Evidence tables

Evidence tables

Table 5 Singh D et al. 2016 (TRILOGY)

Study reference

Singh D, Papi A, Corradi M et al. (2016) Single inhaler triple therapy versus inhaled corticosteroid plus long-acting β2-agonist therapy for chronic obstructive pulmonary disease: a double-blind, parallel group, randomised controlled trial. Lancet 388: 963–73

Unique identifier

NCT01917331

Study type

Randomised, parallel group, double blind, active-controlled study.

Aim of the study

Compared the efficacy and safety of single inhaler triple therapy with beclometasone dipropionate, formoterol fumarate, and glycopyrronium bromide with that of dual therapy with beclometasone dipropionate and formoterol fumarate in people with COPD with severe or very severe airflow limitation, symptoms despite treatment and a history of exacerbations.

Study dates

21 March 2014 to 14 January 2016.

Setting

159 sites in 14 countries: 18 primary care, 99 secondary care, 28 tertiary care and 14 specialist investigation units.

Number of participants

1,368 participants were randomly assigned to treatment (1 person did not receive the allocated therapy).

Population

Adults aged 40 years or older who were current or ex-smokers and had a diagnosis of COPD for at least 12 months (76% male, 100% white, mean age 63 years, 47% current smokers and 53% ex-smokers, mean time since diagnosis 7.7 years, 84% with at least 1 concurrent disease).

Inclusion criteria

  • Post-bronchodilator FEV1 <50% predicted (mean 37%) and FEV1/FVC ratio <0.7 (mean 0.4).

  • At least 1 moderate or severe COPD exacerbationa in the previous 12 months (mean 1.2 exacerbations).

  • Use for at least 2 months before screening of:

    • an ICS plus a LABA (as a free or fixed combination, 73%),

    • an ICS plus a LAMA (1%),

    • a LABA plus a LAMA (as a free or fixed combination, 15%) or

    • LAMA monotherapy (11%).

  • Symptomatic, classified as a CAT total score of ≥10 (mean 20.8) and a BDI focal score of ≤10 at screening (mean 5.4), with the BDI criterion also confirmed at the randomisation visit.

Exclusion criteria

  • Diagnosis of asthma.

  • History of allergic rhinitis or atopy.

  • A COPD exacerbation in the 4 weeks before screening or during the run-in period.

  • Clinically significant cardiovascular conditions or laboratory abnormalities.

  • Unstable concurrent disease that might have affected efficacy or safety (as judged by the investigator).

  • Current triple therapy with an ICS, LABA and LAMA.

Intervention(s)

Beclometasone dipropionate 100 micrograms, formoterol fumarate 6 micrograms and glycopyrronium bromide 12.5 micrograms in a single pressurised metered dose inhaler (2 puffs twice daily) (n=687).

Comparator(s)

Beclometasone dipropionate 100 micrograms and formoterol fumarate 6 micrograms in a single matching metered dose inhaler (2 puffs twice daily) (n=681).

Length of follow-up

During a 2-week open-label run-in period, all participants received beclometasone dipropionate and formoterol fumarate.

After the run-in period, they were randomly assigned 1:1 to 1 of the 2 treatment groups for a 52-week treatment period (median exposure 365 days, compliance 95%).

Outcomes

Co-primary outcomes (assessed at week 26):

  • change from baseline in pre-dose (morning) FEV1,

  • change from baseline in 2-hour post-dose FEV1, and

  • TDI focal score (change in dyspnoea severity from baseline).

Secondary outcomes:b

  • pre-dose FEV1 at all other clinic visits, averaged over the treatment period

  • FEV1 responsec at weeks 26 and 52

  • 2-hour post-dose FEV1 at all other clinic visits

  • TDI focal score at all other clinic visits

  • TDI responsed at weeks 26 and 52

  • SGRQ total score at all clinic visits

  • SGRQ responsee at weeks 26 and 52

  • percentage of days without rescue medication use

  • average number of puffs of rescue medication (salbutamol 100 micrograms) per day

  • moderate-to-severe COPD exacerbationf frequency over 52 weeks

  • time to first moderate-to-severe COPD exacerbation.

Safety outcomes:

  • treatment-emergent adverse events

  • treatment-related adverse events.

Source of funding

Chiesi Farmaceutici SpA.

Overall risk of bias/quality assessment (CASP RCT checklist)

Did the trial address a clearly focused issue?

Yes

Was the assignment of patients to treatments randomised?

Yesg

Were patients, health workers and study personnel blinded?

Yes

Were the groups similar at the start of the trial?

Yes

Aside from the experimental intervention, were the groups treated equally?

