Comments
Abstract
Rationale: Randomized data comparing triple therapy with dual inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA) therapy in patients with chronic obstructive pulmonary disease (COPD) are limited.
Objectives: We compared the effects of once-daily triple therapy on lung function and health-related quality of life with twice-daily ICS/LABA therapy in patients with COPD.
Methods: The FULFIL (Lung Function and Quality of Life Assessment in Chronic Obstructive Pulmonary Disease with Closed Triple Therapy) trial was a randomized, double-blind, double-dummy study comparing 24 weeks of once-daily triple therapy (fluticasone furoate/umeclidinium/vilanterol 100 μg/62.5 μg/25 μg; ELLIPTA inhaler) with twice-daily ICS/LABA therapy (budesonide/formoterol 400 μg/12 μg; Turbuhaler). A patient subgroup remained on blinded treatment for up to 52 weeks. Co–primary endpoints were change from baseline in trough FEV1 and in St. George’s Respiratory Questionnaire (SGRQ) total score at Week 24.
Measurements and Main Results: In the intent-to-treat population (n = 1,810) at Week 24 for triple therapy (n = 911) and ICS/LABA therapy (n = 899), mean changes from baseline in FEV1 were 142 ml (95% confidence interval [CI], 126 to 158) and −29 ml (95% CI, −46 to −13), respectively, and mean changes from baseline in SGRQ scores were −6.6 units (95% CI, −7.4 to −5.7) and −4.3 units (95% CI, −5.2 to −3.4), respectively. For both endpoints, the between-group differences were statistically significant (P < 0.001). There was a statistically significant reduction in moderate/severe exacerbation rate with triple therapy versus dual ICS/LABA therapy (35% reduction; 95% CI, 14–51; P = 0.002). The safety profile of triple therapy reflected the known profiles of the components.
Conclusions: These results support the benefits of single-inhaler triple therapy compared with ICS/LABA therapy in patients with advanced COPD.
Clinical trial registered with www.clinicaltrials.gov (NCT02345161).
Although inhaled triple pharmacologic therapy is recommended for patients with advanced chronic obstructive pulmonary disease and is often used clinically as step-up treatment, few randomized controlled trials have assessed the benefit of triple therapy compared with dual inhaled corticosteroid/long-acting β2-agonist therapy.
Results from the FULFIL (Lung Function and Quality of Life Assessment in Chronic Obstructive Pulmonary Disease with Closed Triple Therapy) study demonstrated the clinical benefit of once-daily fluticasone furoate/umeclidinium/vilanterol combination therapy using a single inhaler compared with twice-daily budesonide/formoterol combination therapy. Once-daily furoate/umeclidinium/vilanterol improved lung function and health-related quality of life, as well as reduced exacerbation frequency, compared with twice-daily budesonide/formoterol.
The use of inhaled triple pharmacologic therapy by patients with chronic obstructive pulmonary disease (COPD) is common. Researchers in a UK study found that after 2 years, 46% of patients initially prescribed a long-acting bronchodilator and 39% of those prescribed an inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA) or an ICS plus a long-acting muscarinic antagonist (LAMA) progressed to triple therapy (1). In a U.S. study, 25.5% of patients with COPD who had received at least one LAMA, LABA, ICS, or phosphodiesterase-4 inhibitor received triple therapy within 2 years of being diagnosed (2). The Global Initiative for Chronic Obstructive Lung Disease strategy document recommends inhaled triple pharmacologic therapy (ICS/LAMA/LABA) for patients with advanced COPD with persistent symptoms and risk of exacerbations (3).
Despite the current widespread use of triple therapy, there are few randomized controlled trials demonstrating a sustained benefit in terms of lung function and patient-reported outcome measures compared with ICS/LABA alone (4). Recently, a once-daily single-inhaler triple therapy of fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100 μg/62.5 μg/25 μg was developed for patients with moderate to very severe COPD. This “closed triple therapy” may offer clinically important improvements in lung function and quality of life compared with ICS/LABA dual therapy, as well as eliminating the need for delivering the medications using multiple inhalers. Single-inhaler triple therapy may reduce the risk of medication errors and may help to ensure that a patient receives all three medications.
