Study reference

Study characteristics

Patient characteristics ²

Intervention (I)

Comparison / control (C) ³

Follow-up

Outcome measures and effect size ⁴

Comments

Bremner, 2018

Type of study:
a randomized noninferiority

Study.

Setting and country:

USA

Funding and conflicts of interest:
This study was funded by GSK (GSK study CTT200812; ClinicalTrials.gov identifier

NCT02729051). ELLIPTA is owned by or licensed to the GSK group of companies. RB, NB, ASI, C-QZ, and DAL are employees of GSK and hold stocks/shares in

the company. ASI is also an unpaid faculty member at McMaster University,

Canada. PRB has no conflicts of interest to disclose.

Inclusion criteria:

COPD Assessment Test™ (CAT) score ≥ 10 (13, 14);

a post-albuterol/salbutamol FEV₁/forced vital capacity ratio

< 0.70; and a post-bronchodilator FEV₁< 50% of predicted

and ≥1 moderate/severe exacerbation in the previous

12 months or a post-bronchodilator FEV₁≥ 50% to < 80%

of predicted and ≥2 moderate exacerbations or ≥1 severe

exacerbation requiring hospitalisation in the previous

12 months.

Exclusion criteria:

a current diagnosis of asthma

(patients with a prior history of asthma were eligible if they

had a current diagnosis of COPD that was the primary cause

of their respiratory symptoms); α1-antitrypsin deficiency; active tuberculosis; other respiratory disorders that were the

primary cause of respiratory symptoms; lung resection surgery

in the previous 12 months; risk factors for pneumonia

(including immunosuppression and neurological disorders

affecting control of the upper airway (e.g. Parkinson’s disease

or myasthenia gravis); pneumonia and/or moderate/severe

exacerbation that had not resolved at least 14 days prior to

screening; respiratory infections; abnormal findings on chest

X-ray; clinically significant comorbidities; unstable liver or

cardiac disease; and cancer. Patients with a high risk for

pneumonia (e.g. very low body mass index, severely malnourished,

or very low FEV₁) were only to be included at

the discretion of the investigator.

N total at baseline:

Intervention: 527

Control: 528

Important prognostic factors²:

age ± SD:

I: 66.7 ± 8.5

C: 65.9 ± 8.8

Sex:

I: 74% M

C: 75% M

Groups comparable at baseline?

Yes

24 weeks of FF/UMEC/VI 100 μg/62.5 μg/25 μg in a single inhaler and placebo (second inhaler). all treatments/placebo

were delivered using the ELLIPTA inhaler once daily in the morning.

24 weeks of FF/VI 100 μg/25 μg and UMEC 62.5 μg, in separate inhalers. all treatments/placebo were delivered using the ELLIPTA inhaler once daily in the

morning.

Length of follow-up:

One week after treatment.

Loss-to-follow-up:

Intervention: 6%

Reasons: n.r.

Control: 6%

Reasons: n.r.

Incomplete outcome data:

n.r.

COPD exacerbations rate
Defined as the number of exacerbations.

Effect measure: Risk ratio (95% CI):
0.91 (95% CI: 0.74 to 1.12) in favour of fixed triple therapy.

Mortality
n.r.

Quality of life

Defined as the proportion of responders to the SGRQ.

Effect measure: Risk ratio (95% CI):
0.92 (95% CI 0.71 to 1.20) in favour of fixed triple therapy.

FEV₁

Defined as the between treatment difference in FEV₁

Effect measure: mean difference (95% CI)
18 mL (95% CI -13 to 50) in favour of fixed triple therapy.

Pneumonia

Defined as the number of participants with pneumonia.

Effect measure: Risk ratio (95% CI):

Serious adverse events

Defined as the number of serious adverse events.

Effect measure: Risk ratio (95%

Pneumonia:

0.67 (0.34 to 1.30) in favour of fixed triple therapy.

Other SAEs

0.91 (95% CI 0.64 to 1.30) in favour of fixed triple therapy.

