Treatment Trials in Young Patients with Chronic Obstructive Pulmonary Disease and Pre–Chronic Obstructive Pulmonary Disease Patients: Time to Move Forward

Fernando J Martinez; Alvar Agusti; Bartolome R Celli; MeiLan K Han; James P Allinson; Surya P Bhatt; Peter Calverley; Sanjay H Chotirmall; Badrul Chowdhury; Patrick Darken; Carla A Da Silva; Gavin Donaldson; Paul Dorinsky; Mark Dransfield; Rosa Faner; David M Halpin; Paul Jones; Jerry A Krishnan; Nicholas Locantore; Fernando D Martinez; Hana Mullerova; David Price; Klaus F Rabe; Colin Reisner; Dave Singh; Jørgen Vestbo; Claus F Vogelmeier; Robert A Wise; Ruth Tal-Singer; Jadwiga A Wedzicha

doi:10.1164/rccm.202107-1663SO

. 2021 Oct 21;205(3):275–287. doi: 10.1164/rccm.202107-1663SO

Treatment Trials in Young Patients with Chronic Obstructive Pulmonary Disease and Pre–Chronic Obstructive Pulmonary Disease Patients: Time to Move Forward

Fernando J Martinez ^1,^*,^‡,^✉, Alvar Agusti ^2,^3,^4,^5,^*, Bartolome R Celli ^6,^*, MeiLan K Han ^7,^‡, James P Allinson ^8,^‡, Surya P Bhatt ⁹, Peter Calverley ^10,^‡, Sanjay H Chotirmall ^11,^‡, Badrul Chowdhury ¹², Patrick Darken ¹³, Carla A Da Silva ¹⁴, Gavin Donaldson ^8,^‡, Paul Dorinsky ¹³, Mark Dransfield ⁹, Rosa Faner ¹⁵, David M Halpin ¹⁶, Paul Jones ¹⁷, Jerry A Krishnan ^18,^‡, Nicholas Locantore ¹⁹, Fernando D Martinez ^20,^‡, Hana Mullerova ²¹, David Price ^22,²³, Klaus F Rabe ^24,^25,^‡, Colin Reisner ²⁶, Dave Singh ²⁷, Jørgen Vestbo ²⁸, Claus F Vogelmeier ²⁹, Robert A Wise ³⁰, Ruth Tal-Singer ^31,^‖, Jadwiga A Wedzicha ^8,^‖,^‡

^¹Weill Cornell Medicine, NewYork-Presbyterian Hospital, New York, New York;

^²Catedra Salut Respiratoria and

^¹⁵Department of Biomedical Sciences, University of Barcelona, Barcelona, Spain;

^³Institut Respiratorio, Hospital Clinic, Barcelona, Spain;

^⁴Institut d’investigacions biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain;

^⁵Centro de Investigacion Biomedica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain;

^⁶Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts;

^⁷University of Michigan Health System, Ann Arbor, Michigan;

^⁸National Heart and Lung Institute, Imperial College, London, United Kingdom;

^⁹Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama;

^¹⁰Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, United Kingdom;

^¹¹Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore;

^¹²Savara Pharmaceuticals, Inc., Austin, Texas;

^¹³AstraZeneca, Gaithersburg, Maryland;

^¹⁴Clinical Development, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden;

^¹⁶Royal Devon and Exeter Hospital, Exeter, United Kingdom;

^¹⁷St. George’s University of London, London, United Kingdom;

^¹⁸University of Illinois, Chicago, Illinois;

^¹⁹Nimirga LLC, Durham, North Carolina;

^²⁰University of Arizona, Tucson, Arizona;

^²¹AstraZeneca, Cambridge, United Kingdom;

^²²Observational and Pragmatic Research Institute, Singapore;

^²³Centre of Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, United Kingdom;

^²⁴LungenClinic Grosshansdorf, Member of the German Center for Lung Research, Grosshansdorf, Germany;

^²⁵Department of Medicine, Christian Albrechts University Kiel, Member of the German Center for Lung Research Kiel, Germany;

^²⁶DevPro Biopharma, Basking Ridge, New Jersey;

^²⁷Medicines Evaluation Unit and

^²⁸Manchester University NHS Trust, Manchester, United Kingdom;

^²⁹Department of Medicine, Pulmonary and Critical Care Medicine, University of Marburg, Member of the German Center for Lung Research, Marburg, Germany;

^³⁰Johns Hopkins Medicine, Baltimore, Maryland; and

^³¹COPD Foundation, Washington, DC

^✉

Correspondence and requests for reprints should be addressed to Fernando J. Martinez, M.D., M.S., 1305 York Avenue, Box 96, Room Y-1059, New York, NY 10021. E-mail: fjm2003@med.cornell.edu.

Co–first authors.

^{^‡}

J.A.K. was Editor-in-Chief, F.J.M. and F.D.M. were Deputy Editors, M.K.H., P.C., S.H.C., G.D., J.A.K., and K.F.R. were Associate Editors, and J.P.A. was part of the Early Career Group of AJRCCM when this manuscript was submitted. Their participation complies with American Thoracic Society requirements for recusal from review and decisions for authored works.

^{^‖}

These authors contributed equally to this work.

^✉

Corresponding author.