Yes

Were all of the patients who entered the trial properly accounted for at its conclusion?

Yes

How large was the treatment effect?

See table 8

How precise was the estimate of the treatment effect?

See table 8

Can the results be applied in your context? (or to the local population)

Yes

Were all clinically important outcomes considered?

Yes

Are the benefits worth the harms and costs?

See key points

Study limitations

  • The study included people with COPD with severe or very severe airflow limitation, symptoms despite treatment and a history of exacerbations and at least 1 moderate-to-severe exacerbation in the previous 12 months, who were symptomatic despite treatment. The results of the study may not apply to other populations with COPD.

  • People who had asthma, allergic rhinitis or atopy, clinically significant cardiovascular conditions or laboratory abnormalities, or unstable concurrent disease were excluded from the study, as were people with COPD exacerbations in the 4 weeks before screening or during the run-in period. The results of the study may not apply to these populations.

  • 2 of the co-primary outcomes are disease-oriented, rather than patient-oriented outcomes.

  • Measuring TDI relies on participants remembering what their symptoms were like previously, which may be difficult, especially over 52 weeks. This can lead to recall bias.

  • 73% of participants formerly took an ICS/LABA and the results may not apply to those formerly using other treatments such as a LABA/LAMA.

  • It is not known from the study how the efficacy and safety of beclometasone/formoterol/glycopyrronium compares with treatments for COPD apart from beclometasone/formoterol, such as other combinations of ICS/LABA (alone or with a separate LAMA).

  • It is also not known from the study whether the triple-therapy inhaler has any advantages over using a ICS/LABA with a separate LAMA in terms of patient factors such as adherence to treatment and ease of use of the device.

  • The exacerbation rate seen during the study was lower than that seen before the study even in the control group whose treatment was generally similar in both time periods. This may have been because of regular follow up and improved compliance with treatment.

Comments

a Defined as sustained worsening of the person's condition (dyspnoea, cough and/or sputum production or purulence), from the stable state and beyond normal day-to-day variations, that is acute in onset and necessitates a change in regular medication in a person with underlying COPD that includes prescriptions of systemic corticosteroids and/or antibiotics or need for hospitalisation.

b Not all of these secondary outcomes are discussed in this evidence summary. See the paper for more details.

c Change from baseline in pre-dose FEV1 ≥0.100 litre.

d A TDI focal score of ≥1 was deemed the minimum clinically important difference.

e A decrease from baseline in SGRQ total score ≥4 was deemed the minimum clinically important difference.

f Defined as a worsening of the person's respiratory symptoms that in the view of their healthcare provider required treatment with systemic corticosteroids, antibiotics, or hospital admission, or a combination of these. Severe exacerbations were those requiring hospital admission or resulting in death.

g The method of randomisation used suggests allocation was concealed.

Abbreviations: BDI, Baseline Dyspnoea Index; CAT, COPD Assessment Test; COPD, chronic obstructive pulmonary disease; FVC, forced vital capacity; FEV1, forced expiratory volume in 1 second; ICS, inhaled corticosteroid; LABA, long-acting beta-2 agonist; LAMA, long-acting muscarinic antagonist; SGRQ, St George's Respiratory Questionnaire (measuring health-related quality of life); TDI, Transition Dyspnoea Index.

Table 6 Vestbo J et al. 2017 (TRINITY)

Study reference

Vestbo J, Papi A, Corradi M et al. (2017) Single inhaler extrafine triple therapy versus long-acting muscarinic antagonist therapy for chronic obstructive pulmonary disease (TRINITY): a double-blind, parallel group, randomised controlled trial. Lancet 389: 1919–29

Unique identifier

NCT01911364

Study type

Randomised, parallel group, double blind, double dummy, active-controlled study.

Aim of the study

Primarily compared the efficacy and safety of single inhaler triple therapy with beclometasone dipropionate, formoterol fumarate, and glycopyrronium bromide with that of monotherapy with tiotropium in people with COPD with severe or very severe airflow limitation, symptoms despite treatment and a history of exacerbations.

Also compared the triple-therapy inhaler with a dual-therapy inhaler containing beclometasone dipropionate and formoterol fumarate plus a monotherapy inhaler containing tiotropium (fixed triple versus open triple).

Study dates

21 January 2014 to 18 March 2016.

Setting

224 sites in 15 countries (including the UK): 17 primary care, 121 secondary care, 48 tertiary care and 38 specialist investigation units.

Number of participants

2,691 participants were randomly assigned to treatment (2 people did not receive the allocated therapy. 1 person randomised to the open triple-therapy group received only tiotropium and was included in the tiotropium arm for the safety analyses).