The Lung Function and Quality of Life Assessment in COPD with Closed Triple Therapy (FULFIL) trial is the first study to compare once-daily single-inhaler triple therapy (ICS/LAMA/LABA) with twice-daily dual therapy (ICS/LABA) in patients with advanced, symptomatic COPD, who are at risk of exacerbations. The FULFIL study was designed in part to support the registration of once-daily FF/UMEC/VI in Europe and other countries globally. In consultation with European regulators, the sponsor was asked to provide a comparison with an ICS/LABA dual-combination product that was indicated to treat patients with COPD and was well known and well understood by physicians. Twice-daily budesonide/formoterol (BUD/FOR) was chosen because it is a commonly prescribed medication for patients with COPD. The study provides comparative information not just between classes of therapies but also between different molecules with different dosing regimens.
FULFIL was specifically designed to have a close resemblance to real-world clinical practice. A once-daily triple pharmacologic therapy was compared with a current standard-of-care ICS/LABA therapy, and the run-in period allowed patients to continue on their prestudy maintenance therapy up to randomization to mimic switching scenarios in clinical practice. FULFIL also allowed inclusion of patients with commonly observed comorbidities who are often excluded from other trials. The patient’s perspective was carefully evaluated using a health-related quality of life co–primary endpoint. Some of the results of the FULFIL study were previously reported in the form of an abstract (5).
FULFIL was a phase III, randomized, double-blind, double-dummy, parallel-group, multicenter study (www.clinicaltrials.gov [NCT02345161]; GSK study CTT116853). Patients were randomized to receive 24 weeks of either (1) once-daily FF/UMEC/VI (100 μg/62.5 μg/25 μg) using a single ELLIPTA inhaler (Glaxo Operations UK Ltd, Ware, UK) and twice-daily placebo using the Turbuhaler (AstraZeneca AB, Södertälje, Sweden) or (2) twice-daily BUD/FOR (400 μg/12 μg) using the Turbuhaler and once-daily placebo using the ELLIPTA inhaler. Twice-daily BUD/FOR using the Turbuhaler was the comparator because this ICS/LABA is commonly used in this patient population. All patients took one inhalation from the ELLIPTA inhaler in the morning and two inhalations (one in the morning and one in the evening) from the Turbuhaler to minimize the impact of different dosing regimens.
There was a 2-week run-in period during which medications at screening were unchanged, followed by a 24-week treatment period. A subset of the first 430 patients to enroll in the trial and consent to longer-term treatment remained on blinded study treatment for up to 52 weeks. To minimize loss of data, patients who permanently discontinued study treatment (but did not withdraw consent) were not required to withdraw from the study, but could continue to have certain safety and efficacy assessments conducted.
The primary objectives were to evaluate the effects of once-daily single-inhaler triple therapy (FF/UMEC/VI) on lung function and health-related quality of life compared with twice-daily dual ICS/LABA therapy (BUD/FOR) at 24 weeks. The institutional review boards for human studies associated with the clinical sites approved the protocol, and written consent was obtained from the subjects or their surrogates as required by the institutional review boards.
The co–primary endpoints at Week 24 were change from baseline in trough FEV1 and change from baseline in St. George’s Respiratory Questionnaire (SGRQ) total score. Supportive analyses for the primary endpoints included proportion of patients with a clinically meaningful change from baseline in trough FEV1 (≥100 ml) and change from baseline SGRQ total score (≥4-unit decrease), change from baseline in Evaluating Respiratory Symptoms in COPD score (E-RS: COPD; formerly called EXACT RS) over 24 weeks, and the proportion of responders. Population pharmacokinetic analyses were conducted on serial and sparse blood samples collected from a subset of patients (n = 74) to assess FF, UMEC, and VI systemic exposure from a single inhaler. Efficacy and safety endpoints were analyzed up to Week 24 in the intent-to-treat (ITT) population and up to Week 52 in the extension (EXT) population.
FULFIL researchers enrolled patients with COPD aged 40 years or older who were defined as being in Global Initiative for Chronic Obstructive Lung Disease group D: (1) FEV1 less than 50% and COPD Assessment Test score greater than or equal to 10, or (2) patients with FEV1 less than or equal to 50% to less than 80% and COPD Assessment Test score greater than or equal to 10, and either at least two moderate exacerbations or at least one severe exacerbation in the past year. Patients were required to be receiving daily maintenance therapy for COPD for at least 3 months. Patients were excluded if they had a current diagnosis of asthma causing their symptoms or if they had unresolved pneumonia or severe COPD exacerbation. Demographic and disease characteristics were recorded at screening.
