Primary research objective and question (PICOT).

Is 10-weeks of group supervised PTR and individualized HPR equivalent to each other, and are the two interventions superior to usual care (no PR) on improving respiratory symptoms measured using the COPD Assessment Test (CAT) at 10-weeks from baseline in patients with COPD declining participation in center-based PR programs?

1. Population: Patients with COPD and moderate to severe airflow obstruction unable to access conventional center-based PR
2. Intervention: 10-week group supervised PTR or 10-week HPR or Control: Usual care (no intervention, besides routine and acute medical visits)
3. Outcome: Patient-reported respiratory symptoms (CAT score) (primary outcome)
4. Time frame: The primary endpoint is 10-weeks from baseline

Secondary research objective and question (PICOT).

Is 65-weeks of group supervised maintenance-telerehabilitation superior to usual care (no maintenance) on change/maintenance in respiratory symptoms at 75-weeks from baseline, in patients with COPD declining participation in center-based PR programs?

1. Population: Patients completing 10-weeks of group supervised PTR and/or individualized HPR
2. Intervention: 65-weeks of group supervised telerehabilitation once weekly for 60 min.
3. Control: Usual care (no intervention, besides routine and acute medical visits) and patient opting from 65-weeks maintenance program
4. Outcome: Patient-reported respiratory symptoms (CAT score) (primary outcome)
5. Time frame: The secondary endpoint is 75-weeks from baseline

Hypotheses.

Our hypotheses in a three-arm randomized controlled trial (RCT) design are

1. Effect of PTR and HPR will be equivalent to each other on respiratory symptoms (CAT score) at the primary endpoint (10-weeks)
2. Effect of PTR and HPR will be superior to usual care, that is the control group (CON—no intervention) on respiratory symptoms (CAT score) at the primary endpoint (10-weeks)

After completion of intervention in the PTR and HPR group, we consider a between-group difference of 2.5 points or larger (compared to usual care) in the CAT score [25] as a clinically relevant difference (MID) at 10-weeks (primary endpoint). Bounds for the equivalence limits between the interventions PTR and HPR are preset as difference within ± 2.5 for CAT score difference.

For the secondary endpoint (65-weeks maintenance-telerehabilitation) and intermediate measurement (35-weeks), we will also consider a between-group difference of 2.5 points (compared to usual care) in CAT score as a clinically relevant difference.

Initial contact.

Respiratory nurses at out-patient clinics identify potentially eligible patients with COPD at mandatory/scheduled control visits and send information to investigator (CN) who thereafter contacts the patients. In the investigators initial contact to determine patient eligibility to enrollment, reasons for not attending or resigning from conventional PR is explored and documented in the study database. Patients who decline attending the project is likewise documented with reasons in the study database. In cases of doubt concerning patient eligibility, for instance cognitive impairment or comorbid conditions, the projects pulmonologist and primary investigator is sough for advice and a pre-meeting is planned, whereafter the final decision is made. This in acceptance from the patient.

Inclusion- and exclusion criteria.

1. Inclusion criteria.
   1. Indication for PR according to national guidelines
   2. Unable to access and participate in the conventional out-patient hospital- or community-based PR when offered during routine consultation
   3. A post-bronchodilator ratio FEV1/FVC <70% (confirmed physician diagnosis of COPD) [7]
   4. A post-bronchodilator FEV1 <80% (degree of airway obstruction) corresponding to GOLD grade 2–4 (moderate to very severe) [7]
   5. GOLD groups B, C, D (GOLD 2023 update; GOLD E (former groups C and D)) [29] corresponding to severe respiratory symptoms and/or frequent acute exacerbations
   6. Able to stand up from a chair (height 44-46cm) and walk 10 meters independently (with or without a walking aid)
   7. Able to lift both arms to a horizontal level with a minimum of 1 kilograms dumbbells in each hand
2. Exclusion criteria.
   1. Participation in conventional PR in the past 24 months
   2. Cognitive impairment–unable to follow instructions
   3. Impaired hearing or vision–unable to see or hear instruction from a tablet
   4. Unable to understand and speak Danish
   5. Comorbidities where the exercise content is contraindicated (including treatment for diabetic foot ulcer, active cancer treatment, life expectancy <12-months)

All eligible patients receive written information from the nurses about the study; a short version (pamphlet) and a longer version (approved by the Regional Committee of the Capital Region of Denmark). The investigator or project staff hereafter inform the patients verbally about the project. To ensure that all questions or concerns that patients might have, the investigator calls the patient to provide further information before the patient are asked to participate. All patients are encouraged to consider their consent for at least 24 hours before their final decision; this is according to Danish ethical guidelines for medical research. Patients who consent to participate in the study receives a written consent form, which they are asked to fill in upon inclusion in the study. The patient will keep the original consent form and a copy will be archived with the Case Report Form (CRF).

