INCRUSE ELLIPTA should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD. INCRUSE ELLIPTA has not been studied in subjects with acutely deteriorating COPD. The initiation of INCRUSE ELLIPTA in this setting is not appropriate.

INCRUSE ELLIPTA should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. INCRUSE ELLIPTA has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta₂-agonist.

If INCRUSE ELLIPTA no longer controls symptoms of bronchoconstriction; the patient’s inhaled, short-acting beta₂-agonist becomes less effective; or the patient needs more short-acting beta₂-agonist than usual, these may be markers of deterioration of disease. In this setting re-evaluate the patient and the COPD treatment regimen at once. Increasing the daily dose of INCRUSE ELLIPTA beyond the recommended dose is not appropriate in this situation.

As with other inhaled therapies, INCRUSE ELLIPTA can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with INCRUSE ELLIPTA, it should be treated immediately with an inhaled, short-acting bronchodilator; INCRUSE ELLIPTA should be discontinued immediately; and alternative therapy should be instituted.

Hypersensitivity reactions such as anaphylaxis, angioedema, pruritus, rash, and urticaria may occur after administration of INCRUSE ELLIPTA. Discontinue INCRUSE ELLIPTA if such reactions occur. There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of other powder medications containing lactose; therefore, patients with severe milk protein allergy should not use INCRUSE ELLIPTA [see Contraindications (4), Adverse Reactions (6.2)].

INCRUSE ELLIPTA should be used with caution in patients with narrow-angle glaucoma. Prescribers and patients should also be alert for signs and symptoms of acute narrow-angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema). Instruct patients to consult a healthcare provider immediately if any of these signs or symptoms develop.

INCRUSE ELLIPTA, like all therapies containing an anticholinergic, should be used with caution in patients with urinary retention. Prescribers and patients should be alert for signs and symptoms of urinary retention (e.g., difficulty passing urine, painful urination), especially in patients with prostatic hyperplasia or bladder-neck obstruction. Instruct patients to consult a healthcare provider immediately if any of these signs or symptoms develop.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In the 8 clinical trials conducted to support initial approval of INCRUSE ELLIPTA, a total of 1,663 subjects with COPD (mean age: 62.7 years; 89% white; 65% male across all treatments, including placebo) received at least 1 inhalation dose of umeclidinium at doses of 62.5 or 125 mcg. In the 4 randomized, double-blind, placebo- or active-controlled, efficacy clinical trials, 1,185 subjects received umeclidinium for up to 24 weeks, of which 487 subjects received the recommended dose of umeclidinium 62.5 mcg. In a 12-month, randomized, double-blind, placebo-controlled, long-term safety trial, 227 subjects received umeclidinium 125 mcg for up to 52 weeks [see Clinical Studies (14)].

The incidence of adverse reactions associated with INCRUSE ELLIPTA in Table 1 is based upon 2 placebo-controlled trials: one 24-week trial (Trial 1) and one 12-week trial (Trial 2) [see Clinical Studies (14.2)].

Table 1. Adverse Reactions with INCRUSE ELLIPTA with ≥1% Incidence and More Common than Placebo in Subjects with Chronic Obstructive Pulmonary Disease

Adverse Reaction	INCRUSE ELLIPTA (n = 487) %	Placebo (n = 348) %
Infections and infestations
Nasopharyngitis	8%	7%
Upper respiratory tract infection	5%	4%
Pharyngitis	1%	<1%
Viral upper respiratory tract infection	1%	<1%
Respiratory, thoracic, and mediastinal disorders
Cough	3%	2%
Musculoskeletal and connective tissue disorders
Arthralgia	2%	1%
Myalgia	1%	<1%
Gastrointestinal disorders
Abdominal pain upper	1%	<1%
Toothache	1%	<1%
Injury, poisoning, and procedural complications
Contusion	1%	<1%
Cardiac disorders
Tachycardia	1%	<1%

Other adverse reactions with INCRUSE ELLIPTA observed with an incidence <1% but more common than placebo included atrial fibrillation.