This study showed that single-inhaler FF/UMEC/VI

100 μg/62.5 μg/25 μg was non-inferior to FF/VI 100 μg/

25 μg plus UMEC 62.5 μg based on change from baseline

in trough FEV₁ at Week 24 in patients with advanced

COPD. Our findings confirm that single-inhaler triple

therapy with FF/UMEC/VI offers similar efficacy, healthrelated

quality of life, and safety benefits as the same triple

therapy administered using two inhalers.

Vestbo, 2017

Type of study:
a double-blind, parallel group,

randomised controlled trial

Setting and country:

UK

Funding and conflicts of interest:
The work was funded by Chiesi Farmaceutici SpA. All other authors

declare no competing interests.

Inclusion criteria:

Eligible patients were 40 years of age or older; current or

ex-smokers; had a diagnosis of COPD, with postbronchodilator

(salbutamol 400 μg) forced expiratory

volume in 1 s (FEV₁) of less than 50% and a ratio of FEV₁

to forced vital capacity of less than 0·7; had at least

one moderate or severe COPD exacerbation in the

previous 12 months; and used an inhaled corticosteroid

plus long-acting β₂-agonist (as an open or fixed

combination), or inhaled corticosteroid plus long-acting

muscarinic antagonist, or inhaled long-acting β₂-agonist

plus long-acting muscarinic antagonist (as an open or

fixed combination), or long-acting muscarinic antagonist

monotherapy for at least 2 months before screening—

patients receiving triple therapy of inhaled corticosteroid,

long-acting β₂-agonist and long-acting muscarinic

antagonist were not eligible. Additionally, eligible

patients were symptomatic, with a COPD Assessment

Test total score of at least 10.

Exclusion criteria:

We excluded patients from the study if they had a

diagnosis of asthma, or history of allergic rhinitis or

atopy; COPD exacerbation in the 4 weeks before

screening or during the run-in period; clinically

significant cardiovascular conditions or laboratory

abnormalities (including persistent, long-standing, or

permanent atrial fibrillation); or unstable concurrent

disease that could have influenced efficacy or safety (as

judged by the investigator).

N total at baseline:

Intervention: 1077

Control: 537

Important prognostic factors²:

age ± SD:

I: 63.4 ± 8.7

C: 62.6 ± 8.9

Sex:

I: 77% M

C: 74% M

Groups comparable at baseline?

Yes

Patients received extrafine 100 μg

BDP/6 μg FF/12·5 μg GB, two actuations twice daily via pressurised metered-dose inhaler (pMDI; fixed triple group) + placebo

Patients received extrafine 100 μg BDP/6 μg FF,

two actuations twice daily via pMDI plus tiotropium 18 μg,

one inhalation per day via SDDPI (open triple group).

Length of follow-up:

52 weeks.

Loss-to-follow-up:

Intervention: N (%)
92 (8.5%)
Reasons: Withdrawal of consent, death, adverse events, lost to follow-up, violated protocol, lack of efficacy, other.

Control: N (%)

42 (7.8%)

Incomplete outcome data:

n.r.

COPD exacerbations rate
Defined as the number of exacerbations.

Effect measure: Risk ratio (95% CI):
1.05 (95% CI 0.90 to 1.22) in favour of open triple therapy.

Mortality
Defined as the proportion of deaths.

Effect measure: Risk ratio (95% CI): 1.25 (95% CI 0.55 to 2.81) in favour of open triple therapy.

Quality of life

Defined as the proportion of responders to the SGRQ.

Effect measure: Risk ratio (95% CI):

After 24 weeks:
0.92 (95% CI 0.83 to 1.02) in favour of fixed triple therapy.

After 52 weeks:
0.97 (0.87 to 1.08) in favour of fixed triple therapy.

FEV₁

Defined as proportion of patients who improved at least with 100 mL from baseline.

Effect measure: risk ratio (95% CI):

After 24 weeks:
1.03 (95% CI 0.90 to 1.18) in favour of fixed triple therapy.

After 52 weeks:

0.97 (0.85 to 1.11) in favour of fixed triple therapy

Effect measure: Risk ratio (95% CI):

Serious adverse events

Defined as the number of serious adverse events.

Effect measure: Risk ratio (95% CI):

Pneumonia:

After 52 weeks
1.16 (0.54 to 2.52) in favour of open triple therapy.

