Comprehensive Maintenance Program: a Health Haven for COPD in Lleida.The NAPOLEON Project.

Justification Pulmonary rehabilitation programs (PRPs) are a cost-effective therapeutic strategy to reduce dyspnea, improve exercise tolerance, and enhance health-related quality of life in individuals with chronic obstructive pulmonary disease (COPD). Conventional PRPs typically last between 6 and 8 weeks and include physical training, education, and psychosocial support. However, multiple studies have shown that the benefits gained tend to diminish within 3 to 6 months after the initial program ends, especially when structured follow-up and maintenance strategies are not implemented.

In response to this issue, various post-PRP maintenance program modalities have been proposed, such as supervised or unsupervised home-based programs, periodic telephone follow-ups, or group exercise sessions. Despite promising results from some clinical trials, the evidence remains heterogeneous and limited, both in terms of clinical efficacy and feasibility within public health systems. International clinical practice guidelines have emphasized the urgent need to evaluate sustainable and economically viable strategies to maintain the benefits of PRPs, particularly in contexts where structured continuity of care is not guaranteed.

The present study involves the implementation of a supervised maintenance post-pulmonary rehabilitation program (PRP) in an outpatient setting, adequately equipped for the intervention and coordinated by a physiotherapist affiliated with a specialized clinical setting. This intervention will consist of a three-month interdisciplinary maintenance program with biweekly supervised physical exercise sessions, education on COPD and healthy lifestyle habits, and strategies for early detection of exacerbations. It is designed as a randomized controlled trial (RCT) with a 12-month follow-up and clinical evaluations at baseline (T0), 3 months (T1), 6 months (T2), and 12 months (T3).

Specific Objectives

1. To compare general and COPD-specific health-related quality of life between intervention and control groups at T0, T1, T2, and T3 using the EuroQol-5 Dimensions questionnaire (EQ-5D) and the COPD Assessment Test (CAT).
2. To assess the impact of the intervention on mental health by comparing anxiety and depression levels between groups at T0, T1, T2, and T3, measured with the Hospital Anxiety and Depression Scale (HADS).
3. To compare functional and exercise capacity between groups at T0, T1, T2, and T3, based on spirometry values, the six-minute walk test (6MWT), and handgrip strength.
4. To compare self-reported physical activity levels using the short version of the International Physical Activity Questionnaire (IPAQ) across time points.
5. To evaluate the sleep-wake pattern and determine the intervention's effect on its modulation, through analysis of sleep-wake pattern and activity variables (total sleep time, sleep latency, wake after sleep onset, light and deep sleep stages) recorded by wearable devices throughout the follow-up.
6. To compare healthcare utilization at T3, including non-hospitalized exacerbations, hospital admissions, and total hospitalization days between groups.
7. To assess the cost-effectiveness of the intervention from the healthcare system perspective, considering direct healthcare-related costs and the clinical benefits achieved.

Study Design This study will be conducted as a 12-month randomized controlled trial (RCT) with four clinical assessment visits, involving two parallel groups of adults diagnosed with chronic obstructive pulmonary disease (COPD) who have completed an initial eight-week PRP. Clinical evaluations will take place at four time points: baseline (T0), 3 months (T1), 6 months (T2), and 12 months (T3). Comprehensive pulmonary function tests and anthropometric measurements will be performed at T0 and T3. Other variables (symptoms, quality of life, functional capacity, mental health, physical activity, sleep-wake pattern, and healthcare utilization) will be assessed at all four time points. Participants will be randomly assigned in a 1:1 ratio to either the intervention or control group. The intervention group will attend two weekly supervised exercise sessions and two monthly educational sessions at a public health-affiliated center for three months. The control group will receive general physical activity recommendations in line with standard clinical practice. Clinical assessments will be conducted at T0, T1, T2, and T3, covering respiratory symptoms, health-related quality of life, functional capacity, and healthcare service use.

No booster phase is planned beyond the three-month intervention, as one of the study's secondary objectives is to explore the duration of maintenance PRP effects post-intervention. This will help determine whether clinical, functional, and sleep-wake pattern benefits persist in the medium and long term without continued intervention.

