Feasibility of a Home-Based Cognitive-Physical Exercise Program in Patients With Chronic Obstructive Pulmonary Disease: Protocol for a Feasibility and Pilot Randomized Controlled Trial

Background Chronic obstructive pulmonary disease (COPD) is a progressive condition associated with physical and cognitive impairments contributing to difficulty in performing activities of daily living (ADLs) that require dual tasking (eg, walking and talking). Despite evidence showing that cognitive decline occurs among patients with COPD and may contribute to functional limitations and decreased health-related quality of life (HRQL), pulmonary rehabilitation continues to focus mainly on physical training (ie, aerobic and strength exercises). An integrated cognitive and physical training program compared to physical training alone may be more effective in increasing dual-tasking ability among people living with COPD, leading to greater improvements in performance of ADLs and HRQL. Objective The aims of this study are to evaluate the feasibility of an 8-week randomized controlled trial of home-based, cognitive-physical training versus physical training for patients with moderate to severe COPD and derive preliminary estimates of cognitive-physical training intervention efficacy on measures of physical and cognitive function, dual task performance, ADLs, and HRQL. Methods A total of 24 participants with moderate to severe COPD will be recruited and randomized into cognitive-physical training or physical training. All participants will be prescribed an individualized home physical exercise program comprising 5 days of moderate-intensity aerobic exercise (30-50 minutes/session) and 2 days of whole-body strength training per week. The cognitive-physical training group will also perform cognitive training for approximately 60 minutes, 5 days per week via the BrainHQ platform (Posit Science Corporation). Participants will meet once weekly with an exercise professional (via videoconference) who will provide support by reviewing the progression of their training and addressing any queries. Feasibility will be assessed through the recruitment rate, program adherence, satisfaction, attrition, and safety. The intervention efficacy regarding dual task performance, physical function, ADLs, and HRQL will be evaluated at baseline and at 4 and 8 weeks. Descriptive statistics will be used to summarize intervention feasibility. Paired 2-tailed t tests and 2-tailed t tests will be used to compare the changes in the outcome measures over the 8-week study period within and between the 2 randomized groups, respectively. Results Enrollment started in January 2022. It is estimated that the enrollment period will be 24 months long, with data collection to be completed by December 2023. Conclusions A supervised home-based cognitive-physical training program may be an accessible intervention to improve dual-tasking ability in people living with COPD. Evaluating the feasibility and effect estimates is a critical first step to inform future clinical trials evaluating this approach and its effects on physical and cognitive function, ADL performance, and HRQL. Trial Registration ClinicalTrials.gov NCT05140226; https://clinicaltrials.gov/ct2/show/NCT05140226 International Registered Report Identifier (IRRID) DERR1-10.2196/48666

A strong rationale is presented for the study where evidence is provided for both cognitive and physical impairments in COPD and how traditional COPD management strategies have primarily focused on treating the physical limitations. They also present a compelling justification for how cognitive limitations can result in decreased physical performance when they are performed simultaneously (i.e. dual-task interference). The applicants hypothesize that a training modality targeting several cognitive domains accompanied by physical training may offer the desired flexibility and testing effects on daily task performance in COPD patients. For this pilot RCT study they will address two specific aims: 1) To evaluate the feasibility (recruitment rate, program adherence, attrition, safety, and participant satisfaction) of an 8-week home-based C-PT program in COPD patients.
2) To derive preliminary estimates on intervention efficacy with C-PT on dual-task interference, cycling performance, balance, ADL, and HRQL.

Strengths of the Proposed Study
-The study is novel and the combination of cognitive and physical training is interesting and potentially clinically important if it can be effectively administered.
-Team is very strong and appears to have the access, experience, and training necessary to recruit patients, perform the primary and secondary outcomes, and deliver the home-based exercise and cognitive therapy.
-The intervention is interesting and novel (albeit quite a commitment if they are in the combined group), the program is being delivered by exercise professionals but patients having access to exercise videos and COPD-specific manuals is well thought out and could help patients considerably.
-As addressed by the applicants, the study can be performed during the COVID pandemic and could be even more important considering some patients may have been more inactive than normal over the last year.

Weaknesses and Limitations of the Proposed Study
-This is fundamentally a phase III RCT design, comparing usual care (home-based exercise rehabilitation) with usual care + cognitive therapy being proposed as a feasibility and datagenerating study. I understand why the applicants have taken this approach (they want to know the effect of cognitive therapy in addition to the physical training compared to physical training alone) but whether they will get much of a signal with potentially only 9 finishing (12 per arm with the potential for 20% attrition) is a concern. My issues in this regard are 1) the heterogeneity of the patient sample in each group, 2) there will be responders and nonresponders in both arms, and 3) the effects of cognitive therapy on top of a physical training intervention on backward spelling (when the participants are not directly practicing this skill) might be quite small (although I admit there is no way of knowing this). As such, they may not get enough of an effect to accurately power a future study even though the study will be deemed feasible.
-The sample will be stratified for sex but with such a small sample size, large differences in groups for baseline exercise capacity and cognitive function could greatly influence the study findings. How will these important cofounders be taken into consideration? -One of the secondary measures mentioned is a cycling test while reading backwards. However, no details of this test are presented. On a foot peddler with the patient at home potentially on their own, how will this test be performed, how will intensity be set, and how will the measurements be standardized (across the three time points) and monitored? -It is not mentioned whether the person performing the cognitive and exercise assessments at each time point will be blind to the study allocation. In the budget, funding is requested for the RA to train and virtually assess the participants. If the same person does both, this will greatly bias the data.
-Recruiting, training, and assessing 24 individuals with COPD through an 8-week intervention in 9 months is highly challenging and the timeline is ambitious. Confidence in the feasibility of the study could have been strengthened by providing evidence to support previous studies of this nature that have been completed in a similar timeline. Additionally, accrual rates specific to this group's research for previous interventional studies in COPD would have strengthened this aspect of the proposal.

