haemorrhagic stroke and COPD in the UMEC/VI group; respiratory arrest and respiratory failure in the TIO group.

AE = adverse event; FEV1 = forced expiratory volume in 1 second; ITT = intention-to-treat; MN = maintenance-naïve; SAE = serious adverse event; TIO = tiotropium; UMEC/VI = umeclidinium/vilanterol; URTI = upper respiratory tract infection


Kerwin et al., 2017 (active-comparator study)

Efficacy and safety of umeclidinium/vilanterol as step up therapy from tiotropium in patients with moderate COPD5

Umeclidinium/vilanterol (UMEC/VI) step-up therapy provided clinical benefit over tiotropium (TIO) HandiHaler monotherapy in patients with moderate COPD who were symptomatic on TIO alone

Study design

A Phase III, randomised, multicentre, double-blind, double-dummy, parallel-group, active controlled 12-week lung function study comparing the efficacy and safety of UMEC/VI 55/22 mcg OD and TIO 10 mcg OD in patients with moderate COPD.

Details of the blinding process for all tiotropium comparator studies discussed in this Evidence Dossier can be found on page 474 in Decramer M et al., Lancet Respir Med. 2014 Jun;2:472-86. Doi: 10.1016/S2213-2600(14)70065-7.

COPD = chronic obstructive pulmonary disease; FEV1 = forced expiratory volume in 1 second; mMRC = modified Medical Research Council; OD = once daily; R = randomisation; TIO = tiotropium; UMEC/VI = umeclidinium/vilanterol

Patient population

• ≥40 years with clinical diagnosis of moderate COPD

• Post salbutamol FEV1 ≤70% and ≥50% of normal predicted


• Prescribed TIO 10 mcg for ≥3 months

Endpoints

Primary endpoint

• Trough FEV1 at Day 85

Secondary endpoints

• FEV1 3h post-dose on Day 84

• Trough FEV1 on Days 2, 28, 56 and 84

• Mean serial FEV1 on Days 1, 28, 56 and 84

• wmFEV1 over 0–3h post-dose on Days 1, 28, 56, 84 and 85

• Percentage of rescue-free days and the number of puffs of rescue medication during the study

• Transition Dyspnoea Index (TDI) focal score and the proportion of responders (defined as patients with a TDI focalscore of ≥1 unit) on Days 28, 56 and 84


• SGRQ total score and the proportion of responders (defined as patients with a reduction from baseline of ≥4 units)on Days 28 and 84

• CAT score and the proportion of responders (defined as patients with a reduction from baseline of ≥2 units) onDays 28 and 84


• AEs and AEs of special interest



TIO 10 mcg (n=247)

Mean age, years ± SD 64.5 ± 8.7 64.3 ±8.7

Female gender, n (%) 84 (44) 87 (45)

Mean smoking pack-year history, years ± SD 38.6 ± 20.5 40.4 ± 20.2

Post-salbutamol % predicted FEV1, mean ± SD 59.8 ± 5.5 59.4 ± 5.3

Post-salbutamol FEV1/FVC, mean ± SD 53.1 ± 8.2 52.9 ± 8.4 FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity; SD = standard deviation; TIO = tiotropium; UMEC/VI = umeclidinium/vilanterol

Results

Primary endpoint

• Trough FEV1 at Day 85

o UMEC/VI 55/22 mcg resulted in an 88 mL improvement over TIO 10 mcg (95% CI 45, 131; p<0.001)

Secondary endpoints

• FEV1 3 h post-dose on Day 84

o UMEC/VI 55/22 mcg produced a 73 mL improvement over TIO 10 mcg (95% CI 24, 122; p<0.01)

• Trough FEV1 on Days 2, 28, 56 and 84

o Greater improvements in trough FEV1 with UMEC/VI 55/22 mcg over TIO 10 mcg were also observed at allother assessments from Day 2 onward (p<0.01)

o A greater proportion of patients achieved a ≥100 mL improvement in trough FEV1 at Day 85 with UMEC/VI55/22 mcg (44%) compared with TIO 10 mcg (30%); UMEC/VI 55/22 mcg versus TIO 10 mcg resulted inhigher odds of achieving a ≥100 mL improvement in trough FEV1 ratio: 1.89 (95% CI 1.27, 2.81; p<0.01) atDay 85

• Mean serial FEV1 on Days 1, 28, 56 and 84

o Improvements favoured UMEC/VI 55/22 mcg over TIO 10 mcg as early as 5 min postdose on Day 1(difference of 50 mL [95% CI 27, 72]; p<0.001), which was maintained for all serial FEV1 time points up to3h (p<0.05)

• wmFEV1 over 0–3h post-dose on Days 1, 28, 56, 84 and 85

o UMEC/VI 55/22 mcg treatment resulted in statistically significant improvements over TIO 10 mcg inweighted mean FEV1 0–3h postdose and trough FVC

• Percentage of rescue-free days and the number of puffs of rescue medication over 12 weeks

o UMEC/VI 55/22 mcg resulted in a greater improvement in the number of rescue-free days compared withTIO 10 mcg (median estimated difference 2.3 days [95% CI 0.0, 4.8; p<0.01])

o There was a greater reduction in rescue medication use, favouring UMEC/VI 55/22 mcg over TIO 10 mcg(LS mean change difference: −0.1 puffs/d [95% CI −0.2, 0.0]; p<0.05)


• TDI focal score and the proportion of responders (defined as patients with a TDI focal score of ≥1 unit) on Days 28,56 and 84

o TDI focal scores were improved with UMEC/VI 55/22 mcg compared with TIO 10 mcg at Day 28 (difference0.5; 95% CI 0.0, 0.9; p<0.05) but not at Days 56 and 84

o The odds of being a responder versus a non-responder according to TDI score were significantly higher forpatients receiving UMEC/VI 55/22 mcg (63% responders) compared with TIO 10 mcg at Day 84 (49%responders; OR 1.78; 95% CI 1.21, 2.64; p<0.01)

• SGRQ total and CAT score and the proportion of responders on Days 28 and 84

o Both scores and proportion of responders were similar between treatment groups

Safety

• On-treatment AEs were similar in both treatment groups (30–31%)

• On-treatment drug-related AEs were similar in both treatment groups (1–3%)

• On-treatment non-fatal and fatal SAEs were similar between groups (0–2%)

• The most frequent on-treatment AEs were nasopharyngitis (both 7%) and headache (6–7%)

• AEs of special interest:

o The incidence of cardiovascular AEs of special interest was low and similar between groups: 2% forUMEC/VI 55/22 mcg and 1% for TIO 10 mcg

• On-treatment COPD exacerbations were reported for two (<1%) and eight (3%) of patients in the UMEC/VI 55/22mcg and TIO 10 mcg groups, respectively

Table 3. Summary of adverse events


TIO 10 mcg (n=247)

On-treatment AEs, n (%) 75 (30) 77 (31)

AEs leading to withdrawal or discontinuation of medication, n (%)

5 (2) 4 (2)

On-treatment non-fatal SAEs, n (%) 6 (2) 6 (2)

On-treatment fatal SAEs,a n (%) 1 (<1) 0 On-treatment AEs occurring in ≥3% in any group, n (%)

Nasopharyngitis Headache

18 (7) 16 (6)

17 (7) 18 (7)


Cardiac arrhythmia Cardiac failure Ischaemic heart disease CNS haemorrhages and cerebrovascular conditions

Pneumonia LRTI excluding pneumonia

4 (2) 1 (<1)

0 2 (<1) 2 (<1)

1 (<1) 2 (<1)

3 (1) 2 (<1) 1 (<1)

0 0

0 1 (<1)

On-treatment COPD exacerbation, n (%) 2 (<1) 8 (3) a One death occurred during the study due to a cerebrovascular accident in the UMEC/VI group and was identified as not related to study treatment by the investigator

AE = adverse event; AESI = adverse event of special interest; CNS = central nervous system; COPD = chronic obstructive pulmonary disease; CV = cardiovascular; SAE = serious adverse event; SD = standard deviation; TIO = tiotropium; UMEC/VI = umeclidinium/vilanterol


Decramer et al., 2014 (active-comparator study)

Efficacy and safety of umeclidinium plus vilanterol versus tiotropium, vilanterol, or umeclidinium monotherapies over 24 weeks in patients with chronic obstructive pulmonary disease: results from two multicentre, blinded, randomised controlled trials6

Anoro Ellipta (UMEC/VI 55/22 mcg) provides significant improvements in lung function compared with tiotropium (TIO 10 mcg) in patients with COPD, with a similar safety profile

Study design

Two Phase III, randomised, multicentre, double-blind, double-dummy, parallel-group, active controlled 24-week lung function studies comparing UMEC/VI 113/22 mcg OD, UMEC/VI 55/22 mcg OD, TIO 10 mcg OD and either VI 22 mcg OD (study 1) or UMEC 113 mcg OD (study 2) in patients with moderate to very severe COPD.

UMEC 113 mcg, VI 22 mcg and UMEC/VI 113/22 mcg are not licensed in the UK and therefore results have not been included in the efficacy section but have been included in the safety section.