Spirometry was performed in all patients at baseline and at Weeks 2, 4, 12, and 24, as well as at Weeks 36 and 52 in the EXT population, using standardized equipment according to the American Thoracic Society/European Respiratory Society criteria (6). The SGRQ for patients with COPD was completed using a patient-held e-diary at Day 1 and at Weeks 4 and 24 (and at Week 52 in the EXT population). Potential COPD exacerbations were identified on the basis of symptoms reported using the e-diary, which triggered follow-up with the investigator, who confirmed any exacerbations on the basis of an interaction with the patient. Mild exacerbations were defined as worsening symptoms of COPD that were self-managed by the patient (e.g., increase in albuterol use) and not associated with the use of corticosteroids or antibiotics. A moderate exacerbation was defined as having worsening symptoms of COPD that required treatment with oral/systemic corticosteroids and/or antibiotics. A severe exacerbation was defined as worsening symptoms of COPD that required treatment with inpatient hospitalization. The E-RS: COPD questionnaire was completed each evening using the e-diary.
The incidence of adverse events (AEs), serious adverse events (SAEs), pneumonia and supporting radiography, cardiovascular events including prespecified major cardiovascular events analysis, bone fractures, and other adverse events of special interest (AESIs) were evaluated in the study. (AESIs are listed in Table E1 in the online supplement.)
Statistical analyses were performed using SAS version 9.3 software (SAS Institute, Cary, NC). Sample size was calculated on the basis of co–primary endpoints and previous experience with drugs of these classes. The ITT population, stratified by smoking status, comprised all randomized patients, excluding those who were randomized in error who did not receive a dose of study medication. The EXT population comprised the subset of patients in the ITT population who were enrolled into the 52-week extension phase. The co–primary endpoints were analyzed using mixed models for repeated measures and were adjusted for multiplicity using the Hochberg method. Further details of the methods are provided in the online supplement.
In total, 1,810 patients were included in the ITT population (FF/UMEC/VI, n = 911; BUD/FOR, n = 899), and 430 were included in the EXT population (FF/UMEC/VI, n = 210; BUD/FOR, n = 220) (Figure E1). Overall, 94% of patients completed the study, and 90% completed the study on investigational treatment. Premature treatment discontinuations were most frequently due to patient decision (4%), AEs (3%), or lack of efficacy (3%). Patient and disease characteristics at baseline for the ITT and EXT populations are shown in Table 1. COPD medications used during the study run-in period are listed in Table E2.
| Characteristic | FF/UMEC/VI 100/62.5/25 μg | BUD/FOR 400/12 μg | Total |
|---|---|---|---|
| ITT population, 24 wk | |||
| Number of subjects | 911 | 899 | 1,810 |
| Age, yr | 64.2 (8.56) | 63.7 (8.71) | 63.9 (8.64) |
| Female sex, n (%) | 233 (26) | 236 (26) | 469 (26) |
| Current smokers, n (%) | 400 (44) | 394 (44) | 794 (44) |
| Smoking pack-years | 39.5 (21.87) | 39.2 (22.15) | 39.4 (22.00) |
| Cardiovascular risk factors*, n (%) | 599 (66) | 602 (67) | 1,201 (66) |
| Moderate/severe COPD exacerbation in previous 12 mo, n (%) | |||
| 0 | 313 (34) | 317 (35) | 630 (35) |
| 1 | 252 (28) | 253 (28) | 505 (28) |
| ≥2 | 346 (38) | 329 (37) | 675 (37) |
| History of pneumonia, n (%) | 87 (10) | 99 (11) | 186 (10) |
| FEV1 absolute, ml | 1,349 (0.46) | 1,339 (0.48) | 1,344 (0.47) |
| FEV1, % predicted | 45.5 (12.97) | 45.1 (13.64) | 45.3 (13.30) |
| SGRQ total score | 51.8 (16.29) | 50.8 (16.73) | — |
| E-RS: COPD | 13.20 (5.828) | 12.97 (5.928) | — |
| EXT population, 52 wk | |||
| Number of subjects | 210 | 220 | 430 |
| Age, yr | 63.7 (7.76) | 63.3 (8.43) | 63.5 (8.10) |
| Female, n (%) | 53 (25) | 58 (26) | 111 (26) |
| Current smokers, n (%) | 95 (45) | 97 (44) | 192 (45) |
