Time-based Register and Analysis of COPD Endpoints
Conditions: COPD
Sponsor: Fundación Pública Andaluza para la gestión de la Investigación en Sevilla

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FULL STUDY PROTOCOL 
Time-based Register and Analysis of COPD Endpoints (TRACE). 
 
Scientific committee: 
Jose Luis Lopez-Campos Bodineau 
Laura Carrasco Hernández 
María Abad Arranz 
Eduardo Márquez Martín 
Carmen Calero Acuña 
Francisco Ortega Ruiz 
 
Institutions:  
(1) Centro de investigación biomédica en red de enfermedades respiratorias (CIBERES). 
Instituto de Salud Carlos III, Madrid Spain 
(2) Unidad Médico-Quirúrgica de Enfermedades Respiratorias, Instituto de Biomedicina de 
Sevilla (IBiS), Hospital Universitario Virgen del Rocío/Universidad de Sevilla, Seville, 
Spain 
 
NCT number:  NCT03485690 
Date: February 2nd, 2018 
 
 

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Rationale
Rationale 
Although recent studies have shown a constant decrease in mortality (1), chronic obstructive 
pulmonary disease (COPD) continues to be the third leading cause of death in the world (2). In 
addition, the impact of COPD on quality related to health (3) its prognostic implications as well 
as the burden on the health system (4) make it a disease of the first magnitude (5). As an 
obstructive disease, the main parameter to evaluate the progression is the degree of 
obstruction of the air flow measured by the forced expiratory volume in the first second (FEV
1) 
obtained during a forced spirometry and after a bronchodilator. Consequently, clinical trials 
have traditionally focused on the demonstration of improvement in FEV1 either as an isolated 
measurement or as a trend over time (6). Accordingly, old guidelines focused on the 
establishment of treatment strategies according to the degree of impairment of FEV1 (7). 
However, COPD is a heterogeneous and complex disease in which several factors combine to 
give the final clinical expression. Recent studies have shown that, despite being an extremely 
important parameter to predict the progression of the disease, FEV
1 is a poor marker for 
perception symptoms. In the study Evaluation of COPD Longitudinally to Identify Predictive 
Surrogate Endpoints (ECLIPSE), a large, 3-year, observational, multicentre, international study 
aimed at defining clinically relevant subtypes of COPD (8), the authors showed the complex 
interaction between FEV
1 and clinical markers. As a result, although clinical symptoms worsen 
as FEV1 decreases in the patient cohort, when assessing patient-level data, the authors found 
varying degrees of deterioration in symptoms or exacerbations in all grades of COPD as 
measured by the severity of FEV1 deterioration (9). From this and other similar analyzes, there 
is therefore a need to use new markers of clinical expression and disease progression that 
allow a correct, complete and more comprehensive evaluation of patients with COPD. 
In recent years a change towards patient-centered medicine has been proposed and several 
initiatives have been presented to include other clinical variables in the so-called 

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multidimensional evaluation of COPD patients, in which FEV1 continues to play a prominent 
role, but it is modulated by other clinical expressions of the disease (10). Consequently, since 
the 2011 update of the Global Initiative for Obstructive Pulmonary Disease (GOLD) document, 
it incorporates a three-pronged approach (pulmonary function, chronic symptoms and 
exacerbations) to identify the types of patients that may need different treatment strategies 
(11), as previously proposed (12). Although not without controversy (13), one of the strengths 
of this approach is the inclusion of the so-called patient reported outcomes (PRO), as part of 
the evaluation system. PRO have gained popularity as a measure of the impact of treatment 
from the perspective of patients, since they represent the individual's experience of their 
health status, beyond physiological limitations (14, 15). This multidimensional approach helps 
identify different types of patients and individualize pharmacological treatment. 
However, COPD is a dynamic disease that evolves over time. Hence, research projects are 
needed to evaluate the behavior of the disease over time and allow clinicians to learn, 
longitudinally, how the disease behaves and what are the determinants that influence its 
clinical presentation and response to the treatments. For example, from the functional point of 
view, it is possible that other functional markers provide relevant information on the 
evaluation of the patient with COPD. In addition, other markers, such as peripheral blood 
eosinophils, have been proposed as a marker of response to various treatments (16). In this 
sense, cohort studies play an essential role (8, 17).  
The TRACE project (Time-based Register and Analysis of COPD Endpoints) is part of this line of 
prospective and longitudinal observational study of patients with COPD with the idea of 
generating a cohort of patients who provide relevant information on the multidimensional 
behavior of the disease over time and the determinants of the different response to 
treatments. The added value that tries to provide TRACE over other previous cohorts is to 
observe the multidimensional impact of the disease over time, but using tools that are of the 

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usual clinical practice and that are available to all clinicians. In this way, its conclusions may be 
applied directly to the patient with COPD. The present document describes the full 
methodology of TRACE. 
 
