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Treating COPD:Reaching for GOLD

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NOVARTIS

GRANTS AS PRINCIPAL INVESTIGATOR FOR INTERNATIONAL PHASE II & III TRIALS

A randomised, 24-week, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy, safety andtolerability of Ariflo (15 mg twice daily) in patients with Chronic Obstructive Pulmonary Disease (COPD).Protocol number: SB 207499/042Trial period: 13/04/1999 till 26/10/1999Phase: II

A multidose comparison of Tiotropium inhalation capsules, Salmeterol inhalation aerosol and placebo in a six-month,

double-blind, double-dummy, safety and efficacy study in patients with Chronic Obstructive Pulmonary Disease (COPD).Protocol number: BI205.137 (ZA100)Trial period: 10/05/1999 till 20/04/2000Phase: III

A multicentre, open-label extension study to evaluate the safety, tolerability and efficacy of oral SB 207499 (15mg twicedaily) in patients with Chronic Obstructive Pulmonary Disease (COPD).Protocol number: SB 207499/040Trial period: 26/10/1999 till 06/08/2002Phase: III

A randomised, double-blind, double-dummy, placebo- and active controlled, parallel-group efficacy and safetycomparison of 12-week treatment of two doses [5g (2 actuations of 2.5 g) and 10 g (2 actuations of 5 g)] ofTiotropium inhalation solution delivered by Respimat inhaler, placebo and Ipratropium Bromide inhalation aerosol (MDI)in patients with Chronic Obstructive Pulmonary Disease (COPD).Protocol number: BI205.251Trial period: 04/02/200322/06/2004

Phase: III

DECLARATION

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Effect of roflumilast on exacerbation rate in patients with COPD. A 52 weeks, double-blind study with 500 mcg roflumilastonce daily versus placebo. The HERMES study.Protocol number: BY217/M2-125Commenced: 24/05/2006Phase: III

Effect of roflumilast in COPD patients treated with salmeterol. A 12 week, double blind study with 500 mcg roflumilastonce daily versus placebo. (EOS-study)Protocol number: BY217/M2-127Commenced: 28/06/2006Phase: III

A 52-week randomized, double-blind, parallel group, placebo controlled, multicenter clinical trial, to assess the efficacyand safety of 200g of the anti-cholinergic LAS 34273 compared to placebo, both administered once-daily by inhalation,in the maintenance treatment of patients with moderate to severe stable chronic obstructive pulmonary disease(ALMIRAL)Protocol number: M/34273/31Commenced: 13/11/2006Phase: IV

Effect of Roflumilast on exacerbation rate in patients with Chronic Obstructive Pulmonary disease. A 52 week s double-blind study with 500ug Roflumilast once daily versus placebo. (OPUS)Protocol Title: BY217/M2-111

Trial period: 01/12/200316/09/2005Phase: III

A double-blind, randomised, placebo controlled study to investigate chronic intermittent pulse therapy of moxifloxacin asa prevention of acute exacerbation in out-patients with chronic bronchitis.Protocol number: BAY 12-8039 / 11229 / PULSETrial period: 11/10/200410/05/2007Phase: III

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COPD

COPD is a gradually progressivedisease Dyspnoea (persistent & progressive)

is the hallmark symptom and is the

most frequent reason that patientsseek medical attention.

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COPD

Cough is often the first symptom to develop and isfrequently discounted by the patient as an expected

consequence of smoking.

Initially, the cough may be intermittent, but later is

present every day.

Chronic cough associated with COPD can be

unproductive. Notably, some patients can develop

considerable airflow limitation without the presence of acough.

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Stage I-III COPD prevalence: BOLD study

11

19

26

24

18

13

22

19 1920

14

19

0

7

14

21

28

Prevalence

ofCOPD

(40

years

ofage)

Buist al. Lancet 2007;370:741

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COPD is under-diagnosed BOLD

0

8

15

23

30 GOLD Stage I+

GOLD Stage II+

Doctor-diagnosed COPD

Buist, et al. Lancet 2007

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Risk Factors for COPD

Genes

Infections

Socio-economic

status

Aging Populations

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CAUSES OF COPD

50 to 60 fold higher incidence of COPD in HIV independent ofother risk factors

Cannabis: 1 joint = 2.5 - 5 cigarettes thus higher risk of COPD

Passive or environmental tobacco smoke may contribute to

COPD: same risk on average as a smoker (15 - 20% of passive

smokers develop disabling airflow limitation) Pregnancy: smoking may predispose foetus to later COPD

Hubbly bubbly or hookah pipe worse than cigarette smoke - a

session of 20 min equals smoking 200 cigarettes (WHO) and in

an average shared session you would inhale 20 cigarettesnicotine

There are 4500 chemicals in a cigarette

50% of people who smoke will die from the habit with an average

reduction of 8 - 20y of lifespan

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PLV

PL

V

X

Trappedair

Normal COPD

MECHANISM OF COPD

Expiratory Airflow Obstruction

. .

