Protocol for a randomized controlled trial of moderate intensity interval training in individuals with chronic obstructive pulmonary disease and obstructive sleep apnea overlap syndrome who have excessive daytime sleepiness

Abstract

Background:

The term “Overlap Syndrome” (OS) describes the presence of both chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA) in a single individual. Excessive daytime sleepiness (EDS) is a common symptom of OS shown to be associated with an increased risk of cardiovascular disease (CVD) that could be reduced through exercise. Thus, we propose to investigate a novel exercise intervention in individuals with the EDS-OS phenotype as they are at highest risk of CVD yet have the greatest barriers to exercise.

Methods:

We will conduct a single-site, randomized, two-arm, parallel group-controlled exercise trial in individuals with EDS-OS. The Epworth Sleepiness Scale (ESS) will be assessed at baseline. Individuals with OS and the EDS-OS phenotype (ESS >10) (n = 46) will be randomized to a moderate intensity interval training (MIIT, i.e. intervals of 5 min at 50% VO2peak followed by 3 min of active recovery at 10% VO2peak) or a control group of standard of care. We will investigate if MIIT intervention decreases the risk of CVD in EDS-OS, which will be assessed by: 1) quality of life, measured by the 36-Item Short Form Health Survey; 2) physical activity, measured by daily step counts; and 3) cardiovascular health, assessed as VO2peak, flow-mediated dilation and serum high sensitivity C-reactive protein, lipids, and glucose.

Conclusion:

Our findings will guide future development and implementation of exercise interventions that could reduce the risk of CVD in the understudied EDS-OS phenotype.

1. Introduction

Chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea disease (OSA) are each responsible for major morbidity, mortality, and economic burden. The term “overlap syndrome” (OS) describes the presence of both conditions in a single patient [1].

Despite variations in its clinical spectrum, OS classification is frequently linked to single indicators, the forced expiratory volume in 1 s (FEV1) and the apnea hypopnea index (AHI) [2]. Such diagnostic approach, with its lack of stratification by other clinical characteristics, likely contributes to the challenge of better understanding the factors that contribute to increased risk of cardiovascular disease (CVD) [3]. In contrast, diagnostic classification of individuals with OS into phenotypes with similar clinical manifestations provides the possibility of a personalized treatment approach.

Excessive daytime sleepiness (EDS) is a common symptom of OS that frequently persists despite optimal treatment with continuous positive airway pressure (CPAP). Studies have found that EDS is linked to the incidence of cardiovascular diseases (CVD) [4] and that screening for EDS may describe the cardiovascular risk beyond traditional risk factors, especially for patients with an intermediate risk of CVD [5]. Additionally, EDS decreases several functional measures, such as quality of life [6] and physical activity(PA) level [7], which further increase the risk of CVD. Thus, targeting EDS treatment in the individuals with the EDS-OS phenotype could be of critical significance for their primary prevention of CVD. To date, only limited information is available on exercise interventions in EDS-OS phenotype.

Our previous experience showed that patients with OS identify chronic disease limitations, such as breathing problems, as major barriers to exercise in addition to the scheduling conflicts, weather, and lack of motivation [8].

As such, interval training would provide several physiologic advantages over continuous training. These benefits include smaller increases in arterial lactate concentration (<4 mmol/L) and lower degrees of lung dynamic hyperinflation that minimize symptoms of dyspnea and leg discomfort during exercise. Therefore, interval training would allow the completion of a longer cumulative amount of moderate-intensity exercise compared with continuous exercise training which would be self-terminated due to intolerance. The accumulation of shorter sessions of activity was shown to be associated with equivalent benefit with regard to coronary heart disease risk compared with continuous longer sessions, as long as the total amount of energy expended is similar [9]. Wen et al [10] showed that moderate-intensity exercise of 92 min/week in physically active individuals reduced CVD mortality (HR: 0.81; 95% CI: 0.71 to 0.93) compared with their inactive peers.

To fill these gaps, we designed a novel moderate interval exercise intervention (MIIT) that could be easily adapted to a variety of real-life activities of individuals with the EDS-OS phenotype who are at highest risk of CVD. Participants with the EDS-OS phenotype will be randomized to MIIT (intervals of 5 min at 50% VO2peak followed by 3 min of active recovery at 10% VO2peak) or a control group of standard of care. We hypothesize that the MIIT intervention will decrease the risk of CVD in EDS-OS.

