Protocol for the air purification for eosinophilic COPD study (APECS): a randomised controlled trial of home air filtration by HEPA

Study design

This will be a double-blinded, randomised controlled clinical trial, in which participants will be equally divided into the active or sham (placebo) group. Beth Israel Deaconess Medical Centre (BIDMC) of Boston, MA, will be the primary study site. Recruitment will be conducted at BIDMC and several Boston area hospitals. The study will begin in March 2021 with an estimated completion in June 2025.

The study will consist of two clinic visits at the BIDMC Clinical Research Centre (study entry visit and study exit visit at 12 months postrandomisation) and three home visits (at the time of randomisation, at 7 days and 6 months postrandomisation). The first home visit (day 0) at which participants will be randomised (and receive two real or sham air purifiers) will occur approximately 3 months after the first clinic visit at BIDMC. All study participants will provide two baseline 7-day air quality measurements (at 3 months preintervention and the week prior to randomisation) and three air quality measurements postrandomisation during the time period when the real versus sham air purifiers are in the home (at 7 days, 6 months and 12 months). Figure 1 provides an overview of the study visit timeline with tests that will be performed at each visit.

Figure 1

Study design for air purification trial in eosinophilic COPD (n=160). For each exposure assessment, a 7-day air sample will be collected for particle mass by gravimetry, elemental analysis of PM_2.5 by X-ray fluorescence and black carbon (BC) by light transmission. COPD, chronic obstructive pulmonary disease; HEPA, high-efficiency particulate air; 6MWT, 6-Minute Walk Test; NELF, nasal epithelial lining fluid; SGRQ, St. George’s Respiratory Questionnaire.

The treatment assignments will be generated by the data coordinating centre at Boston Children’s Hospital (BCH) using permuted block randomisation (with block sizes of 8 to ensure balance by season). On day 0, a designed unblinded BIDMC staff member will be informed by secure email of the intervention status and selects either two active or two sham air purifiers to place in the participant’s home, one in the living room and one in the bedroom. The actual allocation must not be disclosed to the study participant or any other study personnel, nor should there be any written or verbal disclosure of the allocation code (stored at BCH) in any of the corresponding study documents. The intervention (active) air purifier is a CowayAirmega 400S True HEPA Air Purifier, which captures particles down to 0.1 µm in size and is designed to accommodate rooms up to 1560 square feet. Sham Coway filtration devices are engineered by the Harvard School of Public Health to replicate the sound and appearance of a functional filtration device. All health measurements will be obtained by a research assistant or research nurse who is blinded with respect to intervention status.

Participants and recruitment

Potentially eligible participants will be screened from the electronic medical record using the inclusion and exclusion criteria listed in box 1. Potential participants will then be contacted by phone or mail, after which a member of the study team will complete the screening process by phone. Potentially eligible participants who do not meet eosinophil criteria based on clinical laboratory testing obtained in the previous year will be invited to have a screening blood test to determine study eligibility (eosinophil count >150 cells/µL or >0.15 x 10⁹/L). Participants meeting all study entry criteria who wish to participate in the trial will complete informed consent via phone or in person with research staff prior to receiving the air sampler before the BIDMC entry visit (figure 1).

Participant engagement will be maintained through monthly survey questionnaires (online or by phone) and the five study visits. In addition, the participants will be compensated a total of $450 by study completion. To maintain retention, there will be a 3-month baseline run-in phase during which we will assess if participants are able to complete the monthly questionnaires and schedule their first home visit. Participants unable to complete these assessments will not undergo randomisation or remain in the study. We will aim to recruit 160 participants with eosinophilic COPD following the criteria below. Exposure and outcome measures at each visit are shown in table 1.