Population

Adults aged 40 years or older who were current or ex-smokers and had with a diagnosis of COPD for at least 12 months (76% male, 99% white, mean age 63 years, 48% current smokers and 52% ex-smokers, mean time since diagnosis 8 years, 84% with at least 1 concurrent disease).

Inclusion criteria

  • Post-bronchodilator FEV1 <50% predicted (mean 37%) and FEV1/FVC ratio <0.7 (mean 0.4).

  • At least 1 moderate or severe COPD exacerbationa in the previous 12 months (mean 1.3 exacerbations).

  • Use for at least 2 months before screening of:

    • an ICS plus a LABA (as a free or fixed combination, 74%),

    • an ICS plus a LAMA (3%),

    • a LABA plus a LAMA (as a free or fixed combination, 12%) or

    • LAMA monotherapy (11%).

  • Symptomatic, classified as a CAT total score of ≥10 (mean 21.6).

Exclusion criteria

  • Diagnosis of asthma.

  • History of allergic rhinitis or atopy.

  • A COPD exacerbation in the 4 weeks before screening or during the run-in period.

  • Clinically significant cardiovascular conditions or laboratory abnormalities.

  • Unstable concurrent disease that might have affected efficacy or safety (as judged by the investigator).

  • Current triple therapy with an ICS, LABA and LAMA.

Intervention(s)

Beclometasone dipropionate 100 micrograms, formoterol fumarate 6 micrograms and glycopyrronium bromide 12.5 micrograms in a single pressurised metered dose inhaler (2 puffs twice daily) plus a dummy dry powder inhaler (1 puff daily) (fixed triple therapy; n=1,078).

Comparator(s)

Tiotropium 18 micrograms in a dry powder inhaler (Handihaler; 1 puff daily) plus a dummy pressurised metered dose inhaler (2 puffs twice daily) (n=1,075).

Beclometasone dipropionate 100 micrograms and formoterol fumarate 6 micrograms in a pressurised metered dose inhaler (2 puffs twice daily) plus tiotropium 18 micrograms in a dry powder inhaler (1 puff daily) (open triple therapy; n=538).

Length of follow-up

During a 2-week open-label run-in period, all participants received tiotropium.

After the run-in period, they were randomly assigned 2:2:1 to the fixed triple group, tiotropium group or open triple group for a 52-week treatment period (median exposure 365 days, compliance 94–95%).

Outcomes

Primary outcome.

  • Moderate-to-severe COPD exacerbationb frequency over 52 weeks of treatment for fixed triple therapy versus tiotropium.

Key secondary outcomes: change from baseline in pre-dose

FEV1 at week 52

  • for fixed triple therapy versus tiotropium

  • for fixed triple therapy versus open triple therapy (non-inferiority analysis).

Other secondary outcomes:c

  • time to first moderate-to-severe COPD exacerbation

  • time to first severe COPD exacerbation

  • rate of severe and of moderate COPD exacerbations over 52 weeks of treatment

  • change from baseline in pre-dose FEV1 at other time points

  • mean pre-dose FEV1 averaged over the treatment period

  • FEV1 responsed at weeks 26 and 52

  • pre-dose inspiratory capacity at all clinic visits

  • SGRQ total score at all clinic visits

  • SGRQ responsee at weeks 26 and 52

  • percentage of days without rescue medication use

  • average number of puffs of rescue medication (salbutamol 100 micrograms) per day.

Safety outcomes:

  • treatment-emergent adverse events

  • treatment-related adverse events.

Source of funding

Chiesi Farmaceutici SpA

Overall risk of bias/quality assessment (CASP RCT checklist)

Did the trial address a clearly focused issue?

Yes

Was the assignment of patients to treatments randomised?

Yesf

Were patients, health workers and study personnel blinded?

Yes

Were the groups similar at the start of the trial?

Yes

Aside from the experimental intervention, were the groups treated equally?

Yes

Were all of the patients who entered the trial properly accounted for at its conclusion?

Yes

How large was the treatment effect?

See table 9

How precise was the estimate of the treatment effect?

See table 9

Can the results be applied in your context? (or to the local population)

Yes

Were all clinically important outcomes considered?

Yes

Are the benefits worth the harms and costs?

See key points

Study limitations

  • The study included people with COPD with severe or very severe airflow limitation and at least 1 moderate-to-severe exacerbation in the previous 12 months, who were symptomatic despite treatment. The results of the study may not apply to other populations with COPD.

