Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Drugs for obstructive airway diseases, adrenergics in combination with anticholinergics including triple combinations with corticosteroids, ATC code: R03AL08.

Mechanism of action

Fluticasone furoate/umeclidinium/vilanterol is a combination of inhaled synthetic corticosteroid, long-acting muscarinic receptor antagonist and long-acting beta2-adrenergic agonist (ICS/LAMA/LABA). Following oral inhalation, umeclidinium and vilanterol act locally on airways to produce bronchodilation by separate mechanisms and fluticasone furoate reduces inflammation.

Fluticasone furoate
Fluticasone furoate is a corticosteroid with potent anti-inflammatory activity. The precise mechanism through which fluticasone furoate affects asthma and COPD symptoms is not known. Corticosteroids have been shown to have a wide range of actions on multiple cell types (e.g. eosinophils, macrophages, lymphocytes) and mediators (e.g. cytokines and chemokines) involved in inflammation.

Umeclidinium
Umeclidinium is a long-acting muscarinic receptor antagonist (also referred to as an anticholinergic).
Umeclidinium exerts its bronchodilatory activity by competitively inhibiting the binding of acetylcholine with muscarinic receptors on airway smooth muscle. It demonstrates slow reversibility at the human M3 muscarinic receptor subtype in vitro and a long duration of action in vivo when administered directly to the lungs in pre-clinical models.

Vilanterol
Vilanterol is a selective long-acting, beta2-adrenergic receptor agonist (LABA). The pharmacologic effects of beta2-adrenergic agonists, including vilanterol, are at least in part attributable to stimulation of intracellular adenylate cyclase, the enzyme that catalyses the conversion of adenosine triphosphate (ATP) to cyclic-3’,5’- adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.

Pharmacodynamic effects

Cardiac electrophysiology
The effect of fluticasone furoate/umeclidinium/vilanterol on the QT interval has not been evaluated in a thorough QT (TQT) study. TQT studies for FF/VI and umeclidinium/vilanterol (UMEC/VI) did not show clinically relevant effects on QT interval at clinical doses of FF, UMEC and VI.

No clinically relevant effects on the QTc interval were observed on review of centrally-read ECGs from 1,504 subjects with asthma exposed to fluticasone furoate/umeclidinium/vilanterol for up to 24 weeks, or in a subset of 360 subjects exposed for up to 52 weeks.

No clinically relevant effects on the QTc interval were observed on review of centrally read ECGs from 911 subjects with COPD exposed to fluticasone furoate/umeclidinium/vilanterol for up to 24 weeks, or in the subset of 210 subjects exposed for up to 52 weeks.

Clinical efficacy and safety

Asthma
The safety and efficacy of fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) were evaluated in 2,436 subjects in a randomised, multi-centre, active-controlled, double-blind clinical trial of 24 to 52 weeks’

duration in adult subjects with asthma inadequately controlled on their current treatments of combination therapy (ICS plus a LABA) (Study 205715, CAPTAIN). The trial evaluated the efficacy of FF/UMEC/VI on lung function, annualised rate of moderate and severe asthma exacerbations, asthma symptom control, and health-related quality of life when compared with fluticasone furoate/vilanterol. The primary endpoint was change from baseline in trough Forced Expiratory Volume in 1 second (FEV1) at Week 24. The key secondary endpoint was the annualised rate of moderate/severe asthma exacerbation.

This trial has a 5-week run-in/stabilisation period described as follows: subjects inadequately controlled [Asthma Control Questionnaire (ACQ-6) ≥1.5] on their current asthma treatment of inhaled corticosteroid (greater than fluticasone propionate 250 micrograms per day or equivalent) plus LABA entered a 3-week run-in period of treatment with fluticasone propionate/salmeterol 250/50 micrograms twice daily. Subjects who remained inadequately controlled (ACQ-6 ≥1.5) after the run-in period were transferred to fluticasone furoate/vilanterol (FF/VI) 92/22 micrograms once daily for a 2-week stabilisation period. Across all treatment groups, baseline demographics were similar.

At screening, the mean prebronchodilator percent predicted FEV1 was 58.5% (SD: 12.8%); the mean percent reversibility was 29.9% (SD: 18.1%), with a mean absolute reversibility of 0.484 L (SD: 0.274 L), and the mean ACQ-6 score was 2.5 (SD: 0.6). During the 5-week run-in/stabilisation period, subjects had substantial improvements in both lung function (trough FEV1 improvement of 0.287 L) and asthma control (mean ACQ- 6 score decreased by 0.6). Despite these improvements, a majority of subjects (93%) were not well controlled (mean score ACQ-6 of 1.9), demonstrating the need for additional therapy. At randomisation, the mean prebronchodilator percent predicted FEV1 was 68.2% (SD: 14.8%).