Exposure assessments

Five indoor air samples will be collected 1 week before each visit using a calibrated stationary preassembled air sampler, the Harvard PRPS99, operated at 5 L/min. It will collect fine, coarse and large particles in a single device, with impaction stages with 50% cut points at >10, 2.5–10 and <2.5 µm.20 Teflon filters and polyurethane foam (PUF) discs will be equilibrated and weighed before and after sample collection on an electronic microbalance (Model MT-5, Mettler Toledo, Rainin LLC, Oakland, California, USA) in the controlled temperature and humidity lab at the Harvard School of Public Health, after preparation under a clean air positive flow hood. We will measure the 7-day average mass concentration of PM_2.5, PM_2.5–10 and PM₁₀₊ in µg per m³ of air sample. The black carbon (BC) concentration on the Teflon filter will be determined by the SootScan OT21 Transmissometer (Magee Scientific, Berkeley, California, USA).21 22 Trace elemental concentrations will be measured from the Teflon filter using an energy-dispersive X-ray fluorescence (EDXRF) analyzer (Epsilon 5, MarvernPanalytical, UK).

Settled dust will be collected from the participant’s living and bedroom by vacuuming approximately 100 cm squared (1 US square foot) area for 2 min. This will be performed twice in the bedroom and twice in the living room at randomisation and 6 months postrandomisation. Samples will be collected into Dustream collection filters and tubes (Indoor Biotechnologies #DU-FL-2, Charlottesville, Virginia, USA)23 24 and stored at −80°C.

To document participant activity patterns and time spent outside the home, we will administer a brief questionnaire every 3 months to assess where participants typically spend their time (eg, home, work, commuting and outdoors) during weekdays and weekends. We will also assess exposure to pets every month.

Clinical trial outcomes

The primary trial outcome will be the change in forced expiratory volume in 1 s (FEV₁). The secondary outcomes will include the changes in (1) health status, quantified using the St. George’s Respiratory Questionnaire (SGRQ)25 26; (2) respiratory symptoms, measured through the Breathlessness, Cough and Sputum Scale (BCSS)27; and (3) functional capacity assessed by the 6-Minute Walk Test (6MWT) (online supplemental table 1).28–30 Other outcome measures will include nasal inflammatory mediators measured in the nasal epithelial lining fluid (NELF) by nasosorption.31 32

Health measurements

Questionnaire assessments

The change in health status will be quantified using the SGRQ, a validated 50-item questionnaire scored from 0 to 100, with higher scores indicating more health impairment, with a 3-month recall that measures respiratory symptoms, limitations in daily life and perceived well-being in patients with COPD.25 26 SGRQ will be administered via electronic questionnaire at baseline (3 months before intervention and on the day of intervention) and postintervention (at 6 months, 9 months and 12 months). The change in respiratory symptoms will be measured monthly through the Breathlessness, Cough and Sputum Scale (BCSS) administered electronically. The BCSS has been validated to assess the severity of COPD symptoms (breathlessness, cough and sputum)27 and is scored between 0 and 12, with higher scores indicating greater symptom severity. The Modified Medical Research Council (mMRC) Dyspnoea Scale will also be administered every 3 months to ask participants to describe disability due to breathlessness.38 In addition, a COVID-19 questionnaire will be administered every 3 months to ask about a COVID-19 diagnosis or treatment in the last 3 months. Each month, we also ask about the severity of COPD symptoms, any new healthcare diagnoses, any hospitalisations and any changes to medications.

Power calculations

We plan to enrol 160 participants with eosinophilic COPD. For the primary outcome of change in forced expiratory volume in 1 s (FEV₁), we estimated power using a simulation-based approach that repeatedly generated data under a linear mixed model applied to all of the data collected for each individual, including two baseline and three postrandomisation lung function measurements. We calculated the proportion of time; we rejected the null hypothesis of no intervention effect within this modelling framework. With an alpha=0.05 and a total of n=160 participants, we estimate that we will have 80% power to detect an intervention effect of at least 20 mL in FEV₁ and 90% power to detect a difference of 24 mL in FEV₁ due to the intervention. If we have a dropout rate of 12.5%, we will have 80% power to detect an intervention effect of at least 22 mL and 90% power for an effect of at least 26 mL in a completers-only analysis among 140 participants. We anticipate that our 1-year indoor air quality intervention will result in a difference in FEV₁ that is greater than the effect associated with variability in daily and annual air pollution levels in observational studies.39–42 Still, we are adequately powered to detect an effect size as small as what is reported in these studies.

