The Role of Tetradynamic

Mucoactive on COPD Exacerbations:

the RESTORE Study

Susanthy Dj

Department of Pulmonology and Respiratory Medicine, Faculty of

Medicine Universitas Brawijaya, Saiful Anwar Regional Hospital, Malang
The Objectives
• Understand management of
obstructive pulmonary disease
(COPD)

• Evaluate components and

effectiveness of COPD disease
management programs

• Know more about Restore Study

 COPD Definition

►Chronic Obstructive Pulmonary Disease

(COPD) is a common, preventable and
treatable disease that is characterized
by persistent respiratory symptoms and
airflow limitation that is due to airway
and/or alveolar abnormalities usually
caused by significant exposure to
noxious particles or gases.
 ABCD Assessment Tool

© 2018 Global Initiative for Chronic Obstructive Lung Disease

 Management of Stable COPD

► Once COPD has been diagnosed, effective management

should be based on an individualized assessment to reduce
both current symptoms and future risks of exacerbations.

© 2017 Global Initiative for Chronic Obstructive Lung Disease

 Definition of COPD
Exacerbations

►An exacerbation of COPD is defined as an

acute worsening of respiratory symptoms that
results in additional therapy.

►Exacerbations of COPD can be precipitated by

several factors. The most common causes are
respiratory tract infections..

© 2018 Global Initiative for Chronic Obstructive Lung Disease

Management of Exacerbations

►The goal for treatment of COPD exacerbations

is to minimize the negative impact of the
current exacerbation and to prevent
subsequent events.

►Short-acting inhaled beta2-agonists, with or

without short-acting anticholinergics, are
recommended as the initial bronchodilators to
treat an acute exacerbation.

© 2018 Global Initiative for Chronic Obstructive Lung Disease

Dal Negro RW, Wedzicha JA, Iversen M, et al. Effect of
erdosteine on the rate and duration of COPD
exacerbations: the RESTORE study. Eur Respir J 2017;
50: 1700711
 STUDY OBJECTIVES

• to reduce the number of exacerbations

• to reduce the duration of exacerbations
• to improve the health status of COPD patients
• to verify the long-term safety profile
 STUDY DESIGN GUIDANCE

• Relevant number of patients & centers

Well balanced population
Study drug dosage as approved in the leaflet

OUTLINE RESTORE BRONCUS PEACE HIACE PANTHEON

2016 2005 2008 2014 2014
Pts. Screened >500 >500 >700 120 1006

Centres 48 50 22 1 34

Drug investigated Erdosteine NAC Carbocisteine NAC NAC

Study drug daily dose 600 mg 600 mg 1,500 mg 1,200 mg 1,200 mg

Approved daily dose 600 - 900 mg 600 mg 900 mg* 600 mg 600 mg

* Approved daily dose at the study start

THE STUDY AT GLANCE

12-month randomised, double-blind,

placebo-controlled, parallel-group, multinational,

multicenter study in 528 patients (screened)

with COPD exacerbation

aimed to assess the efficacy and safety of

Erdosteine caps
at the approved minimum dosage (600 mg)
in the long-term therapy of COPD
BOARD AND CENTRES

Steering Committee

•Prof. R. Dal Negro, Lung Department, “Orlandi” Hospital,

Verona (Italy)
•Prof. P. Calverley, University Hospital Aintree,
Liverpool (UK)
•Prof. M. Iversen, Copenhagen University Hospital,
Copenhagen (DK)

Investigators

•>100 respiratory specialists involved

•48 clinical sites in 10 European Countries
 MAIN INCLUSION CRITERIA

• Outpatients of both sexes, between 40 and 80 years old,

with a clinical diagnosis of COPD (stage II and III
according to GOLD 2007)

• On a stable COPD therapeutic regimen for at least 8

weeks prior to inclusion and having experienced at least
2 COPD exacerbations in the 2-12 months prior to
inclusion
STUDY TREATMENTS

Patients received double-blind:

•Erdosteine 300 mg capsule b.i.d. (i.e. 600
mg/day)* or
•Placebo one capsule b.i.d. for 12
consecutive months

on top of the ongoing background COPD

treatment
All COPD treatments were allowed, but
regimen and dose should have been stable
in the 8 weeks prior to inclusion

*Standard approved dose 600-900 mg/day (depending on countries)

CONCOMITANT MEDICATION

Treatments NOT allowed:

●Mucolytics

N-acetylcysteine, ambroxol, carbocysteine

alone or in association with other drugs

●Cough suppressants
codeine, dextrometorphane, dropropizine alone
or in
association with other drugs
PATIENT FLOW CHART
 PATIENTS’ BASELINE FEATURES

VARIABLES Erdosteine Placebo Means p value

AGE (years) 64.3 65.1 64.8 ns

SEX (M/F %) 73/27 75/25 74/26 ns

FEV1 % pred. 51.4 52.2 51.8 ns

FEV1/FVC % pred. 52.9 54.5 53.7 ns

N° of exacerbations 2.4 2.3 2.3 ns

during last 12 m.
Mean Cough Severity 2.0 2.1 2.1 ns
(BCSS 0-4)
Mean Sputum Severity 2.0 2.0 2.0 ns
(BCSS 0-4)
Breathlessness Problems 19.7% Marked 21.0% Marked 20.3% Marked ns
(BCSS 0-4) 59.4% Moderate 60.5% Moderate 60.0% Moderate
17.0% Mild 13.6% Mild 15.3% Mild
 FREQUENCY OF EXACERBATIONS