| Smoking pack-years | 39.8 (19.92) | 39.6 (23.12) | 39.7 (21.59) |
| Cardiovascular risk factors*, n (%) | 144 (69) | 152 (69) | 296 (69) |
| Moderate/severe COPD exacerbations in previous 12 mo, n (%) | |||
| 0 | 62 (30) | 72 (33) | 134 (31) |
| 1 | 77 (37) | 79 (36) | 156 (36) |
| ≥2 | 71 (34) | 69 (31) | 140 (33) |
| History of pneumonia, n (%) | 18 (9) | 20 (9) | 38 (9) |
| FEV1 absolute, ml | 1,425 (0.50) | 1,368 (0.51) | 1,396 (0.51) |
| FEV1, % predicted | 47.1 (13.30) | 45.4 (14.85) | 46.2 (14.13) |
| SGRQ total score | 53.0 (16.14) | 50.8 (15.49) | — |
| E-RS: COPD | 13.54 (5.439) | 13.00 (5.576) | — |
In the ITT population, FF/UMEC/VI demonstrated clinically meaningful improvements from baseline in trough FEV1 at all time points over the 24-week treatment period (Figure 1A, Table 2). At Week 24, the mean changes from baseline in trough FEV1 were 142 ml (95% confidence interval [CI], 126 to 158) for FF/UMEC/VI and −29 ml (95% CI, −46 to −13) for BUD/FOR; the difference between FF/UMEC/VI and BUD/FOR was statistically significant (171 ml; 95% CI, 148 to 194; P < 0.001) (Table 2). The treatment differences ranged from 123 to 171 ml and were statistically significant in favor of FF/UMEC/VI at all time points (P < 0.001).
Figure 1. Mean change from baseline in trough FEV1 over (A) 24 weeks (ITT population) and (B) 52 weeks (EXT population). The bars indicate 95% CIs. BUD = budesonide; CI = confidence interval; EXT = extension; FF = fluticasone furoate; FOR = formoterol; ITT = intent-to-treat; LS = least squares; UMEC = umeclidinium; VI = vilanterol.
[More] [Minimize]| FF/UMEC/VI 100/62.5/25 μg | BUD/FOR 400/12 μg | |
|---|---|---|
| ITT population, 24 wk | ||
| Number of subjects | 911 | 899 |
| Trough FEV1, ml | ||
| LS at Week 24, mean (95% CI) | 1,418 (1,401 to 1,434) | 1,247 (1,230 to 1,263) |
| LS change from baseline, mean (95% CI) | 142 (126 to 158) | −29 (−46 to −13) |
| FF/UMEC/VI vs. BUD/FOR difference (95% CI); P value | 171 (148 to 194); <0.001 | |
| Proportion of trough FEV1 responders*, n | 907 | 892 |
| Responders, n (%) | 453 (50) | 184 (21) |
| FF/UMEC/VI vs. BUD/FOR, OR (95% CI); P value | 4.03 (3.27 to 4.97); <0.001 | |
| Change from baseline in SGRQ total score, n | 846 | 791 |
| LS at Week 24, mean (95% CI) | 44.7 (43.8 to 45.5) | 46.9 (46.0 to 47.8) |
| LS change, mean (95% CI) | −6.6 (−7.4 to −5.7) | −4.3 (−5.2 to −3.4) |
| FF/UMEC/VI vs. BUD/FOR difference (95% CI); P value | −2.2 (−3.5 to −1.0); <0.001 | |
| Proportion of responders†, n | 904 | 893 |
| Responders, n (%) | 448 (50) | 368 (41) |
| FF/UMEC/VI vs. BUD/FOR OR (95% CI); P value | 1.41 (1.16 to 1.70); <0.001 | |
| EXT population, 52 wk | ||
| Number of subjects | 210 | 220 |
| Trough FEV1, ml | ||
| LS at Week 52, mean (95% CI) | 1,429 (1,395 to 1,462) | 1,250 (1,216 to 1,284) |
| LS change from baseline, mean (95% CI) | 126 (92 to 159) | −53 (−87 to −20) |
| FF/UMEC/VI vs. BUD/FOR difference (95% CI); P value | 179 (131 to 226); <0.001 | |
| Proportion of trough FEV1 responders*, n | 210 | 219 |
| Responders, n (%) | 96 (46) | 34 (16) |
| FF/UMEC/VI vs. BUD/FOR, OR (95% CI); P value | 4.79 (3.02 to 7.61); <0.001 | |
| Change from baseline in SGRQ total score, n | 182 | 174 |
| LS at Week 52, mean (95% CI) | 47.3 (45.3 to 49.3) | 50.0 (48.0 to 52.0) |
| LS change, mean (95% CI) | −4.6 (−6.5 to −2.6) | −1.9 (−3.9 to 0.1) |
| FF/UMEC/VI vs. BUD/FOR difference (95% CI); P value | −2.7 (−5.5 to 0.2); 0.065 | |
| Proportion of responders†, n | 209 | 219 |
| Responders, n (%) | 91 (44) | 73 (33) |
| FF/UMEC/VI vs. BUD/FOR, OR (95% CI); P value | 1.50 (1.01 to 2.24); 0.046 | |
In the ITT population, at Week 24, clinically meaningful improvements in SGRQ total score were observed in both treatment groups. The changes from baseline in SGRQ were −6.6 units (95% CI, −7.4 to −5.7) with FF/UMEC/VI and −4.3 (95% CI, −5.2 to −3.4) with BUD/FOR. The between-treatment difference in improvement in SGRQ total score was statistically significant for FF/UMEC/VI (−2.2 units; 95% CI, −3.5 to −1.0; P < 0.001) compared with BUD/FOR (Table 2).