Other SAEs

After 52 weeks:
1.03 (95% CI 0.78 to 1.35) in favour of open triple therapy.

In conclusion, in TRINITY treatment with extrafine

fixed triple therapy had clinically beneficial effects

compared with long-acting muscarinic antagonist

monotherapy on different components of COPD, namely

exacerbations, FEV₁, hyperinflation, and health-related

quality of life. This consistent improvement in different

disease domains suggests that stepping up a patient

from long-acting muscarinic antagonist to triple therapy

will have a clinically meaningful impact.

Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Ferguson, 2020

SR of 2 RCTs

No literature search applicable.

A: Study 207608

B: Study 207609

Study design:

A: replicate Phase IV, 12-week, randomized, double-blind, triple-dummy, parallel-group, multicenter, non-inferiority trials.

B: replicate Phase IV, 12-week,

randomized, double-blind, triple-dummy, parallel-group, multicenter, non-inferiority trials.

Setting and Country:

A: 59 centres in 4 countries.
B: 58 centres in 3 countries.

Source of funding and conflicts of interest:

Funded by GSK.

N Brown, C Compton, TC Corbridge, K Dorais, C Harvey, MC Kaisermann, DA

Lipson, N Martin, M Stiegler, and C-Q Zhu are employees of GlaxoSmithKline

(GSK) and are shareholders in GSK. GT Ferguson received grants, personal

fees, and non-financial support from Boehringer Ingelheim, Novartis,

AstraZeneca, Pearl Therapeutics, Sunovion, Theravance, and GSK, grants and

personal fees from Verona, and Sanofi, and personal fees from Mylan,

Innoviva, and Circassia, and grants from Altavant, unrelated to this work. C

Fogarty has nothing to disclose. F Sciurba received research support from

the COPD Foundation, Department of Defense Beta Blocker, Gala

Therapeutics, Inc., GSK, NIH, Nuvaira, PCORI, PneumRX, Inc., PulmonX, and

ResMed Corp, participated in advisory board for GSK, PneumRX, Inc.,

Theravance, and Verona and previously received research support from

Astellas and AstraZeneca, unrelated to this work. D Bernstein has received

grants and personal fees from GSK and ALK America, grants from Aimmune,

Amgen, AstraZeneca, Genentech, Merck, Mylan, Novartis, Pearl, Shire, Teva,

Adare, Knopp, Leo, Mandala, Gossamer, and Regeneron, and personal fees

from Gerson Lehman, Guidepoint Global, and Covis, unrelated to this work.

Inclusion criteria SR: Informed consent, outpatients, 40 years and older, male and female, COPD diagnosis, smoking history, severity of COPD symptoms (10 or higher on the CAT), severity of FEV₁ of <50% predictued to normal or post-brochodilatator FEV₁ <80% of predicted normal, history of 2 or more moderate/severe exacerbations in previous 12 months, post albuterol/salbutamol FEV₁/FVC ratio of <70, existing COPD maintenance treatment.

Exclusion criteria SR:

Pregnancy, asthma, alpha1-antitrypsin deficiency, other respiratory disorders, lung resection, risk actors for pneumonia, pneumonia and/or moderate or sever COPD exacerbations, respiratory tract infection, abnormal chest x-ray, other diseases/abnormalities, unstable liver disease, unstable or life threatening cardiac disease, abnormal and clinically significant 12-lead ECG finding, contraindications, cancer, oxygen therapy, medication prior to spirometry, pulmonary rehabilitation, drug/alcohol abuse, non-complicance, questionable validity of consent, affiliation with investigator site, inability to read, medication prior to screening.

2 studies included

Important patient characteristics at baseline:

N, mean age

A: 728 patients, 65.1y

B: 732 patients, 65.3y

Sex:

A: 52.7% Male

B: 51.0% Male

Groups comparable at baseline?

Yes.

Describe intervention:

A: single-inhaler triple

therapy (FF/UMEC/VI) 100/62.5/25 μg once daily

(in the morning) via Ellipta plus two inhalations of placebo

twice daily via MDI (in the morning and evening)

plus placebo once daily via HandiHaler (in the morning).