After the 5-week run-in/stabilisation period, eligible subjects were randomised to receive once-daily inhalations of FF/UMEC/VI 92/55/22 micrograms (n = 406), FF/UMEC/VI 184/55/22 micrograms (n = 408), FF/UMEC/VI 92/27.5/22 micrograms (n = 405), FF/UMEC/VI 184/27.5/22 micrograms (n = 404),
FF/VI 92/22 micrograms (n = 407), or FF/VI 184/22 micrograms (n = 406).

While 4 doses of FF/UMEC/VI were studied in the trial, efficacy data results shown are for FF/UMEC/VI 92/55/22 micrograms and FF/UMEC/VI 184/55/22 micrograms, the recommended doses for the treatment of asthma. In the evaluation of efficacy, the non-lung function endpoint analyses included prespecified pooled comparisons of FF/UMEC/VI (92/55/22 and 184/55/22 micrograms) with FF/VI (92/22 and 184/22 micrograms).

The change from baseline in trough FEV1 at Week 24 (primary efficacy endpoint) showed statistically significant improvements in lung function for both FF/UMEC/VI 92/55/22 micrograms and FF/UMEC/VI 184/55/22 micrograms compared with FF/VI 92/22 micrograms and FF/VI 184/22 micrograms, respectively (see Table 1, Figures 1 and 2).

Table 1. Lung function endpoints at Week 24 (Study 205715)

FF/VI          FF/UMEC/VI              FF/VI           FF/UMEC/VI
92/22            92/55/22             184/22             184/55/22
(n=407)            (n=406)             (n=406)             (n=408)
Trough FEV1 (L)
LS mean change from      0.024 (0.0157)      0.134 (0.0155)     0.076 (0.0156)      0.168 (0.0155) baseline (SE)
FF/UMEC/VI
92/55/22 vs. FF/VI
92/22
Treatment difference       Reference             0.110                ---                --- 95% CI                                        0.066, 0.153 p-value                                         p<0.001
FF/UMEC/VI
184/55/22 vs. FF/VI
184/22

Treatment difference            ---            ---           Reference          0.092 95% CI                                                                       0.049, 0.135 p-value                                                                        p<0.001 FF/UMEC/VI
184/55/22 vs.
92/55/22a
Treatment difference            ---         Reference           ---             0.034 95% CI                                                                      -0.009, 0.077 FF/UMEC/VI
92/55/22 vs. FF/VI
184/22a
Treatment difference            ---           0.059          Reference           --- 95% CI                                     0.015, 0.102
FF/UMEC/VI
184/55/22 vs. FF/VI
92/22a
Treatment difference        Reference          ---              ---             0.143 95% CI                                                                       0.100, 0.187 FEV1 at 3 hours post doseb (L)
LS mean change from      0.132 (0.0160)   0.243 (0.0158)   0.168 (0.0159)   0.286 (0.0158) baseline (SE)
FF/UMEC/VI
92/55/22 vs. FF/VI
92/22
Treatment difference        Reference         0.111             ---              --- 95% CI                                     0.067, 0.155
FF/UMEC/VI
184/55/22 vs. FF/VI
184/22
Treatment difference            ---            ---           Reference          0.118 95% CI                                                                       0.074, 0.162 FF/UMEC/VI
184/55/22 vs.
92/55/22
Treatment difference            ---         Reference           ----            0.044 95% CI                                                                       0.000, 0.087 FF/UMEC/VI
92/55/22 vs. FF/VI
184/22
Treatment difference            ---           0.075          Reference           --- 95% CI                                     0.031, 0.119
FF/UMEC/VI
184/55/22 vs. FF/VI
92/22
Treatment difference        Reference          ---              ---             0.155 95% CI                                                                       0.110, 0.199 Trough FEV1                    32%            49%              37%               51% b, c
Responder (%)
FF/UMEC/VI
92/55/22 vs. FF/VI
92/22
Odds Ratio                  Reference          2.16             ---              --- 95% CI                                      1.61, 2.88



FF/UMEC/VI
184/55/22 vs. FF/VI
184/22
Odds Ratio                          ---                  ---               Reference                1.82 95% CI                                                                                           1.37, 2.41 FF/UMEC/VI
184/55/22 vs.
92/55/22a
Odds Ratio                          ---              Reference                 ---                  1.08 95% CI                                                                                           0.82, 1.43 FF/UMEC/VI
92/55/22 vs. FF/VI
92/22a
Odds Ratio                          ---                 1.68               Reference                 --- 95% CI                                               1.26, 2.23
FF/UMEC/VI
184/55/22 vs. FF/VI
92/22a
Odds Ratio                      Reference                ---                   ---                  2.33 95% CI                                                                                           1.74, 3.11 CI=confidence interval; FEV1=forced expiratory volume in 1 second; L=litres; LS=least squared; n=number in the intent-to-treat population; SE=standard error a
These comparisons were not in the predefined testing hierarchy and were not adjusted for multiplicity.
b
Endpoint was not in the predefined testing hierarchy, therefore not adjusted for multiplicity.
c
Responder defined as >=100mL improvement from baseline



