Secondary prevention of stroke. A telehealth-delivered physical activity and diet pilot randomized trial (ENAbLE-pilot)

Background: Improving physical activity levels and diet quality are important for secondary stroke prevention. Aim: To test the feasibility and safety of 6-month, co-designed telehealth-delivered interventions to increase physical activity and improve diet quality. Methods: A 2 × 2 factorial trial (physical activity (PA); diet (DIET); PA + DIET; control) randomized, open-label, blinded endpoint trial. Primary outcomes were feasibility and safety. Secondary outcomes included stroke risk factors (blood pressure, self-report PA (International Physical Activity Questionnaire (IPAQ)) and diet quality (Australian Recommended Food Score (ARFS)), and quality of life. Between-group differences were analyzed using linear-mixed models. Results: Over 23 months, 99 people were screened for participation and 40 (40%) randomized (3 months to 10 years post-stroke, mean age 59 (16) years). Six participants withdrew, and an additional five were lost to follow-up. Fifteen serious adverse events were reported, but none were deemed definitely or probably related to the intervention. Median attendance was 32 (of 36) PA sessions and 9 (of 10) DIET sessions. The proportion of missing primary outcome data (blood pressure) was 3% at 3 months, 11% at 6 months, and 14% at 12 months. Between-group 95% confidence intervals showed promising, clinically relevant differences in support of the interventions across the range of PA, diet quality, and blood pressure outcomes. Conclusion: Our telehealth PA and diet interventions were safe and feasible and may have led to significant behavior change. Trial Registration: ACTRN12620000189921.


Introduction
Low levels of physical activity (PA) and poor-quality diet are among the top-10 independent risk factors for stroke and influence other important risk factors including hypertension, dyslipidemia, and obesity. 1 International Clinical Guidelines recommend increasing PA and improving diet quality to reduce risk of recurrent stroke. 2 Exercise interventions for people with stroke are effective for reducing blood pressure but only when supervised aerobic exercise is provided. 3There are no trials of dietary interventions for secondary stroke prevention, but the Mediterranean-style diet holds the most promise. 4ncreasing PA and improving diet quality involves behavior change.Effective behavior change strategies include monitoring, tailored education, personalized goal setting, prompts, and social support. 5People living with stroke face additional barriers and therefore require personalized support.Transport and access to services in regional and remote areas are additional barriers.Telehealth-delivered services are a potential solution.
Our trial tested the feasibility and safety of two telehealth-delivered interventions for reducing stroke risk factors, co-designed in partnership with people with stroke, researchers and healthcare clinicians and included evidence-based behavior change strategies.
Our primary research question was:

Design
A prospective 2 × 2 factorial (4 arm) pilot randomized, open-label, blinded endpoint trial was conducted in accordance with the CONSORT checklist for pilot studies. 6Ethics approvals obtained from the Hunter New England Human Research Ethics Committee (2019/ETH11533) and University of Newcastle Human Research Committee (H-2020-0022).Full details of the trial design are reported elsewhere. 7All aspects of the trial were conducted via telehealth with no in person contact.

Participants
Participants were recruited from around Australia via referral from hospital-based stroke clinics, rehabilitation facilities, and word of mouth (including promotion via non-government organizations and social media).In brief, inclusion criteria were adults who experienced a stroke or transient ischaemic attack between 3 months and 10 years previously; living at home; able to walk independently indoors; sufficient cognitive ability (or a carer to support) to engage in the interventions.Exclusion criteria included: currently meeting PA guidelines or adhering to a Mediterranean-style diet (assessed via International Physical Activity Questionnaire (IPAQ) 8 and Mediterranean Diet Score (MDS) 9 respectively).Participants provided written informed consent.

Baseline assessment
Baseline assessment included demographic information, details about participants' stroke event, stroke severity (National Institutes of Health Stroke Scale, measured at baseline assessment), disability level (modified Rankin Scale score, Functional Ambulation Classification) and exercise self-efficacy (Short Self-efficacy for Exercise Scale).Participants were randomized with block allocation (block size of 4 prepared by an independent statistician and coded into the trial database) after baseline assessment.
Further assessments occurred at 3-, 6-, and 12 months by a blinded assessor.

