COPD Working Group Meeting

COPD WORKING GROUP MEETING

– COPD CONTROL STUDY UPDATE – OTHER RESEARCH IDEAS

CHAIR: Marc Miravitlles

DATE: Saturday September 3rd

TIME: 13.45–14.45

VENUE: Royal College of General Practitioners;

30 Euston Square, London, UK

Agenda

13.45-14.30 COPD Control

– UK Pilot

– Spanish Prospective Studies

– International Prospective Validation Trial

14.30-14.45 Other Research Ideas & Group Discussion

– Real-life WISDOM

– Natural History of Alpha-1 Antitrypsin Deficiency

(UK database study)

PROSPECTIVE VALIDATION OF COPD CONTROL

MARC MIRAVITLLES 13.45–14.30

Background (I) •  The concept of disease control has been extensively developed in asthma;

less so in COPD… traditionally

•  A new definition of COPD has recently been proposed, defined as the product of two components:

o  Impact of the condition

o  Its clinical stability

•  Controlled COPD = stable low impact disease (i.e. low impact over time)

•  The concept of COPD control is intended as a:

o  Complementary management tool

o  Tool to support day-to-day management decisions in routine care

•  Its utility practical requires validation in routine care

Low clinical impact

Clinical control

Stability

Impa

ct

High clinical impact

Cross-sectional evaluation of impact

Stability (Improvement or

absence of changes)

Inestability (Clinical worsening)

V1 V2 V3 V4

Cross-sectional, non-interventional database study using the Optimum Patient Care Research Database (OPCRD) as a lead-in to the prospective trials

UK Database pilot

Validation of concept study:

Aims: •  Characterize COPD patients treated in UK routine primary care in terms

of their COPD control

•  Evaluate the clinical implications of control status

Data sources: •  The UK’s Optimum Patient Care Research Database

(OPCRD)

•  Fully anonymised UK primary care data

•  Historical medical records for >2.5 million patients from >550 primary care practices across the UK

•  Ethical approval for medical research & used for multiple peer-review publications

Study Design:

•  Baseline: 3-month period for COPD stability assessment •  Index date: the date of receipt of the patients completed COPD Assessment

Test (CAT) and date of Baseline COPD Control Assessment

•  Outcome: 12-months (primary) and 3-months (secondary)

12-months (primary) outcome period

Index date: Date of receipt of patients completed COPD questionnaire / CAT score &

date of “Baseline Control” evaluation

Time to first COPD exacerbation

3-month baseline period COPD Stability

Assessment (exacerbation

evaluation)

3-month (secondary)

outcome period

Inclusion/Exclusion Criteria:

Inclusion Criteria

COPD diagnosis (physician-diagnosed COPD),

Aged ≥40 years

Current or ex-smokers

Recorded COPD Questionnaire data •  ≥3 months continuous clinical records immediately prior to the index date •  ≥1 year of continuous clinical records immediately following the index date

Exclusion Criteria

Any chronic respiratory condition other than COPD, asthma or bronchiectasis (e.g. cystic fibrosis, lung fibrosis)

Patients with potential severe comorbidity at index date, defined as those with a recorded data of death within the 24 months following index date

1

Exclusion criteria

Inclusion criteria OPCRD- Patient completed a

COPD questionnaire n=14,173

Valid period n=4,530

Patients completed a COPD questionnaire

COPD diagnosis n=4,410

Age n=4,400

No other chronic respiratory disease n=4,333

Current or ex-smoker n=3,683

3 months of baseline and 12 months of outcome data available

Physician-diagnosed COPD and spirometry confirmed-COPD

Age ≥40 at index date

No chronic respiratory condition other than COPD, asthma or

bronchiectasis

Valid period unavailable n=9,643

No COPD diagnosis code or spirometry confirmed definition

n=120

Aged <40 at index date n=10

Chronic respiratory condition other than COPD, asthma or

bronchiectasis n=67

Recorded as current or ex-smoker

Non-smoker n=650

No severe comorbidity n=3,549

No death date recorded or death date 24 months or more after index

date Patients with potential severe comorbidity at index date

n=134

Final Patient Cohort n=2788

Mild to moderate (BODEx ≤4)

n=2511

Recorded data to assess impact and stability criteria 1

Patients did not have data to assess impact and/or stability criteria

n=761

Severity assessment: BODEx stratification

Severe to very severe (BODEx ≥5)

n=277

Patient Population

Definition of COPD Control

Mild/Moderate COPD: Control status

BODEx ≤4

Mild/Moderate (n=2511)

