Clean Air for Rare MUcociliary Clearance dIsorders

The goal of this clinical trial is to learn whether using a high efficiency particulate air (HEPA) air purifier can improve respiratory health in children and adults with Cystic Fibrosis (CF) or Primary Ciliary Dyskinesia (PCD). The main questions it aims to answer are: Can using a HEPA air purifier at home reduce respiratory symptoms in people with CF or PCD? Can it improve lung function and overall health? Researchers will compare participants' health outcomes before and after the use of the HEPA air purifier to see if cleaner indoor air makes a measurable difference. Participants will: Visit the clinic for baseline health assessments (such as lung function and symptom questionnaires). Have two HEPA air purifiers installed in their home. One device will be placed in the main living area and one in the bedroom. Undergo exposure assessments during home visits to measure indoor air quality.

Introduction Exposure to airborne particulate matter (PM) is a well-established risk factor for respiratory morbidity, especially in vulnerable populations. While the health effects of PM are well documented in asthma and chronic obstructive pulmonary disease, much less is known about its impact on rarer congenital pulmonary disorders, such as cystic fibrosis (CF) and primary ciliary dyskinesia (PCD). These conditions are characterized by severely impaired mucociliary clearance (MCC), a primary defence mechanism of the airways against inhaled pollutants and pathogens. Defective MCC predisposes people with CF (pwCF) and PCD (pwPCD) to chronic infections, persistent airway inflammation, and progressive lung function decline. While airborne PM are relatively less harmful to healthy and/or less susceptible individuals, the inability of pwCF and pwPCD to effectively expel mucous from their airways enables inhaled pathogens and particles with the toxic substances they carry to remain in the airways for greater time periods compared to the general population. Although there are no reports in pwPCD, evidence from observational studies in pwCF suggests that exposure to air pollution accelerates disease progression. To date, no interventional studies have evaluated indoor air quality improvements as a protective measure in either of these populations. The Eastern Mediterranean region, and Cyprus in particular, frequently experiences exceedances of World Health Organization (WHO) thresholds for PM levels, due to both anthropogenic emissions and transboundary desert dust events. As most of the time in western societies is spent in indoor environments, use of indoor air purification may result in an important exposure reduction to airborne PM. Previous studies from Cyprus and elsewhere have reported that indoor air purification can reduce the negative impacts of air particulates on chronic lung diseases such as asthma. In the recent MEDEA project, air purifiers with high efficiency particulate air (HEPA) filters were found to reduce indoor levels of fine particles by about 50% during both dust and non-dust storm days and led to improvement in asthma symptoms and lung function compared with the control leg. Beyond filtering air pollutants, most commercial HEPA air purifiers also filter several types of bacteria and viruses, and thus they can also reduce transmission of infectious agents indoors. These effects of HEPA filters may be beneficial for pwCF and pwPCD who are predisposed to severe life-long respiratory morbidity. The objective of the CARMUCI trial is to assess for the first time the impact of indoor air purification on respiratory health outcomes among pwCF and pwPCD, using a randomized, cross-over, sham-controlled design. More specifically, CARMUCI will 1) provide field-based evidence for the effectiveness of air purification to reduce concentrations of indoor PM in the households of pwCF and pwPCD; and, 2) demonstrate the benefits of indoor air purification on respiratory morbidity particularly on lung function, clinical exacerbations, symptoms control, inflammatory biomarkers and health-related quality of life (HRQoL) in pwCF and pwPCD. Methods and Analysis Study Design CARMUCI is a randomized, double-blind, cross-over, sham-controlled trial designed to evaluate the impact of indoor air purification on respiratory outcomes in children and adults with CF and PCD. The study will be conducted over a 6-month period at participants' homes across Cyprus. In total, 62 CF and PCD patients in Cyprus will be recruited and randomized into two parallel groups with custom-configured air purifiers, which will be installed in their houses. Devices will be identical in appearance and have the following operational characteristics: 1. intervention configuration - air purifiers equipped with HEPA and three other filters for efficient particle filtration 2. control configuration - air purifier config¬ured to provide sham particle filtration Each participant will undergo two 3-month study periods-one 3-month period with an active air purifier and one 3-month period with a sham device-in a randomly assigned sequence. Each patient will be monitored for the first 3-month study period and then cross-over to the second 3-month study period. Therefore, participants who during the first period (first 3 months) have entered the intervention group (HEPA filter) during the second period (3 subsequent months) will enter the control group (sham particle filtration) and vice versa. Assessment of health outcomes will be carried out in the two parallel arms of the study and data collection from all patients will be completed by April 2027. The study design also offers the opportunity to assess continuously indoor exposure to PM. Study Population and Eligibility Criteria Eligible participants will be recruited from the national CF and PCD registries maintained by the Respiratory Physiology Laboratory of the Medical School at the University of Cyprus. Potential participants have been contacted from May 2025 via telephone and have been invited to participate in