PMCID: PMC8886994 PMID: 34672872

Abstract

Chronic obstructive pulmonary disease (COPD) is the end result of a series of dynamic and cumulative gene–environment interactions over a lifetime. The evolving understanding of COPD biology provides novel opportunities for prevention, early diagnosis, and intervention. To advance these concepts, we propose therapeutic trials in two major groups of subjects: “young” individuals with COPD and those with pre-COPD. Given that lungs grow to about 20 years of age and begin to age at approximately 50 years, we consider “young” patients with COPD those patients in the age range of 20–50 years. Pre-COPD relates to individuals of any age who have respiratory symptoms with or without structural and/or functional abnormalities, in the absence of airflow limitation, and who may develop persistent airflow limitation over time. We exclude from the current discussion infants and adolescents because of their unique physiological context and COPD in older adults given their representation in prior randomized controlled trials (RCTs). We highlight the need of RCTs focused on COPD in young patients or pre-COPD to reduce disease progression, providing innovative approaches to identifying and engaging potential study subjects. We detail approaches to RCT design, including potential outcomes such as lung function, patient-reported outcomes, exacerbations, lung imaging, mortality, and composite endpoints. We critically review study design components such as statistical powering and analysis, duration of study treatment, and formats to trial structure, including platform, basket, and umbrella trials. We provide a call to action for treatment RCTs in 1) young adults with COPD and 2) those with pre-COPD at any age.

Keywords: COPD, clinical trials, early, pre-COPD, young age

Chronic obstructive pulmonary disease (COPD) is a major global public health problem. Conventionally believed to be a self-inflicted disease owing to tobacco smoking that affects the elderly (1), recent research has shown that COPD is the end result of a series of dynamic and cumulative gene–environment interactions over the lifetime that go beyond smoking (2), can begin early in life (in utero, infancy, and/or adolescence) (3–6), and result in varying lung function trajectories (trajectome), several of which lead to COPD in adulthood (7–9) (Figure 1). This new understanding of COPD provides novel opportunities for prevention, early diagnosis, and intervention (10). This state-of-the-art review seeks to launch a call to action to investigators, funding agencies, industry, and regulators to initiate treatment trials in 1) young adults with COPD and 2) those with pre-COPD, which includes those with respiratory symptoms, abnormal imaging, and/or lung function without evidence of airflow limitation who may (or may not) develop COPD with time (11, 12).

Figure 1. — Examples of lung function trajectories from birth to death. The red shaded area highlights the population of young adults with chronic obstructive pulmonary disease to be included in treatment trials. Gray shaded areas indicate that these age limits are somewhat arbitrary (based on normal peak + plateau lung function), and therefore some age variability may be acceptable. Note also that this age range includes trajectories with normal peak lung function (100% reference) as well as those with reduced peak lung function (<80% reference) and that both can have a normal or an enhanced decline with time. For further explanations, *see* the main text.

Nosology

A first key step to this end is to avoid nosological confusion. Accordingly, we propose to adopt the following terminology (Table 1).

Table 1.

Nosology Used in This Review

Term	Definition
Early COPD	Biological term that indicates that the disease is near its beginning (at any age); requires validated biomarkers to be identified/quantified in clinical practice
Mild COPD	Functional term that indicates that the disease is associated with mild airflow limitation (at any age)
COPD in Young Patients	Age-dependent term that identifies a subpopulation of patients with COPD (FEV₁/FVC < 0.7) between 20 and 50 years of age (independent of the severity of airflow limitation present)
Pre-COPD	Individuals (of any age) who present chronic respiratory symptoms, with or without structural and/or functional abnormalities, in the absence of airflow limitation (FEV₁/FVC > 0.7) who may (or may not) develop persistent airflow limitation (i.e., COPD) over time
Disease activity	Biological term that relates to the level of activation of the pathobiological processes (endotypes) that cause the disease; it can ideally be identified and quantified by validated biomarkers (currently lacking in COPD)
Disease progression	Clinical term that refers to a progressive deterioration in an objective marker of pathology or lung function
Primary prevention	Aimed at preventing the disease before it occurs by eliminating exposures to risk factors and/or increasing resistance to disease should exposure occur
Secondary prevention	Aimed at reducing the impact of a disease that has already occurred by diagnosing and treating it as soon as possible to halt or slow its progress
Tertiary prevention	Aimed at mitigating the impact of an ongoing illness

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Definition of abbreviation: COPD = chronic obstructive pulmonary disease.

For further explanations, see the main text.

COPD

As defined by the Global Initiative for Chronic Obstructive Lung Disease, COPD is a disease “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 and influenced by host factors including abnormal lung development” (13).

Early COPD

According to the Merriam-Webster dictionary, “early” means “near the beginning of a process.” Because COPD can start early in life (3–5) and generally takes a long time to manifest clinically (8), defining whether someone suffers “early” COPD is difficult (14). Some studies have used “mild” airflow limitation as a surrogate for “early” disease (15). This assumption would be correct if all patients started their journey from a normal peak lung function in early adulthood, and COPD would have progressed similarly in all of them. Alas, this assumption is incorrect (Figure 1) (8). “Mild” (like moderate or severe) airflow limitation can occur at any age (Figure 1) and only describes the “severity” of airflow limitation. Therefore, we propose that “mild” should not be used to identify “early” COPD. Likewise, we recognize that mild airflow limitation may not always be COPD, at least according to the current definition of airway diseases. Finally, a biological “early,” related to the initial mechanisms that eventually lead to COPD, should be differentiated from a clinical “early,” which reflects the initial perception of symptoms, functional limitation, and/or structural abnormalities noted (16). Accordingly, we propose to use the term “early COPD” only to discuss “biological early.”

COPD in Young Patients

The term “young” directly relates to the age of the subject and may seem straightforward and less confusing. However, to some extent, “young” is also a value judgment that depends on the age of the observer and the part of the globe in which the individual lives, as life expectancy varies greatly in different parts of the world. For the discussion that follows, given that lung growth and development reach their peak at around 20–25 years of age and begin to decline at 45–50 years (17), we propose to operationally consider “young” patients with COPD as those included in an age range of 20–50 years (Figure 1). In population-based studies, these younger individuals have a higher prevalence of prior asthma diagnosis (18). It is anticipated that in young patients with COPD, preventive measures and pharmacological interventions may result in better outcomes than in older patients (10, 19, 20) and may slow down disease progression (10). Importantly, this age range can include patients who never achieved normal peak lung function in early adulthood and/or those with early accelerated lung function decline (Figure 1), which may have different underlying mechanisms (i.e., endotypes [21]) and may therefore require different therapeutic interventions (5, 22, 23).