Impact (cross-sectional)

(i) Clinical Features

Low impact (n=126)

Stability (temporal)

No changes (0 exacerbations)

Controlled (n=112)

Worsening (≥1 exacerbations)

Uncontrolled (n=14)

High Impact (n=2385)

Uncontrolled (n=2385)

(ii) CAT Score

Low Impact (n=633)



Controlled (n=541)


Uncontrolled (n=92)

High Impact (n=1878)


Characteristics by Control status: Mild/Moderate COPD

Severe / Very Severe COPD: Control status

BODEx ≥5 Severe/Very severe

(n=277)

Impact (cross-sectional)

(i) Clinical Features

Low impact (n=0)

High Impact (n=277)


(ii) CAT Score

Low Impact (n=71)



Controlled (n=23)


Uncontrolled (n=48)

High Impact (n=206)


Characteristics by Control status: Severe/Very Severe COPD

Control Status & Time to First Exacerbation

Control Status & Time to First Exacerbation 0.

000.

250.

500.

751.

00C

umul

ativ

e P

ropo

rtio

n S

urvi

ving

0 100 200 300 400Time (days) to first exacerbation

Controlled Uncontrolled

0.00

0.25

0.50

0.75

1.00

Cum

ulat

ive

Pro

porti

on S

urvi

ving



B. Mild/Moderate COPD Low impact based on CAT score (p<0.001)

A. Mild/Moderate COPD Low impact based on Clinical Features (p<0.001)

0.00

0.25

0.50

0.75

1.00

Cum

ulat

ive

Pro

porti

on S

urvi

ving



C. Severe/Very Severe COPD Low impact based on CAT score (p=0.825)

No severe/very severe patients were controlled at baseline based on their clinical features

Next steps

•  Manuscript in preparation

•  ERS poster being presented tomorrow: o  Sunday Sept 4th: 12.5014.40 by Dr Juan Jose Soler-Cataluna o  Thematic Poster Session: Comorbidities and Exacerbations in COPD

STUDY 1: changes in control vs changes in severity over 6 months STUDY 2: comparison of control and symptoms over 6 months

Observational Pilot Work in Spain

Study 1: changes in control vs severity

•  Objectives o Compare variability in control with variability in

severity (FEV1 and BODE/BODEx) over a 6-month observational outcome period.

•  Update o  44 centers and 393 patients included

o  LPLV 30/09/2016 o Results expected by the end of 2016

Study 2: comparison of symptoms & control

•  Objectives o Compare the changes in control with the prevalence

and changes in EXACT Respiratory Symptoms (E-RS).

•  Update o Sample size 144 patients

o  Follow-up 6 months o  FPFV 01/06/2016

International Prospective Validation Study Multicenter, international and prospective study to validate the concept of control in COPD and its implications for clinical practice

Hypothesis

Control in COPD is a new conceptual dimension requiring demonstration of both low impact and clinical stability. The

developers of the concept hypothesize that a status of control in COPD will be associated with better clinical outcomes (reduced frequency of exacerbations and mortality and improved health-related quality of life);

reduced rate of decline in lung function and/or BODE/BODEx and reduced direct COPD-related healthcare

costs.

Objectives

Primary: to evaluate, in an international cohort of routine care/unselected COPD patients, the: •  Levels of COPD control (vs poor COPD control), and

•  Clinical implications of control status.

Secondary: •  Compare the utility of the COPD Control (as defined) as a tool to

identify COPD impact and stability with the CAT and CCQ; •  Evaluate the role of “adequate” (i.e. guideline-recommended) treatment

prescribing on COPD control. •  Identify demographic and clinical characteristics associated with COPD

control status •  Evaluate the cost-utility of patients with controlled (as compared to

poorly controlled) COPD.