Similar findings regarding change from baseline in trough FEV1 were observed in the EXT population at Week 52 (Figure 1B, Table 2). The mean changes from baseline in trough FEV1 were 126 ml (95% CI, 92 to 159) for FF/UMEC/VI and −53 ml (95% CI, −87 to −20) for BUD/FOR. The mean changes from baseline in SGRQ total score in the EXT population were −4.6 units (95% CI, −6.5 to −2.6) with FF/UMEC/VI and −1.9 units (95% CI, −3.9 to 0.1) with BUD/FOR, and although the between-treatment difference was of a similar magnitude to that observed in the ITT population, it did not reach statistical significance (Table 2).
In the ITT population at Week 24, an increase of at least 100 ml from baseline in trough FEV1 was achieved by a larger proportion of patients in the FF/UMEC/VI group (n = 453 [50%]) than in the BUD/FOR group (n = 184 [21%]). The odds ratio (OR) of achieving versus not achieving this increase was statistically significant in favor of FF/UMEC/VI (OR, 4.03; 95% CI, 3.27–4.97; P < 0.001).
A larger proportion of patients in the FF/UMEC/VI group (n = 448 [50%]) than in the BUD/FOR group (n = 368 [41%]) experienced a clinically meaningful improvement from baseline (≥4-unit decrease) in SGRQ total score in the ITT population at Week 24. The OR of response versus nonresponse was statistically significant in favor of FF/UMEC/VI (OR, 1.41; 95% CI, 1.16–1.70; P < 0.001) (Table 2).
The incidence rates of moderate/severe COPD exacerbations over the 24-week treatment period were 10% (n = 95) and 14% (n = 126) for FF/UMEC/VI and BUD/FOR, respectively. The mean annualized rates of moderate/severe exacerbations were 0.22 and 0.34 for FF/UMEC/VI and BUD/FOR, respectively, and the reduction in the annualized rate was statistically significant (35%; 95% CI, 14–51%; P = 0.002) based on data up to 24 weeks in the ITT population (Table 3). Similar statistically significant results were observed for mild/moderate/severe exacerbations (Table 3). Fewer patients were hospitalized for exacerbations in the FF/UMEC/VI treatment group (n = 12 [1%]) than in the BUD/FOR group (n = 22 [2%]).
| Up to 24 wk (ITT Population) | Up to 52 wk (EXT Population) | |||
|---|---|---|---|---|
| FF/UMEC/VI 100/62.5/25 μg (n = 911) | BUD/FOR 400/12 μg (n = 899) | FF/UMEC/VI 100/62.5/25 μg (n = 210) | BUD/FOR 400/12 μg (n = 220) | |
| Population, n | 907 | 892 | 210 | 219 |
| Moderate and severe exacerbations | ||||
| Mean rate | 0.22 | 0.34 | 0.20 | 0.36 |
| Ratio (95% CI); P value | 0.65 (0.49–0.86); 0.002 | 0.56 (0.37–0.85); 0.006 | ||
| Reduction in rate, % (95% CI) | 35 (14–51) | 44 (15–63) | ||
| Mild, moderate, and severe exacerbations | ||||
| Mean rate | 0.25 | 0.39 | 0.22 | 0.40 |
| Ratio (95% CI); P value | 0.65 (0.50–0.84); <0.001 | 0.55 (0.37–0.81); 0.003 | ||
| Reduction in rate, % (95% CI) | 35 (16–50) | 45 (19–63) | ||
For the ITT population, at each 4-week interval over the 24-week treatment period, FF/UMEC/VI produced greater reductions from baseline in E-RS: COPD total score than BUD/FOR, and the treatment differences were statistically significant (P < 0.001) (Figure 2). The ORs for response versus nonresponse for each 4-week interval were statistically significant in favor of FF/UMEC/VI (ORs ranging from 1.59 to 1.76; P < 0.001). Similar results were observed for each E-RS: COPD subscale (breathlessness, cough and sputum, chest symptoms).
