A Prospective Cohort Study to Assess Obstructive Respiratory Disease Phenotypes and Endotypes in Japan: The TRAIT Study Design

Figures & data

Figure 1 TRAIT study design.

Abbreviations: FU, follow-up; Tel, telephone.

Table 1 Inclusion and Exclusion Criteria of the TRAIT Study

Inclusion Criteria
Asthma Cohort	A physician’s diagnosis of asthma, and be a regular user of ICS maintenance medication regardless of concomitant LABA and/or LAMA use
ACO Cohort*	A physician’s diagnosis of ACO, and be a regular user of LAMA, and/or LABA, and/or ICS maintenance medication
COPD Cohort	A physician’s diagnosis of COPD, and be a regular user of LAMA, and/or LABA maintenance medication regardless of concomitant ICS use
Exclusion Criteria
	Major lung surgery (eg, lung reduction, lobectomy, or lung transplant)
	Known history of significant inflammatory disease other than COPD (eg, rheumatoid arthritis or lupus) (ACO and COPD Cohorts only)
	Serious, uncontrolled disease (including serious psychological disorders) likely to interfere with the study or impact on participant safety
	Cancer diagnosis within the last 5 years (participants in remission for ≥5 years are eligible)
	Current primary diagnosis of diffuse pan-bronchiolitis, or a primary diagnosis of bronchiectasis or pulmonary fibrosis
	Diagnosis of chronic bronchitis or pulmonary emphysema and demonstrate no spirometric evidence of obstructive lung disease
	Participant is currently participating in another study involving investigational study treatment intervention
	Participant is unable to perform spirometry

Notes: *The ACO cohort will include participants with guideline-defined ACO, COPD with features of asthma, or asthma with features of COPD.

Abbreviations: ACO, asthma–chronic obstructive pulmonary disease overlap; COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroid; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist.

Table 2 Endpoints of the TRAIT Study

Primary endpoint (Part 1)

The proportion of participants presenting with combinations of clinical characteristics seen at Visit 1:

Participants with a pre-bronchodilator FEV1 ≥30% and <85%, airway reversibility^a, at least one event^b in the 24 months prior to Visit 1, an ACQ-5 score ≥1.5

Participants with a smoking history^c, post-bronchodilator FEV1/FVC <0.7, at least one event^b in the 24 months prior to Visit 1, a CAAT^Citation4 score ≥10, and peripheral blood EOS ≥100 cells/μL

Secondary endpoints (Part 1 and Part 2)

Clinical characteristics

The proportion of participants presenting with combinations of clinical characteristics at each visit

The mean annual rate of events^d

The mean annual rate of moderate and severe exacerbations^e

Pre- and post-bronchodilator FEV1, FVC, and FEV1/FVC ratio at each visit

Airway reversibility (increase from pre-bronchodilator FEV1 of ≥12% and 200 mL) at each visit

CAAT, ACQ-5, SGRQ, mMRC dyspnea scale score at each visit

Proportion of participants experiencing a clinically important deterioration in their obstructive respiratory disease per year^f

Time to lung cancer-related, respiratory-related but not lung cancer-related, and all-cause death

Biomarkers

DLCO and FeNO at each visit

CT scans for evaluating the degree of airways disease and emphysema

Total and differential white blood cell count at each visit

Proportion of participants with peripheral blood EOS count ≥100 cell/μL at each visit

Levels of blood biomarkers* associated with respiratory disease progression and outcomes

Physician-assessed parameters

Medical history and comorbidities at each visit

The proportion of participants whose physician’s diagnosis of asthma, COPD or ACO changes during the study

Respiratory medications and nondrug therapies received by participants

Type of modifications to maintenance medication for asthma/ACO/COPD during the study

The proportion of participants who meet the GINA, 2018 definition of asthma at each visit

The proportion of participants who meet the JRS, 2018 definition of ACO at each visit

The proportion of participants who meet the GOLD, 2019 definition of COPD at each visit: having dyspnea, chronic cough, or sputum production, a history of exposure to risk factors, and persistent airflow limitation (post-bronchodilator FEV1/FVC <0.7)

Mean annual rate of respiratory-related HRU

Mean annual rate of respiratory-related and all-cause hospitalizations

Notes: *Blood markers assessed will include total and differential white blood cell count; serum high-sensitivity C-reactive protein (hsCRP); serum IgE; plasma fibrinogen; serum soluble form of receptor for advanced glycation end products (sRAGE); lung matrix turnover markers; inflammatory cytokines associated with disease activity such as interleukin (IL)-17, IL-33, or chemokine ligand (CXCL)-10. ^aAirway reversibility is defined as follows; post-bronchodilator spirometry values show the change in FEV₁ ≥12 as a percentage on pre-bronchodilator values in combination with increase in absolute FEV₁ ≥200 mL compared with pre-bronchodilator values. ^bEvent includes: symptoms of respiratory tract infection requiring antibiotics and/or systemic corticosteroids, moderate-to-severe asthma/ACO/COPD exacerbation, and asthma attacks requiring additional short-acting β₂-agonist (SABA) treatment or SMART treatment. ^cParticipants with a smoking history are defined as those with a smoking history of ≥10 pack-years. ^dEvent for the mean annual rate includes: symptoms of respiratory tract infection requiring antibiotics and/or systemic corticosteroids and moderate-to-severe asthma/ACO/COPD exacerbation. ^eA moderate exacerbation is defined as a worsening of asthma/ACO/COPD that requires treatment with systemic corticosteroids and/or antibiotics. A severe exacerbation is defined as a worsening of asthma/ACO/COPD that requires hospitalization. ^fA clinically important deterioration is a composite measure including the worsening of key clinical features: lung function, symptoms, and exacerbation events.