Figure 1. Least Squares (LS) Mean Change from Baseline in Trough FEV1 (L) for FF/UMEC/VI 100/62.5/25 micrograms (Trelegy Ellipta 92/55/22 mcg)



Figure 2. Least Squares (LS) Mean Change from Baseline in Trough FEV1 (L) for FF/UMEC/VI 200/62.5/25 micrograms (Trelegy Ellipta 184/55/22 mcg)



Moderate/severe asthma exacerbations were assessed over the 52-week treatment period (see Table 2). In the pooled analysis, the annualised rate of moderate/severe exacerbations was numerically lower with FF/UMEC/VI (92/55/22 and 184/55/22 micrograms) compared with FF/VI (92/22 and 184/22 micrograms) 

(13% reduction in rate; 95% CI: -5.2, 28.1). Descriptive analyses of unpooled treatment comparisons for the annualised rate of moderate/severe exacerbations are also provided.

Table 2. Annualised Rate of Moderate/Severe Exacerbationsa (Up to 52 Weeks) (Study 205715)

FF/VI            FF/UMEC/VI               FF/VI            FF/UMEC/VI 92/22              92/55/22              184/22              184/55/22 (n=407)              (n=406)              (n=406)              (n=408) Mean Annualised Rate            0.87                 0.68                 0.57                 0.55 FF/UMEC/VI
92/55/22 vs. FF/VI
92/22
Reduction in Rate (%)        Reference              21.8%                  ---                  --- 95% CI
-1.1,39.5
FF/UMEC/VI
184/55/22 vs. FF/VI
184/22
Reduction in Rate (%)            ---                  ---              Reference               3.2% 95% CI
-28.2, 27.0
FF/UMEC/VI
184/55/22 vs.
92/55/22
Reduction in Rate (%)            ---              Reference                ---                19.1% 95% CI
-6.4, 38.5
FF/UMEC/VI
92/55/22 vs. FF/VI
184/22
Change in Rate (%)               ---               -19.6%b             Reference                --- 95% CI
-57.2, 9.0
FF/UMEC/VI
184/55/22 vs. FF/VI
92/22
Reduction in Rate (%)        Reference                ---                  ---                36.7% 95% CI
17.6, 51.5
CI=confidence interval; n=number in the intent-to-treat population.
a
These comparisons were not in the predefined testing hierarchy and were not adjusted for multiplicity.
b
Negative percentage reflects an increase in exacerbation rate for FF/UMEC/VI 92/55/22 vs. FF/VI 184/22.

In addition, severe asthma exacerbations were assessed. In a descriptive pooled analysis, a difference in the mean annualised rate of severe exacerbations was not observed for FF/UMEC/VI (92/55/22 and 184/55/22 micrograms) compared with FF/VI (92/22 and 184/22 micrograms) (2.6% reduction in rate; 95% CI: -26.2, 24.9).

The mean annualised rates of severe exacerbations were 0.41 and 0.23 for FF/UMEC/VI 92/55/22 micrograms and FF/UMEC/VI 184/55/22 micrograms, respectively. The mean annualised rates of severe exacerbations were 0.38 and 0.26 for FF/VI 92/22micrograms and FF/VI 184/22 micrograms, respectively.

Patient symptoms and health-related quality of life were assessed using the ACQ (see Table 3). In a descriptive pooled analysis, the treatment difference for the ACQ-7 change from baseline at Week 24 for FF/UMEC/VI (92/55/22 and 184/55/22) compared with FF/VI (92/22 and 184/22) was -0.089 (-0.156, - 0.023). The ACQ-7 responder rate was 63% for FF/UMEC/VI (92/55/22 and 184/55/22 micrograms) compared with 55% for FF/VI (92/22 and 184/22 micrograms) at Week 24 (OR: 1.43; 95% CI: 1.16, 1.76).
Descriptive analyses of unpooled treatment comparisons are also provided.