Ethics and consent to participate.

The trial protocol is approved by the Ethics Committee of The Capital Region of Denmark (H-22015777; 29.08.2022), by the Danish Data Protection Agency (P-2022-245-13101, 25.05.2022) and the trial is registered at ClinicalTrials.gov, identifier: NCT05664945 (23.12.2022).

The Ethics Committee will be informed about important protocol modifications for approval and if unexpected adverse advents should occur as mandatory by law. The study will be performed in accordance with the Declaration of Helsinki. A completed patient informed consent form is required from all patients participating in the study and must be signed by the patient and the informing physiotherapist or respiratory nurse. All investigators obtaining consent are qualified and appropriately trained.

Healthcare professionals.

The PTR and HPR interventions are supervised and performed by skilled physiotherapists and respiratory nurses who have at least two years of experience with PR. The delivery of the interventions is ensured from the project group located at Hvidovre Hospital, Respiratory Department, Denmark.

Equipment.

The Capital Region of Denmark will provide and deliver all equipment and full day-to-day service.

Training equipment.

All patients in the intervention groups receive a tablet, dumbbells 1–5 kg. with the possibility of progression to 6–20 kg. or higher if needed and a two-level adjustable step box.

Technology equipment (hardware and software).

All patients in the intervention groups are provided an android tablet with a conference system and internet installed. The android tablet is a Samsung touch screen, size 10.1 inch, with a single interface that can be operated by all patients. The tablet ensures that the patients can communicate, visually and verbally, via a virtual platform (conference system: Pexip Inifinity Connect, version 1.10.3) with the project staff at Hvidovre Hospital and the remaining group participants. The screen for healthcare professionals is a 50.0 inch widescreen with access to a professional video conferencing system (Pexip Infinity Connect, version 1.10.3) that makes it possible to see multiple patients during a training session and train the group synchronously in real time. Furthermore, the system enables the possibility to show presentations and videos in patient education. The group TELE-sessions are delivered from Hvidovre Hospital, a room located in the Pulmonary Outpatient Clinic. The individual sessions are delivered from a room located at Hvidovre Hospital, Bispebjerg Hospital or an office where anonymity is possible.

The system is approved by Center for IT and Medico-Technology (CIMT) and the data protection Agency, The Capital Region of Denmark. The product supports the possibility of group training via video conference and is already used in other telemedical consultations.

Prior experience with the technology.

The research staff has in-dept knowledge and experience with the technology. From our previous telerehabilitation study, we documented, that technical issues leading to cancellation and/or rescheduling of group sessions affected only 2 of 360 group sessions [14]. Minor temporary technical issues (that is sound artefacts, screen freezes) not leading to cancellation or delay were present in 14% of the total group session (49 of 360). Individual patient cancellation caused by technical problems occurred in 12 of 1902 individual connections [14].

Warm-up and cool-down in PTR and HPR intervention groups.

The purpose of warm-up in the intervention groups are to familiarize the exercise movements, ensure adequate range of motion, stimulation of joints, and muscles and cardiorespiratory warm-up according to the recommendations of the American College of Sports Medicine [30]. Warm-up have a duration of 5 min. in each group. The purpose for cool-down is to promote recovery and return to body to pre-exercise level.

Each stretch will be held for 30 sec. in according with ACSM [30] targeting the pectoralis major, neck lateral flexors, hamstrings and triceps surae muscles. Cool-down has the duration of 5 min. in each group. Warm-up and cool-down protocol are presented in Table 1.

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Table 1. Warm-up and cool-down protocol for PTR and HPR group.

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Pulmonary tele-rehabilitation group.

The PTR group will consist of 4–6 patients who exercise at home and communicate via tablet, that is a home-based procedure that allows patients to avoid transportation to/from center-based PR. Each session is 60 min., i.e., 35 min. of exercise and 25 min. of patient education, two times a week for 10-weeks. The specific exercises performed in the PTR intervention have been used in more randomized intervention studies on patients with COPD [14, 31] and follow the exact same protocol. The exercises involve the larger muscle groups targeting 50% exercises for upper extremities and 50% for lower extremities [6, 14, 19, 31]. The specified volume, intensity and content for the exercise protocol are in accordance with national and international exercise recommendations [4, 6]. As the patients are expected to improve their mental and physical capacity during the intervention period a relative progression every fourth week are included in the exercise sessions.

Additionally, to the supervised program, patients are instructed to perform daily physical activity of at least 30 min. by modalities accessible to the patient, e.g. in- or outdoor walking activities in bouts of minimum 10 min.