Eligibility: inclusion criteria

Eligible patients must meet the following inclusion criteria: •  Spirometry-defined COPD (i.e. post-bronchodilator FEV1/

FVC<0.7)

•  Age ≥40 years •  Smokers or ex-smokers of at least 10 pack-years

•  In stable state (as judged by the investigator) at point of recruitment

Eligibility: exclusion criteria

Patients will be excluded from the trial they:

•  Have any chronic concomitant respiratory condition other than asthma or bronchiectasis (e.g. cystic fibrosis, lung

fibrosis)

•  Have severe comorbidity with a life expectancy shorter

than 2 years

•  Are unable to understand the instructions of the study or to

fill the questionnaires

•  Are unwilling to sign the informed consent

•  Are participating in another clinical study or clinical trial.

Endpoints: primary

Difference between patients controlled vs uncontrolled at baseline in (annualized) rates of the composite endpoint:

•  Unscheduled visits to the physician or emergency room attendance for COPD

•  An exacerbation of COPD

•  All-cause: hospitalization or mortality

Endpoints: secondary •  Difference between patients controlled vs uncontrolled at baseline in terms of:

o  The (annualized) rate of exacerbations

o  Time to the first composite event

o  Time to the first exacerbations

•  Comparison of CAT and CCQ as tools to identify impact and stability in COPD

•  Distribution of control level across in those receiving guideline vs non-

guideline recommended therapy (i.e. stratification of control across different

treatment groups)

•  Demographic and clinical characteristics associated with poor control of

COPD

•  Differences in utilities between patients controlled and uncontrolled

(measured by the EQ-5D).

Design: prospective non-interventional

21 months prospective pragmatic trial, comprising 5 evaluation points: one screening evaluation and 4 follow-up evaluations

3 months 6 months (9 months from screening visit)

6 months (15 months from screening visit)

6 months (21 months from screening visit)

Visit -1 (Screening visit)

Visit 0 (Screening visit)

Visit 1 (Follow-up visit)



Clinician-guided (“usual care”) treatment throughout the study

Screening assessment

Baseline assessment

Control 1

Control 2

Control 3

Visit Summary

Visit number -1 0 1, 2 and 3

Time of Visit Inclusion Baseline 3 months

9, 15 and 21 months or discontinuation

Inclusion/Exclusion criteria ✔ Information & Informed consent ✔

Clinical assessment ✔ ✔ ✔ Assessment of exacerbations since last visit*

✔ ✔ ✔

Assessment of clinical status since last visit

✔ ✔ ✔

CAT/CCQ/EQ-5D* ✔ ✔ ✔ Adverse events ✔ ✔

!

Data capture by e-CRF

Recruitment

•  Study power: o  ≥285 patients are required to power the primary endpoint o  >285 patients may will permit subgroup analyses to be

conducted and give sufficient power to evaluated significant differences in some of the secondary endpoints

o  Total patient recruitment = 328 (to allow for ~12% drop outs)

•  Recruitment distribution: o  To include ≥6 countries

o  To recruit ~50 patients per country o  To achieve ~even distribution between national contributions

Recruiting Investigators & Centres

Country Site Name Principal Investigator Status

Ireland Royal College of Surgeons, Dublin Richard Costello Recruiting

Spain

Pneumology Department, Vall d' Hebron University Hospital, Barcelona

Marc Miravitlles Recruiting

Pneumology Department, Hospital Arnau de Vilanova, Valencia, Spain

Juan José Soler-Cataluña Recruitment still to commence

Respiratory Department, Hospital de Alta Resolucion, Granada

Bernardino Alcazar Navarrete Recuiting

Instituto de Investigacíon Sanitaria de Palma (IdISPa), Palma de Mallorca, Spain

Miguel Roman Rodriguez Recruiting

Singapore Singapore General Hospital

Jessica Tan (formerly Therese Lapperre)