COPD = chronic obstructive pulmonary disease; FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity; MRC = Medical Research Council; OD = once daily; TIO = tiotropium; UMEC = umeclidinium; UMEC/VI = umeclidinium/vilanterol; VI = vilanterol

• The studies used a double-dummy design for dosing; patients were given two inhalers, one containing active drugand the other placebo

• Salbutamol was permitted throughout the study run-ins and treatment periods, but withheld for ≥4h beforespirometry testing

• Inhaled corticosteroids at a stable dose of up to 1000 mcg per day of fluticasone propionate or equivalent werepermitted throughout the study

Patient population

• ≥40 years with clinical diagnosis of moderate-to-very severe COPD


• Post bronchodilator FEV1/FVC ratio <0.70


• FEV1 ≤70% predicted

• MRC dyspnoea score ≥2

Endpoints

Primary endpoint

• Pre-dose (trough) FEV1 on Day 169, defined as the mean of FEV1 values obtained 23h and 24h after dosing on Day168 (Week 24 visit)

Secondary endpoints and other endpoints

• wmFEV1 over 0–6h post-dose on Day 168

• Trough FEV1 and 0–6h post-dose wmFEV1 at other timepoints

• Peak FEV1 on Day 168

• Trough FVC on Day 169

• Proportion of patients achieving an increase in FEV1 of ≥12% and ≥0.2 L above baseline at any time during 0–6hpost-dose on Day 1

• Proportion of patients achieving an increase of ≥0.1 L above baseline in trough FEV1 on Day 169

• TDI focal score and the proportion of TDI responders, defined as patients with a TDI focal score ≥1 unit

• Shortness of Breath with Daily Activity (SOBDA) diary score and the proportion of SOBDA responders, defined as adecrease of ≥0.1 units from baseline

• SGRQ score and the proportion of SGRQ responders, defined as a decrease from baseline in SGRQ total score of ≥4units

• Rescue salbutamol use (percentage of rescue-free days and mean puffs/day)

• Time to first COPD exacerbation

• Device preference (as measured by the COPD device preference questionnaire)


• AEs, vital signs, 12-lead ECG, clinical chemistry and haematology


Study 1 UMEC/VI 55/22 mcg (n=212) TIO 10 mcg (n=208)

Age (years), mean ± SD 63.0 ± 8.7 62.6 ± 9.4

Female gender, n (%) 64 (30) 68 (33)

Mean smoking pack-year history, years 44.8 41.9


Post-salbutamol FEV1/FVC, mean ± SD 47.7 ± 11.1 48.3 ± 11.9

Study 2 UMEC/VI 55/22 mcg (n=217) TIO 10 mcg (n=215)

Age (years), mean ± SD 65.0 ± 8.6 65.2 ± 8.3

Female gender, n (%) 77 (35) 62 (29)

Mean smoking pack-year history, years 47.8 54.0


Post-salbutamol FEV1/FVC, mean ± SD 46.2 ± 11.9 45.8 ± 11.6 FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity; SD = standard deviation; TIO = tiotropium; UMEC/VI = umeclidinium/vilanterol


Results

Primary endpoint


o In study 1, trough FEV1 at Day 169 (least squares mean; LSM) was significantly improved from baselinewith UMEC/VI 55/22 mcg (90 mL; 95% CI 39, 141; p≤0.001) compared with TIO 10 mcg. Significantimprovements were also seen at all other visits (p<0.01)

Figure 3: Repeated measures analysis for change from baseline in trough FEV1 over 24 weeks of treatment (Study 1, ITT population)

Adapted from Decramer et al., 2014 FEV1 = forced expiratory volume in 1 second; ITT = intention-to-treat; TIO = tiotropium; UMEC/VI = umeclidinium/vilanterol

o In study 2, trough FEV1 at Day 169 (LSM) was improved from baseline UMEC/VI 55/22 mcg (60 mL; 95% CI10, 109; p=0.0182*) compared with TIO 10 mcg

Figure 4: Repeated measures analysis for change from baseline in trough FEV1 over 24 weeks of treatment (Study 2, ITT population)

Adapted from Decramer et al., 2014 FEV1 = forced expiratory volume in 1 second; ITT = intention-to-treat; TIO = tiotropium; UMEC/VI = umeclidinium/vilanterol

o In the pooled analysis of trough FEV1 for both studies, there was a significant improvement on Day 169 forUMEC/VI 55/22 mcg compared with TIO 10 mcg (75 mL; 95% CI 39, 110; p<0.0001)

* This p value (<0.05) is nominal only, because of the restrictions of the predefined statistical testing hierarchy


Secondary endpoints


o In study 1, wmFEV1 over 0–6h post-dose on Day 168 was significantly improved from baseline withUMEC/VI 55/22 mcg (74 mL; 95% CI 22, 125; p=0.0052) compared with TIO 10 mcg. Significantimprovements were also seen at all other visits

o In study 2, wmFEV1 over 0–6h post-dose on Day 168 was improved from baseline with UMEC/VI 55/22mcg (96 mL; 95% CI 50, 142; p<0.0001) compared with TIO 10 mcg. Similar improvements were also seenat all other visits

• Peak FEV1 on Day 168

o In study 1, peak FEV1 on Day 168 was significantly improved from baseline with UMEC/VI 55/22 mcg (72mL; 95% CI 19, 125; p=0.0018) compared with TIO 10 mcg

o In study 2, peak FEV1 on Day 168 was improved from baseline with UMEC/VI 55/22 mcg (93 mL; 95% CI44, 142; p=0.0002) compared with TIO 10 mcg

• Trough FVC on Day 169

o In study 1, trough FVC on Day 169 was similar with UMEC/VI 55/22 mcg (68 mL; 95% CI –20, 157; p=0.13)compared with TIO 10 mcg

o In study 2, trough FVC on Day 169 was improved from baseline with UMEC/VI 55/22 mcg (98 mL; 95% CI20, 176 mL; p=0.0143) compared with TIO 10 mcg


o In study 1, significantly more patients achieved the defined increase from baseline with UMEC/VI 55/22mcg (OR 2.5; 95% CI 1.7, 3.7; p<0.0001) compared with TIO 10 mcg

o In study 2, more patients achieved the defined increase from baseline with UMEC/VI 55/22 mcg (OR 2.1;95% CI 1.4, 3.1 mL; p=0.0002) compared with TIO 10 mcg

• Proportion of patients achieving an increase of ≥0.1 L above baseline in trough FEV1 on Day 169

o In study 1, significantly more patients achieved the defined increase from baseline with UMEC/VI 55/22mcg (OR 2.1; 95% CI 1.4, 3.1; p=0.0003) compared with TIO 10 mcg

o In study 2, a similar proportion of patients achieved the defined increase from baseline with UMEC/VI55/22 mcg compared with TIO 10 mcg (OR 1.4; 95% CI 1.0, 2.1; p=0.06)

• TDI focal score and the proportion of TDI responders, defined as patients with a TDI focal score ≥1 unit at Day 168

o UMEC/VI 55/22 mcg and TIO 10 mcg produced clinically meaningful improvements (≥1 unit) in LSM TDIfocal score at Day 168 (Study 1 LSM: UMEC/VI 55/22 mcg 2.3, TIO 10 mcg 2.4; Study 2 LSM: UMEC/VI55/22 mcg 2.3, TIO 10 mcg 2.1)

o No significant differences were noted in TDI score or odds of being a TDI responder on Day 168 betweenUMEC/VI 55/22 mcg and TIO 10 mcg

• SOBDA diary score and the proportion of SOBDA responders, defined as a decrease of ≥0.1 units from baseline

o At Week 24, all treatments were associated with improvements in LSM changes from baseline in SOBDAscore of 0.1 or greater (Study 1 LSM: UMEC/VI 55/22 mcg –0.18, TIO 10 mcg –0.18; Study 2 LSM: UMEC/VI55/22 mcg –0.29, TIO 10 mcg –0.21)

• SGRQ score and the proportion of SGRQ responders, defined as a decrease from baseline in SGRQ total score of ≥4units

o All treatments resulted in a decrease in SGRQ of ≥4 units (Study 1 LSM: UMEC/VI 55/22 mcg –6.87,TIO 10 mcg –7.62; Study 2 LSM: UMEC/VI 55/22 mcg –9.95, TIO 10 mcg –9.78)

o There were no significant differences between treatments with respect to change from baseline in SGRQ


• Rescue salbutamol use (percentage of rescue-free days and mean puffs/day)

o In study 1, UMEC/VI 55/22 mcg significantly reduced the use of rescue salbutamol treatment over 24weeks compared with TIO 10 mcg (treatment difference: –0.7, 95% CI –1.2, –0.1, p=0.0220)

o In study 2, there was no significant difference in the use of rescue salbutamol treatment over 24 weekscompared with TIO 10 mcg (treatment difference: –0.6 (–1.2, 0.0; p=0.07)

• Time to first COPD exacerbation†

o No differences in risk of a COPD exacerbation were observed between the UMEC/VI 55/22 mcg and TIO 10mcg groups in either study

• Device preference (as measured by the COPD device preference questionnaire)

o Ellipta was preferred to HandiHaler across the treatment groups, according to the results of the COPDdevice preference questionnaire

Safety

• On-treatment AEs ranged from 39% to 62% across treatment groups

• Treatment-related AEs ranged from 3% to 13% across treatment groups

• The most frequent on-treatment AEs were nasopharyngitis (3–10%), headache (4–11%), upper respiratory tractinfection (2–8%), and back pain (1–5%)

• No notable differences were reported for blood pressure, heart rate, or QT interval in either study, and notreatment-related changes in ECG or clinical laboratory parameters were recorded


Study 1 UMEC/VI 55/22 mcg (n=212)

UMEC/VI 113/22 mcg (n=214)

VI 22 mcg (n=209)

TIO 10 mcg (n=208)

On-treatment AEs, n (%) 108 (51) 94 (44) 99 (47) 82 (39)

Most common AE type, n (%) Nasopharyngitis Headache URTI Back pain

21 (10) 20 (9) 8 (4)

10 (5)

14 (7) 14 (7) 7 (3) 7 (3)

17 (8) 21 (10)

5 (2) 3 (1)

16 (8) 9 (4) 8 (4) 4 (2)

Treatment-related AEs, n (%) 11 (5) 9 (4) 12 (6) 7 (3)

AEs leading to discontinuation or study withdrawal, n (%)

10 (5) 15 (7) 10 (5) 9 (4)

On-treatment SAEs, n (%) 7 (3) 5 (2) 15 (7) 13 (6)

Severe intensity AEs reported by >1% of patients in any treatment group,a n (%)

Acute exacerbation of COPDb

4 (2) 1 (<1) 2 (<1) 2 (<1)

Fatal AEs,c n (%) 1 (<1) 0 1 (<1) 0

† Anoro Ellipta is indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD


Study 2 UMEC/VI 55/22 mcg (n=217)

UMEC/VI 113/22 mcg (n=215)

UMEC 113 mcg (n=222)

TIO 10 mcg (n=215)

On-treatment, n (%) 127 (59) 133 (62) 131 (59) 126 (59)

Most common AE type, n (%)

Nasopharyngitis

Headache

URTI Back pain

14 (6)

21 (10)

6 (3) 8 (4)

16 (7)

20 (9)

10 (5) 6 (3)

6 (3)

25 (11)

17 (8) 10 (5)

17 (8)

15 (7)

14 (7) 11 (5)

Treatment-related AEs, n (%) 16 (7) 17 (8) 28 (13) 16 (7)

AEs leading to discontinuation or study withdrawal, n (%)

20 (9) 15 (7) 17 (8) 11 (5)

On-treatment SAEs, n (%) 22 (10) 15 (7) 15 (7) 9 (4)

Severe intensity AEs reported by >1% of patients in any treatment group,a n (%)

Acute exacerbation of COPDb

6 (3) 0 6 (3) 1 (<1)

Fatal AEs,a n (%) 1 (<1) 1 (<1) 0 2 (<1)a Intensity was assessed from the maximum intensity of the AE throughout its duration; b Only acute exacerbations of COPD that were classified as SAEs were recorded as safety findings; c Includes on-treatment and post-treatment events. Two on-treatment deaths occurred during Study 1 (one in the UMEC/VI 55/22 mcg group [cardiac arrest and COPD exacerbation] and one in the VI 22 mcg group [acute heart failure]) and four deaths occurred during Study 2 (one in the UMEC/VI 55/22 mcg group [haemorrhagic stroke], one in the UMEC/VI 113/22 mcg group [upper-gastrointestinal haemorrhage] and two in the TIO 10 mcg group [upper-gastrointestinal haemorrhage and respiratory arrest]). No deaths were considered by the reporting investigator related to study drug.