In a long-term safety trial (Trial 3), 336 subjects (n = 227 umeclidinium 125 mcg, n = 109 placebo) were treated for up to 52 weeks with umeclidinium 125 mcg or placebo. The demographic and baseline characteristics of the long-term safety trial were similar to those of the efficacy trials described above. Adverse reactions that occurred with a frequency ≥1% in subjects receiving umeclidinium 125 mcg that exceeded that in placebo in this trial were: nasopharyngitis, upper respiratory tract infection, urinary tract infection, pharyngitis, pneumonia, lower respiratory tract infection, rhinitis, supraventricular tachycardia, supraventricular extrasystoles, sinus tachycardia, idioventricular rhythm, headache, dizziness, sinus headache, cough, back pain, arthralgia, pain in extremity, neck pain, myalgia, nausea, dyspepsia, diarrhea, rash, depression, and vertigo.

The safety and efficacy of INCRUSE ELLIPTA in combination with an inhaled corticosteroid/long-acting beta₂-adrenergic agonist (ICS/LABA) were also evaluated in four 12‑week clinical trials (Trial 4, Trial 5, Trial 6, and Trial 7). A total of 1,637 subjects with COPD across four 12‑week, randomized, double-blind clinical trials received at least 1 dose of INCRUSE ELLIPTA (62.5 mcg) or placebo administered once daily in addition to background ICS/LABA (mean age: 64 years, 88% white, 65% male across all treatments). Two trials (Trials 4 and 5) evaluated INCRUSE ELLIPTA in combination with fluticasone furoate/vilanterol (FF/VI) 100 mcg/25 mcg administered once daily, and 2 trials (Trials 6 and 7) evaluated INCRUSE ELLIPTA administered once daily in combination with fluticasone propionate/salmeterol (FP/SAL) 250 mcg/50 mcg administered twice daily [see Clinical Studies (14.3)]. Adverse reactions that occurred with INCRUSE ELLIPTA in combination with an ICS/LABA were similar to those reported with INCRUSE ELLIPTA as monotherapy. In addition to the umeclidinium monotherapy adverse reactions reported above, adverse reactions occurring with INCRUSE ELLIPTA in combination with an ICS/LABA, at an incidence of ≥1% and exceeding ICS/LABA alone, were oropharyngeal pain and dysgeusia.

In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postapproval use of INCRUSE ELLIPTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to INCRUSE ELLIPTA or a combination of these factors.

Eye Disorders

Eye pain, glaucoma, vision blurred.

Immune System Disorders

Hypersensitivity reactions, including anaphylaxis, angioedema, pruritus, and urticaria.

Renal and Urinary Disorders

Dysuria, urinary retention.

Respiratory, Thoracic and Mediastinal Disorders

Dysphonia, oropharyngeal pain.

There is potential for an additive interaction with concomitantly used anticholinergic medicines. Therefore, avoid coadministration of INCRUSE ELLIPTA with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects [see Warnings and Precautions (5.4, 5.5)].

Risk Summary

There are insufficient data on the use of umeclidinium in pregnant women to inform a drug‑associated risk. Umeclidinium administered via inhalation or subcutaneously to pregnant rats and rabbits was not associated with adverse effect on embryofetal development at exposures approximately 50 and 200 times, respectively, the human exposure at the maximum recommended human daily inhaled dose (MRHDID). (See Data.)

The estimated risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data: In separate embryofetal developmental studies, pregnant rats and rabbits received umeclidinium during the period of organogenesis at doses up to approximately 50 and 200 times the MRHDID, respectively (on an AUC basis at maternal inhalation doses up to 278 mcg/kg/day in rats and at maternal subcutaneous doses up to 180 mcg/kg/day in rabbits). No evidence of teratogenic effects was observed in either species.

