Fluticasone furoate, vilanterol and lung function decline in

patients with moderate COPD and heightened

cardiovascular risk

Peter MA Calverley,1 Julie A. Anderson,2 Robert D Brook,3 Courtney Crim,4 Natacha Gallot, 5 Sally

Kilbride, 2 Fernando Martinez,3,6 Julie Yates,4 David E Newby,7 Jørgen Vestbo,8 Robert Wise 9 and

Bartolome R Celli10 on behalf of the SUMMIT Investigators

1. University of Liverpool, Department of Medicine, Clinical Sciences Centre, University

Hospital Aintree, Liverpool, UK

2. Research & Development, GlaxoSmithKline, Stockley Park, Middlesex, UK

3. University of Michigan Health System, Ann Arbor, Michigan, USA

4. Research & Development, GlaxoSmithKline, Research Triangle Park, North Carolina, USA

5. Veramed Ltd., Twickenham, UK

6. Division of Pulmonary and Critical Care Medicine, Weill Cornell Medicine, New York, New

York, USA

7. Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK

8. Division of Infection, Immunity and Respiratory Medicine, Manchester Academic Health

Sciences Centre, The University of Manchester and University Hospital South Manchester

NHS Foundation Trust, Manchester, UK

9. Division of Pulmonary and Critical Care Medicine, Johns Hopkins Medicine, Baltimore,

Maryland, USA

10. Division of Pulmonary and Critical Care Medicine. Brigham and Women’s Hospital. Harvard

Medical School. Boston, Massachusetts. USA.

Address correspondence to:

1

Professor Peter M. A. Calverley, MD

Clinical Science Centre (Aintree Campus), University Hospital Aintree

Longmoor Lane, Liverpool, L9 7AL, UK

Tel: +44 151 529 5886;

Fax: +44 151 529 5888

E-mail: pmacal@liverpool.ac.uk

Running title: Fluticasone Furoate and Vilanterol on rate of decline in FEV1

Study funded by GlaxoSmithKline; NCT01313676, 113782

Word Count (abstract): 243

Word Count (main text): 2905

Author contributions:

PMAC, JA, RB, CC, FJM, JY, DN, JV and BC made substantial contributions to the conception or design of the work reported

JY and JA participated in the acquisition of reported data

PMAC, JA, RB, CC, NG, SK, FJM, JY, DN, JV and BC participated in the analysis of reported data

PMAC, JA, RB, CC, NG, SK, FJM, JY, DN, JV, RW and BC participated in the interpretation of reported data

All authors reviewed and/or critically revised the manuscript for important intellectual content and provided final approval of the version to be published.

2

Abstract

Rationale: Many patients with chronic obstructive pulmonary disease (COPD) have an accelerated loss of lung function. It is unclear whether drug treatment can modify this in moderately severe disease.

Objectives: In a pre-specified analysis of the key secondary outcome in the Study to Understand Mortality and MorbidITy (SUMMIT), we investigated whether the inhaled corticosteroid fluticasone furoate 100 μg (FF), the long-acting beta-agonist vilanterol 25 µg (VI) or the combination (FF/VI) modified the rate of decline in FEV1 compared with placebo. We also investigated how baseline co-variates affected this decline.

Methods: Spirometry was measured every 12 weeks in this event-driven randomized, placebo controlled trial of 16,485 patients with moderate COPD and heightened cardiovascular risk. An average of 7 spirometry assessments per subject in the 15,457 patients with at least one on-treatment measurement were used in the rate of FEV1 decline analysis. All statistical comparisons are considered nominal.

Main results: The adjusted rate of FEV1 decline was -46 mL/year (-3.0% of baseline) with placebo, -47 mL/year (-3.1%) with VI, -38 mL/year (-2.5%) with FF and -38 mL/year (-2.3 %) with FF/VI. FF-containing regimes had lower rates of decline than placebo (p<0.03) and FF/VI had lower rate of decline than VI alone (p<0.005). The FEV1 decline was faster in current smokers, those with a lower body-mass index, males and patients with established cardiovascular disease.