The exercise program consists of six exercises and are presented in Table 2. The exercises are executed in four sets consecutive to achieve peripheral muscle failure and secondary dyspnea. Each set is carried out in a predefined period; week 1–2: 20 sec. active period and 40 sec. pause, week 3–6: 30 sec. active period and 30 sec. pause, week 7–10: 40 sec. active period and 20 sec. pause (Table 2). The goal for each set is to perform a maximum number of repetitions within the active period, i.e. 8 to 25 repetitions depending on patients exercise capacity and motivation, but with the aim of 12 to 20 repetitions. The exercise velocity is based on recommendations applying to high-repetitive exercises, (> 15 repetitions) [30], i.e. moderate to high speed equal to 1–2 sec. for both the concentric and eccentric phrases of the movement. The exercise load consists of body weight supplemented with external dumbbells (1–20 kg.). The intensity is estimated to be equivalent to 40–80% of one repetition maximum (8–25 repetitions) and exercises are performed as high repetitive time-based muscle endurance at least 80% of the exercise time corresponding to a weekly volume of 60 min. (30 min. x 2). In practice, patients assess their training intensity using the self-rated Borg CR-10 scale, with a range from 0–10, aiming to exercise at a level of score 4–7 (moderate to very strong shortness of breath during exercises) and/or reaching peripheral muscular failure. For each session, the number of completed sets and the weight of the dumbbells used for each exercise are documented in an exercise log for all exercises to track progression.

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Table 2. Exercise protocol PTR group.

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The initial 2 weeks are dedicated to serve as a familiarization phase with the purpose of adapting to exercising, adjusting and optimizing load and preventing musculoskeletal overload injuries.

Exercises for the lower extremities (Table 2: exercise # 1,3,5) are carried out without dumbbells at the first session. If a patient can perform three consecutive sets without requiring rest during the active period, external load is added at the subsequent training session. The external load increase ranges from 2–4 kg. (total weight for two dumbbells) when progression adjustments are made. Exercises for the upper extremities (Table 2: exercise # 2,4,6) are carried out with the lightest weights (1 kg. / pcs.) at the first session. If a patient can perform three consecutive sets without requiring rest during the active period external load is added at the following training session. The external load increase ranges from 2–4 kg. (total weight for two dumbbells) when progression adjustments are made. Progressions are evaluated on an individual basis from session to session [32–35]. Additionally, patients are asked to count the number of repetitions in each set every 6^th session. If the number of repetitions exceeds 25, the external load is increased at the following training session.

Patient-education.

The education topics follows the national guidelines [4] and are conducted as a combination of dialogue, reflection exercises, and practical exercises. Overall, the topics are similar in the PTR and HPR groups, but in the PTR group it is delivered as 20 min. sessions two times a week in total of 20 sessions. In the HPR group it is delivered as appr. 15 min. sessions once a week in a total of 10 sessions. The primary focus is to promote smoke cessation, correct intake of medication and increasing physical activity/reducing sedentary behavior. PTR topics are presented in Table 3, HPR topics in Table 4.

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Table 3. Educational topics for PTR group.

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Table 4. Educational topics for HPR group–based on individual needs.

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Home-based pulmonary rehabilitation group.

Patients allocated to the HPR group will participate in individualized self-initiated home-based PR. The patient exercises at home in sessions preferably three times a week at least for 20 min. during the 10-week intervention. Weekly, stepwise and motivational goal setting are used to reach the overall exercise goal. For more motivated patients exercising more than three times a week is welcomed to meet the individual desires.

The individualized exercise prescription will follow the Frequency-Intensity-Time-Type-Volume-Progression principles (FITT-VP) [30] combined with the patient’s motivation and goals (please see Tables 5 and 6). Exercises are evidence-based and used in several intervention studies on patients with COPD and involves larger muscle groups exercises for upper/lower extremities [6, 14, 19]. All patients are recommended to start with a minimum of three exercises (Table 5, core exercises #1,2,3). Add-on exercises are determined based on patient motivation, wishes and goals. A quality check of exercises will be performed online twice during the 10-week intervention.

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Table 5. Exercise protocol HPR group.

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Table 6. Home-based pulmonary rehabilitation–overview.

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The first session is a visit held at the patient’s home. During the visit the respiratory physiotherapist/nurse establishes exercise goals with the patient, writes a formal exercise prescription of 3–6 exercises, and educates the patient in the use of an exercise-log. The physiotherapist supervises the prescribed exercises and assists in filling out in the exercise-log. Secondly, the patient is encouraged to complete a mindfulness program of choice for 15 min. at least once a week if it appeals to the patient (optional). Furthermore, the patients are given a COPD educational booklet, a pamphlet on diet and COPD, medication etc.