Methodology
Methodology 
TRACE is a prospective observational cohort study that will include patients diagnosed with 
COPD and followed up by our monographic COPD-dedicated outpatient clinic since 2012. 
Inclusion criteria 
Patients evaluated in the COPD-dedicated outpatient clinic since the year 2012 will be selected 
for longitudinal follow-up. The inclusion criteria are: 
- Adult patients, both genders 
- Aged 40-90 years. 
- Diagnosed of COPD, according to the current recommendations (11, 18). 
- Evaluated in our COPD-dedicated outpatient clinic since 2012 
- Followed up by our team for at least 3 years. 
Exclusion criteria 
Another relevant comorbidity that conditions their care, as judged by the research team. 
Sample size 
Since the main objective of the project is to generate a cohort of patients, the total number of 
patients seen in one of our COPD-dedicated outpatient clinics during the year were to be 
selected through our electronic medical records system (SIDCA) at our institution. The number 
of patients seen for a consultation, in a year, is estimated at around 15 patients a day, for 4 
days a week, for 48 weeks a year, a total of 2880 cases. Of these approximately 20% have 
alternative diagnosis to COPD, 20% are discharged at the first visit and we estimate a 10% loss 

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in follow-up. For this reason, we estimate an initial cohort of patients from 1440 cases with a 
minimum follow-up of 3 years. 
Protocol 
To include new cases, a retrospective review of patients who meet the inclusion / exclusion 
criteria will be done. For this, proceed as follows: the COPD-dedicated outpatient clinic of the 
principal investigator will be reviewed to evaluate all the patients that were evaluated in this 
consultation. Once identified, those who are still in follow-up will be selected and the data will 
be collected for inclusion. Subsequently, the patients included will be followed up 
prospectively with annual visits until their death or loss of follow-up, as per clinical practice in 
our institution. 
Outcome measures 
Primary outcome measures will be survival. Secondary outcomes measures include: 
- Symptoms perception: dyspnea measured by mMRC scale (19) 
- Number of moderate or severe exacerbations, defined as in the GOLD document (20) 
- Time to first moderate or severe exacerbation 
- FEV1 annual decline 
- Forced expiratory flow at 25-75% of expiration (FEF25-75) 
- Peak expiratory flow (PEF) 
- Peripheral blood eosinophils count expressed in cells/µL and in percentage of the 
white cell count 
- Serum Alpha1-antitrypsin 
- Total IgE 
- Positive bronchial colonization 
- Inhaled and oral COPD-related medication use 

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Registered data 
The clinical data that will be collected at each annual visit include: 
Filiation data: 
- Gender 
- Birth date 
Previous history: 
- - Smoking history 
- - Comorbidities, collecting 4 indices: Charlson (21), COTE (22), COMCOLD (23) and 
Functional Comorbidity Index (24). 
- History of COPD: type of disease according to GOLD (11) and the Spanish guideline: 
GesEPOC (18), updating the database with subsequent updates of these documents. 
Current Anamnesis: 
- Current symptoms: dyspnea according to the mMRC scale (19), cough, expectoration, 
self-listening wheezing 
- Exacerbations in the previous year, as the patient remembers and recorded in his 
medical record. 
- Current treatment, pharmacological and non-pharmacological. Compliance and 
adverse effects of the medication. 
Complementary studies: 
- Spirometry pre- and post-bronchodilation, collecting body mass index, forced vital 
capacity (FVC), FEV
1, FEV
1/FVC ratio, FEF25-75, and PEF. 
- Alpha1-antitrypsin in serum 
- Eosinophils in peripheral blood in absolute and relative values. 
- Total IgE 

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- Sputum culture, spontaneous. 
Follow-up status: 
- Vital status 
- Lost to follow up 
- Date of end of follow-up 
- Death caused by a respiratory condition 
At each annual visit, the same information will be collected, updating the comorbidities index 
according to new clinical conditions that may occur. 
Ethics 
The present protocol has been approved by the Coordinating Committee of Ethics of the 
Biomedical Research of Andalusia (CCEIBA), Spain (approval acta 08/2015 and 07/2017), and it 
will observe the principles of the Declaration of Helsinki for research projects with human 
beings. During the study, the patient's personal data will not be collected as a study participant 
to identify the subject. The data obtained will be kept under strict confidentiality (Spanish 
Organic Law 15/1999, of protection of personal data) and only the principal investigator of the 
project will have access to them. Each case will be anonymous in the database and will be 
numbered
 with
 a
 code to guarantee the confidentiality of
 the data.
 In the database there will
 be
 
no data
 that can
 identify patients. As
 this
 is an
 observational non-intervention study in which no 
diagnostic tests or therapeutic interventions of any nature will be performed outside of medical
 
practice and given that the collected data will be anonymized, informed consent will not be 
requested. The ethical committee was aware of this circumstance and approved the procedure. 
 
 

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References
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