AE = adverse event; TIO = tiotropium; UMEC = umeclidinium; UMEC/VI = umeclidinium/vilanterol; URTI = upper respiratory tract infection; VI = vilanterol


Kalberg et al., 2016 (active-comparator study)

Dual Bronchodilator Therapy with Umeclidinium/Vilanterol Versus Tiotropium plus Indacaterol in Chronic Obstructive Pulmonary Disease: A Randomized Controlled Trial7,8

Treatment over 12 weeks with Anoro Ellipta 55/22 mcg OD resulted in improvements in measures of lung function, symptoms and health status, similar to those achieved with the free combination of tiotropium HandiHaler (TIO 10 mcg) and IND 150 mcg OD in patients with moderate to very severe COPD, with comparable safety profiles

Study design

A multicentre, randomised, blinded, triple-dummy, parallel-group, 12-week lung function study comparing UMEC/VI 55/22 mcg OD against TIO 10 mcg OD + IND 150 mcg OD, in patients with moderate to very severe COPD. This was a non-inferiority study to investigate whether treatment with UMEC/VI 55/22 mcg was non-inferior to TIO 10 mcg OD + IND 150 mcg OD.


COPD = chronic obstructive pulmonary disease; FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity; IND = indacaterol; OD = once daily; PBO = placebo; PP = per-protocol; R = randomisation; TIO = tiotropium; UMEC/VI = umeclidinium/vilanterol

• After screening, patients entered a 5–7-day run-in period prior to randomisation

• The use of short-acting muscarinic antagonists, ICS and salbutamol were permitted during the run-in period

• After the run-in period, patients were randomised (1:1) to receive either UMEC/VI 55/22 mcg OD via an Elliptainhaler, plus placebo OD via a Handihaler, plus placebo OD via a Breezhaler; or TIO 10 mcg OD via a Handihaler,plus IND 150 mcg OD via a Breezhaler, plus placebo OD via an Ellipta for 12 weeks

• Patients were randomised to treatment only if they had not experienced a COPD exacerbation between visits 1 and2, and if they had not used any prohibited medication during the run-in period or at visit 2

• Clinic visits took place on Days 2, 14, 28, 56, 84, and 85, with a follow-up period of approximately 7 days

• Patients were provided with salbutamol for use as a rescue medication

Patient population


• An established clinical history of COPD


• Current or former cigarette smoker with ≥10 pack-years

• Pre- and post-bronchodilator FEV1 values ≤70% predicted normal

• Pre- and post-bronchodilator FEV1/forced vital capacity (FVC) ratios of <0.70

• Modified Medical Research Council (mMRC) dyspnoea score ≥2

• Corrected QT interval <450 ms (or <480 ms for patients with bundle branch block)

Endpoints

Primary endpoint

• Trough FEV1 on Day 85 (defined as the mean of the FEV1 values obtained 23h and 24h after dosing on Day 84) inthe PP population

o There was a prespecified non-inferiority margin of –50 mL in treatment difference, which if met,demonstrated non-inferiority

Secondary and other efficacy endpoints (ITT population)



• Trough FEV1 on Days 28 and 56

• 0–6h serial FEV1 at Days 1 and 84

• Serial and trough FVC

Patient-reported outcomes (ITT population)

• Mean number of puffs of rescue medication per day over Days 1–84

• Percentage of rescue-free days over Days 1–84

• Transition Dyspnoea Index (TDI) focal score and proportion of TDI responders (those with ≥1 unit TDI focal score)on Days 28, 56 and 84

• St George’s Respiratory Questionnaire (SGRQ) total score and proportion of responders (those with reduction frombaseline of ≥4 units total SGRQ score) on Days 28, 56 and 84

• Inhaler preference evaluating number of steps to use the inhaler, time required for use and overall inhalerpreference

Safety and tolerability (ITT population)

• Safety of study treatments was assessed by monitoring the incidence of AEs, vital sign measurements and COPDexacerbations

Demographics and baseline characteristics (ITT population)

Characteristic UMEC/VI 55/22 mcg

(n=482) TIO 10 mcg + IND 150 mcg

(n=479)

Age (years), mean ± SD 64 ± 7.8 64 ± 8.4

Female gender, n (%) 127 (26) 138 (29)

Current smoker at screening, n (%) 198 (41) 218 (46)

Smoking pack-years,a mean ± SD 43.2 ± 22.7 42.3 ± 23.1

Post-salbutamol FEV1 (L),b mean ± SD 1.369 ± 0.46 1357 ± 0.48

Post-salbutamol FEV1/FVC,b mean ± SD 45.7 ± 11.1 45.6 ± 11.1 a Smoking pack-years = (number of cigarettes smoked per day/20) x number of years of smoking; b n = 479 in UMEC/VI 55/22 mcg OD, n = 477 in TIO 10 mcg OD + IND 150 mcg OD FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity; IND = indacaterol; ITT = intention-to-treat; SD = standard deviation; TIO = tiotropium; UMEC/VI = umeclidinium/vilanterol


Results

Primary endpoint

• Trough FEV1 on Day 85 (PP population)

o The LS mean change from baseline in trough FEV1 at Day 85 was similar for both treatment groups(difference 1 mL; 95% CI –29, 30; p=0.964)

▪ The lower limit of the CI was greater than the prespecified non-inferiority margin of –50 mL,demonstrating UMEC/VI 55/22 mcg is non-inferior to TIO 10 mcg + IND 150 mcg for the primaryendpoint of trough FEV1 at Day 85

o Across all time points, similar improvements from baseline in trough FEV1 were observed in the twotreatment groups

o Similar results for trough FEV1 at Day 85 were observed in the ITT population in UMEC/VI 55/22 mcgversus TIO 10 mcg + IND 150 mcg (difference 7 mL; 95 % CI –22, 35, p=0.640)

Figure 5: LS mean change from baseline in trough FEV1 (PP population)

Adapted from Kalberg et al., 2016 CI = confidence interval; FEV1 = forced expiratory volume in 1 second; IND = indacaterol; LS = least squares; PP = per-protocol; TIO = tiotropium; UMEC/VI = umeclidinium/vilanterol

Secondary and other efficacy endpoints (ITT population)

• wmFEV1 over 0–6h post-dose on Days 1 and 84

o The mean change from baseline between treatments in trough FEV1 at Day 1 in the 0–6 hours post-dosewas –1 mL (95% CI –20, 18, p=0.908)

o Similar improvements from baseline were demonstrated at Day 84 in the UMEC/VI 55/22 mcg group andthe TIO 10 mcg + IND 150 mcg group (difference –23 mL; 95% CI –54, 8, p=0.145)

• Trough FEV1 on Days 28 and 56

o The LS mean change from baseline in trough FEV1 at Days 28 and 56 in the ITT population was similar forboth treatment groups (Day 28 difference 4 mL; 95% CI –23, 31; p=0.774; Day 56 difference 11 mL; 95% CI–17, 40; p=0.438)

• Serial FEV1 at Days 1 and 84

o Similar patterns of improvement were observed from baseline in both treatment groups at Days 1 and 84(Day 1 difference 7 mL; 95% CI –13, 26; p=0.500; Day 84 difference –3 mL; 95% CI –25, 19; p=0.784)


• Serial and trough FVC

o Similar mean baseline trough FVC was observed between the UMEC/VI 55/22 mcg (2,806 mL) and TIO 10mcg + IND 150 mcg (2,775 mL) groups. Improvement from baseline was observed for both groups at alltime points from Day 2 through to Day 85 (Day 2 difference 16 mL; 95% CI –25, 57; p=0.437; Day 85difference 20 mL; 95% CI –29, 68; p=0.433)

o Similar patterns of improvement were observed in serial FVC at each time point for Day 1 and Day 84between treatment groups

Patient reported outcomes

• Mean number of puffs of rescue medication per day over Days 1–84

o Overall difference in mean puffs per day from baseline between the UMEC/VI 55/22 mcg and TIO 10 mcg+ IND 150 mcg treatment groups was 0.1 puffs (95% CI –0.1, 0.3; p=0.215)

o No difference was detected in percentage of rescue-free days between the UMEC/VI 55/22 mcg and TIO10 mcg + IND 150 mcg treatment groups (median difference 0 days; 95% CI 0, 2.6; p=0.265)

• TDI focal score and proportion of TDI responders on Days 28, 56 and 84 (ITT population)

o TDI focal scores in both groups were similar across all visits. Groups demonstrated a clinically meaningfulimprovement in LS mean TDI focal score at all visits (at Day 84; 2.32 and 2.62 LS mean change, in patientsreceiving UMEC/VI 55/22 mcg and TIO 10 mcg + IND 150 mcg, respectively)

▪ Day 28 (difference 2.07; 95% CI –0.29, 0.39; p=0.772)



o The proportion of responders (TDI focal score ≥1 unit) was similar between treatment groups at Days 28,56 and 84