  • People who had asthma, allergic rhinitis or atopy, clinically significant cardiovascular conditions or laboratory abnormalities, or unstable concurrent disease were excluded from the study, as were people with COPD exacerbations in the 4 weeks before screening or during the run-in period. The results of the study may not apply to these populations.

  • 74% of participants formerly took an ICS/LABA and the results may not apply to those formerly using other treatments such as a LABA/LAMA.

  • It is not known from the study how the efficacy and safety of beclometasone/formoterol/glycopyrronium compares with treatments for COPD apart from tiotropium alone and open triple therapy.

  • It is also not known from the study whether the triple-therapy inhaler has any advantages over using a ICS/LABA with a separate LAMA in terms of patient factors such as adherence to treatment and ease of use of the device.

  • The exacerbation rate seen during the study was lower than that seen before the study even in the control group whose treatment was generally similar in both time periods. This may have been because of regular follow up and improved compliance with treatment.

Comments

a Defined as sustained worsening of the person's condition (dyspnoea, cough and/or sputum production or purulence), from the stable state and beyond normal day-to-day variations, that is acute in onset and necessitates a change in regular medication in a person with underlying COPD that includes prescriptions of systemic corticosteroids and/or antibiotics or need for hospitalisation.

b Defined as a worsening of the person's respiratory symptoms that in the view of their healthcare provider required treatment with systemic corticosteroids, antibiotics, or hospital admission, or a combination of these. Severe exacerbations were those requiring hospital admission or resulting in death.

c Not all of these secondary outcomes are discussed in this evidence summary. See the paper for more details.

d Change from baseline in pre-dose FEV1 ≥0.100 litre.

e A decrease from baseline in SGRQ total score ≥4 was deemed the minimum clinically important difference.

f The method of randomisation used suggests allocation was concealed.

Abbreviations: CAT, COPD Assessment Test; COPD, chronic obstructive pulmonary disease; FVC, forced vital capacity; FEV1, forced expiratory volume in 1 second; ICS, inhaled corticosteroid; LABA, long-acting beta-2 agonist; LAMA, long-acting muscarinic antagonist; SGRQ, St George's Respiratory Questionnaire (measuring health-related quality of life).

Table 7 Papi A et al. 2018 (TRIBUTE)

Study reference

Papi A, Vestbo J, Fabbri L et al. (2018) Extrafine inhaled triple therapy versus dual bronchodilator therapy in chronic obstructive pulmonary disease (TRIBUTE): a double-blind, parallel group, randomised controlled trial. Lancet 391: 1076–84

Unique identifier

NCT02579850

Study type

Randomised, parallel group, double blind, double dummy, active-controlled study.

Aim of the study

Compared the efficacy and safety of single inhaler triple therapy with beclometasone dipropionate, formoterol fumarate, and glycopyrronium bromide with that of dual therapy with indacaterol maleate and glycopyrronium bromide in people with COPD with severe or very severe airflow limitation, symptoms despite treatment and a history of exacerbations.

Study dates

29 May 2015 to 10 July 2017.

Setting

187 sites in 17 countries: 37 primary care, 104 secondary care, 1 tertiary care and 45 specialist investigation units.

Number of participants

1,532 participants were randomly assigned to treatment.

Population

Adults aged 40 years or older who were current or ex-smokers and had a diagnosis of COPD (72% male, 92% white, mean age 64 years, 45% current smokers and 55% ex-smokers, mean time since diagnosis 8 years, 85% with at least 1 concurrent disease).

Inclusion criteria

  • Post-bronchodilator FEV1 <50% predicted (mean 36%) and FEV1/FVC ratio <0.7 (mean 0.4).

  • At least 1 moderate or severe COPD exacerbationa in the previous 12 months (mean 1.2 exacerbations).

  • Symptomatic, classified as a CAT total score of ≥10.

  • Use for at least 2 months before screening of:

    • an ICS plus a LABA (61%),

    • an ICS plus a LAMA (4%),

    • a LABA plus a LAMA (25%) or

    • LAMA monotherapy (10%).

Exclusion criteria

  • Diagnosis of asthma, which needed corticosteroid treatment.

  • Clinically significant cardiovascular conditions or laboratory abnormalities.

  • Unstable concurrent disease that might have affected efficacy or safety (as judged by the investigator).

  • Current triple therapy with an ICS, LABA and LAMA.

Intervention(s)

Beclometasone dipropionate 100 micrograms, formoterol fumarate 6 micrograms and glycopyrronium bromide 12.5 micrograms in a single pressurised metered dose inhaler (2 puffs twice daily) plus a dummy dry powder inhaler (1 puff daily) (n=764).