Conclusions:

In patients with moderate COPD and heightened cardiovascular risk, FF alone or in combination with VI appears to reduce the rate of FEV1 decline.

Key Words: COPD; cardiovascular disease; fluticasone furoate; vilanterol; combination

therapy, rate of decline in FEV1

Introduction

Chronic obstructive pulmonary disease (COPD) is characterised by an accelerated loss of lung

function over time as compared with people of a similar age without airflow obstruction (1, 2). This

original observation by Fletcher and Peto (3) has been confirmed in subsequent studies of mild (4) and

severe (5) COPD, although recent data with 3 -10 years of follow-up suggest that this is not universally

the case (6-8). Tobacco smoking is the most important aetiological factor and cross-sectional and

longitudinal data (4, 9) show that the rate of decline of forced expiratory volume in 1 second (FEV1) is

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slower when people stop smoking, although the timing of smoking cessation affects the magnitude

of the subsequent change in lung function decline. (10, 11)

Several studies have examined whether inhaled drugs can modify the rate of FEV1 decline, with

mixed results. An inhaled short-acting anti-muscarinic drug did not change disease progression in the

Lung Health Study (4). However, a post -hoc analysis of data from the Understanding Potential Long-

Term Impacts on Function study (UPLIFT) of a once daily long-acting anti-muscarinic agent (LAMA)

suggested a drug effect in patients naïve to therapy and those with moderate airflow obstruction (12,

13). The initial studies of treatment with inhaled corticosteroids (ICS) failed to identify any change in

the rate of decline over a wide range of spirometrically defined COPD severity. However, the

combination of an inhaled corticosteroid and a long-acting beta-agonist (LABA) did reduce airway

inflammation in moderate COPD patients (14) and was associated with a change in FEV1 decline in the

TORCH study (15). More recently, in carefully selected patients with moderately severe COPD the ICS

fluticasone propionate decreased lung function decline and reduced airway inflammation in a 3 year

trial (16). Hence, there is continuing uncertainty about the impact of ICS on this marker of disease

progression.

SUMMIT was a randomised double blind, placebo controlled parallel group comparison of the ICS

fluticasone furoate, the LABA vilanterol and the combination of the two with placebo in patients

with moderate airflow limitation and either a history of, or significant risk of developing

cardiovascular disease (17). The primary endpoint of all-cause mortality did not differ between

treatments (18). However, given the size of the study and the potential for interaction between

respiratory and cardiovascular disease, the pre-specified key secondary outcome was the effect of

therapy on the rate of FEV1 decline. Here we examine how ICS and LABA therapy alone and in

combination impacts lung function decline in COPD patients with moderate spirometric impairment

and consider whether the factors associated with decline are similar to those seen in studies of more

severe COPD where cardiovascular co-morbidity was less prevalent.

Methods

Details of the study design and the analysis approach have been published previously (17,18). Patients

were current or former smokers with at least a 10-pack-year history, 40 to 80 years old, with a post-

bronchodilator FEV1 ≥50 and ≤70% of predicted value, FEV1/ forced vital capacity (FVC) ratio ≤0·70,

and ≥2 on the modified Medical Research Council dyspnoea scale. Patients with a current diagnosis

of asthma were excluded. All patients provided written informed consent. The study was approved

4

by local ethics committees, conducted in accordance with Good Clinical Practice guidelines and

registered on clinicaltrials.gov as NCT01313676 (Study: 113782).

Study Design

This was a prospective double blind parallel group placebo controlled event-driven randomised trial

conducted at 1,368 centres in 43 countries. Participants were randomly assigned through a

centralised randomisation service in permuted blocks to one of four treatments (placebo, fluticasone

furoate (100 μg; GlaxoSmithKline), vilanterol (25 µg; GlaxoSmithKline) or the combination of

fluticasone furoate and vilanterol (100/25 μg; Relvar®/Breo®, GlaxoSmithKline) administered once

daily with a dry powder inhaler (Ellipta®, GlaxoSmithKline). The use of all inhaled corticosteroids and

long-acting bronchodilators was discontinued at least 48 hours before study entry. Other COPD

medications such as theophyllines were permitted. Patients unable to tolerate withdrawal of

therapy were excluded.