▪ Day 28 (OR 1.01; 95% CI 0.77, 1.33; p=0.927)

▪ Day 56 (OR 0.95; 95% CI 0.73, 1.25; p=0.720)

▪ Day 84 (OR 0.88; 95% CI 0.67, 1.16; p=0.364)

• SGRQ total score and proportion of responders on Days 28, 56 and 84 (ITT population)

o Both treatments resulted in similar improvements from baseline in SGRQ score (at Day 84; –4.93 and –5.01 LS mean change, in patients receiving UMEC/VI 55/22 mcg and TIO 10 mcg + IND 150 mcg,respectively)

▪ Day 28 (difference –1.12; 95% CI –2.50, 0.26; p=0.112)

▪ Day 56 (difference –0.37; 95% CI –1.86, 1.12; p=0.627)


o The proportion of responders was similar between treatment groups on Days 28, 56 and 84

▪ Day 28 (OR 1.19; 95% CI 0.92, 1.55; p=0.190)

▪ Day 56 (OR 1.04; 95% CI 0.80, 1.35; p=0.764)

▪ Day 84 (OR 1.05; 95% CI 0.81, 1.37; p=0.690)

• Inhaler preference

o A greater number of patients indicated preference for the Ellipta inhaler across the evaluations for thenumber of steps, time to use, and overall preference compared with the Breezhaler and Handihaler

o Overall 65% of users across both treatment groups reported a preference for the Ellipta inhaler, statingthe reason as ease of use


Safety

• The overall incidence of AEs during treatment was similar between the treatment groups in the ITT population(42% in the UMEC/VI 55/22 mcg group and 39% in the TIO 10 mcg + IND 150 mcg group), with headache andnasopharyngitis reported most frequently

• There were low incidences of non-fatal serious adverse events (SAEs) and AEs leading to study withdrawal in bothtreatment groups (2% in both)

• During the 12-week treatment period, the mean changes from baseline in vital signs were similar betweentreatment groups

• The incidence of COPD exacerbations during treatment was low and the same in both treatment groups (10% inboth)


UMEC/VI 55/22 mcg

(n=482)

TIO 10 mcg + IND 150 mcg

(n=479)

On-treatment AE, n (%) 202 (42) 186 (39)

Drug-related AE, n (%) 30 (6) 37 (8)

AEs leading to permanent discontinuation of study drug or withdrawal from study, n (%)

12 (2) 8 (2)

AEs reported in ≥3% of patients, n (%)

Nasopharyngitis Headache

Cough

36 (7) 32 (7)

16 (3)

28 (6) 27 (6)

17 (4)

On-treatment non-fatal SAE, n (%) 17 (4) 15 (3)

On-treatment fatal SAE,a n (%) 4 (<1) 1 (<1)

Patients experiencing COPD exacerbation, n (%) 48 (10) 49 (10)

AEs of special interest, n (%) Cardiovascular effects

Cardiac arrhythmia

Cardiac failure

Ischaemic heart disease CNS haemorrhages and cerebrovascular conditions

Pneumonia

LRTI excluding pneumonia

11 (2)

7 (1)

4 (<1)

2 (<1) 0

4 (<1)

7 (1)

9 (2)

3 (<1)

3 (<1)

4 (<1) 1 (<1)

2 (<1)

9 (2) a Five on-treatment deaths occurred during the study (pneumonia and respiratory failure, ventricular fibrillation, circulatory collapse and cardiac arrest in the UMEC/VI group and pneumonia in the TIO + IND group); the cardiac arrest was reported by the investigator as being related to the study medication and no other deaths were identified as being related to the study medication.

AE = adverse event; COPD = chronic obstructive pulmonary disease; IND = indacaterol; LRTI =lower respiratory tract infection; SAE = serious adverse event; TIO = tiotropium; UMEC/VI = umeclidinium/vilanterol


Donohue et al., 2013 (placebo-controlled study)

Efficacy and safety of once-daily umeclidinium/vilanterol 55/22 mcg in COPD9,10

Anoro Ellipta significantly improved lung function and symptoms in patients with COPD compared with placebo and was well tolerated

Study design

A Phase III, randomised, multicentre, double-blind, placebo-controlled, parallel-group 24-week lung function study comparing UMEC/VI 55/22 mcg OD against its constituents, UMEC 55 mcg OD and VI 22 mcg OD, and placebo in patients with COPD.

VI 22 mcg is not licensed for the treatment of COPD in the UK and therefore the results have not been included in the efficacy section but have been included in the safety section

COPD = chronic obstructive pulmonary disease; FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity; OD = once daily; R = randomisation; UMEC = umeclidinium; UMEC/VI = umeclidinium/vilanterol; VI = vilanterol

• Inhaled corticosteroids (ICS) were allowed at a stable dose of ≤1000 mcg/day of fluticasone propionate orequivalent

• Concomitant use of inhaled salbutamol as rescue medication was allowed

Patient population

• ≥40 years with clinical history of COPD with airflow limitation that is not fully reversible


• Post-salbutamol FEV1/FVC ratio <0.70

• Post-salbutamol FEV1 ≤70%


Endpoints

Primary endpoint



Secondary and other endpoints

• Weighted mean (wm) FEV1 over 0–6h post-dose on Day 168

• Serial FEV1 assessments

• Time to onset during 0–6h post-dose on Day 1


• Proportion of patients achieving an increase of ≥0.1 L above baseline in trough FEV1

• Peak FEV1 and serial and trough FVC

• Transition Dyspnoea Index (TDI) focal score

• Mean SOBDA score

• Rescue salbutamol use

• COPD exacerbations

• SGRQ


• AEs, vital signs, 12-lead ECG and 24h Holter monitoring, clinical chemistry and haematology


Characteristic UMEC/VI 55/22

mcg (n=413) UMEC 55 mcg

(n=418) Placebo (n=280)

Age (years), mean ± SD 63.1 ± 8.7 64.0 ± 9.2 62.2 ± 9.0

Female gender, n (%) 108 (26) 120 (29) 85 (30)

Smoking pack-year history, years ± SD 46.5 ± 25.8 46.8 ± 27.0 47.2 ± 27.1

Post-salbutamol % predicted FEV1, mean ± SD 47.8 ± 13.2 46.8 ± 13.4 46.7 ± 12.7

Post-salbutamol FEV1/FVC, mean ± SD 48.0 ± 11.4 46.8 ± 11.1 47.1 ± 11.5 FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity; UMEC = umeclidinium; UMEC/VI = umeclidinium/vilanterol

Results

Primary endpoint

• Pre-dose (trough) FEV1 on Day 169

o Trough FEV1 at Day 169 (LSM) was significantly improved from baseline with UMEC/VI 55/22 mcg (167 mL;95% CI 128, 207) and UMEC 55 mcg (115mL; 95% CI 76, 155) compared with placebo (all p<0.001)

o A statistically significant improvement from baseline in trough FEV1 was demonstrated for UMEC/VI 55/22mcg compared with UMEC 55 mcg (52 mL; p=0.004)


Figure 6: Change from baseline in trough FEV1 (ITT population)

Adapted from Donohue et al., 2013 CI = confidence interval; FEV1 = forced expiratory volume in 1 second; ITT = intention-to-treat; LS = least squares; UMEC = umeclidinium; UMEC/VI = umeclidinium/vilanterol; VI = vilanterol



o wmFEV1 at Day 168 (LSM) was significantly improved from baseline with UMEC/VI 55/22 mcg (242 mL;95% CI 202, 282) and UMEC 55 mcg (150mL; 95% CI 110, 190) compared with placebo (both p<0.001)

o Statistically significant improvements in wmFEV1 over 0–6h were also demonstrated for UMEC/VI 55/22mcg compared with UMEC 55 mcg (92 mL; p<0.001)

• Serial FEV1 assessments

o In the subset of patients with serial spirometry over 24h, significant improvements in serial FEV1 valueswere obtained with UMEC/VI 55/22 mcg and UMEC 55 mcg compared with placebo for the majority oftimepoints over 24h on Day 168

o Improvements in serial FEV1 values over 24h with UMEC/VI 55/22 mcg were greater compared with UMEC55 mcg for the majority of timepoints

• Time to onset during 0–6h post-dose on Day 1

o The median time to onset, defined as a post-dose FEV1 ≥100 mL above baseline, during 0–6h post-doseDay 1 was 27 minutes with UMEC/VI 55/22 mcg and 56 minutes with UMEC 55 mcg

o Subjects in the UMEC/VI 55/22 mcg treatment group had a higher likelihood of achieving an increase inFEV1 ≥100 mL above baseline on Day 1 than subjects in the UMEC 55 mcg treatment groups (p<0.001)


o The odds of achieving the defined increase in FEV1 was higher for UMEC/VI 55/22 mcg and UMEC 55 mcgcompared with placebo (OR 9.0, 95% CI 6.1, 13.2; and OR 5.9, 95% CI 4.0, 8.6 respectively; both p<0.001)

o The odds of achieving the defined increase in FEV1 was higher for UMEC/VI 55/22 mcg versus UMEC 55mcg (OR 1.5, 95% CI 1.2, 2.0, p=0.003)


• Proportion of patients achieving an increase of ≥0.1 L above baseline in trough FEV1

o The odds of achieving ≥0.1 L increase in FEV1 above baseline was higher for UMEC 55 mcg and UMEC/VI55/22 mcg compared with placebo (OR 3.2, 95% CI 2.2, 4.5 and OR 4.1, 95% CI 2.9, 5.9, respectively; bothp<0.001)

o There was no statistically significant difference in the odds of achieving ≥0.1 L increase in FEV1 abovebaseline was higher for UMEC/VI 55/22 mcg compared with UMEC 55 mcg (OR 1.3, 95% CI 1.0, 1.7,p=0.055)

• Peak FEV1

o Peak FEV1 increases from baseline (LSM) at Day 168 were significantly greater with UMEC/VI 55/22 mcg(224 mL, 95% CI 182, 267) and UMEC 55 mcg (130 mL, 95% CI 88, 172) compared with placebo (bothp<0.001)

o Peak FEV1 increases from baseline (LSM) at Day 168 were significantly greater with UMEC/VI 55/22 mcgcompared with UMEC 55 mcg (94 mL, 95% CI 57, 132; p<0.001)