The results for the secondary and other endpoints described here were also observed up to 52 weeks in the EXT population (see respective tables and figures).
Figure 2. Mean change from baseline in 4-weekly Evaluating Respiratory Symptoms in COPD total score (intent-to-treat population). The error bars indicate 95% CIs. BUD = budesonide; CI = confidence interval; FF = fluticasone furoate; FOR = formoterol; LS = least squares; UMEC = umeclidinium; VI = vilanterol.
[More] [Minimize]The incidence rates of on-treatment AEs in the ITT population up to Week 24 were 38.9% in the FF/UMEC/VI group and 37.7% in the BUD/FOR group. The most common AEs were nasopharyngitis (7% and 5% for FF/UMEC/VI and BUD/FOR, respectively) and headache (5% and 6% for FF/UMEC/VI and BUD/FOR, respectively) (Table 4). A similar pattern was observed in the EXT population up to Week 52: The most common AEs were nasopharyngitis (11% and 10% for FF/UMEC/VI and BUD/FOR, respectively) and headache (8% and 10% for FF/UMEC/VI and BUD/FOR, respectively). COPD worsening was one of the most common AEs in the BUD/FOR group (10%), but it was less common in the FF/UMEC/VI group (2%) in the EXT population up to Week 52.
| ITT Population (24 wk) | EXT Population (52 wk) | |||
|---|---|---|---|---|
| FF/UMEC/VI 100/62.5/25 μg (n = 911) | BUD/FOR 400/12 μg (n = 899) | FF/UMEC/VI 100/62.5/25 μg (n = 210) | BUD/FOR 400/12 μg (n = 220) | |
| Adverse events occurring in ≥2% of patients in either population | ||||
| Nasopharyngitis | 64 (7) | 43 (5) | 23 (11) | 22 (10) |
| Headache | 44 (5) | 53 (6) | 17 (8) | 22 (10) |
| URTI | 20 (2) | 19 (2) | 6 (3) | 10 (5) |
| COPD | 15 (2) | 23 (3) | 5 (2) | 22 (10) |
| Back pain | 19 (2) | 18 (2) | 4 (2) | 5 (2) |
| Arthralgia | 17 (2) | 13 (1) | 5 (2) | 6 (3) |
| Pneumonia | 19 (2) | 7 (<1) | 4 (2) | 4 (2) |
| Pharyngitis | 15 (2) | 9 (1) | 5 (2) | 1 (<1) |
| Oropharyngeal pain | 9 (<1) | 10 (1) | 6 (3) | 1 (<1) |
| Dizziness | — | — | 1 (<1) | 6 (3) |
| Blood pressure increased | 4 (<1) | 8 (<1) | 0 | 4 (2) |
| Dyspnea | — | — | 0 | 4 (2) |
| Vertigo | — | — | 0 | 4 (2) |
| Adverse events of special interest | ||||
| Cardiovascular effects | 39 (4.3) | 47 (5.2) | 18 (8.6) | 22 (10.0) |
| Pneumonia | 20 (2.2) | 7 (0.8) | 4 (1.9) | 4 (1.8) |
| Local steroid effects* | 19 (2.1) | 24 (2.7) | 8 (3.8) | 7 (3.2) |
| Anticholinergic syndrome* | 16 (1.8) | 17 (1.9) | 4 (1.9) | 12 (5.5) |
| Hypersensitivity | 10 (1.1) | 10 (1.1) | 3 (1.4) | 1 (0.5) |
| Hyperglycemia/diabetes† | 5 (0.5) | 4 (0.4) | 0 | 4 (1.8) |
| Decreased bone mineral density | 4 (0.4) | 6 (0.7) | 1 (0.5) | 1 (0.5) |
| LRTI (excluding pneumonia) | 3 (0.3) | 4 (0.4) | 1 (0.5) | 0 |
| Ocular effects* | 1 (0.1) | 4 (0.4) | — | — |
| Urinary retention | 1 (0.1) | 0 | — | — |
| Asthma/bronchospasm | 0 | 1 (0.1) | — | — |
For FF/UMEC/VI and BUD/FOR, respectively, the incidence rates of on-treatment SAEs in the ITT population up to Week 24 were 5.4% and 5.7%, and the most common on-treatment SAEs were COPD exacerbation (1.3% and 2.3%) and pneumonia (1.0% and 0.3%). There were 12 on-treatment deaths in this study (6 in each treatment group), which was in line with expectations for patients with advanced COPD and multiple comorbidities. The incidence rates of adjudicated on-treatment nonfatal SAEs in the ITT population were 4.9% in the FF/UMEC/VI group and 5.2% in the BUD/FOR group. Of these (for FF/UMEC/VI and BUD/FOR, respectively), COPD exacerbations (1.5% and 2.4%) and pneumonia and/or respiratory tract infection without COPD exacerbation (0.9% and 0.3%) were the most common. An overview of the rates of drug-related AEs and SAEs is provided in the Results section of the online supplement.