B: single-inhaler triple

therapy (FF/UMEC/VI) 100/62.5/25 μg once daily

(in the morning) via Ellipta plus two inhalations of placebo

twice daily via MDI (in the morning and evening)

plus placebo once daily via HandiHaler (in the morning).

Describe control:

A: multiple-inhaler

triple combination therapy (BUD/FOR+TIO) 200/6 μg twice daily via MDI (in the morning and evening) plus TIO 18 μg once daily via HandiHaler (in the morning) plus placebo once daily (in the morning) via Ellipta for 84 days

B: multiple-inhaler

triple combination therapy (BUD/FOR+TIO) 200/6 μg twice daily via MDI (in the morning and evening) plus TIO 18 μg once daily via HandiHaler (in the morning) plus placebo once daily (in the morning) via Ellipta for 84 days.

End-point of follow-up:

A: After four weeks of treatment, after 12 weeks of treatment, 7 days after treatment.

B: After four weeks of treatment, after 12 weeks of treatment, 7 days after treatment.

For how many participants were no complete outcome data available?

(intervention/control)

A: 29/40

B: 35/26

COPD exacerbations rate
n.r.

Mortality
Defined by the proportion of deaths (intervention/control)
A: 0 (0%) / 0 (0%)
B: 0 (0%) / 1 (0.3%)

Effect measure: risk ratio (95% CI):
Pooled effect: 0.33 (0.01 to 8.06) in favour of fixed triple therapy.

Quality of life

Defined as the proportion of responders to the SGRQ.

(intervention/control)

A: 117 (34%) / 117 (34%)
B: 124 (36%) / 119 (35%)

Effect measure: risk ratio (95% CI): Pooled effect:

1.02 (95% CI 0.88 to 1.19) in favour of open triple therapy.

FEV₁

n.r.

Serious adverse events

Defined as the number of serious adverse events (intervention / control)

Pneumonia

A: 5 (1%) / 6 (2%)
B: 2 (0.5%) / 3 (0.8%)

Effect measure: Risk ratio (95% CI): Pooled effect: 0.78 (95% CI 0.29 to 2.08) in favour of fixed triple therapy.

Other serious adverse events
A: 25 (7%) / 14 (4%)
B: 12 (3%) / 17 (5%)

Effect measure: Risk ratio (95% CI): Pooled effect: 1.20 (95% CI 0.75 to 1.91) in favour of open triple therapy.

Author’s conclusion

Once-daily single-inhaler triple therapy with FF/UMEC/VI

provides similar overall improvements in weighted mean FEV₁ and health status, and a similar safety profile, including a low incidence of pneumonia, as twice-daily multipleinhaler triple therapy with BUD/FOR+TIO. These results suggest that FF/UMEC/VI is a viable treatment option for

patients who wish to simplify their treatment regimen from

multiple- to single-inhaler triple therapy. The greater improvements with FF/UMEC/VI over BUD/FOR+TIO in

trough FEV₁ at 12 and 24 h further suggest that once-daily

FF/UMEC/VI therapy may offer more consistent and sustained lung function benefits throughout the dosing interval compared with twice-daily BUD/FOR + once-daily TIO therapy.

Personal remarks on study quality, conclusions, and other issues (potentially) relevant to the research question.

Risk of bias

Study reference

(first author, publication year)

Was the allocation sequence adequately generated? ^a

Definitely yes

Probably yes

Probably no

Definitely no

Was the allocation adequately concealed?^b

Definitely yes

Probably yes

Probably no

Definitely no

Blinding: Was knowledge of the allocated

interventions adequately prevented?^c

Were patients blinded?

Were healthcare providers blinded?

Were data collectors blinded?

Were outcome assessors blinded?

Were data analysts blinded?