Table 3. Asthma Control Questionnaire (ACQ)-7 Resultsa at Week 24 (Study 205715) 
FF/VI         FF/UMEC/VI            FF/VI          FF/UMEC/VI
92/22           92/55/22           184/22            184/55/22
(n=407)           (n=406)           (n=406)            (n=408)
Responderb (%)               52%              62%                58%               64% FF/UMEC/VI
92/55/22 vs. FF/VI
92/22
Odds Ratio                Reference            1.59               ---               --- 95% CI                                      1.18, 2.13
FF/UMEC/VI
184/55/22 vs. FF/VI
184/22
Odds Ratio                    ---               ---           Reference             1.28 95% CI                                                                           0.95, 1.72 FF/UMEC/VI
184/55/22 vs.
92/55/22
Odds Ratio                    ---           Reference             ---               1.08 95% CI                                                                           0.80, 1.45 FF/UMEC/VI
92/55/22 vs. FF/VI
184/22
Odds Ratio                    ---              1.19           Reference             --- 95% CI                                      0.88, 1.60
FF/UMEC/VI
184/55/22 vs. FF/VI
92/22
Odds Ratio                Reference             ---               ---               1.71 95% CI                                                                           1.27, 2.30 Change from Baselinea
LS mean change from     -0.638 (0.0340)   -0.754 (0.0335)   -0.717 (0.0339)   -0.779 (0.0339) baseline (SE)
FF/UMEC/VI
92/55/22 vs. FF/VI
92/22
Treatment difference      Reference           -0.116              ---               --- 95% CI                                    -0.210, -0.023

FF/UMEC/VI
184/55/22 vs. FF/VI
184/22
Treatment difference          ---               ---           Reference            -0.062 95% CI                                                                         -0.156, 0.032 
FF/UMEC/VI
184/55/22 vs.
92/55/22
Treatment difference          ---           Reference             ---              -0.025 95% CI                                                                         -0.118, 0.068 
FF/UMEC/VI
92/55/22 vs. FF/VI
184/22
Treatment difference             ---                  -0.037            Reference                  --- 95% CI                                            -0.130, 0.057
FF/UMEC/VI
184/55/22 vs. FF/VI
92/22
Treatment difference         Reference                  ---                 ---                 -0.142 95% CI                                                                                      -0.236, -0.047 CI=confidence interval; n=number in the intent-to-treat population.
a
These comparisons were not in the predefined testing hierarchy and were not adjusted for multiplicity.
b
Defined as an ACQ-7 score ≥0.5 below baseline.

The ACQ-5 (comprising the 5 questions on symptoms from ACQ-7) results at Week 24 were similar to the ACQ-7 results. In a pooled descriptive analysis, the treatment difference for the ACQ-5 change from baseline for FF/UME/VI (92/55/22 and 184/55/22) compared with FF/VI (92/22 and 184/22) was -0.043 (- 0.121, 0.035). The ACQ-5 responder rate was 64% for FF/UMEC/VI (92/55/22 and 184/55/22 micrograms) compared with 60% for FF/VI (92/22 and 184/22 micrograms) (OR: 1.23; 95% CI: 1.00, 1.52) at Week 24.

In an unpooled descriptive analysis, the treatment difference for the ACQ-5 change from baseline at Week 24 for FF/UMEC/VI 92/55/22 compared with FF/VI 92/22 was -0.080 (-0.189, 0.030) and for FF/UMEC/VI
184/55/22 compared with FF/VI 184/22 was -0.006 (-0.116, 0.103). The ACQ-5 responder rate was 63% for FF/UMEC/VI 92/55/22 micrograms compared with 58% for FF/VI 92/22 micrograms (OR: 1.28; 95% CI: 0.96, 1.72) at Week 24. The ACQ-5 responder rate was 66% for FF/UMEC/VI 184/55/22 micrograms compared with 62% for FF/VI 184/22 micrograms (OR: 1.19, 95% CI: 0.88, 1.60) at Week 24.


COPD

The efficacy of Trelegy Ellipta (92/55/22 micrograms), administered as a once-daily treatment, has been evaluated in patients with a clinical diagnosis of COPD in two, active-controlled studies and in a single, non- inferiority study. All three studies were multicentre, randomised, double-blind studies that required patients to be symptomatic with a COPD Assessment Test (CAT) score ≥10 and on daily maintenance treatment for their COPD for at least three months prior to study entry.

FULFIL (CTT116853) was a 24-week study (N=1810), with an extension up to 52 weeks in a subset of subjects (n=430), that compared Trelegy Ellipta (92/55/22 micrograms) with budesonide/formoterol 400/12 micrograms (BUD/FOR) administered twice-daily. At screening, the mean post-bronchodilator percent predicted FEV1 was 45% and 65% of patients reported a history of one or more moderate/severe exacerbation in the past year.

IMPACT (CTT116855) was a 52-week study (N=10355) that compared Trelegy Ellipta (92/55/22 micrograms) with fluticasone furoate/vilanterol 92/22 micrograms (FF/VI) and umeclidinium/vilanterol 55/22 micrograms (UMEC/VI). At screening, the mean post-bronchodilator percent predicted FEV1 was 46% and over 99% of patients reported a history of one or more moderate/severe exacerbation in the past year.

At study entry, the most common COPD medications reported in the FULFIL and IMPACT studies were ICS +LABA+LAMA (28%, 34% respectively), ICS+LABA (29%, 26% respectively), LAMA+LABA (10%, 8% respectively) and LAMA (9%, 7% respectively). These patients may have also been taking other COPD medications (e.g. mucolytics or leukotriene receptor antagonists).