In a perinatal and postnatal developmental study in rats, dams received umeclidinium during late gestation and lactation periods with no evidence of effects on offspring development at doses up to approximately 26 times the MRHDID (on an AUC basis at maternal subcutaneous doses up to 60 mcg/kg/day).

Risk Summary

There is no information available on the presence of umeclidinium in human milk, the effects on the breastfed child, or the effects on milk production. Umeclidinium was detected in the plasma of offspring of lactating rats treated with umeclidinium suggesting its presence in maternal milk. (See Data.) The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for INCRUSE ELLIPTA and any potential adverse effects on the breastfed child from umeclidinium or from the underlying maternal condition.

Data

Subcutaneous administration of umeclidinium to lactating rats at greater than or equal to 60 mcg/kg/day resulted in a quantifiable level of umeclidinium in 2 of 54 pups, which may indicate transfer of umeclidinium in milk.

The safety and effectiveness of INCRUSE ELLIPTA have not been established in pediatric patients. INCRUSE ELLIPTA is not indicated for use in pediatric patients.

Based on available data, no adjustment of the dosage of INCRUSE ELLIPTA in geriatric patients is necessary, but greater sensitivity in some older individuals cannot be ruled out.

Clinical trials of INCRUSE ELLIPTA included 810 subjects aged 65 years and older, and, of those, 183 subjects were aged 75 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger subjects.

Patients with moderate hepatic impairment (Child-Pugh score of 7-9) showed no relevant increases in C_max or AUC, nor did protein binding differ between subjects with moderate hepatic impairment and their healthy controls. Studies in subjects with severe hepatic impairment have not been performed [see Clinical Pharmacology (12.3)].

Patients with severe renal impairment (CrCl <30 mL/min) showed no relevant increases in C_max or AUC, nor did protein binding differ between subjects with severe renal impairment and their healthy controls. No dosage adjustment is required in patients with renal impairment [see Clinical Pharmacology (12.3)].

Umeclidinium is a long-acting muscarinic antagonist, which is often referred to as an anticholinergic. It has similar affinity to the subtypes of muscarinic receptors M1 to M5. In the airways, it exhibits pharmacological effects through inhibition of M3 receptors at the smooth muscle leading to bronchodilation. The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations. In preclinical in vitro as well as in vivo studies, prevention of methacholine- and acetylcholine-induced bronchoconstrictive effects was dose-dependent and lasted longer than 24 hours. The clinical relevance of these findings is unknown. The bronchodilation following inhalation of umeclidinium is predominantly a site-specific effect.

Cardiac Electrophysiology

QTc interval prolongation was studied in a double-blind, multiple-dose, placebo- and positive-controlled, crossover study in 86 healthy subjects. Following repeat doses of umeclidinium 500 mcg once daily (8 times the recommended dosage) for 10 days, umeclidinium does not prolong QTc to any clinically relevant extent.

Linear pharmacokinetics was observed for umeclidinium (62.5 to 500 mcg).

Absorption

Umeclidinium plasma levels may not predict therapeutic effect. Following inhaled administration of umeclidinium in healthy subjects, C_max occurred at 5 to 15 minutes. Umeclidinium is mostly absorbed from the lung after inhaled doses with minimum contribution from oral absorption. Following repeat dosing of inhaled INCRUSE ELLIPTA, steady state was achieved within 14 days with up to 1.8-fold accumulation.

Distribution

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

Elimination

Metabolism: In vitro data showed that umeclidinium is primarily metabolized by the enzyme cytochrome P450 2D6 (CYP2D6) and is a substrate for the P-glycoprotein (P-gp) transporter. The primary metabolic routes for umeclidinium are oxidative (hydroxylation, O-dealkylation) followed by conjugation (e.g., glucuronidation), 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.

Excretion: The effective half-life after once-daily orally inhaled dosing is 11 hours. Following intravenous dosing with radiolabeled umeclidinium, mass balance showed 58% of the radiolabel in the feces and 22% in the urine. The excretion of the drug-related material in the feces following intravenous dosing indicated elimination in the bile. Following oral dosing to healthy male subjects, radiolabel recovered in feces was 92% of the total dose and that in urine was <1% of the total dose, suggesting negligible oral absorption.