In this report, the principal outcome was the rate of post-bronchodilator FEV1 decline. At visit 1

(screening), the highest of three FEV1 measurements was recorded before and 30min after,

inhalation of 400µg albuterol (19). At visit 2 (randomization) and at every 3 months, post-

bronchodilator measurements of FEV1 were obtained while subjects remained on treatment.

Spirometers were calibrated regularly according to the manufacturer recommendations and a

calibration log was kept. Lung function data were reviewed centrally during the study and queried if

values differed significantly between consecutive visits (see online supplement for further details).

In order to be included in the main analysis, patients needed a baseline and at least one post-

baseline assessment.

Statistical Analysis

This was an event-driven study where follow up continued until at least 1,000 deaths had occurred.

As the treatment effect on the primary end point was not statistically significant, the statistical

testing reported here should be interpreted as descriptive only (18). The effect of treatment on rate

of decline in FEV1 was a predefined secondary endpoint and was analyzed using a random

coefficients model. Additional analyses in this report were conducted post-hoc to further investigate

rate of decline in FEV1.

 The rate of decline of FEV1 was analysed using a random coefficients model (20) allowing for covariates

of age, gender and baseline FEV1. The slope in each treatment arm was modelled by treatment, time

and treatment by time interaction terms (base model). The treatment by time interaction was used

5

to assess whether the slopes were different between treatment arms. The slope was calculated from

post-randomization Day 90, to ensure that any initial short term increase in FEV1 did not

overestimate any treatment benefit on the slope. A sensitivity analysis was performed using

baseline as the first time point for response that also included patients with only a baseline value;

this analysis also calculated the slope from Day 90. For further details see supplementary appendix

to Primary publication.

The effects of treatment and various covariates on the rate of decline were modelled using

the random coefficients model on the absolute scale [FEV1 (ml) and % predicted FEV1] as well

as the relative scale (% change, using a log transformation). The predicted values were those

of Hankinson et al derived from the NHANES study (21, 22). Analyses of relative rate of decline

in FEV1 were carried out on the logarithmic scale, using the same model but with log FEV1 and

log baseline FEV1. Estimates of slopes were exponentiated and expressed as percentage

change.

To investigate the effects of a particular covariate, terms for the covariate and covariate by

time interaction were added to the base model described above. The covariate by time

interaction gave the effect of the covariate on the slope. The slopes were estimated for each

subgroup after adjusting for the covariates in the base model. When the effect of age on the

rate of decline was investigated, it was fitted as a categorical variable. To investigate whether

the treatment effect was consistent for various subgroups of patients, estimates of the rate of

decline by treatment were obtained from a separate model for each subgroup. A p-value for

the interaction of treatment by subgroup by time was obtained from a model that included

this term as well as the subgroup by time and subgroup by treatment interactions, in addition

to the base model.

The percentage of patients who experienced a change from baseline to 90 days of ≥100mls

was summarised.

Results

There were 16 590 subjects randomized. Of these, 22 participants never took study medication and the safety population therefore consists of 16 568 patients. Data from five centres (83 patients) were excluded from the efficacy analysis because of failure to meet the standards of Good Clinical Practice and ethical practice, and were closed before the study ended. Thus, a total of 16 485 patients were included in the intention-to-treat efficacy (ITT-E) population, of whom 1,037 died before the study ended.