Pre-COPD

The term pre-COPD has been recently proposed to identify individuals of any age who have respiratory symptoms with or without structural and/or functional abnormalities, in the absence of airflow limitation (FEV₁/FVC ⩾0.7), and who may (or may not) develop persistent airflow limitation (i.e., COPD) over time (11, 12). This term includes a heterogeneous population of patients. So far, several subtypes of pre-COPD have been reported. The best studied one includes patients with nonobstructive chronic bronchitis, in whom symptoms are associated with significant morbidity regardless of whether they ultimately progress to airflow limitation (11). Other, less well-studied subtypes of pre-COPD are subjects without airflow limitation who have emphysema detected with computed tomography (CT) (24), individuals with preserved ratio impaired spirometry (postbronchodilator FEV₁ <80% predicted and FEV₁/FVC ⩾0.70) (25), and subjects with low Dl_CO (26) or rapid FEV₁ decline (27). The natural history and potential response to treatment for these heterogenous conditions is unknown.

Disease Activity versus Disease Progression

These two terms are related but not synonymous. Disease “activity” relates to the level of activation of the pathobiological processes that cause the disease (14), whereas disease “progression” refers to a deterioration over time in an objective marker of pathology, such as by CT, or function. The relationship between disease “activity” and disease “progression” in COPD remains unclear. Disease activity is probably a necessary but insufficient condition for disease progression. For instance, a given patient may suffer frequent exacerbations (a clinical surrogate marker of an “active” disease”) without a clear deterioration in lung function (a marker of disease “progression”). We currently lack validated biomarkers to identify whether or not specific endotypes are “active” in COPD (28) and, as a result, disease “activity” in COPD is often estimated post hoc by evidence of disease “progression” (29). Of note, however, in older patients with moderate to severe COPD, persistent systemic inflammation has been associated with increased all-cause mortality and exacerbation frequency (30), and the use of inflammometry and multidimensional assessment to guide treatment improved several patient-related outcomes (PROs) at 3 months in a small pilot randomized controlled trial (RCT) (31). Whether these limited preliminary data apply to younger patients is unknown. Likewise, patients with milder airflow limitation appear to progress (in terms of FEV₁ decline) faster than those with more severe airflow limitation (32), so identifying biomarkers of disease activity associated with different lung function trajectories (Figure 1) would be of great value (33, 34). In any case, future treatment trials in young patients should ideally target individuals at risk of disease progression based on validated biomarkers of disease activity.

Primary, Secondary, and Tertiary Prevention

Primary prevention aims at preventing a disease before it occurs by eliminating exposures to risk factors and/or increasing resistance to it should exposure occur. Primary prevention of COPD is key in children and adolescents (Figure 1) but likely relates more to public health measures than to therapeutic interventions, although we acknowledge that boosting “catch-up” of impaired lung function in early life may deserve specific investigation (8, 24, 35, 36). Secondary prevention aims to reduce progression once disease has already manifested. This is, precisely, the goal of this call for action for treatment trials in young patients. Finally, tertiary prevention aims at reducing the impact of an ongoing illness, has been more frequently considered in the setting of COPD in older patients, and has been extensively investigated in previous RCTs.

Treatment Trials in Young Patients with COPD and Pre-COPD Patients

The discussion that follows focuses on treatment trials in young (20–50 years of age) adults with COPD or pre-COPD (any age). These trials are needed, as young patients with COPD or pre-COPD may already suffer a significant burden of disease (37, 38). In these patients, treatment cannot be neglected, although the scientific evidence supporting the best therapeutic alternatives has not been generated. In addition, it is likely that a therapeutic intervention in younger individuals with the drugs currently available, before advanced tissue destruction, multimorbidity, and effects of aging become clinically relevant, may be more effective (10) and may reduce/arrest disease progression. Finally, the combination of primary and secondary preventive measures aimed at avoiding all of those factors associated with low lung function in different age bins with appropriate, evidence-based treatment of younger patients with COPD has the potential to reduce the societal burden of disease, promote respiratory health, and eventually the development of COPD (39).

Although the results of large multicenter RCTs have driven our current understanding and management of COPD, they have historically faced a number of limitations (Table 2) (40–43). These and other considerations may also apply to future treatment trials in young patients and are discussed below.

Table 2.

Historical Factors Complicating Randomized Controlled Trials in COPD

1. Definition of the disease and its severity has been primarily focused on a single parameter (spirometry)

2. The paucity of regulatory accepted “qualified” intermediate efficacy endpoints and validated biomarkers

3. The nonnormal distribution of important trial outcomes

4. Differing patterns of disease progression

5. Slow FEV₁ decline, which is further compounded by dropout or death among the sickest

6. Disease heterogeneity: described as different phenotypes and endotypes (e.g., emphysema, airways disease, lung microbiome, neutrophilic vs. eosinophilic inflammation, aberrant tissue repair)

7. Variability of endpoints and their confounders (e.g., washout of background medications, diurnal variation, seasonal effect)

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Definition of abbreviation: COPD = chronic obstructive pulmonary disease.