Recuiting

Changi General Hospital (CGH) Augustine Tee Recruiting

Korea Department of Internal Medicine, Seoul St. Mary's Hospital Chin Kook Rhee Recruiting

UK Optimum Patient Care Clinical Review Service David Price Recruitment still to commence (targeted service to run in October)

Poland Institute of Tuberculosis and Lung Diseases, Warsaw, Poland

Pawel Sliwinski Recruitment complete

Canada Montreal Chest Institute, Montreal, Quebec Jean Bourbeau; Ron Dandurand; Meena Patel

Withdrew – time delays owing to hospital move

Timelines: Initial

*based on estimated completion Dec 2016

Study Element Initial Actual Ethics & contracts October 2015–April 2016 Recruitment Oct 2015–July 2016 May 2016–ongoing

Complete data collection July 2018 December 2018*

Baseline cross-sectional impact measurements November 2016 January 2017*

Final report, including longitudinal study and control measurements December 2018 March 2019*

Baseline characteristics January 2017 May 2017*

Final manuscript April 2019 October 2019*

Recruitment to date (May-Aug)

Total enrolled (26 August) 2016

20-May-16

27-May-16

07-Jun-16

17-Jun-16

23-Jun-16

29-Jun-16

08-Jul-16

15-Jul-16

25-Jul-16

05-Aug-16

11-Aug-16

19-Aug-16

26-Aug-16

Site Totals

Spain 0 0 8 4 5 7 5 1 7 0 0 0 0 37

Ireland 1 2 3 4 3 5 5 1 3 1 2 1 1 31

South Korea 0 1 6 0 0 0 0 18 9 2 0 0 0 36

Singapore 0 3 7 2 6 1 0 4 8 4 5 9 1 50

Poland 0 0 0 0 0 0 0 14 34 0 0 3 3 51

UK 0 0 0 0 0 0 0 0 0 0 0 0 0 0

0

10

20

30

40

50

60

Nu

mb

er o

f p

atie

nts

Recruitment by Country by country by week

0

50

100

150

200

250

Tota

l pat

ien

t n

um

ber

20-May-16

27-May-16

07-Jun-16 17-Jun-16 23-Jun-16 29-Jun-16 08-Jul-16 15-Jul-16 25-Jul-16 05-Aug-16 11-Aug-16 19-Aug-16 24-Aug-16

Series1 1 7 31 41 55 68 78 116 177 184 191 205 208

Recruitment (May–August)

64% of total n=208 of 328

Current status

•  64% of total (n=208 of 328)

•  UK Service to commence ~October

•  Recruitment estimated to conclude by December 2016

•  Baseline assessments for first patients now commencing

Real-time Study Tracker (II)

Planned Revisions: •  Include UK

•  Update data for Poland •  Include baseline visit data

Real-time Study Tracker (II)

Planned Revisions: Colour-match trend lines with regional location indicators to help identify geographical origin of patients recruited to date

ICS Cessation in COPD: ‘Real-Life WISDOM’

DIRKJE POSTMA & HELGO MAGNUSSEN FOR DISCUSSION

FUNDING…?

Background – ICS use in COPD

•  Studies seeking to address whether combination ICS/LABA therapy improves COPD stability have traditionally concluded that withdrawal of ICS therapy is associated with:1–3 o  An increase in exacerbations and symptoms; o  Reduction in health-related quality of life o  An acceleration in lung function decline.

•  Investigators have also concluded that ICS lack sustained disease-modifying effects after ICS cessation following a recent comparative study of lung function decline, AHR, and QOL over a 5-year follow-up period.4

1. Wouters EF, et al. Thorax. 2005;60:480-7; 2. Lapperre TS, et al. Ann Intern Med. 2009 Oct 20;151:517-27. 3. van der Valk P, et al. Am J Respir Crit Care Med. 2002;166:1358-63;

4. Kunz LI, et al. Chest. 2015;148:389-96.

Background – WISDOM

•  WISDOM evaluated the effect of gradual ICS withdrawal in COPD patients (n=2485) on triple therapy (ICS/tio/salmeterol) within an

RCT environment and observed that:

o  Exacerbation rates were similar in patients continuing versus discontinuing ICS therapy

o  No significant differences in outcomes between ICS withdrawal and triple

therapy patients across subgroups in which a greater degree of dependence on ICS might be expected

o  No significant between group difference in the rate of dropout

o  However… a greater decrease in lung function decline was observed in

patients discontinuing ICS therapy in the final step of ICS withdrawal.