• Trough FVC

o Improvements in trough FVC change from baseline (LSM) at Day 169 were significantly greater withUMEC/VI 55/22 mcg (248 mL, 95% CI 184, 313, p≤0.001) and UMEC 55 mcg (175 mL, 95% CI 110, 239,p=0.002) compared with placebo

o Improvements in trough FVC change from baseline (LSM) at Day 169 were significantly greater withUMEC/VI 55/22 mcg compared with UMEC 55 mcg (74 mL, 95% CI 16, 131, p=0.012)

• TDI focal score

o Clinically meaningful improvements in mean TDI scores from baseline (>1 demonstrating an improvementin dyspnoea) were observed with UMEC/VI 55/22 mcg (2.4 units) and UMEC 55 mcg (2.2 units) at Day 168

o Statistically significantly greater LSM TDI focal scores were demonstrated for the UMEC/VI 55/22 mcg andUMEC 55 mcg treatment groups compared with placebo at Day 168 (1.2 and 1.0 units, respectively, bothp<0.001)

o Differences in LSM TDI focal scores between UMEC/VI 55/22 mcg and UMEC 55 mcg were not statisticallysignificant

• Mean SOBDA score

o At Week 24, UMEC/VI 55/22 mcg and UMEC 55 mcg were associated with significant improvements inSOBDA score compared with placebo (UMEC/VI 55/22 mcg –0.17, p<0.001 and UMEC 55 mcg –0.10,p=0.043)

o Differences in SOBDA scores between UMEC/VI 55/22 mcg and UMEC 55 mcg were not statisticallysignificant

• Rescue salbutamol use

o Over the 24-week study period, both active treatments resulted in less rescue salbutamol use comparedwith placebo (UMEC/VI 55/22 mcg –0.8 puffs/day, p=0.001 and UMEC 55 mcg –0.3 puffs/day, p=0.276)

o Rescue medication use was significantly lower with UMEC/VI 55/22 mcg compared with UMEC 55 mcg(–0.6 puffs/day, p=0.014)


• COPD exacerbations‡

o On-treatment COPD exacerbations were reported in 13% of patients in the placebo group, 8.4% ofpatients in the UMEC 55 mcg group and 7.0% of patients in the UMEC/VI 55/22 mcg group

o The analysis of time to first COPD exacerbation indicated that UMEC/VI 55/22 mcg and UMEC 55 mcgresulted in a lower risk of COPD exacerbation compared with placebo (HR 0.5, p=0.004 for UMEC/VI 55/22mcg and HR 0.6, p=0.035 for UMEC 55 mcg)

o The analysis of time to first COPD exacerbation indicated that the risk of COPD exacerbation was notstatistically significantly different between UMEC/VI 55/22 mcg and UMEC 55 mcg

• SGRQ

o Both the UMEC/VI and UMEC treatments resulted in an improvement (i.e. a reduction) in SGRQ score atDay 168 (UMEC/VI 55/22 mcg –5.51; UMEC 55 mcg –4.69; both p<0.001)

o Differences in SGRQ scores between UMEC/VI 55/22 mcg and UMEC 55 mcg were not statisticallysignificant

Safety

• On-treatment AEs were similar across treatment groups (46–52%)

• Treatment-related AEs occurred in 8%, 6%, 6% and 7% of patients in the UMEC 55 mcg, UMEC/VI 55/22 mcg, VI 22mcg, and placebo groups, respectively

• The most frequent on-treatment AEs were headache (6–9%), nasopharyngitis (6–9%), and upper respiratory tractinfections (3–5%)

• No clinically meaningful changes were observed in vital signs, 12-lead ECG and 24h Holter ECG parameters, orclinical laboratory tests for UMEC/VI 55/22 mcg, UMEC 55 mcg and VI 22 mcg, compared with placebo

• Fatal AEs occurred in nine patients: three in the UMEC 55 mcg group (COPD/acute respiratory failure, suddendeath, cholecystitis and peritonitis); three in the UMEC/VI 55/22 mcg group (COPD exacerbation/respiratoryfailure, myocardial infarction, unknown cause); and three in the VI 22 mcg group (sudden death, COPDexacerbation, COPD exacerbation/renal failure)

‡ Anoro Ellipta is indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD and Incruse Ellipta is indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD. This study was not specifically designed to evaluate the effect of treatments on COPD exacerbations and in order to minimise the impact of acute worsening of disease and related treatments on the lung function assessments, subjects were to be withdrawn if an exacerbation occurred.



Placebo (n=280)

UMEC 55 mcg (n=418)

VI 22 mcg (n=421)


On-treatment AE, n (%) 130 (46) 216 (52) 204 (48) 212 (51)

Treatment-related AE, n (%) 19 (7) 34 (8) 26 (6) 25 (6)

AEs leading to permanent discontinuation of study drug or withdrawal from 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 (%) 0 3 (<1) 3 (<1) 3 (<1) Most frequent on-treatment AEs occurring in ≥5% in any group, n (%)

Headache Nasopharyngitis URTI

26 (9) 16 (6) 14 (5)

32 (8) 29 (7) 21 (5)

25 (6) 26 (6) 18 (4)

35 (8) 39 (9) 13 (3)


Acquired long QT Cardiac arrhythmias Cardiac failure Cardiac ischaemia Hypertension Sudden death Stroke

Effects on glucose Effects on potassium Tremor Urinary retention Ocular effects Gallbladder disorders Pneumonia Intestinal obstruction Anticholinergic syndrome

26 (9) 0

12 (4) 5 (2) 3 (1) 6 (2)

0 2 (<1) 1 (<1) 1 (<1) 1 (<1)

0 2 (<1) 1 (<1) 2 (<1)

0 8 (3)

41 (10) 1 (<1) 20 (5) 7 (2) 7 (2)

12 (3) 0

1 (<1) 7 (2)

0 3 (<1)

0 3 (<1) 3 (<1) 6 (1)

0 18 (4)

31 (7) 0

18 (4) 3 (<1) 3 (<1) 7 (2)

1 (<1) 2 (<1) 7 (2)

0 0 0

2 (<1) 2 (<1) 4 (<1)

0 14 (3)

33 (8) 0

18 (2) 3 (<1) 7 (2)

15 (4) 0 0

6 (1) 0 0 0

4 (<1) 0

8 (2) 1 (<1) 10 (2)

a Includes both on-treatment and post-treatment AEs; b Fatal AEs occurred in nine patients: three in the VI 22 mcg group (sudden death, COPD exacerbation, COPD exacerbation/renal failure), three in the UMEC/VI 55/22 mcg group (COPD exacerbation/respiratory failure, myocardial infarction, unknown cause) and three in the UMEC 55 mcg group (COPD/acute respiratory failure, sudden death, cholecystitis and peritonitis).

AE = adverse event; OD = once daily; SAE = serious adverse event; UMEC = umeclidinium; UMEC/VI = umeclidinium/vilanterol; URTI = upper respiratory tract infection; VI = vilanterol


Donohue et al., 2014 (safety study)

Safety and tolerability of once-daily umeclidinium/vilanterol 125/25 mcg and umeclidinium 125 mcg in patients with chronic obstructive pulmonary disease: results from a 52-week, randomised, double-blind, placebo-controlled study11

This safety study was done with unlicensed doses but has been included in the Evidence Dossier for safety transparency purposes.

UMEC/VI 113/22 mcg and UMEC 113 mcg were well tolerated over 12 months of treatment in patients with COPD

Study design

A Phase III, randomised, multicentre, double-blind, placebo-controlled, parallel-group, 52-week study to assess the safety and tolerability of 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 not licensed in the UK COPD = chronic obstructive pulmonary disease; FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity; OD = once daily; R = randomisation; UMEC = umeclidinium; UMEC/VI = umeclidinium/vilanterol; VI = vilanterol

• Patients who experienced a COPD exacerbation or lower respiratory tract infection (LRTI) during the run-in periodor at Visit 2 were allowed to re-screen and repeat the run-in period

• All treatments were administered in the morning via the Ellipta dry powder inhaler

• Rescue medications permitted throughout the run-in and treatment periods included salbutamol and/oripratropium bromide, administered via metered dose inhaler or nebules

Patient population

• Current or former smokers with a smoking history of ≥10 pack-years


• Clinical history of COPD


• Post-salbutamol FEV1 ≥35% and ≤80% of predicted values

Endpoints

• Incidence of AEs, SAEs, drug-related AEs and AEs of special interest throughout the course of the study

• Clinical laboratory assessments and vital sign evaluations

• 12-lead ECG and 24h Holter ECG assessment


• Trough FEV1 and trough FVC mean change (mL) from baseline

• COPD exacerbations (incidence and time to first COPD exacerbation) and rescue medication use

• All endpoints were assessed in the ITT population

Baseline demographics and clinical characteristics

Characteristic UMEC 113 mg

(n=227) UMEC/VI 113/22 mg

(n=226) Placebo (n=109)

Mean age, years ± SD 61.7 ± 9.1 61.4 ± 9.0 60.1 ± 8.3 Female gender, n (%) 82 (36) 70 (31) 36 (33) Smoking pack-years, mean ± SD 39.2 ± 21.2 43.7 ± 27.5 42.8 ± 24.7 Current medical condition, n (%) 196 (86) 190 (84) 88 (81) Pre-bronchodilator FEV1 (L), mean ± SD

1.432 ± 0.005 n=225

1.498 ± 0.005 n=225

1.579 ± 0.006 n=108

Post-salbutamol % predicted FEV1 (mL), mean ± SD

54.2 ± 11.8 n=225

55.0 ± 12.1 n=224

55.1 ± 11.7 n=109

FEV1 = forced expiratory volume in 1 second; SD = standard deviation; UMEC = umeclidinium; UMEC/VI = umeclidinium/vilanterol

Results

• Incidence of AEs, serious AEs, drug-related AEs and AEs of special interest throughout the course of the study

o The incidence of on-treatment AEs, SAEs and drug-related AEs was similar across treatment groups andplacebo (AEs: 52–58%; SAEs: 6–7%; drug-related AEs: 12–13%)