Case Finding/Recruitment

In a recent large epidemiological study in China, the prevalence of COPD in adults aged 20–49 years was 16.4% in males and 7.4% in females (Figure 2) (44), so finding and recruiting these patients into an RCT may require a combined strategy. Although widespread population spirometric screening has not been traditionally advocated (45), targeted case finding approaches are promising (46). Indeed, there has been a recent proposal supporting the use of forced spirometry in the general population (even in children and adolescents) as a marker of not only respiratory diseases but also global health (47). Symptom-based instruments (e.g., COPD Population Screener [48], International Primary Care Airways Guideline [49], COPD Questionnaire [50], and Lung Function Questionnaire [51]) and PROs questionnaires (e.g., COPD Assessment Test [52], COPD Assessment in Primary Care to Identify Undiagnosed Respiratory Disease and Exacerbation Risk [53, 54], or COPD Assessment Test/Chronic Airways Assessment Test [55]) have been developed or adapted for case findings in patients with established COPD. Their utility in young patients is unclear, as most were developed and tested in those over 40 years of age. Mucus hypersecretion can be better identified using the symptoms component of the St. George’s Respiratory Questionnaire (SGRQ) or the phlegm question in the CAT rather than the Medical Research Council definition for chronic bronchitis (11, 56–59). Physical activity, measured by daily accelerometer recordings, is reduced in patients with COPD detected by spirometry screening (60), so PROs measuring physical activity (e.g., Clinical visit-PROactive Physical Activity in COPD [61]) could potentially be used to identify these patients. Primary care networks may be particularly crucial in identifying potential young patients from electronic medical records (62), either by identifying patterns of risk factors or biomarkers or in identifying symptoms before COPD is diagnosed (63). Finally, public advertising campaigns via traditional print or electronic media, social media campaigns, and collaboration with nonprofit advocacy organizations can be useful aids to boost patient recruitment. The power of the patient-led collaborative “Venture Philanthropy” effort by the Cystic Fibrosis Foundation (64) transformed Cystic Fibrosis from a highly mortal disease in early life to a disease that can be treated with precision (65). The COPD Foundation has recently launched a multidisciplinary collaborative initiative, COPD360Net, with the mission to support the development and adoption of novel digital health tools, medical devices, and therapeutics that treat COPD, prevent its progression, and improve the lives of patients with COPD and related chronic lung conditions at all stages of disease (Figure E1 in the online supplement). COPD360Net is currently seeking partners to conduct a collaborative platform trial in young patients with pre-COPD and nonobstructive chronic bronchitis.

Smoking Exposure/Status

Previous RCTs in COPD have studied (older) current or former smokers. As prior studies suggested that variation in smoking status impacted the range of lung function decline (66) and mortality (67), previous history and current active smoking should be carefully monitored and adjusted for in future therapeutic trials. This is particularly relevant, as smoking cessation should be encouraged given its beneficial effects (66, 68) and is facilitated by numerous interventions (69). Notably, about one-third of patients with COPD around the world are never-smokers (70), and many other environmental risk factors are associated with low lung function through life. For example, early studies of electronic cigarette exposure have suggested that it results in altered pulmonary function and structure (71, 72). Similarly, occupational exposure and air pollution (73, 74) have been associated with respiratory disease and should be considered in study design, conduct, and analyses. It is imperative to study young never-smokers with COPD (5, 35, 75–79) exposed or not to other known (indoor pollution) or unknown environmental factors as well as those impacted by abnormal lung development before the age of 20.

Nonrespiratory Medications

It is possible that nonrespiratory medications may influence the development of COPD or its complications. For example, it remains unclear if statin therapy can favorably influence noncardiovascular complications of COPD (80). Preclinical data with metformin have suggested improvement in the development of emphysema, with cohort studies providing variable clinical correlates (81, 82). It will be important during therapeutic trials to carefully record nonrespiratory medications.

Outcome Measures

The outcome measure of any trial should be reproducible over time, have known biological variability, be responsive to treatment, and be relevant to the targeted trait. In young patients, the following outcomes could be considered.

Lung function

FEV₁ is a simple, relatively inexpensive, reproducible measure recognized as an outcome measure by regulatory authorities, including the U.S. Food and Drug Administration and the European Medicines Agency. Furthermore, FEV₁ decline has been traditionally used as a measure of disease progression in COPD (83). However, in young patients, there are important additional considerations. First, in these patients, a reduced FEV₁ value may result from abnormal lung development and/or early enhanced decline (Figure 1) (7), and, in the absence of historic data, these two trajectories are difficult to define (7). Second, absolute decline in FEV₁ is faster in patients with milder airflow limitation (32) who might be younger. If so, this may facilitate studying the impact of interventions on FEV₁ decline in younger patients. Absolute FEV₁ decline is also subject to bias from starting lung size, which is influenced by factors such as height and sex. Table 3 enumerates the change in FEV₁ among RCTs targeting patients with mild to severe COPD with average ages of 50–65. A systematic review of RCTs suggests that a 5.0 ml/yr reduction (95% confidence interval, 0.8–9.1 ml/yr) has been suggested in the rate of FEV₁ decline in active treatment arms compared with placebo (84). Arguably, younger individuals show faster FEV₁ decline (32) because they have more lung function left to lose, and this might make it easier to study the impact of interventions on FEV₁ decline. However, a single FEV₁ measurement is not a good predictor of the future FEV₁ trajectory, and rapid FEV₁ decliners can only be identified in retrospect (85, 86). Thus, it may be more pragmatic to enrich the study population using surrogate markers of accelerated FEV₁ decline (87), including chronic mucus hypersecretion (88), prior frequent exacerbations (32, 89), or imaging features as described below.

Table 3.