The overall safety and demographic characteristics of the patients in this study have been published

previously in the primary report (18). Patients were 75 % male, 47% current smokers, mean body

6

mass index (BMI) of 28 kg/m2 and 39% with a history of 1 or more COPD exacerbations in the year

prior to the study. Mean reversibility as a % of pre-bronchodilator was 8.1%. Baseline respiratory

therapy before randomisation was similar between groups with 33% (ranging from 33% to 34%)

using ICS and 35% (ranging from 34% to 36%) using LABA drugs. Full demographic information for

the patients included in this analysis is presented in online supplemental table s3. There were no

differences in the demographic variables between the treatment arms. The distribution of the

patients between the study treatment arms is shown in Figure 1. More patients withdrew from

placebo than in the active treatment arms, [placebo 29%, FF 26%, VI 25%, FF/VI 23%].

Rate of decline in FEV1

Of the 16,485 participants, 15,457 contributed an average of 7 post-bronchodilator spirometry

measurements (assessed every 3 months). There were 112,159 on-treatment spirometry

assessments used in the primary analysis. The average treatment exposure was 1.7 years.

The absolute and relative rate of FEV1 decline with each therapy is presented in Table 1a. Data are

also expressed as a change in %predicted post-bronchodilator FEV1 and are shown in Figure 2 and in

Table 1. Irrespective of the way the data are expressed, patients receiving FF, either alone or with

VI, had a slower rate of FEV1 decline than either the placebo or VI alone groups. This represented an

8mL/year improvement in decline between FF/VI and placebo or approximately a 20% difference

(Table 1a) in annual %predicted FEV1 decline between these groups. Sensitivity analyses did not

change these findings (Table 1b) and the findings were also similar for those patients who withdrew

from ICS/long acting bronchodilators (LABD) prior to study start (see on-line supplement table s1).

Between baseline and Day 90, FEV1 increased more in the treatment arms than placebo. Overall,

27% of placebo patients, 32% FF, 35% VI and 38 % of FF/VI patients achieved a 100ml increase in

post-bronchodilator FEV1 at this time. Although FEV1 increased in all three active arms, rate of

decline only improved in arms containing FF.

Determinants of rate of FEV1 decline

The effect of the baseline variables on the overall rate of decline in lung function is shown in table 2.

The rate of decline of FEV1, however expressed, was more rapid in males and in current smokers.

Lower BMI values were also associated with faster lung function loss. In patients over 60 years of

age, the presence of CV disease was accompanied by a more rapid decline in FEV1 compared with CV

risk. Patients with an FEV1 above 60% predicted appeared to decline faster irrespective of whether

the data were expressed as an absolute value or as a percentage of predicted. However, if the

decline was expressed as a relative change from the initial value, this effect of baseline FEV1 on

7

decline was no longer significant. Age and self-reported exacerbation history were not associated

with differences in rate of FEV1 decline. Patients in the placebo arm who experienced exacerbations

while on treatment had a faster decline in FEV1 than did those who never exacerbated (mean FEV1

decline 59ml /year if >0.5 event per year compared with 40ml/year in non-exacerbators) (on line

supplementary table s2-). The same relationship between treatment and rate of decline was seen

in patients without incident exacerbations as in the overall study population.

The effect of treatment was consistent regardless of the other baseline characteristics reported

above. (Table 3).

Discussion

SUMMIT is the largest study to date, to characterise the rate of decline of lung function in COPD and

its interaction with inhaled treatment. Moreover, SUMMIT is the only study to have evaluated

patients with symptomatic COPD and moderate airflow obstruction who either have or are at risk of

developing cardiovascular disease, a major co-morbidity of COPD. Our data show that when used

alone or in combination with a LABA, ICS reduces the rate of decline in lung function compared with

placebo. These findings have implications for how we approach patients with COPD and how we

study disease progression.