▪ Headache (8–11%), nasopharyngitis (5–9%) and ventricular extrasystoles (5% in each treatmentgroup) were the most frequently reported AEs

▪ Patients in the UMEC 113 mcg group reported ≥2% higher incidences of headache andnasopharyngitis compared with placebo. Patients in the UMEC/VI 113/22 mcg group reportedsimilar (≤1% difference) or fewer incidences of the most common AEs when compared withplacebo

▪ The incidence of AEs resulting in permanent discontinuation or withdrawal was less in the UMEC113 mcg group and the UMEC/VI 113/22 mcg group compared with placebo (9% and 8% ofpatients respectively, compared with 12% for placebo)

▪ The only on-treatment SAEs reported by ≥1% of patients in any treatment group were COPD andpneumonia (all incidences ≤3%)

▪ The incidence of predefined AEs of special interest (pneumonia and glucose effect) and furtherspecial interest groups was low and generally similar across treatment groups, with no individualon-treatment AE reported by >5% of patients

▪ In the pneumonia special interest group, a higher overall incidence of AEs was reported withUMEC 113 mcg (5%) compared with UMEC/VI 113/22 mcg or placebo (both 2%)

▪ In the glucose effect special interest group, a higher overall incidence of AEs was reported withUMEC/VI 113/22 mcg (4%) compared with UMEC 113 mcg (<1%) or placebo (0%)

▪ In the cardiovascular special interest group, a lower overall incidence of AEs was reported withUMEC 113/22 mcg (15%) compared with the UMEC 113 mcg group (22%) or placebo (23%)


Table 7: Summary of AEs

UMEC 113 mg (n=227)

UMEC/VI 113/22 mg (n=226)

Placebo (n=109)

On-treatment AE, n (%) 132 (58) 120 (53) 57 (52)

On-treatment SAE, n (%) 17 (7) 14 (6) 7 (6) On-treatment deaths,a n (%) None were considered related to the study treatment

4 (2) 0 1 (<1)

Most common AEs reported by ≥ 4% patients, n (%)

Headache Nasopharyngitis Ventricular extrasystoles Extrasystoles Back pain Hypertension Sinusitis Influenza Upper respiratory tract infection Ventricular tachycardia

25 (11) 20 (9) 12 (5) 10 (4) 9 (4) 4 (2) 6 (3) 5 (2) 8 (4)

3 (1)

20 (9) 11 (5) 11 (5) 10 (4) 10 (4) 8 (4) 8 (4) 6 (3)

2 (<1)

4 (2)

9 (8) 5 (5) 5 (5) 4 (4) 3 (3) 5 (5) 3 (3) 5 (5) 3 (3)

4 (4) Most common SAEs reported by ≥1% patients, n (%)

COPD Pneumonia

4 (2)

0

2 (<1)

3 (1)

3 (3)

0 AESI reported by ≥2% patients, n (%)

Cardiovascular Pneumonia Anticholinergic syndrome Effects on glucose

34 (15) 5 (2) 5 (2)

8 (4)

49 (22) 11 (5) 5 (2)

1 (<1)

25 (23) 2 (2) 2 (2)

0 Proportion of patients with one or more abnormal, clinically significant ECG interpretation

At any time post baseline 26% 24% 23% Proportion of patients with one or more abnormal, clinically significant 24-hour Holter ECG interpretation

At any time post baseline 55% 55% 52% COPD exacerbations,b n (%)

Proportion of patients reporting Proportion resulting in hospitalisation HR vs placebo (time to first exacerbation)

15%

7% 0.4; 95% CI: 0.3, 0.8;

RR = 60%

13%

6% 0.6; 95% CI: 0.3, 1.0;

RR = 40%

24%

12% -

a On-treatment deaths occurred in five patients: four patients in the UMEC 113 mcg group (spine metastases; liver metastases; pneumonia; cardiac failure) and one patient in the placebo group (coronary artery insufficiency). None were considered related to the study treatment. b Anoro Ellipta is indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD and Incruse Ellipta is indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD

AE = adverse event; AESI = adverse event of special interest; ECG = electrocardiogram; SAE = serious adverse event; UMEC = umeclidinium; UMEC/VI = umeclidinium/vilanterol


• Clinical laboratory assessments and vital sign evaluations

o Clinical laboratory assessments and vital sign evaluations showed no clinically significant change frombaseline or treatment-related effect in any parameter across treatments

• 12-lead ECG and 24h Holter ECG assessment

o A similar proportion of patients measured on 12-lead ECG at any time post-baseline reported one or moreabnormal clinically significant interpretation across treatment groups (23–26%)

o A similar proportion of patients with one or more abnormal, clinically significant Holter ECG interpretationat any-time post-baseline was reported across treatment groups (52–55%)

• COPD exacerbations§ (incidence and time to first COPD exacerbation)

o COPD exacerbations were reported less frequently with UMEC 113 mcg (15%) and UMEC/VI 113/22 mcg(13%) compared with placebo (24%). COPD exacerbations resulting in hospitalisation were also fewer withUMEC 113 mcg (7%) and UMEC/VI 113/22 mcg (6%) compared with placebo (12%). UMEC 113 mcg andUMEC/VI 113/22 mcg were associated with a lower risk of COPD exacerbation compared with placebo,based on analysis of time to first exacerbation (hazard ratio [HR] = 0.4, 95% CI 0.3, 0.8; risk reduction 60%;HR = 0.6, 95% CI 0.3, 1.0, risk reduction 40%, respectively)

§ Anoro Ellipta is indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD


Feldman et al., 2012 (safety study)

Safety and tolerability, pharmacodynamics (PD) and pharmacokinetics (PK) of umeclidinium/vilanterol in patients with moderate to very severe COPD12

This safety study was done with unlicensed doses but has been included in the Evidence Dossier for safety transparency purposes.

Once-daily dosing with UMEC 500 mcg in combination with VI 25 mcg in patients with moderate to very severe COPD was well tolerated over 28 days

Study design

A multicentre, double-blind, placebo-controlled, parallel group study of UMEC/VI 500/25 mcg** in patients with moderate to very severe COPD.

UMEC/VI 500/25 mcg is not licensed in the UK

COPD = chronic obstructive pulmonary disease; FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity; OD = once daily; R = randomisation; UMEC/VI = umeclidinium/vilanterol; wm = weighted mean

Patient population


• Clinical history of COPD

• Smoking history of ≥10 pack-years


• Post-salbutamol FEV1 ≤80% of predicted values

Endpoints

Primary endpoint

• Change from baseline in wm pulse rate during 0–6h post-dose on Day 28


• wm pulse rate during 0–6h post-dose on Days 1 and 14

• Maximum and minimum pulse rate during 0–6h post-dose on Days 1, 14 and 28

• wm systolic and diastolic blood pressure 0–6h post-dose on Days 1, 14 and 28

** UMEC/VI 500/25 mcg is not licensed in the UK


• Maximum systolic and minimum diastolic blood pressure on Days 1, 14 and 28

• 24h Holter ECG parameters at screening and Day 28

• Maximum QTc with interval corrected by Fridericia’s method (QTcF) (during 0–6h post-dose) on Days 1, 14, and 28(measured using 12-lead ECG)

• Changes in haematological and clinical chemistry parameters from baseline on Days 14 and 29

• Incidence of AEs and SAEs throughout the 28-day treatment period and follow-up

• Incidence of COPD exacerbations

• Plasma concentrations and derived PK (maximum plasma concentration (Cmax), time to maximum plasmaconcentration (tmax), area under the curve (AUC) for UMEC and VI parameters)



Placebo (n=9)

Age (years), mean ± SD 59.2 ± 9.5 58.7 ± 9.8

Female gender, n (%) 18 (43) 2 (22)

Smoking pack-years, mean ± SD 58.4 ± 26.0 75.7 ± 44.7

Pre-bronchodilator FEV1 (L), mean ± SD 1.482 ± 0.58 1.642 ± 0.46

Post-bronchodilator % predicted FEV1 (mL), mean ± SD 48.4 ± 15.3 50.6 ± 15.6 FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity; SD = standard deviation; UMEC/VI = umeclidinium/vilanterol

Results

Primary endpoint

• Change from baseline in wm pulse rate during 0–6h post-dose on Day 28

o UMEC/VI 500/25 mcg was non-inferior to placebo in wm pulse rate over 0–6h at Day 28 (difference of–0.5 bpm; 95% CI –5.5, 4.5)


• wm pulse rate during 0–6h post-dose on Days 1 and 14

o On Day 1 the adjusted mean changes from baseline in wm pulse rate (0–6h) were similar for UMEC/VI500/25 mcg (–0.6 bpm) and placebo (–1.2 bpm)

o On Day 14 the adjusted change from baseline for UMEC/VI 500/25 mcg was 3.1 bpm and for placebo was–1.7 bpm

o The adjusted mean treatment differences between UMEC/VI 500/25 mcg, and placebo for wm pulse rate(0–6h) was 0.6 bpm (95% CI –3.9, 5.2) on Day 1 and 4.8 bpm (95% CI –1.2, 10.9) on Day 14

• Maximum and minimum pulse rate during 0–6h post-dose on Days 1, 14 and 28

o The adjusted mean treatment differences between UMEC/VI 500/25 mcg and placebo during 0–6hmaximum pulse rate were 2.0 bpm (95% CI –3.7, 7.6) on Day 1; 4.8 bpm (95% CI –1.8, 11.3) on Day 14,and –1.3 bpm (95% CI –6.9, 4.3) on Day 28

o The adjusted mean treatment differences between UMEC/VI 500/25 mcg, and placebo for 0–6h minimumpulse rate were 0.3 bpm (95% CI –4.3, 5.0) on Day 1; 4.0 bpm (95% CI –2.3, 10.2) on Day 14, and 1.7 bpm(95% CI –3.6, 7.1) on Day 28

• wm systolic and diastolic blood pressure 0–6h post-dose on Days 1, 14 and 28

o The adjusted mean changes in 0–6h weighted mean systolic/diastolic blood pressure from baseline onDays 1, 14, and 28 were 130.8/79.2 mmHg, 131.0/79.3 mmHg and 134.6/81.3 mmHg for placebo and134.0/80.1 mmHg, 131.1/78.7 mmHg and 130.9/77.8 mmHg for UMEC/VI 500/25 mcg, respectively

