Results tables

Results tables

Table 8 Singh D et al. 2016 (TRILOGY)

Beclometasone/ formoterol/ glycopyrronium bromide (100/6/12.5 micrograms)

Beclometasone/ formoterol (100/6 micrograms)

Analysis

n a

687

680

Co-primary outcomes

Mean change from baseline in pre-dose (morning) FEV1 at week 26

0.082 litre

(95% CI 0.062 litre to 0.102 litre)

0.001 litre

(95% CI −0.019 litre to 0.021 litre)

Adjusted mean difference 0.081 litre

(95% CI 0.052 litre to 0.109 litre)

p<0.001

Mean change from baseline in 2-hour post-dose FEV1 at week 26

0.261 litre

(95% CI 0.240 litre to 0.283 litre)

0.145 litre

(95% CI 0.123 litre to 0.166 litre)

Adjusted mean difference 0.117 litre

(95% CI 0.086 litre to 0.147 litre)

p<0.001

TDI focal score (change in dyspnoea severity from baseline) at week 26

1.71

(95% CI 1.50 to 1.92)

1.50

(95% CI 1.29 to 1.71)

Adjusted mean difference 0.21

(95% CI −0.08 to 0.51)

p=0.160

No statistically significant difference

Selected secondary outcomes

Pre-dose FEV1 responseb at week 26

287/687 (42%)

165/680 (24%)

OR 2.30

(95% CI 1.82 to 2.91)

p<0.001

Pre-dose FEV1 responseb at week 52

259/687 (38%)

158/680 (23%)

OR 2.06

(95% CI 1.62 to 2.62)

p<0.001

TDI responsec at week 26

394/687 (57%)

352/680 (52%)

OR 1.28

(95% CI 1.03 to 1.59)

p=0.027

TDI responsec at week 52

370/687 (54%)

354/680 (52%)

OR 1.09

(95% CI 0.88 to 1.36)

p=0.430

SGRQ responsed at week 26

321/687 (47%)

246/680 (36%)

OR 1.52

(95% CI 1.21 to 1.91)

p<0.001

SGRQ responsed at week 52

297/687 (43%)

244/680 (36%)

OR 1.33

(95% CI 1.06 to 1.66)

p=0.014

Rate of moderate-to-severe COPD exacerbationse over 52 weeks

0.41

0.53

RR 0.77

(95% CI 0.65 to 0.92)

p=0.005

Time to first moderate-to-severe COPD exacerbatione over 52 weeks

Not applicable

Not applicable

HR 0.80

(95% CI 0.67 to 0.97)

p=0.020

Percentage of days without rescue medication use during weeks 5 to 12

6.23%

(95% CI 4.19% to 8.27%)

3.18%

(95% CI 1.12% to 5.24%)

Adjusted mean difference 3.05%

(95% CI 0.15% to 5.95%)

p=0.039

Change from baseline in average number of puffs per day of rescue salbutamol during weeks 13 to 26

−0.21 puffs

(95% CI −0.32 puffs to −0.09 puffs)

−0.02 puffs

(95% CI −0.14 puffs to 0.10 puffs)

Adjusted mean difference −0.19 puffs

(95% CI −0.35 puffs to −0.02 puffs)

p=0.029

Safety and tolerability outcomes f

n g

687

680

Treatment-emergent adverse events

368/687 (54%)

379/680 (56%)

58% and 63% of these respectively were COPD-related

Serious treatment-emergent adverse events

106/687 (15%)

123/680 (18%)

Treatment-emergent adverse events leading to discontinuation

35/687 (5%)

33/680 (5%)

Treatment-emergent adverse events leading to death

15/687 (2%)

16/680 (2%)

Treatment-emergent major adverse cardiovascular eventsh

15/687 (2%)

15/680 (2%)

Treatment-related adverse events

26/687 (4%)

14/680 (2%)

Primarily oral candidiasis, muscle spasms and dry mouth

Serious treatment-related adverse events

1/687 (<1%)

0/680 (0%)

1 person developed atrial fibrillation

a The intention-to-treat population includes all randomly assigned participants who received at least 1 dose of study medication and had at least 1 post-baseline efficacy assessment.