Rate of FEV₁ Decline (ml/yr) Study Results

Study	Length (yr)	n	Mean FEV₁ (%)	Mean Age	Active	Placebo	Difference (95% CI)	Estimated Effective SD	Implied n/Group for 90% Power to Detect (2)
Study	Length (yr)	n	Mean FEV₁ (%)	Mean Age	Active	Placebo	Difference (95% CI)	Estimated Effective SD	12 ml/yr Difference	15 ml/yr Difference
SUMMIT (138)	1–4^*	16,485	60	65	38	46	−8 (−15, −1)	154	3,462	2,216
Zhou and colleagues (15)	2	841	78	64	29	51	−22 (−37, −6)	110	1,766	1,131
Copenhagen CHS (166)	3	290	86	59	45	42	3 (−13, 19)	69	695	445
EUROSCOPE (167)	3	1,277	77	52	57	69	−12 NS	UNK	NS	NS
TORCH (168)	3	6,112	44	65	42/43/39	55	−16 (−25, −8)	113	1,864	1,193
BRONCUS (169)	3	523	57	62	56	47	8 (−10, 25)	97	1,374	879
ISOLDE (170)	3	751	50	64	50	59	−9 (−3, 20)	76	843	540
Lung Health Study II (171)	3.5–4.5^*	1,116	68	56	44	47	−3 (−11, 5)	70	716	458
UPLIFT (40, 172)	4	5,993	48	65	40	42	−2 (−6, 2)	72	757	485
Lung Health Study I (68)	5	5,887	78	48	30	66	−31 UNK	57	475	304

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Definition of abbreviations: BRONCUS = Bronchitis Randomized on NAC Cost-Utility Study; CI = confidence interval; COPD = chronic obstructive pulmonary disease; Copenhagen CHS = Copenhagen City Heart Study; EUROSCOPE = European Respiratory Society Study on Chronic Obstructive Pulmonary Disease; ISOLDE = Inhaled Steroids in Obstructive Lung Disease in Europe; NS = not stated; SUMMIT = Study to Understand Mortality and Morbidity in COPD; TORCH = Towards a Revolution in COPD Health; UNK = unknown; UPLIFT = Understanding Potential Long-Term Impact on Function with Tiotropium.

Variable length follow up.

Longer trials extending beyond 3 years (the minimum currently required by regulators) reduce FEV₁ decline variability and, accordingly, the sample size required. Table 3 highlights that trials to evaluate rate of decline have generally been long in duration and that longer trials reduce variability. The common approach to conduct a 3-year trial still requires a relatively large sample. For example, if we assume an SD of 100 ml/yr and wish to detect a difference of 12 ml/yr, approximately 1,500/group are required to be 90% powered for α = 0.05. If instead an SD of 80 ml/yr and effect size of 15 ml/yr are assumed, then this requirement for 90% power drops to approximately 600/arm. The advantage of longer trials needs to be counterbalanced by the challenge of retaining sufficient subjects and avoiding issues with biases introduced by differential withdrawal. As such, it will be key to carefully and prospectively define the estimand (90) that we are trying to estimate with consideration of how subjects who prematurely discontinue the intervention and/or leave the trial will be handled. In any case, FEV₁ decline should be measured in studies of young patients to characterize the population and to evaluate potential disease modification. Other lung function measures, such as novel spirometric parameters (91–93), inspiratory capacity, body plethysmography (to quantify hyperinflation), oscillometry, and Dl_CO, may also deserve investigation in this population.

Symptoms/health status/PROs

The CAT is likely to be the preferred option in most cases, irrespective of whether participants have been recruited on the basis of mucus hypersecretion, breathlessness, or exercise limitation, as its multidimensional nature will capture changes in each of these features. Unless study participants are symptomatic, symptom scores, PROs, and health-related quality of life measures will not be able to detect improvement with interventions, as CAT score values <10 are not associated with a noticeable effect on daily life (94). Yet, available evidence shows that young patients are not asymptomatic (37) and that patients with COPD with mild airflow obstruction (not necessarily young) do have marginally elevated SGRQ and CAT scores (57, 58, 95, 96), suggesting that there is potential for improvement. In fact, a trial in patients at an average age of 65 years old with COPD and mild to moderate airflow limitation showed an effect on CAT scores (15), and a subgroup analysis of the Early MAXimisation of bronchodilation for improving COPD stability (EMAX) study (mean age, 65 years) showed that the magnitude of symptomatic benefit of dual bronchodilator compared with monotherapy was similar in patients with CAT scores of ∼10 or ∼20 (97). Measures of physical activity (e.g., Daily-PROactive Physical Activity in COPD [61]) may also be considered. Bronchodilator trials in Global Initiative for Chronic Obstructive Lung Disease grade 1 patients showed variable results (98, 99). What constitutes a minimal clinically important difference (MCID) in patients with a low level of symptoms (100, 101), and whether therapeutic interventions in these patients would have a large enough effect to be detected, are uncertain. In summary, the optimum symptom score, PRO, or health-related quality of life measure to use in a particular trial will depend on the inclusion criteria. Lastly, measures of healthcare use should also be considered as relevant endpoints given their impact on patients and the healthcare system (102, 103).

Exacerbations

Exacerbations of COPD (ECOPD) remain a central, valid, and important tenet for the adequate assessment of clinical disease and therapeutic needs, and for RCTs, they represent an important outcome measure (18, 102, 104, 105). Their prevalence and severity in young patients are still not well defined, but they do indeed occur (37). ECOPD in young individuals may be influenced by symptom reporting. This, in turn, may be subject to individual variability in perception (106) and further prejudiced by societal and cultural norms for interpreting and reporting respiratory symptoms as well as by local primary care setup and its interface with tertiary hospitals. We do not know if frequent “exacerbator” phenotypes exist in young patients, so more epidemiological work on this group would assist in developing interventional studies.

Lung imaging

Imaging biomarkers can be used to identify both individuals at high risk for disease progression and endpoints in treatment trials in young patients. In particular, CT metrics of small airway abnormality may be most helpful to enrich the study population with young patients at higher risk for disease progression. Density-based metrics have the strongest supportive data for reproducibility, making them attractive as clinical endpoints, although they may be relevant only for specific therapeutic interventions.