Specific Populations

Population pharmacokinetic analysis showed no evidence of a clinically significant effect of age (40 to 93 years) (Figure 1), gender (69% male) (Figure 1), inhaled corticosteroid use (48%), or weight (34 to 161 kg) on systemic exposure of umeclidinium. In addition, there was no evidence of a clinically significant effect of race.

Patients with Hepatic Impairment: The impact of hepatic impairment on the pharmacokinetics of INCRUSE ELLIPTA has been evaluated in subjects with moderate hepatic impairment (Child-Pugh score of 7-9). There was no evidence of an increase in systemic exposure to umeclidinium (C_max and AUC) (Figure 1). There was no evidence of altered protein binding in subjects with moderate hepatic impairment compared with healthy subjects. INCRUSE ELLIPTA has not been evaluated in subjects with severe hepatic impairment.

Patients with Renal Impairment: The pharmacokinetics of INCRUSE ELLIPTA has been evaluated in subjects with severe renal impairment (CrCl <30 mL/min). There was no evidence of an increase in systemic exposure to umeclidinium (C_max and AUC) (Figure 1). There was no evidence of altered protein binding in subjects with severe renal impairment compared with healthy subjects.

Figure 1. Impact of Intrinsic and Extrinsic Factors on the Systemic Exposure of Umeclidinium

Drug Interaction Studies

Umeclidinium and P-glycoprotein Transporter: Umeclidinium is a substrate of P-gp. The effect of the moderate P-gp transporter inhibitor verapamil (240 mg once daily) on the steady-state pharmacokinetics of umeclidinium was assessed in healthy subjects. No effect on umeclidinium C_max was observed; however, an approximately 1.4-fold increase in umeclidinium AUC was observed (Figure 1).

Umeclidinium and Cytochrome P450 2D6: In vitro metabolism of umeclidinium is mediated primarily by CYP2D6. However, no clinically meaningful difference in systemic exposure to umeclidinium (500 mcg) (8 times the approved dose) was observed following repeat daily inhaled dosing to normal (ultrarapid, extensive, and intermediate metabolizers) and CYP2D6 poor metabolizer subjects (Figure 1).

Umeclidinium produced no treatment-related increases in the incidence of tumors in 2-year inhalation studies in rats and mice at inhaled doses up to 137 and 295/200 mcg/kg/day (male/female), respectively (approximately 20 and 25/20 times, respectively, the MRHDID for adults on an AUC basis).

Umeclidinium tested negative in the following genotoxicity assays: the in vitro Ames assay, in vitro mouse lymphoma assay, and in vivo rat bone marrow micronucleus assay.

No evidence of impairment of fertility was observed in male and female rats at subcutaneous doses up to 180 mcg/kg/day and at inhaled doses up to 294 mcg/kg/day, respectively (approximately 100 and 50 times, respectively, the MRHDID for adults on an AUC basis).

Dose selection for umeclidinium in COPD was supported by a 7-day, randomized, double-blind, placebo-controlled, crossover trial evaluating 4 doses of umeclidinium (15.6 to 125 mcg) or placebo dosed once daily in the morning in 163 subjects with COPD. A dose ordering was observed, with the 62.5- and 125-mcg doses demonstrating larger improvements in FEV₁ over 24 hours compared with the lower doses of 15.6 and 31.25 mcg (Figure 2).

The differences in trough FEV₁ from baseline after 7 days for placebo and the 15.6-, 31.25-, 62.5-, and 125-mcg doses were -74 mL (95% CI: -118, -31), 38 mL (95% CI: -6, 83), 27 mL (95% CI: -18, 72), 49 mL (95% CI: 6, 93), and 109 mL (95% CI: 65, 152), respectively. Two additional dose-ranging trials in subjects with COPD demonstrated minimal additional benefit at doses above 125 mcg. The dose-ranging results supported the evaluation of 2 doses of umeclidinium, 62.5 and 125 mcg, in the confirmatory COPD trials to further assess dose response.