2. Materials and methods

2.1. Study objectives

We will investigate if a 12-week MIIT intervention decreases the risk of CVD in EDS-OS, which will be assessed by: 1) quality of life, measured by Short Form-36; 2) physical activity, measured by daily step counts; and 3) cardiovascular health, assessed as VO2peak, flow-mediated dilation, and serum high sensitivity C-reactive protein, lipids, and glucose. The primary study objective is to determine the effect of MIIT on CVD risk in EDS-OS. The secondary objective is to explore behavioral barriers to translation of MIIT into sustainable healthy lifestyle change. Outcomes will be collected at baseline and after 12-weeks.

2.2. Study design

The Experimental Design is a single-site, randomized, two-arm, parallel group-controlled trial of MIIT in individuals with EDS-OS compared with standard of care controls. All study procedures have been approved by the local institutional review board.

The Participant flowchart for parallel design, based on the Consolidated Standards of Reporting Trials (CONSORT) guidelines for transparent reporting [11] is presented in Fig. 1.

Fig. 1.

CONSORT diagram. OS: Overlap Syndrome; EDS-OS: Overlap Syndrome with Excessive Daytime Sleepiness phenotype; CVD: cardiovascular; QoL: Quality of Life; CRF: cardiorespiratory fitness: FMD: flow mediated dilation: hs-CRP: high sensitivity C-reactive protein; MIIT: moderate intensity interval training; SEE: self-efficacy for exercise.

2.3. Settings and participants

The study will take place at the Salem Veterans Medical Center (VAMC) in Salem, Virginia. Participants will be recruited from pulmonary and sleep clinics. Eligible participants will be adults with the EDS-OS phenotype defined as Epworth Sleepiness Scale (ESS) > 10. The Standard Protocol Items Recommendations for Interventional Trials (SPIRIT) flowchart of enrollment, interventions and assessments is presented in Fig. 2.

Fig. 2.

SPIRIT flowchart of the schedule of enrolment, interventions, and assessments.

The inclusion and exclusion criteria are presented in Table 1:

Table 1.

The inclusion and exclusion criteria.

INCLUSION CRITERIA:

1. Diagnosis of COPD and OSA Overlap Syndrome (OS) (i.e., post-bronchodilator FEV1/FVC <70 and a polysomnogram or home-based study showing an Apnea Hypopnea Index >5

2. EDS-OS phenotype (ESS >10)

3. Treatment with Continuous Positive Airway Pressure (CPAP).

EXCLUSION CRITERIA

1. Montreal Cognitive Assessment (MoCA) <20.

2. Coronary artery disease, as defined by any of the following: history of coronary artery bypass grafting, prior positive stress test for ischemia, infarction, or angina

3. Orthopedic problems as defined by joint pain limiting ambulation

4. Fall risk, defined as >2 falls in the prior month

5. Hospitalization in prior month

6. Daytime home oxygen

7. Participation in structured exercise, defined as >1 h of moderate intensity activity and any high intensity activity performed over prior 7 days. Four questions adapted from the PASE questionnaire will be used to assess participation in moderate and high intensity exercise, over the previous week.

EDS-OS: Overlap Syndrome with Excessive Daytime Sleepiness phenotype; ESS: Epworth Sleepiness Scale; PASE: Physical Activity Scale for the Elderly.

2.4. Screening visit

Patients with OS and COPD will be recruited from the pulmonary clinics. Those who agree to participate in the study will attend an in-person screening visit. Prior to any study procedures, the principal investigator will obtain written informed consent from the participant. Participants will then complete the ESS, MOCA and PASE questionnaires and brief physical examination to confirm eligibility for the trial. If all eligibility criteria are met, baseline visits will be conducted.

2.5. Baseline visits

Eligible participants will attend an in-person baseline visit and complete self-reported questionnaires, flow mediated dilation and fasting blood sampling. The participant will also be provided with a waist-worn accelerometer (ActiGraph Pensacola, Florida, USA) to use for 7 days. The cardiorespiratory fitness testing will be performed on a different day, prior to the randomization. Once all the baseline data has been collected, the participant will be randomized by the study team.