Several airway abnormalities on chest CT scans correlate with dyspnea, quality of life, and functional capacity and predict lung function decline (Table E1) (57, 107). Pi10, a measure of the thickness of medium-size airways, relates to incident COPD over 3–5 years (108, 109) and is sensitive to change over time (110), even over short follow-up periods (111). Parametric response mapping (PRM) matches inspiratory and expiratory images to estimate nonemphysematous gas trapping or functional small airways disease and also predicts lung function decline (112, 113). The normal density E to I Ratio, another measure of gas trapping owing to small airway disease, is also associated with FEV₁ decline (114). Total airway count correlates with the number of terminal bronchioles on micro-CT (115) and is associated with FEV₁ decline, especially in those with mild to moderate disease (116). Airway fractal dimension, a measure of the complexity of airway branching, is lower in patients with more severe airflow limitation and is also associated with FEV₁ decline (117). Finally, the airway surface area–to–volume ratio reflects a combination of airway loss and airway narrowing, is associated with FEV₁ decline, and can be used to phenotype individuals into those with predominant loss versus narrowing of airways (118, 119).

Density-based measures of emphysema are also associated with lung function decline (120, 121) and mortality (117, 119, 122–125). CT emphysema progresses over time, particularly in current smokers (126, 127). The lung density metric is already in use in α-1 antitrypsin deficiency, a known cause of COPD in the young, as the primary endpoint to assess the impact of interventions targeting attenuation of disease progression (128, 129). The correlation between emphysema and lung function is weaker compared with metrics of small airway abnormality (130, 131), but the reproducibility for PRM emphysema is higher (132). This can allow a smaller sample size in RCTs (133). Finally, both PRM emphysema and PRM for functional small airways disease have histologic validation with human lung tissue (134). Studies using CT measures of lung biomechanics suggest that once emphysema is initiated, mechanotransduction can accelerate further development of emphysema; therefore, CT indices that assess alterations in lung biomechanics have been associated with FEV₁ decline and BODE (125, 135). Qualitative assessment of mucus plugs on chest CT has been associated with ECOPD (136).

Other imaging techniques also hold promise. For instance, polarized gas magnetic resonance imaging can identify abnormalities in diffusion and ventilation, which may precede the development of clinically overt disease (137).

Mortality

Several issues need consideration in relation to mortality as a potential outcome in future studies of young patients. First, the comparison of death rates in major COPD trials in the 2000s (40, 43) and 2010s (138) shows that, fortunately, the risk of mortality in COPD is decreasing and may hopefully continue to decrease in the near future. Second, life expectancy varies widely across the world, so geographical variations will have to be considered in any future study in young patients. Finally, death rates are substantially lower in younger (20–50 years) than older patients with COPD included in previous studies (40, 43, 138), and this may have a direct impact on sample size estimation. For instance, in the United States in 2017, the death rate in the 35–54 age group was about 300 per 100,000 persons (139). If we hypothesize that COPD may increase this risk two- or threefold, estimated deaths in a population of young patients would be in the range of 600 to 900 deaths per 100,000 in a given year. Then, if a given therapeutic intervention was to reduce mortality in these patients by 30% (likely an optimistic estimation), an RCT with mortality as a primary endpoint would require recruiting about 80,000 patients, significantly more than those recruited in the Towards a Revolution in COPD Health (TORCH), Understanding Potential Long-Term Impact on Function with Tiotropium (UPLIFT), and Study to Understand Mortality and Morbidity in COPD (SUMMIT) trials, which randomized from 6,000 to 16,000 patients (40, 43, 138). These considerations make mortality an unlikely useful outcome measure in future treatment trials in young patients.

Composite endpoints

A composite endpoint combines different individual endpoints to increase the frequency of events, allowing RCTs to be conducted with fewer participants and/or to be shorter. A composite endpoint also enables different aspects of a disease to be evaluated together, potentially providing a broader view of the impact of a therapeutic intervention, and can be used to reduce bias caused by subjects who prematurely discontinue. The components of a composite endpoint need to be carefully selected to be sufficiently independent and of similar clinical relevance. The frequency of each component should ideally be similar so that more frequently occurring components do not dominate. Alternatively, each component can be weighted differently. For instance, in COPD trials in older patients with severe COPD, although ECOPD is likely more frequent than death, both could be components of a potential composite endpoint. In contrast, the lesser anticipated mortality of young patients suggests that such a composite endpoint may be even more dominated by ECOPD, even if these events are less prevalent than in older patients with COPD. A post hoc analysis of data from the UPLIFT trial of 5,992 patients with COPD randomized to receive tiotropium versus usual care studied over 4 years showed that a composite index consisting of death, respiratory failure, hospitalized exacerbations, and trial dropout owing to COPD worsening could reduce the number of patients needed to achieve a significant outcome by half (140).

The clinically important deterioration (CID) composite endpoint, which combines worsening of PROs and FEV₁ with ECOPD, was designed for short COPD clinical trials (141), and several studies showed significant treatment differences (142–144). Furthermore, longer studies demonstrated that CID events during the first 6 months of the study predict later mortality (145–147), suggesting that pharmacological interventions that modify CID frequency in short-term trials may have longer term benefits. The use of CID in studies in young patients needs to consider several aspects. It is unclear if the MCID threshold values determined in older patients (4-unit worsening for SGRQ and 100-ml decrease for FEV₁) are valid in younger patients (141). Likewise, the frequency and variability of CID components varies between cohorts with different characteristics, so they need to be established in a cohort of young patients, as they dictate the sample size calculations of future studies. In summary, CID provides a framework for a potential composite endpoint in young patients, but methodology work is needed to identify the most appropriate components and define appropriate MCID thresholds. Other potential composite endpoints to consider in this population include the Early Clinically Important Improvement (148) and COPDCompEx (see above) (149). An alternative to using a composite endpoint would be to jointly model the relevant endpoints that indicate deterioration (150), an approach that has been used in oncology trials (151).