Additionally, daily physical activity of at least 30 min. by modalities accessible to the patient, e.g. in- or outdoor walking activities in bouts of minimum 10 min. is recommended.

In the exercise-log the patient is instructed to record when, where and how often she/he plans to exercise, what might obstruct the plans, and what can be done to overcome any perceived barriers. The exercise log includes contact information to enable the patient to contact the physiotherapist/nurse between sessions if required. During the initial home visit the physiotherapist/nurse assesses safety of the home environment in relation to the exercise program.

The first home session is followed by nine sessions, one weekly, with structured motivational and professional counseling, via tablet or telephone (choice of patient’s preference) by a physiotherapist/nurse for 10-weeks using a motivational interviewing approach. Day and time for the weekly call is agreed upon with the patient at their preference in mind on a weekly basis.

The weekly call will begin with a brief talk of what has happened during the exercise program over the past week (prior to the call the patient has sent a text message via phone with a picture of the last week exercise log). Consistent with the principles of motivational interviewing, the physiotherapist/nurse might then ask the patient why she/he might want to increase the exercise program (i.e. time and/or intensity) (desire); how she/he might do this if she/he decides to (ability); what would be the most important benefits in doing more exercise (reasons); and how important it is for the patient to perform more exercise at this time (need). The physiotherapist/nurse will encourage the patient to move towards commitment and action, with specific goals set for the following week (please see Table 6). During the call the patient document their goals in their diaries in the same manner as from the initial home visit session. The discussion will then move on to other issues in relation to COPD. The patient is provided with a written menu of topics relevant for COPD and self-care and encouraged to select a topic of relevance for discussion, providing opportunity for self-management. For a concise overview of the differences between PTR and HPR group, please see Table 7.

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Table 7. Short overview of differences from PTR and HPR intervention groups.

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Control group.

Patients randomized to the control group will receive usual care; medication, scheduled follow-up visits at the respiratory outpatient clinics or general practitioner. Except for assessment visits baseline and 10-week visit, 35-week and 75-weeks visits no intervention is offered. If a patient changes his/her mind and wishes to participate in a conventional hospital- or community-based PR program, it will be granted as this is a highly recommended treatment (e.g. rehabilitation after hospital admission due to exacerbation).

Maintenance program.

After completion of the 10-weeks intervention period, patients randomized to PTR or HPR are offered to continue for free in a 65-week maintenance program (MP), consisting of a supervised group tele-exercise once weekly for 60 min. (appr. 45 min. of exercise and 15 min. to group discussions when relevant).

The overall goal with the MP is to maintain or improve respiratory symptoms and physical functioning, other symptoms as fatigue, pain and sleep and affect behavior change positively (e.g., sustainable exercise habits, increase physical activity level, achieve knowledge on practical exercises) using minimal equipment.

During the 65-week MP patients attend one online session a week and are instructed and encouraged to perform similar online prescribed physical exercises at home. The weekly goal is for the patient to achieve at least 30 min. of muscle-endurance based exercises twice weekly. The patients are asked to count their physical exercises and activity level via a home diary. Furthermore, patients are encouraged to explore available mindfulness exercises via the tablet. The prescribed physical exercises are available on the tablet as an instructed exercise-film. Seven mindfulness exercises are available on the tablet for self-initiated mindfulness-guidance.

The MP consists of four themes during the entire 65-weeks (Table 8). The period for each theme is five weeks and are performed in the following order: a) “standardized program”, b) “balance theme”, c) “eccentric theme”, and d) “partner theme”.

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Table 8. Maintenance program–exercise and theme overview.

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The rationale for a balance theme is that secondary manifestations are detected in patients with COPD in form of impaired balance and deficits in postural control which increases fear of falling and risk of failing [36, 37]. The balance exercises aim to improve balance, increase knowledge on fall prevention strategies and give insight into simple, feasible and modifiable exercises, that can be performed in a home setting and as add-on exercises. The rationale for an eccentric theme is that eccentric movement is a key element of mobility and task performance [38] and more evidence is emerging regarding COPD [39], such as studies investigating eccentric cycling and downhill walking. Eccentric contractions occur during slow movement / deceleration movement thereby stretching the myofilaments due to high external load [38, 39]. This movement usually demands lower oxygen uptake, reduced heart rate and blood pressure [39], more specifically it increases muscle strength. The purpose of applying an eccentric workload is to induce peripheral muscle fatigue rather than dyspnea, create periodization in the scheduled muscle training program, provide the participants insight and knowledge on a difference strategy to muscle training / performing exercises.