2.6. Randomization

Participants with EDS-OS (N = 46) will be randomized 1:1 to MIIT or a control group. As a behavioral intervention, the exercise intervention trial cannot be conducted as a blinded trial. However, we will use an approach based on Good Clinical Practice (GCP) which has been used in numerous similar exercise trials to minimize potential ascertainment bias. The group assignment table will be generated and maintained by a statistician without access to participants or their data (blinded). Randomization will be performed using STATA (StataCorp. 2023. Stata Statistical Software: Release 18. College Station, TX: StataCorp LLC) in blocks of ≥4 individuals to ensure that sufficient exercise equipment and staff are available for all participants who are exercising during the 12-week intervention period. The study team will request a randomization assignment for each participant after baseline testing is complete. Staff who are aware of group assignment will not oversee/analyze these tests.

Since the severity of COPD can be associated with CVD and to ensure equal distribution of COPD severity between small study groups, a stratified random assignment will be used. Participants will be classified by the FEV1 into one of two strata: (1) FEV₁> 50% (mild and moderate COPD); and (2) FEV₁ < 50% (severe COPD). Available participants in each stratum will be assigned at random to 1 of the 2 groups using the closed envelope method.

2.7. Study intervention

2.7.1. Moderate intensity interval training intervention

Participants in the exercise group will train 3 times a week for a total of 12 weeks under the supervision of an exercise physiologist. The primary training modality will be cycling using SciFit upright bike (Tulsa, OK) which allows real-time monitoring of work rate measured in watts. The moderate intensity of the interval training for each participant will be based on the VO2peak measured during the baseline cardiopulmonary exercise testing performed on a bicycle ergometer (Lodi, Groningen, Netherlands) and converted to watts. This approach allows us to include participants on medications that may affect heart rate. Exercise training sessions will consist of intervals of 5 min at 50% VO2peak followed by 3 min of active recovery at 10% VO2peak. Each session will include a 5-min warm up and a 5-min cool down at 10% VO2peak. The training intensity in Watts will be derived from the American College of Sports Medicine leg ergometry equation VO2 mL(kg.min) = 10.8 * [(W/body weight (kg)] + 7 [12]. The exercise progression plan is to start with 2 intervals/session in week one and add 2 intervals each week, reaching 6 intervals at week 3 to meet the target of 30 min of total moderate intensity training. Each training session will have exercise logs that include details on exercise duration, time in target watts and perceived dyspnea. In addition, participants will be monitored for signs and symptoms of overtraining and educated on proper rest and hydration, measures which decrease attrition. The exercise physiologist will monitor overtraining symptoms such as increased muscle soreness, excessive sweating and overheating and plateau or decline in athletic performance.

2.7.2. Control group

Participants in the control group will be instructed to maintain their routine activity level for 12 weeks. To monitor unsupervised activity, participants will undergo weekly telephonic survey of their physical activity using the Physical Activity Scale for the Elderly (PASE).

2.8. Study measures

Demographic, clinical, and pharmacological data will be extracted from the electronic medical records with corroboration from an initial history and physical exam by a clinical investigator

2.8.1. Questionnaires

1. Smoking exposure will be measured by the MONICA questionnaire, a 13-item survey that will assess participants’ current and past smoking habits, and passive smoke exposure [13].

2. Excessive Daytime Sleepiness (EDS) will be measured using the Epworth Sleepiness Scale, a questionnaire containing 8 items that shows the likelihood of dozing during daytime activities. The probability for each item ranges from 0 (never) to 3 (high probability), with a summary score > 10 indicating EDS [14].

3. The quality of life (QoL) will be measured by the Short Form-36 (SF-36), a widely used health-related QoL measure which is sensitive to change in exercise trials. The SF-36 is a multipurpose self-administered health survey consisting of 36 questions divided into 8 individual domains: physical functioning, role physical, bodily pain, general health perceptions, vitality, social functioning, role emotional, and general mental health. The raw scores for each subscale and the 2 summary measures are standardized, weighted, and scored according to specific algorithms. The scores for the multifunction item scale measures range from 0 to 100, with higher scores indicating better quality of life [15].