Previous studies have produced conflicting results about the effect of inhaled bronchodilators and

especially inhaled corticosteroids on FEV1 decline in COPD. Most studies failed to find an effect on

the rate of decline with ICS (5, 23-25) although the GLUCOLD study of moderately severe COPD (16) and

an analysis of the TORCH data found that ICS whether used alone or in combination with a LABA

slowed the decline in FEV1 (15). In SUMMIT, the picture was clearer with only those patients receiving

the ICS showing benefit. The absolute rate of decline in FEV1 was similar to that seen in ICS-treated

patients in TORCH, although the decline in the placebo group was somewhat lower in SUMMIT,

perhaps reflecting differences in patient recruitment and in rate of withdrawal and exacerbations

between these studies. Our results resemble those predicted from earlier pharmaco-epidemiology

studies in patients not necessarily classified by FEV1 severity (26) and those in a meta-analysis of

studies of 2 years or more using ICS without a long-acting bronchodilator where a 7.7mL /year

reduction in decline was seen in ICS treated patients (27). This is consistent with our findings of an 8

mL/year absolute difference or ~20% reduction in mean in FEV1 decline over the mean of 1.7 years

follow up. In practice this is likely to underestimate the true impact in patients able to show a

response. Recent data suggest that only about half of patients with impaired lung function in mid-life

8

have reached this point through an excess loss of lung function (28) and it seems reasonable to

speculate that it is only this subgroup that drives the signal we observed. The mechanisms

underlying such an effect cannot be addressed here, although as noted earlier there is evidence for

an anti-inflammatory effect of ICS in patients with moderate COPD(16). Nonetheless, this positive

impact on lung function decline in SUMMIT was not reflected in the mortality risk in different study

arms, which was driven by cardiovascular and cancer deaths rather than those from respiratory

causes (18).

Unlike the TORCH trial, monotherapy with LABA did not affect rate of FEV1 decline. This might be due

to the drug selected, although the other clinical effects of once daily vilanterol such as exacerbation

prevention are similar to twice daily salmeterol (29). Alternatively the occurrence of fewer

exacerbations in our trial may be relevant, raising the possibility that different therapies may act in

different ways to modify FEV1 decline depending upon disease severity. Support for this idea comes

from the post-hoc analysis of the UPLIFT data in moderate COPD where use of tiotropium was

associated with a slower rate of FEV1 decline.(13) In this UPLIFT population 70% of participants used a

LABA and /or ICS during the trial while only one third of our patients used these drugs before

randomisation. The exacerbation rate in moderate patients in the control arm of UPLIFT was 0.70

events/year compared with the 0.35/year in placebo treated SUMMIT patients [18].

The co-variates of rate of decline were similar to those established in the TORCH data (15). Recently, it

has been suggested that presenting lung function decline as a percentage of the initial value will

overcome the apparent ‘horse racing’ problems in data interpretation (30). Patients with a post-

bronchodilator FEV1 of 60% predicted or more declined on average 11mL/year faster than the

patients with greater impairment in lung function in keeping with earlier observational data (7).

Normalising for the initial FEV1 removed this effect suggesting that the relative change in lung

function was independent of the degree of spirometric impairment. This aside, the use of relative

change in FEV1 decline produced the same results as the more traditional ways of expressing the

data. Age was not a predictor of a different rate of decline but current smoking status had a

relatively large effect, ex-smokers declined 14mL/year more slowly than those who continued to

smoke. There was a gradient of response across the BMI categories with the highest sub-group

declining most slowly; the rates here being very similar to those seen in the TORCH trial. This effect

of BMI may explain some of the differences between studies, as in SUMMIT the mean BMI was 28

kg/m2 compared with a lower mean BMI of 25 kg/m2 observed in TORCH, and FEV1 decline in the

placebo group more rapid than that observed in SUMMIT.