Evaluations of dosing interval by comparing once- and twice-daily dosing supported selection of a once-daily dosing interval for further evaluation in the confirmatory COPD trials.

Figure 2. Adjusted Mean Change from Baseline in Postdose Serial FEV₁ (mL) on Days 1 and 7

Day 1

Day 7

Lung Function

The clinical development program for INCRUSE ELLIPTA included 2 randomized, double‑blind, placebo-controlled, parallel-group trials in subjects with COPD designed to evaluate the efficacy of INCRUSE ELLIPTA on lung function. Trial 1 (NCT01313650) was a 24-week placebo‑controlled trial, and Trial 2 (NCT01387230) was a 12-week placebo‑controlled trial. These trials treated subjects that had a clinical diagnosis of COPD, were 40 years of age or older, had a history of smoking ≥10 pack-years, had a post-albuterol FEV₁ ≤70% of predicted normal values, had a ratio of FEV₁/FVC of <0.7, and had a Modified Medical Research Council (mMRC) score ≥2. Subjects in Trial 1 had a mean age of 63 years and an average smoking history of 46 pack-years, with 50% identified as current smokers. At screening, the mean postbronchodilator percent predicted FEV₁ was 47% (range: 13% to 74%), the mean postbronchodilator FEV₁/FVC ratio was 0.47 (range: 0.20 to 0.74), and the mean percent reversibility was 15% (range: -35% to 109%). The majority of subjects (72%) reported not having a COPD exacerbation in the prior 12 months. Baseline demographics and lung function for subjects in Trial 2 were similar to those in Trial 1.

Trial 1 evaluated umeclidinium 62.5 mcg and placebo. The primary endpoint was change from baseline in trough (predose) FEV₁ at Day 169 (defined as the mean of the FEV₁ values obtained at 23 and 24 hours after the previous dose on Day 168) compared with placebo. INCRUSE ELLIPTA 62.5 mcg demonstrated a larger increase in mean change from baseline in trough (predose) FEV₁ relative to placebo (Table 2). Similar results were obtained from Trial 2.

Table 2. Least Squares Mean Change from Baseline in Trough FEV₁ (mL) at Day 169 in the Intent-to-Treat Population (Trial 1)

n = Number in intent-to-treat population.
Treatment	n	Trough FEV1 (mL) at Day 169
		Difference from Placebo (95% CI) n = 280
INCRUSE ELLIPTA	n = 418	115 (76, 155)

Serial spirometric evaluations throughout the 24-hour dosing interval were performed in a subset of subjects (n = 54, umeclidinium 62.5 mcg; n = 36, placebo) at Days 1, 84, and 168 in Trial 1, and for all patients at Days 1 and 84 in Trial 2. Results from Trial 1 at Day 1 and Day 168 are shown in Figure 3.

Figure 3. Least Squares (LS) Mean Change from Baseline in FEV₁ (mL) over Time (0-24 h) on Days 1 and 168 (Trial 1 Subset Population)

Day 1

Day 168

In Trial 1, the mean peak FEV₁ (over the first 6 hours relative to baseline) at Day 1 and at Day 168 for the group receiving umeclidinium 62.5 mcg compared with placebo was 126 and 130 mL, respectively.

Health-Related Quality of Life

Health-related quality of life was measured using St. George’s Respiratory Questionnaire (SGRQ). Umeclidinium demonstrated an improvement in mean SGRQ total score compared with placebo treatment at Day 168: -4.69 (95% CI: -7.07,-2.31). The proportion of patients with a clinically meaningful decrease (defined as a decrease of at least 4 units from baseline) at Week 24 was greater for INCRUSE ELLIPTA 62.5 mcg (42%; 172/410) compared with placebo (31%; 86/274).