PL= translung pressure; V = ventilation

Reduced recoil

Reduced tethering

Increased airways resistance

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Differential Diagnosis Asthma

CHF

Bronchiectasis Tuberculosis

Obliterative bronchiolitis onset younger age, nonsmokers, h/o RA or fume exposure

Diffuse panbronchiolitis Male nonsmokers, chronic sinusitis, centrilobular nodular opacities and

hyperinflation

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COPD

Symptoms differ from asthma

COPD Asthma

Onset Midlife Early in life (often childhood)

Symptoms Slowly progressive

Dyspnoea during activity

Vary from day to day

More common at night/earlymorning

Airflow limitation Largely irreversible Largely reversible

Main risk factors for

development

Tobacco smoke and

airborne pollutants

Exposure to allergens, infections,

diet, tobacco smoke,

socioeconomic

Additional features Chronic cough & sputum

Family history of COPD

Allergy, rhinitis and eczema also

present

Family history of asthma

GOLD. Global strategy for diagnosis, management, and prevention of COPD. 2013

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Assess COPD Comorbidities

COPD patients are at increased risk for:

Cardiovascular diseases

Osteoporosis Respiratory infections Anxiety and Depression Diabetes Lung cancer

These comorbid conditions may influence mortality and

hospitalizations and should be looked for routinely, and

treated appropriately.

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Investigations

Chest X-ray: Seldom diagnostic but valuable to exclude alternativediagnoses and establish presence of significant comorbidities.

Lung Volumes and Diffusing Capacity / Spirometry:Help to

characterize severity, but not essential to patient management.

Oximetry and Arterial Blood Gases: Pulse oximetry can be used to

evaluate a patients oxygen saturation and need for supplementaloxygen therapy.

Alpha-1 Antitrypsin Deficiency Screening: Perform when COPDdevelops in patients of Caucasian descent under 45 years or with astrong family history of COPD.

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Exercise Testing: Objectively measured exercise impairment,assessed by a reduction in self-paced walking distance (such asthe 6 min walking test) or during incremental exercise testing ina laboratory, is a powerful indicator of health status impairmentand predictor of prognosis.

Composite Scores: Several variables (FEV1, exercise toleranceassessed by walking distance or peak oxygen consumption,weight loss and reduction in the arterial oxygen tension) identify

patients at increased risk for mortality.

Additional Investigations

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Spirometry

What is a spirometer?

A spirometer is a device used to

measure respiratory movements

as a function of time

Spirometry can be used to

measure

forced expiratory volume in

one second (FEV1)

forced vital capacity (FVC)

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Respiratory values

Respiratory parameters

Tidal volume (TV) The amount of air that is either inhaled or exhaled during one bbrespiratory

cycle

Inspiratory reserve volume

(IRV)

The maximal amount of air that can be inhaled from the end-inspiratory position

Expiratory reserve volume

(ERV)

The maximal amount of air that can be exhaled from the resting end-expiratory

level

Forced expiratory volume at

one second (FEV1)

The volume of air forcefully and rapidly expelled in one second following

maximal inspiration

Residual volume (RV) The volume of air remaining in the lungs after maximal expiration

Lung capacities

Total lung capacity (TLC) The volume of air contained in the lungs after maximal inspiration

Vital capacity (VC) The volume of air that can be expelled from the lungs from a position of full

inhalation, with no limit to the duration of exhalation; it is equal to the

inspiratory capacity plus the expiratory reserve volume

Inspiratory capacity (IC) The volume of air that can be taken into the lungs on a full inhalation, starting

from the functional residual capacity; it is equal to the tidal volume plus

inspiratory reserve volume

Functional residual capacity

(FRC)

The volume of air remaining at the end of a normal quiet exhalation

Forced vital capacity (FVC) Vital capacity measured when the patient is exhaling with maximum speed and

effort

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Normal COPD

1 sec

FVC

8

7

6

5

4

3

21

0

-2

-3

-4

-5 IC

Flow(

L/s)

6 5 4 3 2

Volume (L)

1 sec

8

6

4

2

0

-2

-4

-6

Predicted

Actual

IC

8 7 6 5 4 3 2

Volume (L)

Flow(L/s)

Spirometry Loops

Patients with COPD have less elastic airways and consequently it takes longer to expel

a similar proportion of air:

This graph shows how the FEV1:FVC ratio is affected by COPD.

A diagnosis of COPD is made when FEV1 is less than 70% of FVC.

FVC

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Bronchodilator medications are central tosymptom management in COPD

GOLD Strategy: COPD Management

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V

.