Treatable Traits, Endotypes, and Biomarkers

As COPD is complex and heterogeneous, its clinical management requires a personalized approach. To this end, a management strategy based on treatable traits (TTs) has been proposed (152). TTs can be recognized based on their clinical characteristics (i.e., phenotypes) and/or through validated biomarkers of specific pathobiological mechanisms (i.e., endotypes) in the pulmonary, extrapulmonary, and behavioral/environmental domains (152). TTs can coexist, interact, and change with time (spontaneously or as a result of treatment) in the same patient (152). Because management guided by TTs can improve clinical outcomes (31), the design of future treatment trials in young patients needs to consider their presence or absence. Likewise, it should be noted that endotypes may vary with age, so they may differ in young and older patients with COPD, and improved understanding derived from ongoing research in young individuals may inform future treatment guidelines.

A promising biological marker is circulating eosinophils. RCTs in patients with moderate to very severe COPD have shown that higher blood eosinophil counts at baseline are associated with greater benefits from inhaled corticosteroids (ICS) (153). This biomarker is now used in clinical practice to guide ICS use in patients with a history of exacerbations (154). Bronchoscopy and sputum studies in patients with COPD have demonstrated that higher blood eosinophil counts are associated with increased lung eosinophil numbers and a profile of T2 inflammation, providing an explanation for the differential ICS effect (155, 156). Furthermore, lower blood and sputum eosinophils are associated with greater presence of proteobacteria (157, 158), with increased bacterial infections and pneumonia observed in these individuals (159). Clinical trials in younger patients with COPD may be able to use blood eosinophil counts to select subgroups with distinct inflammation and microbiome profiles, and there may be considerable potential for ICS or other interventions targeting T2 inflammation in younger patients with COPD with higher eosinophil counts. It is hoped that with improved understanding of the biological underpinnings of COPD in young individuals or those with pre-COPD, therapeutic approaches to be tested will be targeted to specific TTs.

Type of Intervention

Pharmacological interventions are likely to be central in treatment trials of young adults with COPD, but other types of intervention may also be considered, alone or in combination with drug interventions. For instance, smoking cessation measures will have to be incorporated in any study design, even to get the approval of institutional review boards. Likewise, the promotion of healthy a lifestyle (exercise, diet, sleep, and inhalational substance avoidance) will have to be considered as well.

Placebo or Comparator

Approved treatments for COPD do not have a lower age limit, but the scientific evidence supporting them has been generated in older populations. Thus, young patients are often treated without evidence for their effectiveness in COPD. As there are no specific approved treatments for COPD in young patients, there is no age-specific standard of care comparator. On the other hand, many currently available treatments are used in younger patients with asthma, and the use of a placebo may prove challenging depending on the agent being tested.

Statistical Power

Because of the relative lack of data on outcome measures in young patients, statistical power calculations will rely on information from observational cohorts (such as Early COPD in the United Kingdom; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints [ECLIPSE], COPD Genetic Epidemiology [COPDGene], or SPIROMICS Study of Early COPD Progression [SOURCE] in the United States; Chronic Airways Diseases Early Stratification [CADSET] in Europe [160]; and TRAIT in Japan [161]) and consortia that include a proportion of young patients (Table 4), electronic medical records. Blinded sample size reassessment/adaptive approaches and better define clinical trials duration. Likewise, the expected treatment effect sizes are not well established, although the expectation is that treatment differences might be greater in younger patients with (presumably) milder airflow limitation.

Table 4.

Partnerships That May Enable Treatment Trials in Young Patients

Organization	Contribution
Professional organizations	Individuals at risk based on occupational exposure (e.g., firefighters, veterans, farm workers)
Primary care providers	Identify individuals at risk based on symptoms and risk (or early life events)
Birth cohorts (population based) with long longitudinal follow up	Risk predictors, biomarkers, participants
Population-based cohorts with longitudinal follow up	Risk predictors, biomarkers
Pharmaceutical industry	Partner on platform trials, shared risk
International scientific multidisciplinary team	Collaborate on trial design and implementation
Patient advocacy groups	Coordinate platform trials

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Platform Trials

There is increasing interest in developing innovative approaches to enhance efficiency of clinical trials while testing numerous questions at the same time; master protocols such as umbrella (multiple targeted therapies in the context of a single disease), basket (study a single targeted therapy in the context of multiple diseases or disease subtypes), and platform (multiple targeted therapies in the context of a single disease in a perpetual manner) trials are such an approach (162). Given potential heterogeneity in patient populations, platform trials may reflect a potential alternative to consider, as they can invoke adaptive designs in which progress is periodically reassessed, and participants are reallocated from ineffective treatments to contribute to the overall outcome (163). Master protocol approaches, including platform trials, have been principally used in oncology (64) but have seen a tremendous increase in the setting of the coronavirus disease (COVID-19) pandemic (164). An initial exploratory study in young patients could be done using a master protocol design, which offers the advantage of evaluating multiple therapies (162). This approach would benefit from collaborations among multiple stakeholders successfully used in the COVID-19 era (165), including industry partners and regulatory agencies.

Maintaining Participant Commitment in Long Clinical Trials

Younger patients with COPD may be less motivated to participate in RCTs, as they are likely to be employed and caring for a young family, unlikely to be symptom limited, and more likely to relocate. Hence, developing a strong relationship with participants will be key, as will be conducting trials through mechanisms that have broad geographic reaches (Table 4). Although the primary outcome assessments are likely to be clinic based, the use of digital health technology for interim assessments, monitoring trial medication adherence, and digital trial communication may aid. Regular participant contact to review symptoms and provide updates on trial progress and appropriate subject compensation will be important to reduce dropouts during follow up. Many outcomes can be followed using appropriately anonymized electronic medical records that enhance the quality of the data and assess an intervention’s cost-effectiveness.