Abbreviations: ACO, asthma–COPD overlap; ACQ-5, Asthma Control Questionnaire-5; CAAT, Chronic Airways Assessment Test; COPD, chronic obstructive pulmonary disease; DLCO, diffusing capacity of the lungs for carbon monoxide; EOS, eosinophil; FeNO, fractional exhaled nitric oxide; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; GINA, Global Initiative for Asthma; GOLD, Global Initiative for Chronic Obstructive Lung Disease; HRU, healthcare resource utilization; JRS, Japanese Respiratory Society; mMRC, modified Medical Research Council; SGRQ, St George’s Respiratory Questionnaire.

Table 3 Schedule for Assessment of Disease-Related Variables

Variables	Visits
	SCR	Visit 1	Visit 2	Visit 3	Visit 4
Demography (age/gender)	X
Height, weight, and BMI		X	X	X	X
Vital signs	X	X	X	X	X
Medical history	X	X
Comorbidities	X	X	X	X	X
Diagnosis of and medication for asthma/ACO/COPD	X	X	X	X	X
Smoking status		X	X	X	X
Spirometry testing		X	X	X	X
Collect narratives of any lung CT scans*		X	X	X	X
Record healthcare resource utilization			X	X	X
Blood sampling for biomarker analysis^†		X	X	X	X
DLCO and FeNO testing^‡		X	X	X	X
CAAT, ACQ-5, SGRQ, and mMRC Dyspnea Scale		X	X	X	X
Record occurrence of events^§		X	X	X	X

Notes: *CT scans not required as part of the main study. If a participant has had any lung CT scans performed in the year prior to entering the study or any lung CT scans performed as part of routine clinical management during the study, then the radiologist’s or pulmonologist’s narrative will be collected. ^†Blood samples for analysis of emerging biomarkers will only be collected at Visit 1 and Visit 4. Blood samples for analysis of all other biomarkers will be collected at all study visits. ^‡DLCO testing and FeNO testing are only required to be performed at study sites that have access to equipment. ^§Respiratory tract infection requiring antibiotics and/or systemic corticosteroid, exacerbation, asthma attacks, serious adverse events.

Abbreviations: ACQ-5, Asthma Control Questionnaire-5; ACO, asthma–COPD overlap; BMI, body mass index; CAAT, Chronic Airways Assessment Test; COPD. Chronic obstructive pulmonary disease; CT, computerized tomography; DLCO, diffusing capacity of the lungs for carbon monoxide; FeNO, fractional exhaled nitric oxide; mMRC, modified Medical Research Council; SCR, screening; SGRQ, St George’s Respiratory Questionnaire.

Table 4 Tools to Assess Symptoms in the TRAIT Study

	Description	Scoring
Patient-completed questionnaires
CAAT^Citation24	An 8-item questionnaire, which is a modified version of the COPD Assessment Test (CAT)^Citation39,Citation40 with an adaptation of introductory sentence referring to “chronic airway disease” instead of COPD. This patient-completed questionnaire covers symptoms such as cough, phlegm, chest tightness, and breathlessness, and disease impacts including physical activity, confidence, sleep, and energy	Scores range from 0 to 40, with higher scores indicating a poorer chronic airway disease health status. Items are scored on a 6-point response scale, with a score of 0 representing the patient not experiencing the symptom or the impact at all and a score of 5 representing a maximal symptom or impact.
ACQ-5^Citation25	A 5-item questionnaire for assessing asthma control, completed by the patient based on recall of the past week. Questions relate to asthma symptoms	Each item is scored on a 7-point scale (0=no impairment; 6=maximum impairment). The items are equally weighted and the overall score is the mean of the seven items; between 0 (well controlled) and 6 (extremely poorly controlled)
SGRQ^Citation26	A 76-item questionnaire used to measure health status in patients with asthma and COPD	The total score is based on three domain scores: symptoms, activity, and impacts (on daily life). A decrease in score indicates improvement in health status
Investigator-completed scale
mMRC Dyspnea Scale^Citation27	A 5-point scale used to measure baseline functional impairment due to dyspnea attributable to respiratory disease by considering how daily activities such as walking and climbing stairs are impacted by breathlessness	This 5-point scale ranges from 0=breathless only with strenuous exercise to 4=too breathless to leave the house

Abbreviations: ACQ-5, Asthma Control Questionnaire-5; CAAT, Chronic Airways Assessment Test; CAT, COPD Assessment Test; COPD, chronic obstructive pulmonary disease; mMRC, modified Medical Research Council; SGRQ, St George’s Respiratory Questionnaire.

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