1. Magnussen H, et al. NEJM. 2014;371:1285-94.

Study Concept

•  The aim of the study is to evaluate the effect of ICS cessation (and reduced ICS exposure) on COPD lung function (and exacerbation rates) in patients with COPD managed in a routine care, “real-life” setting.

Design: overview

Using electronic primary care records data from the UK’s Optimum Patient Care Research Database (OPCRD), the study will include 2 x matched analysis.

Index date

Cohort A – Control Arm: continue on baseline therapy (no MPR restrictions)

Baseline

Patients on FDC ICS/LABA and separate LAMA ICS MPR ≥70%

1 year 1 year Annual exploratory endpoints to 5

years post index date

Month -12

Month -6

Month 12

Month 13

Month ……………………………..60

Month 0

Month 3

Cohort A – Cessation Arm: LABA / LAMA therapy (any combination of fixed or separate inhaler devices) No ICS prescriptions fro ≥3 months (i.e. prior to month 3)

ICS Cessation Cohort

ICS Reduction Cohort

Index date

Cohort B – Control Arm: continue on baseline therapy (at no or <50% reduction in ICS dose)

Baseline

Patients on: ICS/LABA/LAMA (any fixed or free combinations) ICS MPR ≥70%

1 year 1 year Annual exploratory endpoints to 5

years post index date

Month -12

Month -6

Month 12

Month 13

Month ……………………………..60

Month 0

Month 3

Cohort B – Reduction Arm (prescribed): continue on baseline therapy but with ICS prescribed at ≥50% reduced dose

Outcome Period & Endpoints

Outcome period: •  Primary: 1 year •  Exploratory:

o  24 months; 36 months; 48 months, 60 months1

o  12-weeks (where evaluable) as used in WISDOM2

Primary endpoints •  Time to first acute COPD exacerbation

Secondary endpoints •  Exacerbation rate •  Change in FEV1 •  Treatment stability (absence of exacerbations and no escalation in

pharmacotherapy)

•  COPD-related hospitalisations (rate and time to first)

1. Kunz LI, et al. Chest. 2015;148:389-96; 2. Magnussen H, et al. NEJM. 2014;371:1285-94;

Interaction analyses The interaction between the follow patient / clinical features and the study outcomes will be explored where feasible:

•  Baseline blood eosinophil level

•  Baseline exacerbation rate •  Presence of atopy

•  Smoking status (current vs ex-) •  Prescribed baseline ICS particle size (extra-fine vs non-

extra-fine)

Feasibility: OPCRD Patient #s COPD patients Number* COPD diagnosis ever 132,962 On Triple Therapy (≥1 prescription for ICS, LAMA and LABA in latest 12-month period)

25,987

On triple therapy and discontinue ICS (on prescription of ICS, LABA and LAMA in baseline with only LABA and LAMA in outcome (using any LABA/LAMA prescription as index date)

687

On triple therapy and discontinue ICS* with ≥1 FEV1 during baseline year and FEV1 reading in the 0-5 years following ICS cessation/reduction

356

*Numbers valid as of September 2015 and will be substantially higher by the time of extraction.

MODERN EPIDEMIOLOGY OF ALPHA1-ANTITRYPSIN DEFICIENCY (AATD) IN THE UK

JOAN SORIANO, RAVI MAHADEVA, MARC MIRAVITLLES AND RUPERT JONES

FOR DISCUSSION FUNDING…?