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As noted elsewhere (15, 31) decline in lung function was slower in women than men and in our trial this

was not fully corrected when the data were adjusted for body size, as was the case in the TORCH

study data. Whether this reflects differences in the way COPD develops between the genders as

recently proposed (32) remains to be clarified. We saw no relationship between reported

exacerbation frequency and subsequent decline in FEV1 as was the case in TORCH (15). However, the

impact of exacerbations resulting is a faster decline was reported in the ECLIPSE trial (7), as was

observed in patients in the placebo arm with more exacerbations during this study. Inference about

the interaction between treatment , exacerbations and FEV1 decline is difficult but ICS use was

associated with the same reduction of decline in patients who never exacerbated (the majority of

the trial population) suggesting that this effect was not mediated by the difference in exacerbation

events reported elsewhere(33) . There was no convincing interaction of therapy effects with any of

these covariates suggesting that the treatment-related changes observed were not confined to a

specific subgroup.

Our study has strengths and limitations. The large population studied and lower dropout rate than

earlier studies (34, 35) allowed us to calculate a more precise estimate of the effect size of therapy that

was smaller than what previous studies had been powered to demonstrate. Our intention to treat

efficacy population is not a true intention to treat analysis population but only reports data from

patients who continued to participate in the trial, a finding common to other large intervention

studies (4, 5, 13, 15, 16). Special care was taken to obtain robust spirometry data, as rate of FEV1 decline

was a pre-specified outcome in SUMMIT. Our patients were taking less background therapy that

could potentially confound the outcome (12). SUMMIT was an event driven study with a shorter total

follow up period than in earlier trials. However, we analysed the decline data using a random

coefficients statistical model, which gives most weight to patients contributing most data points.

These estimates of differences in the rate of decline were supported by the other analyses shown

here and are likely to be robust reflecting the large number of patients contributing to the study.

Recent re-analysis of data from the ISOLDE study suggests that blood eosinophils counts may

identify patients where ICS can reduce FEV1 decline (36). Unfortunately, no eosinophil data were

collected in this study and so we cannot address this possibility. Finally, we recruited patients with

COPD and overt or potential cardiovascular disease who might respond differently from groups

where such pathology was less evident. However, the similarity in the impact of common covariates

and the observed rates of decline between our data and that reported elsewhere suggests that this

is not the case.

10

Our findings have implications for the way in which the lung function progression of COPD is viewed. The positive response to inhaled corticosteroids, an anti-inflammatory drug, provides further evidence that drug treatment can modify the lung function decline characteristic of this condition. Although ICS did not affect survival, the mean absolute change in FEV1 decline in SUMMIT, was close to that observed with smoking cessation in the Lung Health Study (4) and represents a reduction in the likely excess decline in FEV1 in our patients whose normal lung function loss would be 25-30ml/year [36] This effect might be further improved if we could identify responsive patients more effectively and in whom comparable changes in lung function decline could become important over time [37] . As such, our results suggest that large numbers of patients are needed to identify a small average signal, which helps explain why earlier smaller studies were unsuccessful, but also suggest that adequately powered studies conducted in appropriate patient groups can identify a treatment effect in less than 3 years.

In summary, the regular use of FF, either alone or in combination with VI, appears to reduce the rate

of FEV1 decline in patients with moderate COPD and a heightened risk of cardiovascular disease.

This important finding a in a study whose primary mortality endpoint was negative suggests that any

benefit from these drugs is likely restricted to the respiratory system. Future studies to support our

observations would be welcome and will hopefully determine whether anti-inflammatory therapy

and/or other bronchodilator treatment can further ameliorate lung function decline in the natural

history of COPD.

Members of the Steering Committee

Jørgen Vestbo (co-chair, UK), Robert Brook (USA), Peter Calverley (UK), Bartolome Celli

(USA), Fernando Martinez (USA), David Newby (UK), Courtney Crim, (co-chair,

GlaxoSmithKline, USA), Julie Anderson (GlaxoSmithKline, UK), Julie Yates

(GlaxoSmithKline, USA).

Members of the Independent Data Monitoring Committee

Peter Lange (chair, Denmark), Richard Kay (UK), Mark Dransfield (USA), Sanjay

Rajagopalan (USA).

Members of the Clinical Endpoint Committee

Robert Wise (chair, USA), Dennis Niewoehner (USA), Camilo Gomez (USA), Sheldon

Madger (Canada), Martin Denvir (UK), Pierre Amarenco (France).