BD

Air flowDeflation

Improvement in flowFEV1

Improvement in volumesFVC and IC

BD = bronchodilator; FEV1 = forced expiratory volume in 1 secondFVC = forced vital capacity

Bronchodilator therapy deflates the lung

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The MRC breathlessness scale

Stenton C Occup Med (Lond) 2008;58:226-227

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GOLD Strategy:

Pharmacologic management of COPD*

(C) (D)LABA+ICS orLAMA LABA+ICS or LAMA

LABA and LAMA

LABA+ICS and LAMA or

LABA+ICS and PDE4-inh or

LABA and LAMA or

LAMA and ICS or

LAMA and PDE4-inh

SABA orSAMA prn LABA orLAMA

LABAor LAMA or

SABA and SAMA

LABA and LAMA

(A) (B)

GOLD 1

GOLD 2

GOLD 3

GOLD 4

mMRC 2

CAT 10

mMRC 01

CAT

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***p

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50

90

110120120

150

140

160

130

160

180190

Tiotropium 18 g o.d. Indacaterol 150 g o.d. Indacaterol 300 g o.d.

Indacaterol vs Tiotropium

has a faster onset of bronchodilator effect on Day 1

Time post-dose (minutes)

******

******

***

******

***

******

***

**

200

180

160

140

120

100

80

60

40

200

FEV

1difference

versus

place

bo

(m

L)

5 15 30 60

MCID

INTIME

Vogelmeier et al. Respir Res 2010

**p

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Indacaterol vs Tiotropium

significant improves dyspnea score at 12 weeks

0

1

1

2

2

3

TDI total score

Difference

0.58 (p

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GOLD Strategy:

Pharmacologic management of COPD*

(C) (D)LABA+ICS orLAMA LABA+ICS or LAMA

LABA and LAMA

LABA+ICS and LAMA or

LABA+ICS and PDE4-inh or

LABA and LAMA or

LAMA and ICS or

LAMA and PDE4-inh

SABA orSAMA prn LABAorLAMA

LABAor LAMA or

SABA and SAMA

LABA and LAMA

(A) (B)GOLD 1

GOLD 2

GOLD 3

GOLD 4

mMRC 2

CAT 10

mMRC 01

CAT

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Use of ICS in COPD

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GOLD Strategy:

Pharmacologic management of COPD*

(C) (D)LABA+ICSorLAMA LABA+ICSor LAMA

LABA and LAMA

LABA+ICS and LAMA or

LABA+ICS and PDE4-inh or

LABA and LAMA or

LAMA and ICS or

LAMA and PDE4-inh

SABA orSAMA prn LABA orLAMA

LABAor LAMA or

SABA and SAMA

LABA and LAMA

(A) (B)GOLD 1

GOLD 2

GOLD 3

GOLD 4

mMRC 2

CAT 10

mMRC 01

CAT

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Pharmacologic Therapy

ICS - Benefits and harms In severeCOPD, twice daily combination therapy with ICS in

combination with LABA vs. placebo + LABA (TORCH STUDY)

resulted in:

No effect on quality of life, total mortality or COPD related-deaths Reduced frequency of moderate to severe exacerbations, exacerbations

requiring steroids or hospitalization

Effect size very small (0.030.34 exacerbations per year difference)

Increased risk of pneumonia (number needed to harm [NNH] = 14)

ICS alone increased mortality (NNH = 30) and COPD-related deaths(NNH = 46) compared with combination therapy

Calverley, 2007

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The role of inhaled corticosteroids in COPD is

limited to specific indications

Long-term ICS treatment is recommended for patients with

severe/very severe COPD and frequent exacerbations (GOLD groups

C and D) (patients with 2 exacerbations per year)

Long-term ICS monotherapy is not recommended because it is lesseffective than combination of LABA and ICS

Oral steroids no longer recommended for maintenance treatment of

COPD Cochrane database 2005

A therapeutic trial of oral steroids to distinguish responders from nonresponders is no longer recommended. There is no reason ever for a

trial of steroids in COPD - it does not predict prognosis or the future

response to inhaled steroidsGlobal Initiative for Chronic Obstructive

Lung Disease (GOLD) 2013

(www.goldcopd.org)

http://www.goldcopd.org/http://www.goldcopd.org/

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O2 in COPD

Home O2 for patients with secondary effects ofhypoxia: Cor Pulmonale with decompensation,

pulmonary hypertension or polycythaemia

Long term continuous O2 PaO2 < 55mmHg at rest or 2/year) and oral ICS

have no role in treatment

Use O2 appropriately

50% of COPD pts are undiagnosed

COPD evident by age 50 years

At time of diagnosis FEV1 < 50%

50% 5y survival