4. Exercise self-efficacy will be measured using Self-Efficacy for Ex-ercise Scale (SEE-Scale). SEE-Scale is a user friendly, 9-item questionnaire that asks individuals their confidence level from 0% (not at all) to 100% (highly confident) in performing exercise regularly, 3 times per week for 30 min. Total score will be calculated by summing the responses to each question. This scale has a range of total scores from 0 to 90 [16]. A higher score indicates higher self-efficacy for exercise.

5. Physical Activity Scale for the Elderly (PASE) is a 5 min, easily scored survey designed specifically to assess PA in persons aged 65 years and older [17]. The PASE assesses the types of activities typically chosen by older adults (walking, recreational activities, exercise, housework, yard work, and caring for others. It uses frequency, duration, and intensity level of activity, including participation in moderate and high intensity exercise, over the previous week to assign a score, ranging from 0 to 793, with higher scores indicating greater PA.

6. Cognitive Function. We will include an assessment of cognitive function since it can affect participants’ adherence to study procedures. After providing informed consent, all participants will complete a baseline Montreal Cognitive Assessment (MoCA), a well-validated cognitive screening tool that classifies patients who have Mild Cognitive Impairment as a score < 26 [18]. Given the higher false positive rate in older populations [19] and COPD [20], we will use a MoCA cutoff score < 20 rather than 26 to classify Mild Cognitive Impairment and use as exclusion criteria.

2.8.2. Physical activity

ll participants will wear a waist accelerometer (ActiGraph wGT3X-BT) for 7 days at baseline and the end of intervention period to record daily steps. ActiLife 6.13 software (ActiGraph Pensacola, Florida, USA) will be used to calculate mean daily step count. The participants will be instructed to wear the ActiGraph for 7 days from 8 am to 8 pm and remove it when bathing, showering, or swimming, as well as when sleeping at night. A “Participant Log” will be available for participants to record the times when the device was taken off and put back on.

Both uniaxial and triaxial data from will be used to further describe changes in PA. We will use ActiGraph software to set appropriate parameters for cleaning data, deleting non-wear time and spurious activity counts, determining number of valid days of monitoring and for summarizing results according to industry standards [21].

2.8.3. CPAP adherence

Data will be downloaded from AirView, a secure cloud-based patient management system for online CPAP monitoring available at the Salem VAMC. The following data from prior 30-day will be obtained: monthly number of days of CPAP usage and nightly average hours of CPAP at baseline as well as at the end of intervention.

2.8.4. Cardiorespiratory health

1. Cardiorespiratory Fitness. Participants will be asked to exercise tovoluntary exhaustion during a graded exercise test on a cycle ergometer (Lode Corival, Groningen, Netherlands) starting at a work rate of 25 W and progressing by 10 W every 1 min until they can no longer continue. O₂ uptake, CO₂ output, and minute ventilation will be measured using a metabolic cart (ParvoMedics TrueOne 2400). The final two 20 s values of oxygen consumption will be averaged to provide the VO2peak. The cardiorespiratory fitness testing will be performed at baseline as well as at the end of intervention.

2. Endothelial Function will be measured by Flow-Mediated Dilation(FMD). This method involves Doppler ultrasound imaging of brachial artery dilatator response to shear-stress in response to a blood pressure cuff inflated 50MmHg above systolic pressure using a protocol previously described [22]. FMD is expressed as a percentage change in the brachial artery diameter (FMD%).

2.8.5. Behavioral barriers to translation of MIIT into sustainable healthy lifestyle change

Brainwriting Premortem. This is a novel, effective alternative to brainstorming focus groups that was previously used nationwide to test pre-implementation barriers to transitions of care to home [23]. Briefly, Brainwriting is defined as the silent sharing of written ideas in a structured group setting over a period of 10–30 min. Prior to starting the Brainwriting session, participants in the exercise group will be told to imagine that the MIIT will be launched at home, but it failed. They will then be asked to identify what caused the program to fail in a home-setting [24]. This will be administered in subjects who complete the exercise intervention.

3. Outcomes

3.1. Primary outcomes

1) To determine the effect of MIIT on participation in life situations compared to usual care control.

Hypothesis 1. MIIT improves SF-36 physical and mental scores.