Definitely yes

Probably yes

Probably no

Definitely no

Was loss to follow-up (missing outcome data) infrequent?^d

Definitely yes

Probably yes

Probably no

Definitely no

Are reports of the study free of selective outcome reporting?^e

Definitely yes

Probably yes

Probably no

Definitely no

Was the study apparently free of other problems that could put it at a risk of bias?^f

Definitely yes

Probably yes

Probably no

Definitely no

Overall risk of bias

If applicable/necessary, per outcome measure^g

LOW

Some concerns

HIGH

Bremner, 2016

Definitely yes;

Reason: Eligible patients were randomized (1:1) to receive 24 weeks

of FF/UMEC/VI 100 μg/62.5 μg/25 μg in a single inhaler and placebo (second inhaler) or FF/VI 100 μg/25 μg and UMEC 62.5 μg, in separate inhalers; all treatments/placebo

were delivered using the ELLIPTA inhaler once daily in the

morning.

Definitely yes;

Reason: Randomization was stratified by the number of long-acting bronchodilators (0, 1, or 2) per day during the run-in.

Definitely yes;

Reason: patients in both groups received their assigned

study treatment using double-dummy blind inhalers,

and so we were unable to directly assess the impact on

adherence of a simplified single-inhaler triple therapy

regimen versus the same treatments delivered using two

inhalers..

Definitely yes;

Reason: Loss to follow-up was infrequent.

Definitely yes;

Reason: Investigators who did the analyses were masked to group allocation.

Definitely no;

Reason: Funding

This study was funded by GSK (GSK study CTT200812; ClinicalTrials.gov identifier

NCT02729051). ELLIPTA is owned by or licensed to the GSK group of companies.

Some concerns

Ferguson, 2020

Definitely no;

Reason: Following

run-in (Visit 2; Day 1 of study), an Interactive

Web Response System was used to randomize patients 1:1 to receive FF/UMEC/VI or two inhalations of BUD/FOR plus TIO.

Definitely no;

Reason: Neither researchers nor staff involved was blinded to the study drug.

Definitely no;

Reason: Neither researchers nor staff involved was blinded to the study drug. However, dummy inhalers were used in these studies to

ensure blinding and, as such, the studies were not designed

to assess the impact of single or multiple inhalers nor once daily

or twice-daily therapy on adherence.

Probably yes

Reason: Loss to follow-up was infrequent.

Definitely yes

Reason: All relevant outcomes were reported;

Definitely no;

Reason: Funding

The funders of the study had a role in

the study design, data analysis, data interpretation, and writing of the report.

ELLIPTA is owned by or licensed to the GSK Group of Companies.

Patients at risk of non-compliance

with study medication or attendance for scheduled visits,

or unable to comply with the study procedures were

excluded (subjective judgement).

HIGH

Vestbo, 2017

Definitely yes;

Reason: Patients were randomised to treatment by investigators

contacting an interactive response technology (IRT)

system, which used a randomisation list generated by the

IRT provider. Randomisation was in the ratio 2:2:1 to the

fixed triple group, tiotropium group, or open triple

group. Randomisation was stratified by country and

severity of airflow limitation (post-bronchodilator FEV₁

<30% predicted, or 30–50% predicted, with a minimum

of 20% of recruited patients to be <30% predicted).

Definitely yes;

Reason: Patients were randomised to treatment by investigators

contacting an interactive response technology (IRT)

system, which used a randomisation list generated by the

IRT provider. Randomisation was in the ratio 2:2:1 to the

fixed triple group, tiotropium group, or open triple

group. Randomisation was stratified by country and

severity of airflow limitation (post-bronchodilator FEV₁

<30% predicted, or 30–50% predicted, with a minimum

of 20% of recruited patients to be <30% predicted).

Definitely no;

Reason: Patients, investigators, site staff, and funder personnel

were masked to treatment assignment for the duration of

the study. To achieve this masking, a double-dummy

approach was used, with all patients using a pMDI

twice daily (containing BDP/FF/GB, BDP/FF, or placebo)

and an SDDPI once daily (containing tiotropium or

placebo).

Probably yes

Reason: Loss to follow-up was infrequent.

Definitely yes

Reason: All relevant outcomes were reported;

Definitely no;

Reason: The funder was responsible for the design and analysis

of the study, oversaw its conduct and was responsible for

preparing the study report. All authors had full access to

all of the data, with the lead author (JV) responsible for

the decision to submit for publication.

Some concerns