Impact on COPD Research
It is hoped the study will provide preliminary data of the feasibility and efficacy of combined physical and cognitive therapy to power a future RCT. If that future study is successfully funded and performed, positive findings could change how we manage patients with cognitive and physical impairments associated with COPD. I have no additional issues with this study trying to generate preliminary data for a future RCT, which will be important. However, it is unlikely to lead to a meaningful publication on the efficacy aspect of the project due to the comments made regarding the very small sample size for a RCT assessing an exercise intervention + cognitive therapy versus an exercise intervention alone.

Knowledge Translation Plan
A relatively strong knowledge translation plan is presented. The applicants will use national and international platforms (i.e. ATS, CTS) to present the findings of the study, they will also disseminate findings through the diverse professional networks of the study team members. The ATS web committee platform, social media, conference presentations, and traditional journal publications will also be utilized. It is mentioned that they will have two patients involved to help implement the research and facilitate transition across COPD working groups, but it is not really clear how this will be specifically done.

Budget Considerations
Generally, the budget items requested seem appropriate. The applicant is asking for money toward a Kinesiology research assistant, exercise equipment, fitbits, tablets, etc. While the RA is justified and it is fairly obvious how the equipment will be used, it is not justified within the context of the study. Additionally, 20 hours of statistician support ($2000) and 24 x $25 for ECGs from lifelabs are requested but not justified or mentioned in the proposal.

A grant for $150K is submitted at time of application to the University Health Network / Mount
Sinai for what appears to be the same project in COPD and ILD is mentioned and addressed. However, in the PI's CV it is mentioned that they have funding for home-based research in Lung Tx. Overlap between this study and other funds held are not justified.

Ethics Considerations
I have no ethical concerns with the study. The ethics certificate from the institutional REB still needs to be sent in at the time of application.

Summary Comments
This is a strong team proposing an interesting and novel study. The proposed intervention could be highly beneficial for individuals with COPD and impaired cognitive function. If a large effect is seen from the addition of cognitive therapy I believe the idea has the potential to lead to a successful CIHR application. However, the proposed project is ambitious within a one-year timeline and there is the potential that a larger initial study is required to obtain the preliminary data needed.

Applicant(s)
This team of five had a good mix of early, mid-career, and senior researchers. The team is also interprofessional, which will strengthen the research process. The PI is an MD PhD, early career researcher. As the Director of Lung Transplantation, it seems there would be a solid network for KT and dissemination as well as other collaboration if/as needed. The co-PI is a physical therapist with an expansive knowledge. These two people will contribute 10% to the project. There is not a lot of detail on interaction of team (meetings? communication?), and it is difficult to assess how the team will work together.
The PI has an excellent track record in research and publications.
Dr. Campos, as CRC chair, is a strong addition to the team.

Proposed Research Project
The proposed project will compare cognitive + physical training to physical training alone in an 8-week home-based program for people with COPD. They will build off their own previous research and have also submitted a similar proposal for funds.
The proposal notes: "Dual-task cognitive and physical training has not been performed in people living with COPD despite the fact that cognitive impairment has been well described for several decades." This is a novel addition to the literature. This study will focus on 2 aims: 1) to evaluate feasibility of the program, and 2) to derive preliminary estimates on the efficacy of the intervention. These objectives seem fair and feasible within the proposed timeline.
This pilot RCT will randomize 24 patients to receive either PR+ cognitive training or just PR. The plan for both seems to be sound and based on solid evidence.
Concerns about recruitment and COVID were discussed. Concerns about comparisons among the two groups were also discussed, but not convincingly. Given the possible confounding factors (from current Rx to current exercise knowledge), it is not clear that 24 participants would be sufficient. That said, the team aptly describes this as a feasibility pilot only and are aware of these limitations.

STRENGTHS
-Novel -Strong team (good access to conduct research, strong knowledge base and interprofessional team) -Doable within the timeframe WEAKNESSES -Design may not get the necessary results; stratified by sex, usual care of PT vs. PT + cognitive therapy.
-Will 24 be sufficient with 20% attrition? They may not get data needed for future RCT.
-The effects of CT might be quite small because of confounding variables.

Impact on COPD Research
Seems very exciting and easy to add something like this one. I do wonder about the feasibility in terms of cost -is there a cost-benefit to providing extra exercises? Could this be accomplished in a different way? Who would fund this added service in the future?

Knowledge Translation Plan
Plan follows traditional academic KT including journals (x2) and conference presentation. Also noted the network of the research team as a means to distribute findings. They will also make use of social media through established sites like ATS and ETS.

Budget Considerations
Seems appropriate, though there is a significant amount for technology/equipment that was not justified/explained. RA is doing significant amount of work -not sure if enough hours were provided/allotted. NOTE: Other funding being applied for indicated a 50% overlap.

Ethics Considerations
Involves human subjects. Proposal indicates ethics form needed to be sent.

Other Considerations
The proposal mentions patients in the KT plan ("We will also aim to have 2 COPD patient partners to help with research implementation and facilitate translation across COPD working groups"), but there are no further details nor a line item in the budget for patients.

Summary Comments
Overall well written and clear. Involvement of patients seems only cursory. Would be excellent to understand patient perspective after the intervention (i.e. adding qualitative methods of some sort, though I appreciate this may be out of scope and expertise).