Background •  Emphysema in AATD results from an excess of neutrophil elastase in the lung, which

destroys elastin and the elastase inhibitor AAT that protects against proteolytic degradation of elastin.1

•  Cigarette smoking and infection also increase elastase production in the lung, thus

increasing lung degradation.1

•  AATD is considered a rare disease, but it is believed to be largely underdiagnosed2

•  3.4 million individuals in the world have an AATD genotype that leads to a deficiency of

this protein2

•  Previous estimates of AATD prevalence in the UK are outdated; current prevalence of is

unknown.3–7

•  Large UK databases (e.g. the CPRD and OPCRD) have been used to evaluate the

prevalence of COPD and asthma within the UK; little work in AATD has been conducted.7

•  The National Institute for Health and Care Excellence in the UK is currently reconsidering

and reviewing his AATD treatment and management recommendations8

1. Stoller JK, et al. Am J Respir Crit Care Med 2012; 185:246; 2. de Serres FJ, et al. Chest 2002;122:1818–1829; 3. Hutchison DC, et al. Clin Sci 1970;38:19P; 4. Cook PJ, et al. Ann Hum Genet 1975;38:275-87; 5. Hutchison DC, et al. Bull

Eur Physiopathol Respir 1980;16 Suppl:315-9; 6. Hutchison DC. Lung 1990;168 Suppl:535-42; 7. Jones RJ, et al. LRM. 2014;2:267-76; 8. NICE. Proposed HTA Human alpha1-proteinase inhibitor for treating emphysema Draft scope (pre-referral);

March 2016;

Study Aim

•  To determine the epidemiological trends (1990-2015) of Alpha1-antitrypsin deficiency (AATD) in the UK, and its natural history in the population: o Size of the problem o Prevalence

o  Incidence

o Mortality from 1990 to 2015

•  To benchmark AATD with other respiratory and non-respiratory conditions

Data sources

•  A combined dataset of patients from two UK primary care databases (de-duped) will be used: o  Clinical Practice Research Database

o  Optimum Patient Care Research Database (OPCRD)

•  Subpopulation data links – where available: o  Rates of hospitalisations and day cases of treatment for AATD

will be assessed in patients with linked Hospital Episode Statistics (HES) data

o  Mortality rate and cause of death will be assessed in patients with linked Office of National Statistics (ONS) data

Patient Population: inclusion criteria

To be eligible for inclusion in the study, patients must meet the following criteria, for each population group:

•  AATD Population: Physician-diagnosed AATD (presence of a AATD

Read code, ever)

•  COPD Population: Physician-diagnosed COPD (presence of a COPD Read code) and/or spirometry-defined COPD: post-

bronchodilator FEV1/FVC<0.7

•  General Population: Healthy control individuals, or patients with non-severe morbidities randomly identified

Outcomes Co-Primary endpoints (stratified by year) •  AATD Incidence •  AATD Prevalence •  AATD mortality rates.

Secondary endpoints •  Respiratory exacerbations •  Oral steroids courses •  Inpatient hospitalisations for AATD

o  Respiratory, liver, or other, as per HES statistics •  Day cases for AATD treatment •  Other clinical outcomes of particular interest include:

o  Oxygen saturation, imaging, Charlson index, mMRC dyspnoea, …

Subgroup of AATD patients with liver disease: •  Child-Pugh score

But first… a pilot

Data source: OPCRD only (no linked secondary or mortality data)

Population: AATD diagnosis only (i.e. no matched comparisons)

Exploratory patient number: 100

Co-Primary endpoints (stratified by year)

•  AATD Incidence

•  AATD Prevalence

•  AATD mortality rates.

Secondary endpoints

•  Respiratory exacerbations

•  Oral steroids courses

•  Other clinical outcomes of particular interest include:

o  Oxygen saturation, imaging, Charlson index, mMRC dyspnoea

Cohort: AATD …1997 2000 2005 2010 2015

Case%1:"AATD,"Female."25"yrs,"Dx"in"2005;"exitus"in"2008"

Case%2:"AATD,"Male"45"yrs.,"Dx"in"2010"

Figure%1:"Study"Design"Diagram"(exploratory)""(exploratory,"with"two"extreme"AATD"case"examples)"

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