the CARMUCI program. Patients who were interested in the program were invited to give their written consent and participate in the program. For children's participation in the program, consent was obtained from their parents/legal guardians. The enrolment date is the day the participant has met all the screening criteria (both inclusion and exclusion criteria) and the participant signs the informed consent form. Randomization and Blinding Participants will be randomized in a 1:1 ratio to receive either the active air purifier or sham device first. Randomization will be computer-generated (Sealed Envelope Ltd., 2024) to create blocked randomisation and stratified by diagnosis (CF vs PCD). All air purifiers will be visually identical in appearance, sound, and airflow sensation and will be configured and installed by unblinded technicians who will not be involved in data collection or outcome assessment. Participants, clinical assessors, and data analysts will remain blinded to treatment allocation throughout the study. The filter compartment of each device is sealed with tamper evident security seals, preventing participants from opening the unit to inspect the presence or absence of active filtration components. Any attempt to break or remove the seal is detectable by the field team. Exposure and Adherence Assessment Indoor PM exposure will be assessed continuously inside participants' houses by using indoor, commercial low volume air quality sensors (PurpleAir Zen - Air Quality Monitor) that will provide PM10 and PM2.5 measurements during both study legs. Compliance to interventions, i.e. whether the air purifier will be running continuously during the 90-day monitoring period, will be therefore assessed with the use of these indoor, air quality sensors. Furthermore, individual participant exposure profiles for indoor and outdoor localization (time spent at and away from the residence) will be determined with the use of a commercially available wearable device (Garmin Vivosmart5), as described previously by our group. Data will be collected using automation procedures facilitated by a tasker mobile phone application, as reported previously. Baseline and Follow-Up Clinical Assessments Participants enrolled into the study will begin to have baseline assessments in September 2025. During a baseline house visit, participants will provide socio-demographic characteristics and answer a questionnaire on household characteristics. During a baseline clinic visit, and then at the follow-up (two time points) study visits, participants will provide detailed medical and medication use, have assessment of health status using disease-specific HRQoL questionnaires (QOL-PCD Questionnaire for PCD and Cystic Fibrosis Questionnaire-Revised for CF), the EQ-5D questionnaire, and a seven consecutive day sleep-wake diary as well as nitrogen (N2) multiple breath washout (N2MBW) (Exhalyzer D, Spiroware, 3.3.1, EcoMedics AG, Switzerland), forced oscillometry technique (FOT) (Resmon Pro V3, Restech Srl, Milano, Italy) and spirometry (In2itive Spirometer, Vitalograph Ltd., United Kingdom) assessments. Different types of samples will be collected at the baseline and follow-up clinic visits including sputum samples for microbiology, differential cell count and inflammatory biomarkers, nasopharyngeal swabs for assessment of viral abundance and blood samples for assessment of differential cell count and inflammatory biomarkers, and for assessment of total IgE and specific IgE antibodies against hundreds of allergens in the baseline blood samples (macroarray ALEXTM, MADX, Vienna, Austria). Phone interviews at baseline and then at every 1 month throughout the study duration will be performed to obtain detailed medication use, as well as information on emergency unscheduled healthcare visits and on pulmonary exacerbations using respective questionnaires. The follow-up period will span from September 2025 to late April 2027 and includes continuous monitoring of participants' daily exposure profiles for indoor and outdoor localization will be performed using the wristbands. Sample Size Calculation Based on previous observational studies a 10-15% change in LCI is clinically meaningful, and consistent with the mean treatment effect described in prior intervention studies in CF. To detect a statistically significant mean difference of at least 10% change in LCI in a cross-over study design, involving two intervention groups and three visits, and assuming a 0.05 alpha error probability and 0.90 power (1-beta error probability) for a repeated measures analysis, the minimum sample size needed in each intervention group is 28 participants. Allowing a dropout rate of 10%, a total of 62 CF and PCD patients together will be recruited. Data Management and Statistical Analysis All data will be pseudonymized and stored in a secure, password-protected database. Statistical analyses will follow an intention-to-treat approach. We will assess intervention effects on outcomes, by using a within-subjects, repeated measures, multi-level linear mixed model, adjusted for various covariates including age, sex, BMI, history of asthma or aeroallergen sensization. To account for the correlation among the repeated measurements within each subject and within each disease group, the model will be defined by a fixed effects term for the intervention and will include a random effects term for each participant (Level 1) and random effects term for each disease group (Level 2). In addition, for participants with CF, use of highly effective CFTR modulator therapy will be recorded at baseline and accounted for in sensitivity analyses (stratified and adjusted analyses), given its potential influence on lung function stability. Ethics and Dissemination The CARMUCI study has been approved by the Cyprus National Bioethics Committee (application number: EEBK/EΠ/2025/35) and complies with the ethical principles outlined in the Declaration of Helsinki and relevant European Union guidelines for clinical research involving human participants.