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

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

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

e A COPD exacerbation was 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.

f Statistical analyses not reported.

g The safety population includes all randomly assigned participants who received at least 1 dose of study medication.

h Acute myocardial infarction, arrhythmias, cardiovascular death, heart failure and stroke.

Abbreviations: CI, confidence interval; FEV1, forced expiratory volume in 1 second; HR, hazard ratio; OR, odds ratio; RR, rate ratio; SGRQ, St George's Respiratory Questionnaire (measuring health-related quality of life); TDI, Transition Dyspnoea Index.

Table 9 Vestbo J et al. 2017 (TRINITY)

Fixed triple therapy: beclometasone/ formoterol/ glycopyrronium bromide (100/6/12.5 micrograms)

Tiotropium (18 micrograms)

Open triple therapy: beclometasone/ formoterol (100/6 micrograms) plus tiotropium (18 micrograms)

Analysis

n a

1,077 b

1,074 c

538

Primary outcome

Rate of moderate-to-severe COPD exacerbationsd over 52 weeks

0.46

(SD 0.41 to 0.51)

0.57

(SD 0.52 to 0.63)

0.45

(SD 0.39 to 0.52)

Primary outcome, fixed triple versus tiotropium:

RR 0.80

(95% CI 0.69 to 0.92)

p=0.0025

Secondary outcome, fixed triple versus open triple:

RR 1.01

(95% CI 0.85 to 1.21)

p=0.89

No statistically significant difference

Selected secondary outcomes

Mean change from baseline in pre-dose FEV1 at week 52

0.082 litre

(95% CI 0.065 litre to 0.100 litre)

0.021 litre

(95% CI 0.003 litre to 0.039 litre)

0.085 litre

(95% CI 0.061 litre to 0.110 litre)

Fixed triple versus tiotropium:

adjusted mean difference 0.061 litre

(95% CI 0.037 litre to 0.086 litre)

p<0.0001

Fixed triple versus open triple:

adjusted mean difference −0.003 litre

(95% CI −0.033 litre to 0.027 litre)

p=0.85

Non-inferiore

Time to first moderate-to-severe COPD exacerbationd over 52 weeks

Not applicable

Not applicable

Not applicable

Fixed triple versus tiotropium:

HR 0.84

(95% CI 0.72 to 0.97)

p=0.0154

Fixed triple versus open triple:

HR 1.06

(95% CI 0.88 to 1.27)

p=0.57

No statistically significant difference

Time to first severe COPD exacerbationd over 52 weeks

Not applicable

Not applicable

Not applicable

Fixed triple versus tiotropium:

HR 0.70

(95% CI 0.52 to 0.95)

p=0.0208

Fixed triple versus open triple:

HR 1.05

(95% CI 0.70 to 1.56)

p=0.82

No statistically significant difference

Rate of moderate COPD exacerbationsd over 52 weeks

0.37

(SD 0.33 to 0.42)

0.44

(SD 0.39 to 0.49)

0.38

(SD 0.32 to 0.44)

Fixed triple versus tiotropium:

RR 0.84

(95% CI 0.71 to 0.98)

p=0.03

Fixed triple versus open triple:

RR 0.98

(95% CI 0.81 to 1.20)

p=0.87

No statistically significant difference

Rate of severe COPD exacerbationsd over 52 weeks

0.07

(SD 0.05 to 0.09)

0.10

(SD 0.08 to 0.12)

0.06

(SD 0.04 to 0.08)

Fixed triple versus tiotropium:

RR 0.68

(95% CI 0.50 to 0.94)

p=0.0174

Fixed triple versus open triple:

RR 1.18

(95% CI 0.77 to 1.80)

p=0.45

No statistically significant difference

Pre-dose FEV1 responsef at week 26

421/1,077 (39%)

306/1,074 (28%)

204/538 (38%)

Fixed triple versus tiotropium:

OR 1.61

(95% CI 1.34 to 1.93)

p<0.0001

Fixed triple versus open triple:

OR 1.04

(95% CI 0.84 to 1.30)

p=0.69

No statistically significant difference

Pre-dose FEV1 responsef at week 52

408/1,077 (38%)

295/1,074 (27%)

210/538 (39%)

Fixed triple versus tiotropium:

OR 1.62

(95% CI 1.35 to 1.95)

p<0.0001

Fixed triple versus open triple:

OR 0.95

(95% CI 0.76 to 1.18)

p=0.63

No statistically significant difference

SGRQ responseg at week 26

508/1,077 (47%)

438/1,074 (41%)

276/538 (51%)

Fixed triple versus tiotropium:

OR 1.32

(95% CI 1.10 to 1.57)

p=0.0024

Fixed triple versus open triple:

OR 0.81

(95% CI 0.65 to 1.00)

p=0.0486

SGRQ responseg at week 52

494/1,077 (46%)

423/1,074 (39%)

254/538 (47%)

Fixed triple versus tiotropium:

OR 1.33

(95% CI 1.11 to 1.59)

p=0.0019

Fixed triple versus open triple:

OR 0.91

(95% CI 0.73 to 1.13)

p=0.37

No statistically significant difference

Percentage of days without rescue medication use during weeks 41 to 52

12.89%

(95% CI 10.77% to 15.01%)

4.11%

(95% CI 1.94% to 6.29%)

14.13%

(95% CI 11.12% to 17.14%)

Fixed triple versus tiotropium:

adjusted mean difference 8.78%

(95% CI 5.74% to 11.81%)

p<0.0001

Fixed triple versus open triple:

adjusted mean difference −1.24%

(95% CI −4.92% to 2.44%)

p=0.510

No statistically significant difference

Change from baseline in average number of puffs per day of rescue salbutamol during weeks 41 to 52

−0.42 puffs

(95% CI −0.53 puffs to −0.30 puffs)

0.20 puffs

(95% CI 0.08 puffs to 0.32 puffs)

−0.46 puffs

(95% CI −0.63 puffs to −0.30 puffs)

Fixed triple versus tiotropium:

adjusted mean difference −0.61 puffs

(95% CI −0.78 puffs to −0.44 puffs)

p<0.0001

Fixed triple versus open triple:

adjusted mean difference 0.05 puffs

(95% CI −0.16 puffs to 0.25 puffs)

p=0.649

No statistically significant difference

Safety and tolerability outcomes

n h

1,077 b

1,076 c,i

537 i

Treatment-emergent adverse events

594/1,077 (55%)

622/1,076 (58%)

309/537 (58%)

59%,62% and 54% of these respectively were COPD-related

Serious treatment-emergent adverse events

140/1,077 (13%)

164/1,076 (15%)

68/537 (13%)

Treatment-emergent adverse events leading to discontinuation

33/1,077 (3%)

62/1,076 (6%)

15/537 (3%)

Treatment-emergent adverse events leading to death

20/1,077 (2%)

29/1,076 (3%)

8/537 (1%)

Treatment-emergent major adverse cardiovascular eventsj

20/1,077 (2%)

23/1,076 (2%)

7/537 (1%)

Treatment-related adverse events

25/1,077 (2%)

33/1,076 (3%)

27/537 (5%)

Primarily dry mouth, muscle spasms, dysphonia and oral candidiasis

Serious treatment-related adverse events

0/1,077 (0%)

1/1,076 (<1%)

0/537 (0%)

1 person developed angina pectoris

a The intention-to-treat population includes all randomly assigned participants who received at least 1 dose of study medication and had at least 1 post-baseline efficacy assessment.

b 1 person in the fixed triple-therapy group was randomised in error and did not receive the allocated therapy.

c 1 person in the tiotropium group received the first dose of study medication, but withdrew consent before providing any post-baseline data, and is included in the safety population but not the efficacy population.

d A COPD exacerbation was 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.

e The upper limit of the 95% CI was less than the pre-specified margin of −0.050 litre; therefore, fixed triple therapy was shown to be non-inferior to open triple therapy. Non-inferiority was confirmed in a per-protocol analysis.

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

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

h The safety population includes all randomly assigned participants who received at least 1 dose of study medication. Statistical analyses not reported.

i 1 person in the open triple-therapy group received only tiotropium and was included in the tiotropium arm for the safety analyses.

j Acute myocardial infarction, arrhythmias, cardiovascular death, heart failure, and stroke.

Abbreviations: CI, confidence interval; FEV1, forced expiratory volume in 1 second; HR, hazard ratio; OR, odds ratio; RR, rate ratio; SD, standard deviation; SGRQ, St George's Respiratory Questionnaire (measuring health-related quality of life).