Intervention
The two co-designed intervention packages were: "i-REBOUND-Let's get moving" (PA intervention ); and "i-REBOUND-Eat for health" (DIET intervention).We describe these 6 month, telehealth-delivered interventions according to the Template for Intervention Description and Replication checklist (TIDieR) elsewhere. 10,11he intervention sessions were hosted via real-time video conferencing software ("Attend Anywhere" (Attend Anywhere Pty Ltd) or "Zoom" (Zoom Video Communications, Inc.)).
Both the PA and DIET interventions included evidencebased, tailored behavior change support strategies. 5 Use of an activity monitor (provided FitBit™ or own device) or activity diaries were encouraged in the PA intervention.The DIET intervention included completion of the MDS at each DIET session to help identify new goals and strategies for adherence.Manuals were developed to train intervention therapists.Resources including information booklets, blood pressure monitors, activity monitors, recipe books and other diet support resources including a starter pack of key ingredients were mailed to participants.The four arms of the trial are described briefly below: CONTROL: Information and general advice about PA and diet via two telehealth sessions (Months 0 and 3).Dissemination of hard copy documents (and/or links to online resources) about Australian Government PA and healthy eating guidelines.
PA: Months 0-3: Twice weekly in-home telehealthsupervised exercise sessions (24 in total).Each session included (1) supervised, real-time exercise aiming for 20 mins of moderate to vigorous PA, (target heart rate 55% to 90% of age-predicted maximum (HRMax); and/ or rating of perceived exertion (Borg category ratio 10, CR-10) between 3 and 6 points), and (2) discussion of goals and strategies to support PA to achieve a minimum of 150 minutes of moderate to vigorous PA per week.Months 4 to 6: Individually tailored home and community exercise program with once-weekly telehealth support.
DIET: Months 0-3: Telehealth-delivered, individualized dietary counseling sessions in weeks 1 and 2 and fortnightly thereafter (7 in total) to support participants to follow a Mediterranean-style diet.Months 4 to 6: Monthly dietary counseling sessions.
PA + DIET: The PA and diet intervention packages were delivered simultaneously.

Outcome measures
Our co-primary aims were feasibility and safety at 6 months.Feasibility was assessed by trial metrics including proportion of eligible people enrolled, adherence to intervention sessions, participant drop-out rates and missing data for the exploratory clinical outcomes.To assess safety, adverse event data were collected via telehealth at each assessment time point, and during intervention sessions (7).An independent Data Safety Monitor adjudicated adverse event data.Blood pressure was measured using the iHealth Track (KN-550BT) monitor, mailed to participants and collected in accordance with recommended guidelines.Other secondary measures collected via telehealth included selfreported PA (IPAQ), diet quality (Australian Recommended Food Score (ARFS) derived from the Australian Eating Survey, 12 fatigue (Fatigue Severity Scale, 7-item), mood (Depression, Anxiety and Stress Scale, 21-item) and quality of life (EuroQol-5 Dimensions).Our process evaluation (see) 7 will be reported separately.

Data analyses
Participant demographics, feasibility, and safety data were analyzed descriptively.To explore the interventions' effect on stroke risk factors, fatigue mood, and quality of life, we evaluated within-and between-group effects using linearmixed models, which included baseline, mid-intervention (3 month), end-intervention (6 month), and long-term follow-up (12 month) measures with p values < 0.05 considered statistically significant.Mixed-model analysis included imputation of missing data and adjustments for multiple comparisons.We assumed no interaction between the interventions 13 and collapsed groups (supplemental Figure 1) to examine the individual effects of PA and diet on stroke risk factors, fatigue, mood, and quality of life as follows: 1. PA and PA + DIET compared with CONTROL and DIET (exploring effect of PA intervention).2. DIET and PA + DIET compared with CONTROL and PA (exploring effect of DIET intervention).
As this was a pilot trial, formal sample size calculations were not conducted.We aimed to recruit 80 participants, with an interim target of n = 40.

Results
Figure 1 presents the flow of participants through the trial.Table 1 presents baseline characteristics.Mean participant age was 59 (SD 16) years, 16 (40%) were female, and the median time since stroke was 39 (interquartile range (IQR) 7-63) months.There were no substantial differences in International Journal of Stroke, 19 (2)   characteristics between participants retained and lost to follow-up at 12 months.
One intervention therapist (physiotherapist, 15 years' experience) provided the majority (334 (63%) of PA intervention sessions.The remainder were provided by another physiotherapist (20 years' experience), and an exercise scientist (28 years' experience).All DIET intervention sessions were provided by the same dietitian (5 years' experience).

Feasibility
Between March 2020 and January 2022, we screened 99 people: 45 were ineligible, 14 declined, and 40 were randomized (Figure 1).The most common reason for ineligibility was being too physically active (n = 31).Six participants withdrew from the trial, and an additional 5 participants were lost to follow-up (Figure 1).The proportion of missing data for the clinical outcome of blood pressure was 3% at 3 months, 11% at 6 months, and 14% at 12 months (Table 2).
A total of 527 (73% of scheduled) PA sessions were attended.During supervised exercise sessions, participants, on average, exercised for 20 (SD 0.4) minutes, reached 65% (SD 7) of their predicted HRmax, and had a perceived exertion rating of 3.4 (SD 1.0) on the Borg CR-10 scale (Table 2).A total of 182 (91% of scheduled) diet sessions were attended.

Safety
Fifteen serious adverse events occurred (mostly hospitalization for unrelated health issues); none were deemed definitely or probably related to the trial.There were 85 adverse events; 25 were deemed possibly or probably related, and 5 (light-headedness, pain) were deemed definitely related to the intervention.No falls occurred during supervised exercise sessions.See Supplemental Tables.