For our secondary outcome of change in health status measured by SGRQ, with an alpha=0.05, a total of n=160 participants (80 per arm) and SD of SGRQ change of 8.7,17 we will have 80% power to detect a 3.9-point difference and 90% power to detect a 4.5-point difference in SGRQ when testing the group postrandomisation effect in a linear mixed model framework. If we have a dropout rate of 12.5%, we will have >80% power to detect an intervention effect of at least 4.2 points and 90% power to detect a 4.8-point difference in a completers-only analysis among 140 participants. Our true power will be even higher than this due to the repeated measures of SGRQ (two baseline and two postrandomisation) in our study. For clinical trials in COPD, a mean SGRQ change score of 4 units is considered a valid threshold of beneficial treatment.43

Data analysis plan

Our primary analysis will contrast changes in outcome levels in the HEPA intervention and control (sham) arms. For our primary outcome of FEV₁, we will obtain two baseline measures (3 months apart) and three observations postintervention for each participant (spanning 12 months), which will make it possible to assess the effects of the intervention while controlling for the season of measurement. Our primary and secondary outcomes are all continuous measures (change in FEV₁, functional status by SGRQ score, 6MWT, symptom score). We will apply linear mixed-effect models to investigate the effect of air purification on outcome variables:

Y_ij=b0 + b1 grp_i + b2 grp_i × post_j + b3 z_ij + w_i + _eij,

where Y_ij is any continuous outcome for participant i at visit j; grp_i indicates active or sham air purifier; post_j is an indicator variable for postrandomisation (vs prerandomisation) for a given visit; and z_ij is a vector of potential confounders on the day of visit, including season. In this model, the b1 indicates the difference in outcome at baseline and allows us to check for imbalance in the randomisation. In the likely event that there is balance in outcomes at baseline and the main effect of grp_i is absent, we can refit the model removing this main effect. The b2for the grp_i * post_j interaction is the term of scientific interest and indicates how postrandomisation versus prerandomisation changes in FEV₁ differ in the intervention versus control arms. The term w_i represents a normally distributed subject-specific random effect to account for intraindividual correlations among repeated measurements taken on the same individual, and e_ij is a normally distributed within-subject error. In the event of crossovers, the primary analysis will be intention to treat.

Standard regression diagnostics for longitudinal residuals will be employed to check the normality assumption and assumed variance-covariance structure of the residuals, and more flexible structures will be used when necessary. Continuous outcomes will be transformed to meet assumptions of normality required for modelling. Outliers will be identified using the generalised extreme Studentized deviation procedure. If outliers have a substantial influence, we will run sensitivity analyses excluding them.

In secondary analyses, we will examine if the effect of HEPA filtration on respiratory health is modified by time spent at home, characteristics of the home, indoor pollution exposures (eg, gas stove use, secondhand smoke exposure) and occupational exposures.

Ethics and confidentiality

Institutional Review Board (IRB) approval was obtained through BIDMC (2019P001129). Participating study sites have ceded approval to the BIDMC IRB, consistent with current US National Institutes of Health (NIH) policy. We will employ multiple strategies to minimise all potential risks to the participants. Following ethical and IRB guidelines, a participant’s confidentiality will be maintained and respected throughout the study. A unique identifier, rather than the name of the participant, will be used for the collection of data and labelling of specimens. Likewise, all of the databases will use the same identifier with the exception of one database which will contain the tracking and contact information of the participants. Boston Children’s Hospital will serve as the data coordinating centre for the study. All of the databases will be secured on a network drive, and access will only be granted to study staff on a need-to-know basis in all the institutions. Confidentiality and privacy will be maintained with state-of-the-art, password-protected REDCap system used by NIH clinical trial studies. The data reported in medical journals and scientific conferences will be presented in aggregate, and no individual participant will be identified.

Publication of results and data-sharing plan

The study findings will be published in peer-reviewed scientific journals and presentations in scientific and medical conferences. Authorship eligibility will be consistent with scientific norms. Requests for data-sharing and post hoc analyses will be considered after the study is complete and database closed. We will use data-sharing agreements to restrict the transfer of data, requiring that data be used only for research purposes.

Patient and public involvement

Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.