2) To determine the effect of MIIT on physical activity compared to usual care control.

Hypothesis 2. MIIT increases daily step count as measured by accelerometry.

3) To determine the effect of MIIT on cardiovascular health compared to usual care control.

Hypothesis 3. MIIT increases CRF (VO2peak) and FMD and decreases serum levels of hs-CRP, lipids, and glucose.

3.2. Exploratory outcomes

4) To explore behavioral barriers to translation of MIIT into sustainable healthy lifestyle change.

Hypothesis 4. Low self-efficacy for exercise is associated with poor compliance to MIIT.

4. Data collection and management

4.1. Analysis plan

The objective of the intervention is to determine if MIIT changes outcome measures. The dependent variable will be change (post-pre) in outcomes. Paired t-tests will be used to test a significant change with exercise. Analysis of variance with repeated measures (ANOVA) will be used to include baseline values and a potential confounding factor. Between group difference (pre/post * group) will be tested using analysis of covariance with repeated measures (ANCOVA). We do not anticipate needing to adjust for sex or age since the majority of our OS population are men over 60 years old. However, if the groups are unbalanced by a potential confounding factor, which can occur in small trials, the baseline value will be included in the model.

4.2. Sample size calculations

We plan to enroll 46 individuals who meet the criteria for EDS-OSA. We conservatively estimate an overall attrition rate of 40% and expect pre-post data in 28 individuals with EDS-OSA (14/group).

4.2.1. Within group sample size calculations

Calculations for a paired Student’s t-test was used to test for a mean change after exercise training given a range of correlation between pre and post values with assumptions of α = 0.05 and 80% power. Results from exercise trials in a similar population were used [25–30]. In addition, we include results from our published data in the target population showing improved FMD from 8.2% to 20.3% [31]. However, we appreciate that the magnitude of this effect size may be influenced by our small numbers and also include the effect of a 12-week interval intervention on FMD [32].

4.2.2. Between groups sample size calculations

The sample size calculation for a mean change between groups were performed for a paired t-test using the assumptions of 80% power, two-tailed alpha of 0.05 and two independent groups. Based on available data the proposed exercise intervention study will have adequate power to test the difference in primary outcomes in 28 participants who complete the trial.

5. Discussion and significance

Physical inactivity is a leading modifiable risk factors worldwide for cardiovascular disease which is commonly seen in EDS-OS. Therefore, exercise interventions aimed at decreasing sedentary behavior could make a major impact in this understudied OS phenotype.

The adaptation of center-base exercise training designs to local context and individual needs is critical for the long-term sustainability of exercise strategies and their effective translation into durable increases in daily PA. Our previous experience data show that patients with OS identify chronic disease limitations, such as breathing problems, as major barriers to exercise in addition to the scheduling conflicts, weather, and lack of motivation [8]. Our described operational trial of 5-min intervals of moderate intensity interval exercise can be easily adapted to a variety of real-life activities (e.g., stopping at a crosswalk while walking or taking a break while doing house chores) and optimally accommodates the differences in individual preferences for homebased activities. Our overall concept is described in Fig. 3.

Fig. 3.

Proposed translation of the current center-based moderate intensity interval training (MIIT)into a future home-based MIIT and increased daily physical activity.

Evidence supports that physical activity accumulated in bouts <10 min in duration decreases the risk of CVD as assessed by blood pressure, blood lipid and glucose, inflammatory markers, and Framingham Cardiovascular Disease Risk Score [33]. However, these data are provided by longitudinal and cross-sectional studies only. As such, the Office of Disease Prevention and Health Promotion Conduct considers the information provided by randomized controlled trials on the effects of PA accumulated in bouts of <10 min on health outcomes as critical. In addition, our randomized exercise design aligns with the recommendations of recently revised Physical Activity Guidelines for Americans, which recommend that public health initiatives use the tools and resources from the “Move Your Way” Campaign to encourage PA as an important lifestyle behavior regardless of the duration [34]. Thus, the results from this novel exercise intervention will contribute to the knowledge needed to fill a gap in the scientific foundation of the next set of PA guidelines and help tailor the materials from the “Move Your Way” Campaign to the underrepresented population of patients with EDS-OS.

Data availability

No data was used for the research described in the article.