Lung Function

The efficacy of INCRUSE ELLIPTA in combination with an ICS/LABA was evaluated in 4 randomized, double-blind, parallel-group trials in subjects with COPD. These trials, all of similar study design, were of 12-weeks’ treatment duration. Subjects were randomized to INCRUSE ELLIPTA 62.5 mcg + ICS/LABA or placebo + ICS/LABA. Entry criteria for subjects enrolled in these trials were similar to those described above in Section 14.2. The primary endpoint for these trials was change from baseline in trough (predose) FEV₁ at Day 85 (defined as the mean of the FEV₁ values obtained at 23 and 24 hours after the previous dose on Day 84). Baseline FEV₁ was measured while subjects were on background ICS/LABA.

Combination with Fluticasone Furoate + Vilanterol

Trial 4 (NCT01957163) and Trial 5 (NCT02119286) randomized subjects to INCRUSE ELLIPTA 62.5 mcg + FF/VI 100 mcg/25 mcg administered once daily or placebo + FF/VI 100 mcg/25 mcg administered once daily. Trial population demographics and results for Trials 4 and 5 were similar; therefore, only Trial 4 results are presented below.

Subjects in Trial 4 across all treatment arms had a mean age of 64 years and an average smoking history of 50 pack-years, with 42% identified as current smokers. At screening, the mean postbronchodilator percent predicted FEV₁ was 45% (range: 13% to 76%), the mean postbronchodilator FEV₁/FVC ratio was 0.48 (range: 0.22 to 0.70), and the mean percent reversibility was 14% (range: -20% to 71%). The majority of subjects (85%) reported not having a COPD exacerbation in the prior 12 months.

The primary endpoint was change from baseline in trough (predose) FEV₁ at Day 85 (defined as the mean of the FEV₁ values obtained at 23 and 24 hours after the previous dose on Day 84) compared with placebo (INCRUSE ELLIPTA + FF/VI vs. placebo + FF/VI). INCRUSE ELLIPTA + FF/VI demonstrated a larger mean change from baseline in trough (predose) FEV₁ relative to placebo + FF/VI (Table 3).

Table 3. Least Squares Mean Change from Baseline in Trough FEV₁ (mL) at Day 85 in the Intent-to-Treat Population (Trial 4)

FF/VI = fluticasone furoate/vilanterol.
n = Number in intent-to-treat population.
Treatment	n	Trough FEV1 (mL) at Day 85
		Difference from Placebo + FF/VI (95% CI) n = 206
INCRUSE ELLIPTA + FF/VI	n = 206	124 (93, 154)

Combination with Fluticasone Propionate + Salmeterol

Trial 6 (NCT01772134) and Trial 7 (NCT01772147) randomized subjects to INCRUSE ELLIPTA 62.5 mcg + FP/SAL 250 mcg/50 mcg or placebo + FP/SAL 250 mcg/50 mcg. The treatments with INCRUSE ELLIPTA and placebo were administered once daily, while the FP/SAL treatment was administered twice daily. Trial population demographics and results for Trials 6 and 7 were similar; therefore, only Trial 6 results are presented below.

Subjects in Trial 6 across all treatment arms had a mean age of 63 years and an average smoking history of 50 pack-years, with 54% identified as current smokers. At screening, the mean postbronchodilator percent predicted FEV₁ was 47% (range: 12% to 70%), the mean postbronchodilator FEV₁/FVC ratio was 0.47 (range: 0.22 to 0.69), and the mean percent reversibility was 16% (range: -36% to 79%). The majority of subjects (79%) reported not having a COPD exacerbation in the prior 12 months.

The primary endpoint was change from baseline in trough (predose) FEV₁ at Day 85 (defined as the mean of the FEV₁ values obtained at 23 and 24 hours after the previous dose on Day 84) compared with placebo (INCRUSE ELLIPTA + FP/SAL vs. placebo + FP/SAL). INCRUSE ELLIPTA + FP/SAL demonstrated a larger mean change from baseline in trough (predose) FEV₁ relative to placebo + FP/SAL (Table 4).