Table 10 Papi A et al. 2018 (TRIBUTE)

Beclometasone/ formoterol/ glycopyrronium bromide (100/6/12.5 micrograms)

Indacaterol/ glycopyrronium bromide (110/63 micrograms)

Analysis

n a

764

768

Primary outcome

Rate of moderate-to-severe COPD exacerbationsb over 52 weeks

0.50

(95% CI 0.45 to 0.57)

0.59

(95% CI 0.53 to 0.67)

RR 0.85

(95% CI 0.72 to 0.99)

p=0.043

Selected secondary outcomes

Rate of moderate COPD exacerbationsb over 52 weeks

0.41

(95% CI 0.36 to 0.47)

0.47

(95% CI 0.41 to 0.54)

RR 0.87

(95% CI 0.72 to 1.04)

p=0.118

No statistically significant difference

Rate of severe COPD exacerbationsb over 52 weeks

0.07

(95% CI 0.06 to 0.10)

0.09

(95% CI 0.07 to 0.12)

RR 0.79

(95% CI 0.55 to 1.13)

p=0.189

No statistically significant difference

Time to first moderate-to-severe COPD exacerbationb over 52 weeks

Not applicable

Not applicable

HR 0.90

(95% CI 0.76 to 1.06)

p=0.219

No statistically significant difference

Time to first severe COPD exacerbationb over 52 weeks

Not applicable

Not applicable

HR 0.86

(95% CI 0.61 to 1.22)

p=0.405

No statistically significant difference

Mean change from baseline in pre-dose FEV1 over 52 weeks

Not reported

Not reported

Adjusted mean difference 0.022 litre

p<0.05

Pre-dose FEV1 responsec at week 26

176/764 (23%)

156/768 (20%)

OR 1.18

(95% CI 0.92 to 1.50)

p=0.194

No statistically significant difference

Pre-dose FEV1 responsec at week 52

145/764 (19%)

125/768 (16%)

OR 1.19

(95% CI 0.91 to 1.55)

p=0.198

No statistically significant difference

SGRQ responsed at week 26

310/764 (41%)

292/768 (38%)

OR 1.13

(95% CI 0.92 to 1.40)

p=0.255

No statistically significant difference

SGRQ responsed at week 52

311/764 (41%)

279/768 (36%)

OR 1.22

(95% CI 0.99 to 1.51)

p=0.068

No statistically significant difference

Percentage of days without rescue medication use over 52 weeks

8.31%

(95% CI 6.24% to 10.37%)

9.66%

(95% CI 7.60% to 11.73%)

Adjusted mean difference 1.36%

(95% CI −1.56% to 4.28%)

p=0.361

No statistically significant difference

Change from baseline in average number of puffs per day of rescue salbutamol or terbutaline over 52 weeks

−0.29 puffs

(95% CI −0.40 puffs to −0.18 puffs)

−0.24 puffs

(95% CI −0.35 puffs to −0.13 puffs)

Adjusted mean difference −0.05 puffs

(95% CI −0.20 puffs to −0.10 puffs)

p=0.517

No statistically significant difference

Safety and tolerability outcomes e

n f

764

768

Treatment-emergent adverse events

490/764 (64%)

516/768 (67%)

56% of these were COPD-related in both groups

Serious treatment-emergent adverse events

117/764 (15%)

130/768 (17%)

Treatment-emergent adverse events leading to discontinuation

37/764 (5%)

47/768 (6%)

Treatment-emergent adverse events leading to death

16/764 (2%)

21/768 (3%)

Treatment-related adverse events

43/764 (6%)

37/768 (5%)

Primarily oral candidiasis, dry mouth and cough

Serious treatment-related adverse events

1/764 (<1%)

1/768 (<1%)

1 person developed dysuria in the triple-therapy group and 1 person developed atrial fibrillation in the dual-therapy group

a The intention-to-treat population includes all randomly assigned participants who received at least 1 dose of study medication and had at least 1 post-baseline efficacy assessment.

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

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

e Statistical analyses not reported.

f The safety population includes all randomly assigned participants who received at least 1 dose of study medication.

Abbreviations: CI, confidence interval; FEV1, forced expiratory volume in 1 second; HR, hazard ratio; OR, odds ratio; RR, rate ratio; SGRQ, St George's Respiratory Questionnaire (measuring health-related quality of life).