The incidence of prespecified AESIs in the ITT population was also investigated. For FF/UMEC/VI and BUD/FOR, respectively, cardiovascular effects were reported by 4.3% and 5.2% of patients, and the incidence of pneumonia was 2.2% and 0.8% in the ITT population up to Week 24 (Table 4).
The incidence rates of on-treatment SAEs in the EXT population were 10.0% in the FF/UMEC/VI group and 12.7% in the BUD/FOR group. In the EXT population up to Week 52, for FF/UMEC/VI and BUD/FOR, respectively, cardiovascular effects as AESIs were reported by 8.6% and 10.0% of patients, and the incidence rates of pneumonia as an AESI were 1.9% and 1.8% (Table 4).
The incidence rates of major cardiovascular events were 0.4% and 0.8% in the ITT population up to Week 24, and 2.4% and 0.9% in the EXT population up to Week 52, for the FF/UMEC/VI and BUD/FOR groups, respectively. There were no clinically significant differences between treatment groups in vital signs, electrocardiograms, Holter monitor findings, or laboratory values. Population pharmacokinetic analyses showed that systemic drug levels of FF, UMEC, and VI after FF/UMEC/VI administration using a single inhaler (triple therapy) were low and within the range observed after dual therapy (FF/VI and UMEC/VI) and monotherapy (FF, UMEC, and VI) (7, 8).
Our results show that once-daily FF/UMEC/VI offered clinically meaningful and statistically significant improvements at Week 24 in lung function and health-related quality of life compared with BUD/FOR. The improvements in health-related quality of life were reflected in the consistent reduction in total symptoms measured using the E-RS: COPD. At each 4-weekly time point, FF/UMEC/VI demonstrated greater symptom reduction than BUD/FOR. At Week 24, clinically meaningful and statistically significant reductions in exacerbation rates for patients with COPD were also observed with FF/UMEC/VI compared with BUD/FOR. Importantly, the benefits of FF/UMEC/VI on lung function, health-related quality of life, and exacerbation rate were sustained over 52 weeks in the EXT population. The magnitude of the between-treatment difference in SGRQ total score between treatment groups at Week 52 failed to achieve statistical significance, possibly due to the smaller size of this subgroup. The lung function findings reported here are in keeping with the results of shorter studies of triple therapy using FF/VI and UMEC in two separate inhalers (4, 9).
The safety profile of FF/UMEC/VI, including the systemic exposure, was in line with the known profiles of the component drugs, and findings derived from the 52-week EXT population suggest that there are no cumulative adverse effects of once-daily FF/UMEC/VI. Whereas the incidence of pneumonia was higher with FF/UMEC/VI than with BUD/FOR in the ITT population up to 24 weeks, it was similar between the two groups in the smaller EXT population at 52 weeks. The incidence of pneumonia with FF/UMEC/VI observed is consistent with reports of other 24-week studies of FF/VI for COPD in which researchers reported incidence rates of up to 2% (10, 11), as well as in studies of BUD/FOR for COPD (12, 13). The incidence of pneumonia is also similar to that observed in another study of ICS/LAMA/LABA therapy for COPD, in which pneumonia occurred in 3% of patients in both the triple-therapy and ICS/LABA comparator arms (14), and it is less than the incidence reported in 52-week studies of FF/VI (15) and BUD/FOR (16). No excess risk of pneumonia with FF or VI, either alone or in combination, compared with placebo was found in SUMMIT (Study to Understand Mortality and Morbidity in COPD) (although SUMMIT included patients with moderate airflow limitation, and only 39% had a history of exacerbations) (17).