Study 200812 was a 24-week, non-inferiority study (N=1,055) that compared Trelegy Ellipta (92/55/22 micrograms) with FF/VI (92/22 micrograms) + UMEC (55 micrograms), co-administered once daily as a multi-inhaler therapy in patients with a history of moderate or severe exacerbations within the prior 12 months.

Lung Function
In FULFIL, bronchodilatory effects with Trelegy Ellipta were evident on the first day of treatment and were maintained over the 24-week treatment period (mean changes from baseline in FEV1 were 90-222 mL on day 1 and 160-339 mL at week 24). Trelegy Ellipta significantly improved (p<0.001) lung function (as defined by mean change from baseline in trough FEV1 at week 24) (see Table 4) and the improvement was maintained in the subset of patients who continued treatment to week 52.

Table 4. Lung function endpoint in FULFIL
Trelegy                           Treatment difference
BUD/FOR
Ellipta                                (95% CI)
Comparison with
(N= 911)          (N=899)
BUD/FOR
Trough FEV1 (L) at Week 24, LS mean change              0.142            -0.029                  0.171 from baseline (SE)a                                    (0.0083)         (0.0085)              0.148, 0.194 FEV1=forced expiratory volume in 1 second; L=litres; LS=least squares; SE= standard error, N=number in the intent-to- treat population; CI= confidence interval, a Statistically significant treatment difference for FF/UMEC/VI vs. BUD/FOR also observed at the other assessment timepoints (weeks 2, 4 and 12).

In IMPACT, Trelegy Ellipta significantly improved (p<0.001) lung function when compared with FF/VI and UMEC/VI over a 52-week period (See Table 5).

Table 5 – Lung function endpoint in IMPACT
Treatment difference 95%
CI
Trelegy                                          Comparison Comparison Ellipta            FF/VI         UMEC/VI         Trelegy vs.   Trelegy vs.
(N = 4,151)        (N = 4,134)      (N = 2,070)        FF/VI      UMEC/VI Trough FEV1 (L) at Week 52, LS                0.094             -0.003          0.040           0.097        0.054 mean change from baseline (SE) a            (0.004)            (0.004)         (0.006)      0.085, 0.109 0.039, 0.069 FEV1= forced expiratory volume in 1 second; L= litres; LS=least squares; SE= standard error; N= number in the intent- to-treat population; CI= confidence interval; a Statistically significant treatment differences for FF/UMEC/VI vs. FF/VI and FF/UMEC/VI vs. UMEC/VI were also observed at the other assessment timepoints (Weeks 4, 16, 28, and 40).

In Study 200812, Trelegy Ellipta was non-inferior compared with FF/VI+UMEC, co-administered in two inhalers, in the improvement from baseline in trough FEV1 at week 24. The pre-specified non-inferiority margin was 50 mL.

Exacerbations
In IMPACT, over 52 weeks, Trelegy Ellipta significantly reduced (p<0.001) the annual rate of moderate/severe exacerbations by 15% (95% CI:10, 20) compared with FF/VI (rate; 0.91 vs 1.07 events per patient year) and by 25% (95% CI: 19, 30) compared with UMEC/VI (rate; 0.91 vs 1.21 events per patient year). In FULFIL, based upon data up to 24 weeks, Trelegy Ellipta significantly reduced (p=0.002) the annual rate of moderate/severe exacerbations by 35% (95% CI: 14, 51) compared with BUD/FOR.
In IMPACT, Trelegy Ellipta prolonged the time to first moderate/severe exacerbation and significantly decreased (p<0.001) the risk of a moderate/severe exacerbation, as measured by time to first exacerbation, compared with both FF/VI (14.8%; 95% CI: 9.3, 19.9) and UMEC/VI (16.0%; 95% CI: 9.4, 22.1). In FULFIL, Trelegy Ellipta significantly decreased the risk of a moderate/severe exacerbation compared with BUD/FOR over 24 weeks (33%; 95% CI: 12, 48; p=0.004).
In IMPACT, treatment with Trelegy Ellipta reduced the annual rate of severe exacerbations (i.e., requiring hospitalisation or resulting in death) by 13% compared with FF/VI (95% CI: -1, 24; p=0.064). Treatment with Trelegy Ellipta significantly reduced the annual rate of severe exacerbations by 34% compared with UMEC/VI (95% CI: 22, 44; p<0.001).

Health-Related Quality of Life
Trelegy Ellipta significantly improved (p<0.001) Health Related Quality of Life (as measured by the St George’s Respiratory Questionnaire [SGRQ] total score) in both FULFIL (week 24) when compared with BUD/FOR (-2.2 units; 95% CI: -3.5, -1.0) and IMPACT (week 52) when compared with FF/VI (-1.8 units; 95% CI: -2.4, -1.1) and UMEC/VI (-1.8 units; 95% CI: -2.6, -1.0).