Comparator(s)

Indacaterol maleate 110 micrograms and glycopyrronium bromide 54 micrograms in a single dry powder inhaler (Breezhaler; 1 puff daily) plus a dummy pressurised metered dose inhaler (2 puffs twice daily) (n=768).

Length of follow-up

During a 2-week open-label run-in period, all participants had their maintenance therapy switched to indacaterol maleate plus glycopyrronium bromide.

After the run-in period, they were randomly assigned 1:1 to 1 of the 2 treatment groups for a 52-week treatment period (compliance 98.5%).

Outcomes

Primary outcome

  • Moderate-to-severe COPD exacerbationb frequency over 52 weeks of treatment.

Secondary outcomes:c

  • time to first moderate-to-severe COPD exacerbation

  • time to first severe COPD exacerbation

  • rate of severe and of moderate COPD exacerbations

  • change from baseline in pre-dose FEV1 at all treatment visits and averaged over the treatment period

  • pre-dose FEV1 responsed at weeks 26 and 52

  • change from baseline in SGRQ total score at all treatment visits and averaged over the treatment period

  • SGRQ responsee at weeks 26 and 52

  • percentage of days without rescue medication use

  • average number of puffs of rescue medication (salbutamol or terbutaline) per day.

Safety outcomes:

  • treatment-emergent adverse eventsf

  • treatment-related adverse events.

Source of funding

Chiesi Farmaceutici SpA

Overall risk of bias/quality assessment (CASP RCT checklist)

Did the trial address a clearly focused issue?

Yes

Was the assignment of patients to treatments randomised?

Yesg

Were patients, health workers and study personnel blinded?

Yes

Were the groups similar at the start of the trial?

Yes

Aside from the experimental intervention, were the groups treated equally?

Yes

Were all of the patients who entered the trial properly accounted for at its conclusion?

Yes

How large was the treatment effect?

See table 10

How precise was the estimate of the treatment effect?

See table 10

Can the results be applied in your context? (or to the local population)

Yes

Were all clinically important outcomes considered?

Yes

Are the benefits worth the harms and costs?

See key points

Study limitations

  • The study included people with COPD with severe or very severe airflow limitation, symptoms despite treatment and a history of exacerbations and at least 1 moderate-to-severe exacerbation in the previous 12 months, who were symptomatic despite treatment. The results of the study may not apply to other populations with COPD.

  • People who had asthma requiring treatment with corticosteroids, clinically significant cardiovascular conditions or laboratory abnormalities, or unstable concurrent disease were excluded from the study. The results of the study may not apply to these populations.

  • 61% of participants formerly took an ICS/LABA and the results may not apply to those formerly using other treatments. In this study, 25% of people previously took a LABA/LAMA.

  • It is not known from the study how the efficacy and safety of beclometasone/formoterol/glycopyrronium compares with treatments for COPD apart from indacaterol/glycopyrronium.

  • It is also not known from the study whether the triple-therapy inhaler has any advantages in terms of patient factors such as adherence to treatment and ease of use of the device.

  • The exacerbation rate seen during the study was lower than that seen before the study. This may have been because of regular follow up, improved compliance with treatment or more accurate identification of COPD exacerbations by investigators.

  • The study may have had insufficient statistical power to detect differences between the groups for outcomes that occur relatively rarely; for example, severe exacerbations.

  • The 2 groups received different LABAs, from different devices and in different dosing regimens. It is possible that these differences between the treatments could have affected the outcomes observed.

Comments

a Defined as a sustained worsening of respiratory symptoms that required treatment with systemic corticosteroids, antibiotics or hospital admission, or any combination of these.

b Defined as a worsening of the person's respiratory symptoms that in the view of their healthcare provider required treatment with systemic corticosteroids, antibiotics, or hospital admission, or a combination of these. Severe exacerbations were defined as those requiring hospital admission or resulting in death.

c Not all of the secondary outcomes are discussed in this evidence summary. See the paper for more details.

d Change from baseline in pre-dose FEV1 ≥0.100 litre.

e A decrease from baseline in SGRQ total score ≥4 was deemed the minimum clinically important difference.

f Defined as events starting on or after first intake of randomised study medication.

g The method of randomisation used suggests allocation was concealed.

Abbreviations: CAT, COPD Assessment Test; COPD, chronic obstructive pulmonary disease; FVC, forced vital capacity; FEV1, forced expiratory volume in 1 second; ICS, inhaled corticosteroid; LABA, long-acting beta-2 agonist; LAMA, long-acting muscarinic antagonist; SGRQ, St George's Respiratory Questionnaire (measuring health-related quality of life).