11

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Table 1a: Rate of Decline in Post-Bronchodilator FEV1– Random Coefficients Model

PlaceboN=4111

FF 100N=4135

VI 25N=4118

FF/VI 100/25N=4121

Number of patients with data a 3800 3879 3866 3912Rate of Decline in Post-Bronchodilator FEV1

Baseline mean FEV1, mL (SD) 1688 (417) 1685 (425) 1684 (420) 1690 (426)Adjusted rate of decline, mL/yr (SE) -46 (2.5) -38 (2.4) -47 (2.4) -38 (2.4)Active vs. placebo

Difference (SE) 8 (3.5) -2 (3.4) 8 (3.4)95% CI 1, 14 -8, 5 1, 15p-value 0.026 0.654 0.019

Rate of decline in Percent Predicted Post-Bronchodilator FEV1

Baseline mean % predicted FEV1 (SD) 59 (8) 59 (8) 59 (8) 59 (8)Adjusted slope, (%/yr) (SE) -1.6 (0.09) -1.3 (0.08) -1.7 (0.08) -1.3 (0.08)Active vs. placebo

Difference, %/yr (SE) 0.27 (0.12) -0.05 (0.12) 0.30 (0.12)95% CI 0.04, 0.51 -0.29, 0.18 0.07, 0.53p-value 0.023 0.662 0.012

% Rate of Decline in Post-Bronchodilator FEV1

Adjusted rate of decline, %/yr -3.0 -2.5 -3.1 -2.3Active vs. placebo

Difference 0.6 -0.1 0.795% CI 0.2, 1.0 -0.5, 0.3 0.3, 1.1p-value 0.007 0.725 <0.001

a Patients had to have a baseline measurement and at least one on-treatment measurement to be included in this analysis

Table 1b: Random coefficients model using baseline as first time point for response (Sensitivity analysis)

AnalysisPlaceboN=4111

FF 100N=4135

VI 25N=4118

FF/VI 100/25N=4121

Number of patients in analysis a 4111 4135 4118 4120Baseline mean FEV1, mL (SD) 1681 (417) 1681 (426) 1681 (421) 1688 (429)Adjusted rate of decline, mL/yr (SE) -47 (2.5) -40 (2.4) -48 (2.4) -39 (2.4)Active vs. placebo Difference (SE) 8 (3.5) -1 (3.5) 9 (3.5) 95% CI 1, 14 -7, 6 2, 15 p-value 0.029 0.881 0.014aPatients with a baseline post bronchodilator FEV1 measurement regardless of whether they had any on-treatment measurements

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Table 2: Effect of baseline covariates on rate of decline in post-bronchodilator FEV1 slopes

% Predicted (%/yr) Absolute mLs/yr % Decline (%/yr)#of Patients in Analysis

Adjusted Rate ofDecline (SE)

p-value Adjusted Rate of Decline (SE)

p-value Adjusted % Rate ofDecline

p-value

Gender Female (n=4196) Male (n= 12289)

389811559

-1.2 (0.1)-1.6 (0.1)

p<0.001 -28 (2.4)-47 (1.4)

p<0.001 -2.3-2.9

p<0.001

Age, yr ≥40 to <50 (n=542) ≥50 to <60 (n=3082) ≥60 to <70 (n=7585) ≥70 (n=5276)

514290571524886

-1.3 (0.2)-1.4 (0.1)-1.5 (0.1)-1.5 (0.1)

p=0.374-44 (6.6)-44(2.7)-44 (1.8)-38 (2.2)

p=0.089-2.3-2.6-2.9-2.7

p=0.286

% predicted FEV1

<60 (n=9074) ≥60 (n=7410)

84766981

-1.3 (0.1)-1.7 (0.1)

p<0.001 -37 (1.6)-48 (1.8)

p<0.001 -2.7-2.8

p=0.443

Smoking Status Current (n=7678) Former (n=8807)