Effect of the PA intervention on stroke risk factors, fatigue, mood, and quality of life
Table 3 presents results for the effect of the PA intervention on stroke risk factors, fatigue, mood, and quality of life.There were no significant differences for changes in blood pressure over time.There was, however, a trend toward greater systolic and diastolic blood pressure reductions at 3 months in the PA group compared with CONTROL (mean   Participants who received the PA intervention reported spending significantly more time physically active at 3 months, compared with participants who did not (mean between-group difference 744 METmin/wk (95% CI: 73-1415)).This between-group difference was lost at 6 months but was present again at 12 months (mean between-group difference 1071 METmin/wk (95% CI: 271-1871)).Data for device-measured PA will be reported in future papers.
The PA intervention did not have a significant effect on self-reported fatigue, mood, or quality of life.

Effect of the diet intervention on stroke risk factors, fatigue, mood, and quality of life
Table 4 presents results for the effect of the DIET intervention on stroke risk factors, fatigue, mood, and quality of life.Participants receiving the DIET intervention had significantly lower diastolic blood pressure at 6 months compared with baseline (mean within group difference DIET −2.6 mmHg (95% CI: −5.0 to −0.2).There were no other significant within or between-group differences for changes in blood pressure over time.
Data on tolerability of the interventions and participant and therapist feedback will be reported as part of the process evaluation in future papers.

Discussion
Telehealth-delivered PA and diet interventions were feasible and safe to deliver, and led to statistically significant, and clinically meaningful improvements in PA, diet quality, and quality of life.While not powered to detect statistically significant between-group differences, we also found a trend toward lower blood pressure associated with the diet intervention.
Conducting a complex clinical trial for people with stroke entirely via telehealth is novel, and we found it to be feasible.Telehealth delivery was not a barrier to recruitment; only one person was unable to participate due to inadequate Internet connection.Adherence to the intervention sessions was high, and percentage of missing outcome data low.Recruitment was our greatest challenge; we were unable to reach our target sample of n = 80 within the funding and time available.While not quantifiable, the pandemic likely impacted recruitment rates via hospital-based stroke clinics and rehabilitation services.Like many other trials of health behavior change, the people included in our trial lacked diversity and may not represent those at greatest need for the interventions.Most were young, lived in metropolitan areas, were normotensive and had a moderate to high degree of self-efficacy for exercise at baseline.We also had to exclude a large number of people who were already sufficiently physically active.Future trials should include strategies for recruitment to ensure people in most need are represented.
Our safety and feasibility trial was not powered to detect statistically significant results.However, both the PA and DIET interventions led to improvements in PA levels and diet quality, respectively.This, combined with positive trends in blood pressure, suggest our interventions may reduce cardiovascular disease and recurrent stroke risk.Therefore, we plan to further test these interventions within a fully powered trial.

Strengths and limitations
Our trial was robustly designed, adhered to the CONSORT statement for pilot studies and followed international recommendations for developing and reporting complex interventions. 14The drop-out rate of 10% at 6 months was in line with other complex clinical behavioral intervention trials.
The 28% drop-out rate at 12 months may be attributable to the lack of participant contact after 6 months.
A strength of our trial was the comprehensive reporting and adjudication of adverse events.No serious and only five non-serious adverse events were "definitely related" to the interventions.Most adverse events were reported in the PA and PA + DIET groups, where contact between trial staff and participants was more frequent.In several instances of unrelated adverse events, participants were advised to seek medical review, which led to subsequent intervention.Many people with stroke in Australia do not have routine follow-up with stroke specialists after 3 months, so it is possible that by providing a regular point of contact with health professionals, our trial may have led to benefits for participants beyond the intent of the interventions themselves.

Conclusion
Providing telehealth exercise and diet interventions without in-person contact is safe, feasible, and may lead to reductions in important stroke risk factors.Further work to determine whether these interventions can be scaled, and delivered to a more diverse group of people with stroke is needed.

Figure 1 .
Figure 1.Design and flow of participants through the trial.

Table 4 .
activity (PA and PA + DIET groups combined); Con: no physical activity (CONTROL and DIET groups combined); IPAQ: International Physical Activity Questionnaire; FSS-7: Fatigue Severity Scale-7 item; DASS: Depression, Anxiety and Stress Scale; EQ-5D: European Quality of Life Scale.Effect of diet on stroke risk factors, fatigue, mood and health-related quality of life (values are mean (SD), or estimated mean difference (95% confidence interval; bold indicates statistical significance).

Table 1 .
Baseline characteristics of participants.
*Lost to follow-up at any time point.(Continued)

Table 3 .
Effect of physical activity on stroke risk factors, fatigue, mood, and health-related quality of life (values are mean (SD), or estimated mean difference (95% confidence interval; bold indicates statistical significance).