A higher percentage of patients receiving Trelegy Ellipta responded with a clinically meaningful improvement in SGRQ total score in FULFIL at week 24 compared with BUD/FOR (50% and 41% respectively), odds ratios of response vs. non-response (OR) (1.41; 95% CI: 1.16, 1.70) and in IMPACT at week 52 compared with FF/VI and UMEC/VI (42%, 34% and 34% respectively), OR vs. FF/VI (1.41; 95% CI:1.29, 1.55) and OR vs. UMEC/VI (1.41; 95% CI: 1.26, 1.57); all treatment comparisons were statistically significant (p<0.001).

In FULFIL, the proportion of patients who were CAT responders (defined as 2 units below baseline or lower) at week 24, was significantly higher (p<0.001) for patients treated with Trelegy Ellipta compared with BUD/FOR (53% vs. 45%; OR 1.44; 95% CI: 1.19, 1.75). In IMPACT, the proportion of patients who were CAT responders at week 52 was significantly higher (p<0.001) for patients treated with Trelegy Ellipta (42%) compared with FF/VI (37%; OR 1.24; 95% CI: 1.14, 1.36) and UMEC/VI (36%; OR 1.28; 95% CI: 1.15, 1.43).

Symptom Relief
Breathlessness was measured using the Transition Dyspnoea Index (TDI) focal score at week 24 in FULFIL and week 52 in IMPACT (a subset of patients, n=5058). In FULFIL the proportion of responders according to TDI (defined as at least 1 unit) was significantly higher (p<0.001) for Trelegy Ellipta compared with BUD/FOR (61% vs 51%; OR 1.61; 95% CI: 1.33, 1.95). In IMPACT, the proportion of responders was also significantly higher (p<0.001) for Trelegy Ellipta (36%) compared with FF/VI (29%; OR 1.36; 95% CI: 1.19, 1.55) and UMEC/VI (30%; OR 1.33; 95% CI: 1.13, 1.57).

In FULFIL, Trelegy Ellipta improved daily symptoms of COPD as assessed by E-RS: COPD total score, compared with BUD/FOR (≥2 unit decrease from baseline). The proportion of responders during weeks 21-24 was significantly higher (p<0.001) for patients treated with Trelegy Ellipta compared with BUD/FOR
(47% and 37% respectively; OR 1.59; 95% CI: 1.30, 1.94).

Use of Rescue Medication
In FULFIL, Trelegy Ellipta significantly reduced (p<0.001) the use of rescue medication between weeks 1-24 compared with BUD/FOR (treatment difference: -0.2 occasions per day; 95% CI: -0.3, -0.1).

In IMPACT, Trelegy Ellipta significantly reduced (p<0.001) the use of rescue medication (occasions per day) at each 4-week time period compared with FF/VI and UMEC/VI. At weeks 49-52, the treatment difference was -0.28 (95% CI: -0.37, -0.19) when compared with FF/VI and -0.30 (95% CI: -0.41, -0.19) with UMEC/VI.

Nighttime awakenings
In IMPACT, Trelegy Ellipta statistically significantly reduced the mean number of nighttime awakenings due to COPD compared with FF/VI (-0.05; 95% CI: -0.08, -0.01; p=0.005) and with UMEC/VI (-0.10; 95% CI: -0.14, -0.05; p<0.001) at weeks 49 to 52. Significant reductions were observed over all other timepoints for UMEC/VI (p<0.001) and for the all but two of the of timepoints for FF/VI (p≤0.021).

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

When fluticasone furoate, umeclidinium and vilanterol were administered in combination by the inhaled route from a single inhaler in healthy subjects, the pharmacokinetics of each component were similar to those observed when each active substance was administered either as fluticasone furoate/vilanterol (FF/VI) combination or as an umeclidinium/vilanterol (UMEC/VI) combination or umeclidinium monotherapy.

Population pharmacokinetic (PK) analyses were conducted to assess the systemic exposure of fluticasone furoate, umeclidinium, and vilanterol in subjects with asthma. In these analyses, systemic drug levels (steady-state Cmax and AUC0-24) of fluticasone furoate and vilanterol following fluticasone furoate/umeclidinium/vilanterol (92/55/22 micrograms and 184/55/22 micrograms) in one inhaler (triple combination) were within the range of those observed following administration of the dual combination of FF/VI with the respective 92 micrograms and 184 micrograms FF doses; the systemic exposure of umeclidinium 55 micrograms following fluticasone furoate/umeclidinium/vilanterol in one inhaler was within the range of those observed following administration of umeclidinium 55 micrograms as monotherapy.