Future Steps

It is clear that earlier intervention in younger patients with COPD or those at risk with pre-COPD will be a crucial next paradigm in the management of this impactful disorder. The most critical next steps now involve the design and development of specific RCTs in individuals with young COPD and pre-COPD. Table 5 enumerates potential issues and approaches to consider in their design.

Table 5.

Future Steps in the Design and Conduct of Intervention Studies of Young Patients with COPD or Those at Risk with Pre-COPD

	Young Patients with COPD	Pre-COPD
Potential outcomes to explore	• Rate of FEV₁ decline • Time to first COPD exacerbation	• Time to onset of COPD • Time to worsening in CAT (1 point) or SGRQ (4 points)
Study duration	• 3 yr	• 3–5 yr
Interim analysis at 6–12 mo (to assess dropping therapy arms and/or extending trial duration/increase sample size)	• Rate of FEV₁ decline • Time to first COPD exacerbation • CAT change • Composite outcomes^*	• Rate of FEV₁ decline • CAT change • E-RS: COPD • Others (impulse oscillometry and/or lung imaging: airways disease parameters; HCRU events; CompEx COPD) • Composite outcomes^*
Potential intervention arms	Currently approved medications for COPD	Currently approved medications for COPD as well as novel agents capable of modifying disease progression
Placebo control	No (as these are currently approved medications for airflow limitation with no age limits)	Yes (as these medications are not approved for this indication)
Study population as per the definition in the text (plus some other potential characteristics to consider in the study design to enrich the population studied)	• CAT score >10 • A respiratory HCRU event in 2 of the past 3 yr • Biomarker enrichment^†	• Individuals with NOCB symptoms as defined using the CAT or SGRQ • A respiratory HCRU event in the past 24 mo • Subjects with rapid FEV₁ decline • Biomarker enrichment^†

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Definition of abbreviations: CAT = COPD Assessment Test; COPD = chronic obstructive pulmonary disease; E-RS = Evaluating Respiratory Symptoms in COPD tool; HCRU = health care resource utilization; NOCB = nonobstructive chronic bronchitis; SGRQ = St. George’s Respiratory Questionnaire.

Such as clinically important deterioration examining time to FEV₁ decline, exacerbation, or symptom worsening.

^{^†}

Circulating eosinophils and microbial assessments (see the main text).

Conclusions

Designing treatment trials in young patients and patients with pre-COPD is complex. However, the barriers mentioned herein can be overcome, and the potential rewards in terms of knowledge and improved health by conducting successful trials are likely substantial. Now is the time to refine an approach to a collaborative initiative to modify the course of the third leading cause of death in the world and a significant cause of morbidity globally. This requires commitment from industry and government funders and partnerships among diverse international stakeholders to implement platform trials using harmonized methodology and standard outcome measures that will generate robust data. These can be integrated to develop evidence-based personalized preventive and therapeutic interventions that modify disease progression based on risk factors and/or TTs (152). Working together and acting earlier in young patients and patients with pre-COPD (10) can reduce the global burden of COPD (39).

Footnotes

Supported by NIH/NHLBI grants 1R01 HL136682, U01 HL137880, R01 HL 182622, and P01 HL114501 (F.J.M.).

Author Contributions: F.J.M., A.A., B.R.C., R.T.-S., and J.A.W. prepared the first version of manuscript and finalized the last version. F.J.M., A.A., B.R.C., M.K.H., J.P.A., S.P.B., P.C., S.H.C., B.C., P. Darken, C.A.D.S., G.D., P. Dorinsky, M.D., R.F., D.M.H., P.J., J.A.K., N.L., F.D.M., H.M., D.P., K.F.R., C.R., D.S., J.V., C.F.V., R.A.W., and R.T.-S. wrote versions of key sections, reviewed, and approved the final version.

This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org.

Originally Published in Press as DOI: 10.1164/rccm.202107-1663SO on October 21, 2021

Author disclosures are available with the text of this article at www.atsjournals.org.

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PERMALINK

Treatment Trials in Young Patients with Chronic Obstructive Pulmonary Disease and Pre–Chronic Obstructive Pulmonary Disease Patients: Time to Move Forward

Fernando J Martinez

Alvar Agusti

Bartolome R Celli

MeiLan K Han

James P Allinson

Surya P Bhatt

Peter Calverley

Sanjay H Chotirmall

Badrul Chowdhury

Patrick Darken

Carla A Da Silva

Gavin Donaldson

Paul Dorinsky

Mark Dransfield

Rosa Faner

David M Halpin

Paul Jones

Jerry A Krishnan

Nicholas Locantore

Fernando D Martinez

Hana Mullerova

David Price

Klaus F Rabe

Colin Reisner

Dave Singh

Jørgen Vestbo

Claus F Vogelmeier

Robert A Wise

Ruth Tal-Singer

Jadwiga A Wedzicha

Abstract

Figure 1.

Nosology

Table 1.

COPD

Early COPD

COPD in Young Patients

Pre-COPD

Disease Activity versus Disease Progression

Primary, Secondary, and Tertiary Prevention

Treatment Trials in Young Patients with COPD and Pre-COPD Patients

Table 2.

Case Finding/Recruitment

Figure 2.

Smoking Exposure/Status

Nonrespiratory Medications

Outcome Measures

Lung function

Table 3.

Symptoms/health status/PROs

Exacerbations

Lung imaging

Mortality

Composite endpoints

Treatable Traits, Endotypes, and Biomarkers

Type of Intervention

Placebo or Comparator

Statistical Power

Table 4.

Platform Trials

Maintaining Participant Commitment in Long Clinical Trials

Future Steps

Table 5.

Conclusions

Footnotes

References

ACTIONS

PERMALINK

RESOURCES

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