Table 4. Least Squares Mean Change from Baseline in Trough FEV₁ (mL) at Day 85 in the Intent-to-Treat Population (Trial 6)

FP/SAL = fluticasone propionate/salmeterol.
n = Number in intent-to-treat population.
Treatment	n	Trough FEV1 (mL) at Day 85
		Difference from Placebo + FP/SAL (95% CI) n = 205
INCRUSE ELLIPTA+FP/SAL	n = 204	147 (107, 187)

Exacerbations

In Trial 8 (NCT02164513), a total of 10,355 subjects with COPD with a history of 1 or more moderate or severe exacerbations in the prior 12 months were randomized (2:2:1) to receive fluticasone furoate/umeclidinium/vilanterol 100 mcg/62.5 mcg/25 mcg (n = 4,151), fluticasone furoate/vilanterol 100 mcg/25 mcg (n = 4,133), or umeclidinium/vilanterol 62.5 mcg/25 mcg (n = 2,070) administered once daily in a 12-month trial. The population demographics across all treatments were: mean age of 65 years, 77% white, 66% male, and an average smoking history of 46.6 pack-years, with 35% identified as current smokers. At trial entry, the most common COPD medications were ICS + anticholinergic + LABA (34%), ICS + LABA (26%), anticholinergic + LABA (8%), and anticholinergic (7%). The mean postbronchodilator percent predicted FEV₁ was 46% (standard deviation: 15%), the mean postbronchodilator FEV₁/FVC ratio was 0.47 (standard deviation: 0.12), and the mean percent reversibility was 10% (range: -59% to 125%).

The primary endpoint was annual rate of on-treatment moderate and severe exacerbations in subjects treated with fluticasone furoate/umeclidinium/vilanterol compared with the fixed-dose combinations of fluticasone furoate/vilanterol and umeclidinium/vilanterol. Exacerbations were defined as worsening of 2 or more major symptoms (dyspnea, sputum volume, and sputum purulence) or worsening of any 1 major symptom together with any 1 of the following minor symptoms: sore throat, colds (nasal discharge and/or nasal congestion), fever without other cause, and increased cough or wheeze for at least 2 consecutive days. Exacerbations were considered to be of moderate severity if treatment with systemic corticosteroids and/or antibiotics was required and were considered to be severe if resulted in hospitalization or death.

Evidence of efficacy for INCRUSE ELLIPTA on COPD exacerbations was established by the efficacy of the umeclidinium component of fluticasone furoate/umeclidinium/vilanterol in Trial 8. Treatment with fluticasone furoate/umeclidinium/vilanterol statistically significantly reduced the on-treatment annual rate of moderate/severe exacerbations by 15% compared with fluticasone furoate/vilanterol (Table 5). A reduction in risk of on-treatment moderate/severe exacerbation (as measured by time to first) was also observed for the same comparison.

Table 5. Moderate and Severe Chronic Obstructive Pulmonary Disease Exacerbations (Trial 8)

FF/UMEC/VI = Fluticasone furoate/umeclidinium/vilanterol 100 mcg/62.5 mcg/25 mcg, FF/VI = Fluticasone furoate/vilanterol 100 mcg/25 mcg, UMEC/VI = Umeclidinium/vilanterol 62.5 mcg/25 mcg.
a On-treatment analyses excluded exacerbation data collected after discontinuation of study treatment.
Treatment	n	Mean Annual Rate (exacerbations/year)	FF/UMEC/VI Rate Ratio vs. Comparator (95% CI)	% Reduction in Exacerbation Rate (95% CI)	P Value
FF/UMEC/VI	4,145	0.91
FF/VI	4,133	1.07	0.85 (0.80, 0.90)	15 (10, 20)	P<0.001
UMEC/VI	2,069	1.21	0.75 (0.70, 0.81)	25 (19, 30)	P<0.001