Population PK analyses for FF/UMEC/VI 92/55/22 micrograms were conducted using a combined PK dataset from three phase III studies in 821 COPD subjects. Systemic drug levels (steady state Cmax and AUC0-24) of FF, UMEC and VI following FF/UMEC/VI in one inhaler (triple combination) were within the range of those observed following FF/VI + UMEC as two inhalers, dual combinations (FF/VI and UMEC/VI), as well as individual single inhalers (FF, UMEC and VI). Covariate analysis showed higher FF apparent clearance (42%) when comparing FF/VI to FF/UMEC/VI; however, this is not considered clinically relevant.

Absorption

Fluticasone furoate
Following inhaled administration of fluticasone furoate/umeclidinium/vilanterol in healthy subjects, fluticasone furoate Cmax occurred at 15 minutes. The absolute bioavailability of fluticasone furoate when administrated as fluticasone furoate/vilanterol by inhalation was 15.2%, primarily due to absorption of the inhaled portion of the dose delivered to the lung, with negligible contribution from oral absorption.
Following repeat dosing of inhaled fluticasone furoate /vilanterol, steady state was achieved within 6 days with up to 1.6-fold accumulation

Umeclidinium
Following inhaled administration of fluticasone furoate/umeclidinium/vilanterol in healthy subjects, umeclidinium Cmax occurred at 5 minutes. The absolute bioavailability of inhaled umeclidinium was on average 13%, with negligible contribution from oral absorption. Following repeat dosing of inhaled umeclidinium, steady state was achieved within 7 to 10 days with 1.5 to 2-fold accumulation.

Vilanterol
Following inhaled administration of fluticasone furoate/umeclidinium/vilanterol in healthy subjects, vilanterol Cmax occurred at 7 minutes. The absolute bioavailability of inhaled vilanterol was 27%, with negligible contribution from oral absorption. Following repeat dosing of inhaled umeclidinium/vilanterol, steady state was achieved within 6 days with up to 1.5-fold accumulation.

Distribution

Fluticasone furoate
Following intravenous dosing of fluticasone furoate to healthy volunteers, the mean volume of distribution at steady state of 661 litres. Fluticasone furoate has a low association with red blood cells. In vitro plasma protein binding in human plasma of fluticasone furoate was high, on average >99.6%.

Umeclidinium
Following intravenous administration of umeclidinium to healthy volunteers, the mean volume of distribution was 86 litres. In vitro plasma protein binding in human plasma was on average 89%.

Vilanterol
Following intravenous administration of vilanterol to healthy volunteers, the mean volume of distribution at steady state was 165 litres. Vilanterol has a low association with red blood cells. In vitro plasma protein binding in human plasma was on average 94%.

Biotransformation

Fluticasone furoate
In vitro studies showed that fluticasone furoate is primarily metabolised by cytochrome P450 3A4 (CYP3A4) and is a substrate for the P-gp transporter. The primary metabolic route for fluticasone furoate is hydrolysis of the S-fluoromethyl carbothioate group to metabolites with significantly reduced corticosteroid activity. Systemic exposure to the metabolites is low.

Umeclidinium
In vitro studies showed that umeclidinium is primarily metabolised by cytochrome P450 2D6 (CYP2D6) and is a substrate for the P-gp transporter. The primary metabolic routes for umeclidinium are oxidative (hydroxylation, O-dealkylation) followed by conjugation (glucuronidation, etc), resulting in a range of metabolites with either reduced pharmacological activity or for which the pharmacological activity has not been established. Systemic exposure to the metabolites is low.

Vilanterol
In vitro studies showed that vilanterol is primarily metabolised by cytochrome P450 3A4 (CYP3A4) and is a substrate for the P-gp transporter. The primary metabolic routes for vilanterol are O-dealkylation to a range of metabolites with significantly reduced beta1- and beta2-adrenergic agonist activity. Plasma metabolic profiles following oral administration of vilanterol in a human radiolabel study were consistent with high first-pass metabolism. Systemic exposure to the metabolites is low.

Elimination

Fluticasone furoate
The apparent plasma elimination half-life of fluticasone furoate following inhaled administration of fluticasone furoate/vilanterol was, on average, 24 hours. Following intravenous administration, the elimination phase half-life averaged 15.1 hours. Plasma clearance following intravenous administration was 65.4 litres/hour. Urinary excretion accounted for approximately 2 % of the intravenously administered dose.
Following oral administration, fluticasone furoate was eliminated in humans mainly by metabolism with metabolites being excreted almost exclusively in faeces, with <1% of the recovered radioactive dose eliminated in the urine.