• Maximum systolic and minimum diastolic blood pressure on Days 1, 14 and 28


o The adjusted mean changes in maximum systolic blood pressure from baseline on Days 1, 14, and 28 forplacebo and UMEC/VI 500/25 mcg were 138.1 and 143.9 mmHg, 143.8 and 142.7 mmHg and 145.1 and140.6 mmHg, respectively

o The adjusted mean changes in minimum diastolic blood pressure from baseline on Days 1, 14, and 28 forplacebo and UMEC/VI 500/25 mcg were 73.7 and 73.7 mmHg, 73.2 and 71.4 mmHg and 75.7 and 70.6mmHg, respectively

• 24h Holter ECG parameters at screening and Day 28

o 86% of patients on UMEC/VI and 89% of patients on placebo had no change or insignificant changes, and11% of patients in each group had clinically significant unfavourable changes

o The proportion of patients who had a clinically significant unfavourable change from baseline in the 12-lead ECG at any time post-baseline was similar between UMEC/VI 500/25 mcg (29%) and placebo (22%)

• Maximum QTc with interval corrected by Fridericia’s method (QTcF) (during 0–6h post-dose) on Days 1, 14, and 28(measured using 12-lead ECG)

o Analysis of change from baseline in 0–6h maximum QTcF showed no evidence of a difference betweenUMEC/VI 500/25 mcg compared with placebo: Day 1, 3.0 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 haematological and clinical chemistry parameters from baseline on Days 14 and 29

o There were no clinically relevant treatment changes in haematology, clinical chemistry or urinalysisassessments

• Incidence of AEs and SAEs throughout the 28-day treatment period and follow-up

o On-treatment AEs were higher with UMEC/VI than with placebo (26% vs 11%)

o No deaths or SAEs were reported

Table 8. Adverse events reported by at least one patient

Placebo UMEC/VI 500/25 mcg

On-treatment AE, n (%) 1 (11) 11 (26)

Sinusitis 1 (11) 1 (2)

Gastroenteritis 0 1 (2)

Upper abdominal pain 0 1 (2)

Dry mouth 0 1 (2)

Nausea 0 1 (2)

Swollen tongue 0 1 (2)

Cough 0 1 (2)

Dyspnea 0 1 (2)

Pleurisy 0 1 (2)

Allergic rhinitis 0 1 (2)

Gout 0 1 (2)

Hypokalemia 0 1 (2)

Abnormal dreams 0 1 (2)

Anxiety 0 1 (2)

Cholelithiasis 0 1 (2)

Muscle strain 0 1 (2)

Rash 0 1 (2) AE = adverse event; UMEC/VI = umeclidinium/vilanterol


• Incidence of COPD exacerbations††

o Three patients (UMEC/VI 500/25 mcg) had a COPD exacerbation; the primary causes reported by theinvestigator were lack of efficacy (treatment) (n=2) and upper respiratory infection other than thecommon cold (n=1)

• Plasma concentrations and derived PK (maximum plasma concentration (Cmax), time to maximum plasmaconcentration (tmax), area under the curve (AUC) for UMEC and VI parameters)

o Following single and repeat dosing of UMEC in combination with VI, both UMEC and VI were rapidlyabsorbed (median tmax ~6 min for both drugs) with a higher Cmax on Day 14 compared with Day 1

o The observed mean accumulation of Cmax for Day 14 vs. Day 1 was 38% (90% CI 6, 80) for UMEC and 31%(90% CI 5, 63) for VI. No further accumulation was seen on Day 28

o There were no differences in AUC for either drug on Day 1, 14 and 28, with ratios ranging between 0.8 and0.9 for both comparisons (Day 14/Day 1 and Day 28/Day1). PK data on both days showed high variabilitywith a large percent coefficient of variance

o Evaluation of individual steady-state Cmax and change from baseline in pulse rate on Day 28 showed noobvious trends for either UMEC or VI, and the changes from baseline were similar to that observed withplacebo

†† Anoro Ellipta is indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD


Van der Palen et al., 2016 (critical errors)

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 commonly used inhaler devices13

The Ellipta inhaler is easy to use and significantly fewer patients made critical errors compared with other commonly used devices after reading the patient information leaflet

Study design

A randomised, multicentre, single visit, open-label, cross over study comparing the Ellipta inhaler device against other devices in patients with asthma and patients with COPD. The results below focus only on COPD studies; asthma results are not presented here.

COPD = chronic obstructive pulmonary disease; MDI = metered-dose inhaler; R = randomisation

• Patients entering the study were naïve to Ellipta and at least one other device

• Each substudy was individually powered

• Critical errors were assessed by trained respiratory nurses after patients had read the patient information leaflet(PIL). A critical error is defined as an error that is likely to result in the inhalation of significantly reduced, minimal orno medication

• If the patient made errors, the investigator demonstrated the correct use of the inhaler, and the patientdemonstrated inhaler use again

Patient population

• ≥18 years with a physician diagnosis of COPD and currently receiving treatment for COPD

• Naïve to Ellipta inhaler use

Endpoints

Primary endpoint

• Critical errors using the devices after reading the PIL only

Secondary endpoints

• Overall errors using the devices after reading the PIL only

• Instruction from trained respiratory nurse on use of the devices

• Time to correct inhaler use

• Ease of use of the devices

• Patient preference for devices



Characteristic 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 ± SD 67.3 ± 8.3 67.8 ± 7.4 65.6 ± 8.8 68.1 ± 8.7 67.3 ± 9.0 67.2 ± 8.2

Female gender, n (%) 225 (40) 68 (40) 27 (34) 33 (33) 46 (39) 51 (52)

COPD history, n (%)

6 months–10 years

10–25 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)

COPD = chronic obstructive pulmonary disease; MDI = metered-dose inhaler

Results

Primary endpoint

• Critical errors using the devices after reading the PIL only

o After reading the PIL, the proportion of patients with COPD who made at least one critical error wassignificantly lower with the Ellipta device compared with all others (all p<0.001)

o For the Ellipta inhaler, the most common critical error was exhaling directly into the mouthpiece (31/567[5%] patients with COPD)

o For the Accuhaler device, the lever was not pushed back properly by 33% of patients with COPD (56/171)

o For the MDI device, poor press-and-breathe coordination was observed in 43% (34/80) of patients withCOPD

o For the Turbohaler device, 29% (29/100) patients with COPD did not twist the base properly and hear theclick

o For both the HandiHaler and the Breezhaler, the capsule did not rattle with 36% (42/118) and 43% (42/98)of patients with COPD, respectively

Figure 7: Percentage of patients with COPD with at least one critical error after reading the PIL

Adapted from van der Palen et al., 2016 MDI = metered-dose inhaler; PIL = patient information leaflet


Secondary endpoints

• Overall errors using the devices after reading the PIL only

o In all five COPD groups, there were significantly fewer patients who experienced at least one overall errorwith the Ellipta device compared with all the others

▪ 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

• Instruction from trained respiratory nurse on use of the devices

o After reading the PIL, the majority of patients with COPD made no errors using the Ellipta inhaler and didnot require instruction from a trained respiratory nurse. In contrast, for the other devices, the majority ofpatients did require instruction from a trained respiratory nurse. Percentage of patients making no errorsand thus not requiring instruction:

▪ 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)

o The difference in the number of nurse instructions required until correct use was performed wassignificant between the Ellipta inhaler and all the other devices (p<0.001 in all subgroups)

▪ When compared with the Ellipta inhaler, more patients required more than one instruction forthe use of the Accuhaler (7 versus 27 patients), MDI (3 versus 20 patients), Turbohaler (6 versus19 patients), HandiHaler (13 versus 29 patients) and Breezhaler (2 versus 15 patients) devices

• Time to correct inhaler use

o In all substudies, median time to correct inhaler use without trained respiratory nurse support (readingthe PIL only) could only be determined for the Ellipta inhaler as for the other devices more than half ofpatients with COPD could not perform correct use after reading the PIL only

o In all substudies, median time to correct inhaler use reading the PIL and receiving trained respiratorynurse support was significantly shorter for patients using the Ellipta inhaler compared with those using:

▪ Accuhaler (2.75 versus 3.93 min; p<0.001)

▪ MDI (3.79 versus 6.30 min; p<0.001)

▪ Turbohaler (2.87 versus 7.80 min; p<0.001)

▪ HandiHaler (4.32 versus 8.50 min; p<0.001)

▪ Breezhaler (3.15 versus 8.44 min; p<0.001)

• Ease of use of the devices

o A larger proportion in each group rated the Ellipta inhaler very easy or easy compared with the otherdevices

▪ 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)


o Between 96% and 100% of COPD patients reported they found it very easy to determine how muchmedication was left in the Ellipta inhaler; 61%, 63%, 45%, 42% and 60% of patients reported they found itvery easy to determine how much medication was left in Accuhaler, MDI, Turbohaler, HandiHaler andBreezhaler devices, respectively

• Patient preference for devices

o The majority of patients with COPD preferred Ellipta over other commonly used inhalers (all p<0.001)

Figure 8: Overall device preference reported in each substudy

Adapted from van der Palen et al., 2016 MDI = metered-dose inhaler

o The majority of patients preferred the Ellipta inhaler for most individual criteria:

▪ Number of steps for correct use, time taken to use, size of device, dose counter, comfort ofmouthpiece and ease of opening (p<0.001) with some exceptions where there was no difference(listed below)

o Criteria for which there was no difference in patient preference between devices:

▪ Size of the inhaler, % patients preferring:

• Ellipta: 39% or MDI: 33%

• Ellipta: 44% or Turbohaler: 38%

• Ellipta: 41% or Breezhaler: 44%

▪ Comfort of mouthpiece, % patients preferring:

• Ellipta: 33% or HandiHaler: 31%

• Ellipta: 40% or Breezhaler: 37%


References 1. GlaxoSmithKline UK. Anoro Ellipta (umeclidinium/vilanterol 55/22 mcg) Summary of Product Characteristics.