The program includes six educational sessions (20 minutes each), delivered monthly over three months and structured into six key thematic areas:

1. Knowledge about chronic obstructive pulmonary disease (COPD).
2. How dyspnea affects us and how to control it.
3. Importance of physical activity and exercise.
4. Malnutrition and obesity in chronic obstructive pulmonary disease (COPD).
5. Good sleep hygiene is important.
6. Smoking and alcohol cessation.

Adverse Events: Any adverse events observed during the intervention that led to exercise discontinuation will be recorded in an Adverse Event Report Form by the session physiotherapist and reported to the trial's coordinating physiotherapist. As previously stated, if exacerbations are detected, the patient will be referred to the hospital's specialized chronic obstructive pulmonary disease (COPD) clinic. Moreover, as outlined in Table 2, Section 6 (Supervision and Safety), the protocol includes professional supervision during the intervention, individualized adaptation and ongoing monitoring, and supplemental oxygen therapy if necessary.

Randomization: Patients will be randomized 1:1 into two study groups using a sequence generated by an electronic system external to the research team. The randomization sequence will remain concealed from the investigators until an eligible patient has provided written informed consent. Investigators will have secure, password-protected access to the system 24/7.

Blinding: Role separation will allow for blinding of the outcome assessor and personnel involved in data analysis and interpretation of treatment allocation.

Clinical and Functional Variable Evaluation Timeline: Clinical assessments will occur at baseline (T0), 3 months (T1), 6 months (T2), and 12 months (T3). Full spirometry and anthropometric measurements will be conducted at T0 and T3. All other variables (symptoms, quality of life, functional capacity, mental health, physical activity, sleep-wake pattern, and healthcare use) will be assessed at each time point. These include clinical characteristics of chronic obstructive pulmonary disease (COPD) (total number of exacerbations and hospitalizations, and events during the previous year); respiratory symptoms using the Dyspnea-12 questionnaire; mental health via the Hospital Anxiety and Depression Scale (HADS); general quality of life through the EuroQol-5 Dimensions questionnaire (EQ-5D) and COPD-specific quality of life with the COPD Assessment Test (CAT); aerobic capacity via the six-minute walk test (6MWT); handgrip strength using dynamometry; and physical activity levels via the short form of the International Physical Activity Questionnaire (IPAQ). The sleep-wake pattern will be continuously monitored over the 12-month follow-up using wrist-worn devices in both groups to analyze key sleep variables. Adherence to the intervention will be assessed by calculating average session attendance at T3, as will healthcare resource use.

Cost-Effectiveness Analysis: Cost-effectiveness analysis will be conducted using the intention-to-treat principle. Costs during the 12-month study period will be evaluated for both groups. The analysis will adopt a healthcare system perspective, focusing exclusively on patient health outcomes and direct provider-borne costs. The time horizon is 12 months, and all costs will be reported in 2025 euros (€). The intervention's impact on quality of life will be estimated through quality-adjusted life years (QALYs), based on the Health Utilities Index (HUI) derived from EuroQol-5 Dimensions questionnaire (EQ-5D), using the formula: QALYs = 0.5 × baseline HUI + 0.5 × 12-month HUI.

To manage missing data, multiple imputation will be applied independently using the Multivariate Imputation by Chained Equations (MICE) method with predictive mean matching. Initially, the database will be stratified by treatment group to ensure group-specific imputations. The imputation process will include costs, Health Utilities Index (HUI), age, sex, and body mass index (BMI).

To illustrate uncertainty in cost-effectiveness outcomes, 5,000 nonparametric bootstrap replications of cost and effectiveness pairs will be simulated. Pooled cost-effectiveness estimates will be calculated using Rubin's rules and plotted on a cost-effectiveness plane.

Sample Size: Sample size was calculated based on the primary outcome, Dyspnea-12. A clinically relevant difference of 2.83 points at 12-month follow-up was considered. Assuming a common standard deviation of 5 points, a significance level of 0.05, 80% statistical power, and a 10% dropout rate, a total of 43 participants per group is estimated to be required to detect this difference.