Umeclidinium
Umeclidinium plasma elimination half-life following inhaled dosing for 10 days averaged 19 hours, with 3% to 4% active substance excreted unchanged in urine at steady-state. Plasma clearance following intravenous administration was 151 litres/hour. Following intravenous administration, approximately 58% of the administered radiolabelled dose was excreted in faeces and approximately 22% of the administered radiolabelled dose was excreted in urine. The excretion of the drug-related material in the faeces following intravenous dosing indicated secretion into the bile. Following oral administration, 92% of the administered radiolabelled dose was excreted primarily in faeces. Less than 1% of the orally administered dose (1% of recovered radioactivity) was excreted in urine, suggesting negligible absorption following oral administration.

Vilanterol
Vilanterol plasma elimination half-life following inhaled dosing for 10 days averaged 11 hours. Plasma clearance of vilanterol following intravenous administration was 108 litres/hour. Following oral administration of radiolabelled vilanterol, 70% of the radiolabel was excreted in urine and 30% in faeces.
Primary elimination of vilanterol was by metabolism followed by excretion of metabolites in urine and faeces.

Special populations

In the asthma population pharmacokinetic analyses (1,265 subjects for fluticasone furoate; 1,263 subjects for vilanterol; 634 subjects for umeclidinium), the impact of demographic covariates (race/ethnicity, age, gender, weight) on the pharmacokinetics of fluticasone furoate, umeclidinium, and vilanterol was evaluated. In a COPD population pharmacokinetic analysis (n = 821), the impact of demographic covariates (race/ethnicity, age, gender, weight) on the pharmacokinetics of fluticasone furoate, umeclidinium, and vilanterol was evaluated. Renal and hepatic impairment were assessed in separate studies.

Elderly
No clinically relevant effects requiring dose adjustment were observed for subjects with asthma or COPD.

Renal impairment
The effect of fluticasone furoate/umeclidinium/vilanterol has not been evaluated in subjects with renal impairment. However, studies have been conducted with fluticasone furoate/vilanterol and umeclidinium/vilanterol that showed no evidence of an increase in systemic exposure to fluticasone furoate, umeclidinium or vilanterol. In vitro protein binding studies between subjects with severe renal impairment and healthy volunteers were conducted, and no clinically significant evidence of altered protein binding was seen.

The effects of haemodialysis have not been studied.

Hepatic impairment
The effect of fluticasone furoate/umeclidinium/vilanterol has not been evaluated in subjects with hepatic impairment. However, studies have been conducted with fluticasone furoate/vilanterol and umeclidinium/vilanterol.

The fluticasone furoate/vilanterol component of Trelegy Ellipta was assessed in patients with all severities of hepatic impairment (Child-Pugh A, B or C). No clinically relevant effects on weighted mean serum cortisol were observed in patients with mild hepatic impairment (Child-Pugh A). For fluticasone furoate, patients with moderate hepatic impairment showed up to three times higher systemic exposure (FF 184 micrograms); therefore, patients with severe hepatic impairment received half the dose (FF 92 micrograms). At this dose, no effects on systemic exposure were observed. Therefore, caution is advised in moderate to severe hepatic impairment, and for patients with moderate or severe hepatic impairment the maximum dose is Trelegy Ellipta 92/55/22 micrograms (see section 4.2 Posology and method of administration). There was no significant increase in systemic exposure to vilanterol.

Patients with moderate hepatic impairment showed no evidence of an increase in systemic exposure to either umeclidinium or vilanterol (Cmax and AUC). Umeclidinium has not been evaluated in patients with severe hepatic impairment.

Other special populations
The effects of race, gender and weight on the pharmacokinetics of fluticasone furoate, umeclidinium and vilanterol were also evaluated in the population pharmacokinetic analysis. No clinically relevant differences requiring dose adjustment in asthma or COPD based on race, gender or weight were observed in fluticasone furoate, umeclidinium or vilanterol systemic exposure.


In 92 East Asian subjects with asthma (Japanese, East Asian and South East Asian Heritage), who provided FF/UMEC/VI (92/55/22 micrograms and 184/55/22 micrograms) population pharmacokinetic data, estimates of vilanterol Cmax at steady state were approximately 3-fold higher than non-East Asian subjects. There was no effect of race on pharmacokinetics of fluticasone furoate or umeclidinium in subjects with asthma.

In 113 East Asian subjects with COPD (Japanese and East Asian Heritage), who received FF/UMEC/VI 92/55/22 micrograms from a single inhaler (27% subjects), fluticasone furoate AUC(ss) estimates were on 
average 30% higher compared with Caucasian subjects. However, these higher systemic exposures remain below the threshold for FF-induced reduction of serum and urine cortisol and are not considered clinically relevant.
There was no effect of race on pharmacokinetic parameters of umeclidinium or vilanterol in subjects with COPD.


In terms of other patient characteristics, a study in CYP2D6 poor metabolisers showed no evidence of a clinically significant effect of CYP2D6 genetic polymorphism on systemic exposure to umeclidinium.