2. GlaxoSmithKline UK. Incruse (umeclidinium 55 mcg) Summary of Product Characteristics.

3. Feldman GJ, Sousa AR, Lipson DA, et al. Comparative Efficacy of Once-Daily Umeclidinium/Vilanterol andTiotropium/Olodaterol Therapy in Symptomatic Chronic Obstructive Pulmonary Disease: A Randomized Study. Advances intherapy. 2017.

4. Maleki-Yazdi MR, Singh D, Anzueto A, Tombs L, Fahy WA, Naya I. Assessing Short-term Deterioration in Maintenance-naivePatients with COPD Receiving Umeclidinium/Vilanterol and Tiotropium: A Pooled Analysis of Three Randomized Trials. Advances in therapy. 2017;33(12):2188-2199.

5. Kerwin EM, Kalberg CJ, Galkin DV, et al. Umeclidinium/vilanterol as step-up therapy from tiotropium in patients withmoderate COPD: a randomized, parallel-group, 12-week study. International journal of chronic obstructive pulmonarydisease. 2017;12:745-755.

6. Decramer M, Anzueto A, Kerwin E, et al. Efficacy and safety of umeclidinium plus vilanterol versus tiotropium, vilanterol, orumeclidinium monotherapies over 24 weeks in patients with chronic obstructive pulmonary disease: results from twomulticentre, blinded, randomised controlled trials. The Lancet Respiratory medicine. 2014;2(6):472-486.

7. Kalberg C, O'Dell D, Galkin D, Newlands A, Fahy WA. Dual Bronchodilator Therapy with Umeclidinium/Vilanterol VersusTiotropium plus Indacaterol in Chronic Obstructive Pulmonary Disease: A Randomized Controlled Trial. Drugs in R&D. 2016;16(2):217-227.

8. GlaxoSmithKline. Clinical Study Report for Study DB2116961. 2015.

9. Donohue JF, Maleki-Yazdi MR, Kilbride S, Mehta R, Kalberg C, Church A. Efficacy and safety of once-dailyumeclidinium/vilanterol 62.5/25 mcg in COPD. Respiratory medicine. 2013;107(10):1538-1546.

10. GlaxoSmithKline. Clinical Study Report for Study 113373. 2015.

11. Donohue JF, Niewoehner D, Brooks J, O'Dell D, Church A. Safety and tolerability of once-daily umeclidinium/vilanterol125/25 mcg and umeclidinium 125 mcg in patients with chronic obstructive pulmonary disease: results from a 52-week, randomized, double-blind, placebo-controlled study. Respiratory research. 2014;15:78.

12. Feldman G, Walker RR, Brooks J, Mehta R, Crater G. 28-Day safety and tolerability of umeclidinium in combination withvilanterol in COPD: a randomized placebo-controlled trial. Pulmonary pharmacology & therapeutics. 2012;25(6):465-471.

13. van der Palen J, Thomas M, Chrystyn H, et al. A randomised open-label cross-over study of inhaler errors, preference andtime to achieve correct inhaler use in patients with COPD or asthma: comparison of ELLIPTA with other inhaler devices. NPJ primary care respiratory medicine. 2016;26:16079.

How to request additional information from GSK

Should you require any further information, please contact the GSK customer contact centre:

• By phone on 0800 221 441. Lines are open from Monday to Friday 8.30am to 5.30pm. Outside these hours and onbank holidays, an answer phone service is available.

• By email at [email protected]

mailto:[email protected]


Anoro▼Ellipta (umeclidinium bromide/vilanterol [trifenatate]) Prescribing Information

(Please consult the full Summary of Product Characteristics (SmPC) before prescribing)

Anoro Ellipta 55/22mcg (umeclidinium bromide /vilanterol [as trifenatate]) inhalation powder. Each single inhalation provides a delivered dose (the dose leaving the mouthpiece) of 55 micrograms umeclidinium (equivalent to 65 micrograms of umeclidinium bromide) and 22 micrograms of vilanterol (as trifenatate). Indications: Anoro is indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD). Dosage and administration: Inhalation only. One inhalation once daily of Anoro. Contraindications: Hypersensitivity to the active substances or to any of the excipients (lactose monohydrate and magnesium stearate). Precautions: Anoro should not be used in patients with asthma. Treatment with Anoro should be discontinued in the event of paradoxical bronchospasm and alternative therapy initiated if necessary. Cardiovascular effects may be seen after the administration of muscarinic receptor antagonists and sympathomimetics therefore Anoro should be used with caution in patients with severe cardiovascular disease. Anoro should be used with caution in patients with urinary retention, narrow angle glaucoma, convulsive disorders, thyrotoxicosis, hypokalaemia, hyperglycaemia and severe hepatic impairment. No dosage adjustment is required in renal or mild to moderate hepatic impairment. Acute symptoms: Anoro is not indicated for acute episodes of bronchospasm. Warn patients to seek medical advice if short-acting inhaled bronchodilator use increases, a re-evaluation of the patient and of the COPD treatment regimen should be undertaken. Interactions with other medicinal products: Avoid β-blockers. Caution is advised when co-administering with strong CYP3A4 inhibitors

(e.g. ketoconazole, clarithromycin, itraconazole, ritonavir, telithromycin). Anoro should not be used in conjunction with other long-acting β2- adrenergic agonists or medicinal products containing long-acting muscarinic antagonists. Caution is advised with concomitant use with methylxanthine derivatives, steroids or non-potassium-sparing diuretics as it may potentiate possible hypokalaemic effect of β2-adrenergic agonists. Fertility, pregnancy, and breast-feeding: No available data. Balance risks against benefits. Side effects: Common (≥1/100 to <1/10): urinary tract infection, sinusitis, nasopharyngitis, pharyngitis, upper respiratory tract infection, headache, cough, oropharyngeal pain, constipation and dry mouth. Other important side effects include: Uncommon (≥1/1,000 to <1/100) atrial fibrillation, supraventricular tachycardia, rhythm idioventricular, tachycardia, supraventricular extrasystoles, palpitations, and hypersensitivity reactions including rash. Rare (≥1/10,000 to <1/1,000) anaphylaxis, angioedema, and urticaria. Glaucoma, vision blurred, intraocular pressure increased and paradoxical bronchospasm. See SmPC for other adverse reactions. Legal category: POM. Presentation and Basic NHS cost: Anoro Ellipta. 1 inhaler x 30 doses. Anoro Ellipta 55/22mcg - £32.50. Marketing authorisation (MA) no. 55/22mcg 1x30 doses [EU/1/14/898/002]; MA holder: Glaxo Group Ltd, 980 Great West Road, Brentford, Middlesex TW8 9GS, UK. Last date of revision: July 2018. UK/UCV/0095/15(2)c. Anoro and Ellipta are registered trademarks of the GlaxoSmithKline group of companies. All rights reserved. Anoro was developed in collaboration with Innoviva Inc.

Adverse events should be reported. Reporting forms and information can be found at http://www.mhra.gov.uk/yellowcard or search for MHRA Yellowcard in the Google Play or Apple App

store. Adverse events should also be reported to GlaxoSmithKline on 0800 221 441


Incruse▼Ellipta (umeclidinium bromide) Prescribing Information

(Please consult the full Summary of Product Characteristics (SmPC) before prescribing)

Incruse Ellipta 55mcg (umeclidinium) inhalation powder. Each single inhalation provides a delivered dose (the dose leaving the mouthpiece of the inhaler) of 55 micrograms umeclidinium (equivalent to 65 micrograms of umeclidinium bromide). Indications: Incruse is indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD). Dosage and administration: Inhalation only. One inhalation once daily of Incruse Ellipta at the same time of the day each day. Contraindications: Hypersensitivity to the active substances or to any of the excipients (lactose monohydrate and magnesium stearate). Precautions: Incruse Ellipta should not be used in patients with asthma. Treatment with Incruse Ellipta should be discontinued in the event of paradoxical bronchospasm and alternative therapy initiated if necessary. Cardiovascular effects may be seen after the administration of muscarinic receptor antagonists, therefore Incruse Ellipta should be used with caution in patients with severe cardiovascular disorders, particularly cardiac arrhythmias. Incruse Ellipta should be used with caution in patients with urinary retention or narrow angle glaucoma. No dosage adjustment is required in renal or mild to moderate hepatic impairment. Acute Symptoms: Incruse Ellipta is not indicated for acute episodes of bronchospasm. Warn patients to seek medical advice if short-acting inhaled

bronchodilator use increases, a re-evaluation of the patient and of the COPD treatment regimen should be undertaken. Interactions with other medicinal products: Co-administration with other long-acting muscarinic antagonists or medicinal products containing this active substance has not been studied and therefore, is not recommended. Fertility, pregnancy, and breast-feeding: No available human in vivo data. Balance risks against benefits. Side effects: Common (≥1/100 to <1/10): Nasopharyngitis, upper respiratory tract infection, urinary tract infection, sinusitis, headache, tachycardia, cough. Other Important side effects include. Uncommon (≥1/1,000 to <1/100): Atrial fibrillation, rhythm idioventricular, supraventricular tachycardia, supraventricular extrasystoles. Hypersensitivity reactions including rash, urticaria, pruritus. Not Known (cannot be estimated from available data): Glaucoma and vision blurred. Legal category: POM. Presentation and Basic NHS cost: Incruse Ellipta. 1 inhaler x 30 doses. Incruse Ellipta 55mcg - £27.50. Marketing authorisation (MA) nos. 55mcg 1x30 doses [EU/1/14/922/002]; MA holder: Glaxo Group Ltd, 980 Great West Road, Brentford, Middlesex TW8 9GS, UK. Last date of revision: July 2018. UK/INC/0001/17a(1)a. Incruse and Ellipta are registered trademarks of the GlaxoSmithKline group of companies. All rights reserved.

Adverse events should be reported. Reporting forms and information can be found at http://www.mhra.gov.uk/yellowcard or search for MHRA Yellowcard in the

Google Play or Apple App store. Adverse events should also be reported to GlaxoSmithKline on 0800 221 441.

Documents

Evidence Dossier to support COPD formulary decision making ......UMEC 113 mcg, VI 22 mcg, UMEC/VI 500/25 mcg and UMEC/VI 113/22 mcg, included in the Donohue et al., 2014 study, Decramer