The fourth theme is the “partner” theme, and the rationale is to apply “team spirit” / “gamification” perspective. The purpose of this block is to achieve cohesion in the group, create a motivational environment and provide opportunities to competition at an individual level.

The standardized program consists of the same six exercises used in the PTR group and the purpose it to continue with known exercises and for the patients from HPR group to familiarize with the supervised exercises and intensity.

The balance theme consists of the first three standardized exercises (Table 8 #1,2,3) followed by exercises with focus on balance. The exercises are presented in Table 8 and are previously used in other studies with patients with COPD [37]. All exercises are performed on an individual level regarding balance impairments and need of support. The exercises consist of four types: 1) stance exercises, 2) transition exercises, 3) gait exercises, and 4) functional strength exercises. All patients start with static exercises and are progressed after individualized to more challenging means such as eyes closed and cognitive tasks.

The eccentric theme consists of the six standardized exercises (Table 8, #1–6) applying an eccentric focus while performing the exercises. The exercises are performed in the same manner as the standard protocol regarding set and external load. For time-period please see Table 8.

Patients are instructed to perform their exercises individually with focus on deceleration of movement, e.g. 4–8 sec. deceleration and explosive concentric acceleration e.g. 1–2 sec. All patients perform the exercises at their individual level of physical function.

The fourth theme is “partner” theme and the exercises are performed in the same manner as the standard protocol regarding set and external load, however the intensity is defined by the following: 1) team up with a partner (2 and 2) one patient performs as many repetitions as possible (to achieve muscle fatigue) and then the other patient takes over, 2) “Roll the dice”–the number of eyes on the dices (up to four dices) accumulate number of repetitions or the number of eyes on one dice represents the amount of seconds for the set, 3) “Team knowledge” with a partner vs. another team; test of knowledge where the team who gets to correct answer have a break, whereas the other team perform 10 repetitions of a given exercise.

The exercises are presented in Table 8. All exercises will be progressed or regressed, i.e. if a patient are able to perform the exercises with correct intensity and safety then the exercise can be progressed or in case of the opposite then the exercise can be regressed for instance performing balance with more support. During standard protocol and eccentric theme external load is sought increased.

Statistical analyses plan.

Analyses of the outcomes will be performed by the trial statistician who is blinded to the treatment allocations. Secondary analyses will be performed by the investigator (CN).

Baseline data will be reported as means and standard deviations (medians and interquartile ranges) or frequencies and proportions as appropriate. Data analyses of primary and secondary endpoints will be performed using intention-to-treat analyses. Additionally, per-protocol analyses including patients who complete ≥70% of the PTR and HPR rehabilitation program will be performed. Reporting will follow the CONSORT (Consolidated Standards of Reporting Trials) Statement for non-pharmacologic trials [28]. Differences between the groups’ changes of primary and secondary outcomes (10-weeks from baseline; 35-weeks from baseline and 75-weeks from baseline) will be analyzed by mixed effect models. The models include adjustment for treatment groups, age, sex, BMI, FEV₁, Charlson Comorbidity Index and smoking status, and a random effect recruitment site with unstructured covariance matrix. To account for possible regression to the mean effect, the baseline measure for the outcome will be included as a fixed effect variable in the models. Normal distribution of the model residuals is evaluated by inspection of Q-Q plots. All data is expected to be missing at random, and missing values included in the analysis will be imputed by multiple imputation. Specific variables used for imputation will be explained and reported. If only a couple of values are missing sensitivity analysis replacing missing values with extremes may be used instead of multiple imputation.

Survival is visualized by Kaplan-Meier curves. Group differences on proportions of patients being adherent, hospitalization and death are analyzed using chi-squared test. No interim analysis will be performed. Statistical analyses are carried out using R 4.1.2. (R Foundation for Statistical Computing, Vienna, Austria). P-values of less than 0.05 are considered statistically significant.

Compliance.

In addition to the intention-to-treat analysis, we will also perform a per-protocol analysis. The participants in both intervention groups must have completed 70% per cent of the scheduled exercise program to be included in the per-protocol analysis.

Health economic analysis.

In a separate paper we will conduct cost-utility analysis (CUA) of the two new delivery models for PR delivered in a multi-center three-arm randomized controlled trial. The economic evaluation is conducted alongside the RCT calculating incremental cost-effectiveness ration. This CUA will followed international guidelines for the conduction of a CUA alongside a clinical randomized controlled trial [40, 41]. The EQ-5D-3L collected utility score will be used in the estimation of quality-adjusted-life-years (QALY).

Data collection.