72348223

-1.7 (0.1)-1.3 (0.1)

p<0.001 -50 (1.8)-36 (1.6)

p<0.001 -3.1-2.4

p<0.001

BMI <18.5 (n=534) 18.5 - <25 (n=4883) 25 - <30 (n=5662) ≥30 (n=5406)

494456253625039

-2.0 (0.3)-1.8 (0.1)-1.4 (0.1)-1.3 (0.1)

p<0.001-52 (7.2)-50 (2.3)-40 (2.0)-37 (2.1)

p<0.001-3.8-3.3-2.5-2.4

p<0.001

Exacerbations in year prior to study 0 (n=10021) 1 (n=4020) ≥2 (n=2444)

937537952287

-1.6 (0.1)-1.4 (0.1)-1.4 (0.1)

p=0.070 -44 (1.6)-40 (2.4)-38 (3.0)

p=0.098 -2.9-2.6-2.6

p=0.162

CV entry criteria at screening 40-60 with CV Disease (n=3535) 60-80 with CV Disease (n=8127) 60-80 with CV Risk (n=4641)

334575844373

-1.3 (0.1)-1.7 (0.1)-1.3 (0.1) p<0.001

-44 (2.5)-46 (1.7)-34 (2.3) p<0.001

-2.5-3.1-2.3 p<0.001

Random coefficients base model included gender, age, baseline FEV1, treatment, time and treatment by time. Covariate and covariate by time were added to the base model separately for each covariate.

Table 3 – Effect of Treatment in Subgroups

Rate of Decline (mLs/yr)

Subgroup N in Placebo

and FF/VI arms

PlaceboN=4111

FF/VIN=4121

Difference(95% CI)

Treatment by subgroup

interaction p-value

Smoking Status 0.103 Current 3584 -53 -50 3 (-7, 14) Former 4128 -39 -28 11 (2, 19)

Age group (yrs) 0.102 ≥40 to <50 255 -48 -7 41 (-1, 84)

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≥50 to <60 1443 -51 -42 9 (-8,26) ≥60 to <70 3528 -47 -44 3 (-7, 13) ≥70 2486 -40 -30 10 (-1, 20)

CV Entry Criteria 0.791 40-60 years with CV disease

1658 -49 -36 12 (-4, 28)

60-80 years with CV disease

3830 -50 -40 10 (1, 19)

60-80 years with CV risk

2153 -34 -34 0 (-12, 12)

Gender 0.883 female 1885 -28 -24 5 (-6, 16) male 5827 -52 -42 9 (1, 18)

Prev Exac History 0.996 0 4653 -49 -39 10 (1, 19) 1 1923 -42 -37 5 (-8, 19) ≥2 1136 -40 -34 6 (-11, 23)

BMI 0.032 <18.5 243 -75 -73 2 (-48, 51) 18.5 to <25 2261 -48 -48 0 (-12, 13) 25 to <30 2691 -47 -29 18 (7, 29) >=30 2517 -40 -36 4 (-8, 16)

% predicted FEV1 0.221 < 60% 4236 -43 -29 14 (5, 23) >=60% 3476 -49 -49 1 (-10, 11)Note: Interaction p-values are from subgroup by treatment by time term in random coefficients (RC) model containing all 4 treatment arms. Estimates of rate of decline are from RC model including 4 treatment arms, using a separate model for each subgroup. N refers to the number of patients included in the analysis.

FIGURES

Figure 1

CONSORT flow chart for the SUMMIT study participants contributing to this analysis

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[1] 1 subject randomised to Placebo in ITT population is assigned to FF/VI, the treatment the subject received for the majority of the study, in the safety population.

[2] Excluded patients were recruited at sites that were closed due to the result of audit findings or other information implying that the integrity of the data had been compromised.

Figure 2

Rate of decline of FEV1 in each study arm expressed as a change from baseline in the % predicted FEV1

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