• The frequency of exacerbations represents a relevant

event in the natural history of COPD

• Exacerbations cause a faster decline in lung

function, quality of life, and exercise performance

• Exacerbations are associated with increased

morbidity and mortality, and have a significant
socio-economic impact
EXACERBATIONS

N. of exacerbations per patient/yr

Mean n. exacerbations per

patient/yr:

Erdosteine: 0.91
Placebo: 1.13

Summary 1:
Erdosteine decreased
number of exacerbations
by: -19.5%
EXACERBATIONS

Proportion of “exacerbation-free” patients at the

end of the study

Summary 2:
Erdosteine significantly
increased number of
patients who was free
from exacerbations.
(p<0.01)
SEVERITY OF EXACERBATIONS

A large retrospective 3-year-study carried out in

2,501 patients COPD demonstrated that
exacerbations, in a practical setting, were:

•Mild 50.82%

•Moderate 35.31%

•Severe 13.88%

Risk of exacerbations in COPD: a primary care retrospective study

J. Montserrat-Cambell et Al. BMC Fam Pract. 2015; 16-173
 SEVERITY OF EXACERBATIONS
Acute exacerbations of COPD: is it the “stroke of the lungs”?

• COPD is a gradual decline of the lung function.

• 20 to 25% of the accelerated loss in lung function is due to exacerbations.
• The earlier you reduce the number of those episodes, the better is, from a prognostic point of view.
The physical deterioration translates into reduced life expectancy.
• Mild exacerbations are a frequent but underestimated phenomenon.

G. Hillas - International Journal of COPD, 2016

FREQUENCY OF MILD EXACERBATIONS

N. of mild exacerbations per patient/yr

Mean n. exacerbations per

patient:

Erdosteine: 0.23
Placebo: 0.54

Summary 3:
Erdosteine decreased
number of mild
exacerbations by: -57.1%
DURATION OF EXACERBATIONS
“Prolonged exacerbation symptomatic duration is
associated with poorer health status and a greater risk of
a new event”
Impact of Prolonged Exacerbation Recovery in COPD. Donaldson Gc, Wedzicha et AL. Am J
Resp Crit Care Med 2015 Oc; 192 (8): 943-950

“Length of acute exacerbations of

COPD is strongly related with morbidity, hospital
admissions and mortality, and strongly influences
health-related quality of life”
Exacerbations of chronic obstructive pulmonary disease. Wedzicha JA,
Donaldson GC. Respir Care. 2003 Dec;48(12):1204-13
DURATION OF EXACERBATIONS

Mean duration of all exacerbations

Summary 4:
Erdosteine decreased duration of:
•all exacerbations by -24.6%
•mild exacerbations by -22.1%
•moderate-severe exacerbations by -21.3%
HEALTH STATUS

“Chronic obstructive pulmonary disease

is a highly incapacitating health problem,
which not only affects physical functioning,
but also leisure and professional activities

as well as emotional and sexual

relationships.”

Factors affecting health status in COPD patients with co-morbid anxiety or depression
.
Minna J Hyn ninen et Al. Int J Chron Obstruct Pulmon Dis. 2007 Sep; 2(3): 323–328
 HEALTH STATUS

Subject’s Global Assessment of Disease Severity (range 0-

4) was significantly lower in Erdosteine treated patients
(1.5±0.7) than in placebo (1.7±0.7) ones (p=0.022)

Physician’s Global Assessment of Disease Severity (range

0-4) was significantly lower in Erdosteine treated
patients (1.5±0.7) than in placebo (1.7±0.8) ones
(p=0.048)
HEALTH STATUS

Use of reliever medications

Summary 5:
The 10.2% of
Erdosteine patients
vs the 33.7% of
placebo patients
needed to assume
reliever medications
during the trial
 SAFETY PROFILE

Distribution of Adverse Events

Group Related NR R+NR

Erdosteine 3 310 313

Placebo 5 388 393

The percentage of patients with adverse events was similar (not

significant) in both the placebo and erdosteine treatment groups.

Summary 6:
The freedom from adverse events in the ERDOSTEINE group did
mean that treatment was well tolerated and likely contributed to the
low withdrawal rate from the study.
CONCLUSIONS
The RESTORE study demonstrates that Erdosteine
administered in COPD patients :

• reduces the number of exacerbations

• reduces the duration of exacerbations
• improves the health status
• with good safety profile

“Erdosteine can give consistent benefits when added to the

standard therapy in patients with COPD”

This is the first time that these outcomes were

obtainedin COPD with a mucoactive drug assumed “on
label dose”
1
2
3
4
 Trigger
(cigarette, pollutant, infection, etc.)

PATHOPHYSIOLOGY
Mucociliary
OF CB & COPD damage
AN IDEAL CHOICE to combat the
vicious cycle of COPD

VICIOUS
Respiratory CIRCLE OF
Colonization
epithelium CHRONIC of bacteria
damage BRONCHITIS
& COPD

COPD Inflammation
Development Product / response
antigen of
bacteria

Oxidative
stress
 Trigger
(cigarette, pollutant, infection, etc.)

ERDOSTEINE
MECHANISM OF Mucociliary
damage
AN IDEAL CHOICE to combat the
ACTION vicious cycle of COPD

VICIOUS
Respiratory CIRCLE OF
Colonization
epithelium CHRONIC of bacteria
damage BRONCHITIS
& COPD

COPD Inflammation
Development Product / response
antigen of
bacteria

Oxidative
stress
Thank you