All data are collected in CRF’s to uphold stringent data collection. Blinded assessors from three different hospitals (Bispebjerg, Hillerod, and Hvidovre) perform pre-, post- and follow-up test. All hospitals have two blinded assessors available who cover the entire Capital Region. The assessors have clinical experience and practice with patient-reported outcomes in questionnaires and physical performance tests. To ensure that all assessors follow the same test protocol, use standardized instructions and recordings of results, the assessors have completed an assessment calibration course. Furthermore, they have all been observed and evaluated performing live test on patients prior to start as blinded tester. To the extent possible, the same assessor tests a participant at all test times.

Data management.

All CRFs and paper versions of questionnaires will be reviewed and checked for errors and missing data before entered in a secure Research Electronic Data Capture (Redcap, version nr. LTS 13.7.14) approved by Capital Region. All data will be double-checked prior to exporting it to relevant statistical software programs (R, IBM SPSS version 29 and GraphPad Prison version 10.1.2). The principal investigator will have full access to the entire dataset. Co-investigators and steering-committee will have access as needed for random auditing. All CRFs and questionnaires will be anonymized. To ensure confidentiality all CRFs will be placed in a secured and locked filling cabinet where only the principal investigator and co-investigator have access to. Data management will comply with the rules of the Danish Data Protection Agency.

Outcomes.

All outcomes and time of measurements are presented in Table 9. All follow-up test will be conducted by a blinded assessor.

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Table 9. Outcomes and flowchart of study measurements.

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Primary outcome measure.

The COPD Assessment Test (CAT) will be used to measure change in respiratory symptoms. The CAT is a patient completed questionnaire consisting of 8 items on self-reported health-status and symptom [42]. Each item is scored ranging from 0 to 5 points, where 0 indicate no impact or symptoms and 5 representing worst score. A total score range from 0–40 points. CAT is a validated questionnaire with a Cronbach’s α of 0.88 and found responsive to change in self-reported health status and symptoms after pulmonary rehabilitation [25, 43]. A minimal clinical difference (MCID) of -2 to -3 points has been suggested [25]. For this study design we decided a MCID of -2.5 point will be of clinical relevance.

Questionnaires outcomes.

The Hospital Anxiety and Depression Scale (HADS) is questionnaire consisting of 14-items assessing anxiety and depression level in medically ill patients [44]. HADS consists of two sub scores; HADS anxiety (HADS-A) and HADS depression (HADS-D) comprising seven questions assessing anxiety and seven questions assessing depression, respectively. Each question ranges a score from 0–3 (where 0 = no symptoms). HADS has been validated with a Cronbach’s α of 0.83 (HADS-A) and 0.82 (HADS-D) [44]. Scoring from 0–7 on each of the two sub-scales are considered within normal range, whereas scores of 8–10 suggest a potential risk of anxiety and/or depression disorder. Scores of 11 and above suggest the probable presence of anxiety and/or depression disorder [44]. 1.5 point has been suggested as MCID on both [45]. Smid et al suggested MCID ranging between -2.0 and -1.1 points for HADS-A and -1.8 and -1.4 or HADS-D [25]. Nikolovski et al suggested a MCID of ≥ 1.5 in HADS-A, HADS-B and HADS-T [46]. In this study -1.5 point on both scales will be used as MCID.

The EuroQol-5D-3L (EQ-5D-3L) is a generic self-reported global measure for health-related QoL. EQ-5D consists of 5 domains (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and a 20 cm visual analog scale (EQ-VAS) ranging from zero (worst imaginable health) to 100 (best imaginable health). Each item in EQ-5D is scored ranging from 1–3 with 1 indicating no symptoms, producing a utility index range from -0.624 to 1.000. MCID of 6.5 to 8-points in EQ-VAS has been suggested [47]. Bae et al suggested a pooled MCID estimate of 0.028 for EQ-5D utility index [48]. We will use 6.5 point as MCID threshold for EQ-5D-VAS [49].

The Brief Pain Inventory (BPI) will be used to assess pain within a period of seven days [50]. The BPI consists of a “pain drawing” with indication of pain location and eight questions assessing pain on a visual analog scale ranging from 0–10 with 10 representing worst pain. A Cronbach α ranging from 0.91 (BPI magnitude domain) to 0.94 (BPI inference domain) has been suggested [51] The following cut-off scores has been suggested to assess severity of pain; mild pain (0–4), moderate pain (5–6) and severe pain (7–10) [52].

Multidimensional Fatigue Inventory (MFI-20) will be used to assess perceived fatigue [53]. The MFI-20 consists of 20 items with 5 domains (general fatigue, physical fatigue, mental fatigue, reduced motivation, and reduced activity). Each domain has four questions with a score ranging from 1–5, the highest score corresponds to highest level of fatigue. A total of 100 is possible. A systematic review investigated fatigue in patients with COPD and found a fatigue scale cut-off score of ≥ 13 (severe fatigue) [54]. Within early stages of Parkinson’s disease, a screening cut-off score for general fatigue of 11 points and for total MFI of 60 points for clinically significant fatigue has been suggested [55]. In this study we will use a cut-off ≥ 13 points.