Although this study was focused on nonexacerbation outcomes and the proportion of patients with exacerbations in the overall population was low, there were clear efficacy benefits in favor of FF/UMEC/VI on these outcome measures in both the ITT and EXT populations. FULFIL was designed to be as inclusive as possible, allowing patients with COPD who also had significant cardiovascular disease to be enrolled. Furthermore, patients remained on their usual standard medications during the run-in period and were not artificially required to withdraw medications. This means that the study population may more closely reflect the real-world population of patients with COPD and increases the generalizability of the study findings. FULFIL was also designed to minimize data loss by enabling data collection to continue after treatment discontinuation. All SAE reports were independently adjudicated, and a chest radiograph was required for all patients with suspected pneumonia or a moderate/severe exacerbation, which improved the characterization of safety findings.
In this study, we compared an ICS/LAMA/LABA (FF/UMEC/VI) combination with an ICS/LABA (BUD/FOR) using different dosing regimens (once daily vs. twice daily) in different inhalers. The aim of the double-dummy study design was to mitigate some of these differences, so the results reported are a direct comparison of the products rather than the addition of a LAMA to ICS/LABA. However, there is evidence supporting the value of incremental LAMA therapy (4, 9, 14, 18). Two randomized, 3-month studies showed clinically relevant improvements in lung function with UMEC plus FF/VI compared with placebo plus FF/VI in patients with moderate to very severe COPD (9). The TRILOGY study (14) showed that triple therapy compared with ICS/LABA had a modest benefit, with a reduction in exacerbations and an improvement in health-related quality of life; however, this benefit appeared to wane as the study continued. A post hoc analysis of four trials that assessed UMEC or placebo plus ICS/LABA (including the two studies described previously) showed that triple therapy improved lung function and health-related quality of life and also reduced the risk of exacerbations compared with ICS/LABA (4). Of note, in FULFIL, the benefits of FF/UMEC/VI over BUD/FOR seem substantially greater and more persistent than those seen in the comparison of beclomethasone dipropionate/formoterol/glycopyrronium bromide with beclomethasone dipropionate/formoterol (14). This could be due to the advantages of once-daily versus twice-daily dosing, the differences in the individual components, or a combination of the two. Further study is needed to clarify the drivers of these differences.
The results of the FULFIL study demonstrated the clinical value of triple therapy using FF/UMEC/VI compared with dual BUD/FOR therapy for symptomatic patients with advanced COPD who are at risk of exacerbations. Once-daily single-inhaler triple therapy provides a straightforward dosing option for patients with COPD, and this reduction in polypharmacy using multiple inhalers may reduce the likelihood of inhaler use errors, although all inhaler types may be associated with errors in use (19–21). Single-inhaler triple therapy offers clinically important benefits in lung function, health-related quality of life, and reduction in risk of exacerbation, which were observed over 52 weeks.
The authors thank the patients and their families for participating in this study, as well as Eva Gomez (GSK operations lead), Niki Day (GSK clinical safety scientist), Erik Steinberg (GSK data quality leader), and the FULFIL study team. The authors also thank Veramed for support with statistical analyses. Medical writing support in the form of development of the draft outline and manuscript drafts in consultation with the authors, editorial suggestions for draft versions of this paper, assembling tables and figures, collating author comments, copyediting, referencing, and graphic services was provided by Alison Scott, Ph.D., of Gardiner-Caldwell Communications, Macclesfield, United Kingdom, and was funded by GSK.
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*Present address: Roche, Basel, Switzerland.
Supported by GlaxoSmithKline (GSK study CTT116853).
Author Contributions: Literature search: D. A. Lipson, N.B., and H.B.; study design: D. A. Lipson, N.L., M.T., N.B., H.B., R.M., and S.J.P.; data collection: D. A. Lipson, N.L., C.-Q.Z., M.T., N.B., H.B., A.L.-S., R.M., and R.B.; data analysis: D. A. Lipson, N.L., D. A. Lomas, C.-Q.Z., N.B., R.M., and S.J.P.; data interpretation: all authors; writing/reviewing of the manuscript: all authors; final approval of the manuscript: all authors.
This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org
Originally Published in Press as DOI: 10.1164/rccm.201703-0449OC on April 4, 2017
Author disclosures are available with the text of this article at www.atsjournals.org.