Pittsburg Sleep Quality Index (PSQI) is used to assess sleep quality [56]. The PSQI measures sleep disturbances and sleep habits within the past month. The PSQI consists of 11 items that are scored on a four-item likert scale ranging from 0–3. In the present study questions 1–9 are answered by the patient. A global PSQI score of ≥ 5 reliably distinguishes “poor” quality sleepers from “good” quality sleepers (diagnostic sensitivity 89.6% and specificity 86.5%) [56, 57].

Physical activity.

To measure 24-h physical activity patients will be asked to wear an activePAL^TM triaxial accelerometer (PAL Technologies Ltd., Glasgow, UK) [58]. The activePAL will be worn for 5 consecutive days prior to randomization, 5 days after completion of 10-week intervention, 5 days after completion of 35-weeks follow-up assessment and 5 days after completion of 75-weeks follow-up assessment. In this study the level of physical activity is an exploratory variable. Approximately 50% of the included patients will be asked to wear an activePAL^TM and these patients will preferably be living within a 25 km distance of Hvidovre University Hospital for practical reasons. The activePAL^TM accelerometer measures time spent sitting/lying, standing, walking (number of steps, cadence) and number of transitions (i.e. sit-to-stand), steps per day, metabolic equivalent of task (MET) and time in bed. The activePAL^TM is a valid and reliable tool used in several COPD studies to track and measure physical activity [59, 60]. Demeyer et al have suggested a distribution-based MCID of 600–1100 steps per day for patients with COPD, this range has been found consistent by Driver and colleagues [61, 62]. We consider an increase of 600 step per day as clinically important change for this study considering the target group included.

Physical capacity and function.

1-minute sit to stand test (1-min-STS) is used to measure physical capacity. The 1-min-STS test is performed using an armless chair with a height of 44–46 cm, the patient arms are crossed and placed at the chest. If the patient is not able to perform sit-to-stand without the use of arms, the scoring is 0. The patient is asked to perform 1–2 practice attempts before performing the test for 1 min. The patient is instructed to perform as many as possible sit-to-stand at a self-selected pace. The patient will be given a notification when 15 sec. are left of the test, otherwise no other communication will be provided. The patient is allowed to take a pause during the test, but the time will still be ongoing.

1-min-STS have been chosen because of its relationship to submaximal efforts of physical capacity. Furthermore, the test is possible to implement in a home environment. McDonald and colleagues found that 1-min-STS and 6 min. walking test were strongly correlated (r = 0.61) and that the test demonstrated satisfactory validity and responsiveness [63]. A MCID of 2.5 repetitions have been suggested [64, 65].

30-second sit to-stand (30-sec-STS) is used to measure leg muscle strength. 30-sec-STS is a common test for assessing physical capacity for COPD patients [66]. The test is practical and simple in a clinical setting. The 30-sec-STS test is performed using an armless chair with a height of 44–46 cm. Patients are asked for perform as many as possible within 30 sec. No communication is provided during the test. If the patient is not able for perform sit-to-stand without support from the chair, the score is 0. The number of repetitions from the 30-sec-STS will be retrieved during performance of the 1-min-STS. The patients are not aware of this mid-time (30-sec-STS) retrieval when performing the 1-min-STS. A MCID of ≥ 2 has been suggested by Zanini and colleagues [67].

Short Physical Performance Battery and (SPPB) is used to measure physical function and frailty [68]. The test consists of a) standing balance test (Guralnik), b) a 3-meters-walk test and, c) a 5-sit-to-stand. The balance test is performed with three separate tests: stance side-by-side for 10 sec., stance semi-tandem for 10 sec., and tandem stand for 10 sec. A maximum score of balance is 30. The 3-meters-walk test is performed after the balance test. In the gait test the patient walks in her/his normal pace. The time used is recorded and the test is performed twice. If the patient uses a walking aid this is noted. The 5-sit-to-stand test (5-STS) is performed twice with 2 min. apart. It is recorded how fast a patient can perform 5-sit-to-stand without using their arms. If the patient is not able to perform the test without support, then the score is 0 points. The total score of all tests is comprised to a final SPPB score with a possible score of 0 to 12 points [69]. A scoring of 0–7 point is defined as physical frail, 8–9 points physical pre-frail and 10–12 physical non-frail. A change of 0.5 points on the SPPB is considered a small meaningful change, while a change of 1 point on the SPPB is considered a substantial meaningful change within an older community-dwelling population [70, 71].

Hand-grip strength (Jamar dynamometer) is used to measure muscle strength in the upper extremity [72]. The Hand-grip strength (HGS) is measured on both sides in a seated position. The patient keeps her/his arm slightly abducted, the elbow flexed at 90 degrees and the forearm in a neutral position between supination and pronation. All measurements are repeated three times in each side, and the individual average are calculated and used for analysis. To our knowledge no MCID exists for HGS in patient with COPD. Pragmatically, we will consider a percentual strength increase of 15% relative to the peak baseline HGS as clinically relevant when interpretating changes over time.

Descriptive variables.

Lung function test, medication for COPD, age, sex, arthrometries (weight, height, body mass index), marital status, length of education, smoking status, years with COPD, and Charlson comorbidity index (CCI). Furthermore, Body-mass index, airflow Obstruction, Dyspnea and Exericse (BODE index) are registered, and it is a multidimensional scoring system and capacity index used for patients with COPD. The BODS index is developed from the original BODE index using 5-STS and the index demonstrate prognostic value for predicting mortality risk for patients with COPD [73]. The lung function test is conducted at the respiratory department of the referral hospitals by a pulmonologist or respiratory nurse before baseline assessment. All hospitals in the study have clinically approved spirometry equipment.

Other variables.

Adverse events, hospitalizations and deaths will be extracted from Statistic Denmark throughout the trial. Data extraction include number of outpatient visits, number of hospitalizations, hospitalization days and number of deaths. Data will be analyzed as all-cause, respiratory related admissions and outpatient visits. Self-reported falls and bone-fractures during the intervention will be -recorded.

Adverse events.

Any adverse events (AE) during testing and during training will be recorded in the CRF and training protocol, respectively. A standardized method will be used; event description (i.e., a clear identification of the AE), onset dates (dates for when the even began and resolved), intensity (classification of the AE’s severity–e.g., mild, moderate, severe) and causality assessment (evaluation of the relationship of the AE to the study, e.g., probably related, possibly related, not related). To minimize bias the investigators are trained to ask neutral questions about the AE’s during patient interview to ensure data collection is as objective as possible.

Serious AEs are reported to the principal investigator within 24 hours. A pulmonologist, a respiratory nurse and a clinical physiotherapist will survey and evaluate serious AEs.

Dropouts.

All dropouts and reasons for these will be recorded by the research team. Dropout will occur when a patient informs the investigators that he/she is unwilling to participate in the study any longer. If a patient does not participate in an exercise session, without cancellation, the patient is contacted to establish reason for not attending. In cases where it is not possible to contact the patient, he/she will be recorded as drop-out after 3 months (from the maintenance program, unless there is a valid reason for not attending the sessions, for instance hospitalization, disease or family circumstances). If a patient is withdrawn from one of the intervention groups, all equipment will be collected. The patient will still be eligible for follow-up assessments, if the patient wishes to, and data will be analyzed according to the intention-to-treat analysis.

Change to initial plan.

As per February 2024 we have started a collaboration with the municipality of Copenhagen, Center for pulmonary diseases. The center will begin recruitment in the early spring of 2024. We plan to establish collaboration to other surrounding municipalities close to Bispebjerg and Hvidovre University Hospitals.

Furthermore, a Facebook site has been launched with the purpose of recruiting patients with COPD that are not referred to the hospital, but where the general practitioner has the overall treatment responsibility.

Publication.

The intervention study will be disseminated in two separate publications. A 10-weeks (primary endpoint) RCT effect study and subsequently a publication on the effects from a 65-weeks maintenance program (that is 75 weeks from baseline, secondary endpoint).

Furthermore, we plan to publish the following: A) An original qualitative article with focus on data from a mixed-method study using qualitative interviews and a generic survey to gain insight into patients’ thoughts, experience and attitudes towards new rehabilitation models and the maintenance program. B) Reliability calculations. Intra- and inter tester reliability will be calculated on physical outcome measures (1min-STS and 30-sec-STS, handgrip strength, SPPB) in fifty consecutively recruited patients. The retest is completed seven to 10 days after baseline assessment and prior to intervention start. The reliability in the patient reported questionnaires (CAT, HADS, EQ-5D, PSQI, MFI and BPI) will be calculated in the same sample of 50 patients. The reliability for the physical outcome measures and patient reported outcomes will be published in separate articles. C) An original article with focus on CUA of the two new delivery models for PR targeting patients with COPD who opt out of outpatient PR service. D) Other hypothesis generating explorative articles with focus for example on sleep, fatigue, dose-response between physical activity and PR, responder- and non-responder analysis.