Remote Ischaemic Conditioning for Fatigue After Stroke 2 (RICFAST 2) (RICFAST 2)

Background

Post-stroke fatigue (PSF) is a feeling of exhaustion that persists even after rest. It affects more than half of stroke survivors during their recovery, and around half of those affected report it as one of their worst symptoms. Stroke survivors and clinicians identify fatigue as a key limitation to post-acute rehabilitation. In the longer term, PSF impairs functional recovery, social engagement and return to work, and it is associated with reduced quality of life. Identifying effective treatments for PSF has been highlighted as a research priority for life after stroke both nationally and internationally, but no intervention has robust evidence of benefit.

The causes of PSF are multifactorial and include altered cortico-motor excitability, elevated inflammation and psychosocial factors. There is also mounting evidence implicating impaired mitochondrial function and cellular bioenergetics as a cause of fatigue in several clinical conditions. Impaired mitochondrial energy metabolism has been demonstrated in cancer-related fatigue, chronic fatigue syndrome, and neurological conditions with a very high prevalence of fatigue, including motor neurone disease and Parkinson's disease. Reduced muscle mitochondrial enzyme content has been found in severely fatigued older adults compared with non-fatigued counterparts, and impaired aerobic energy metabolism has been shown in the mitochondria of people with PSF. Addressing mitochondrial function is therefore likely to be an important component of PSF management.

Remote ischaemic conditioning as a potential treatment for PSF

Remote ischaemic conditioning (RIC) delivers brief, reversible episodes of limb ischaemia and reperfusion by cyclically inflating and deflating a blood pressure cuff on the upper arm. RIC improves cerebral blood flow in preclinical models and in clinical studies of vascular cognitive impairment and stroke, which is potentially relevant to the altered cortico-motor excitability seen in PSF. The release of vasoactive substances such as nitric oxide and adenosine in response to RIC improves endothelial reactivity and skeletal muscle perfusion in healthy people, which may mitigate the impaired sustained muscle contraction seen in post-stroke muscle fatigue. RIC may also moderate the inflammatory component of PSF by reducing inflammatory mediators such as TNF-α, IL-1β and IL-6.

Most importantly, animal studies indicate several cellular pathways through which RIC may preserve mitochondrial oxidative capacity. RIC preserves mitochondrial respiratory chain function in the brain in mice and slows ATP depletion in porcine skeletal muscle after experimental ischaemic stress. In 22 chronic stroke survivors, two weeks of ischaemic conditioning significantly increased the duration of submaximal isometric paretic knee extension compared with sham, and our group has shown that RIC can increase walking speed and distance in people with multiple sclerosis. More than 48 clinical trials of ischaemic conditioning in stroke and cerebrovascular disease have not raised concerns about serious adverse events. These multimodal effects, particularly on cellular bioenergetics, make RIC a compelling therapeutic candidate for PSF.

Preliminary data: the RICFAST pilot trial

Investigators recently completed a pilot randomised controlled trial of the safety and tolerability of RIC for PSF (RICFAST; NCT03794947). Twenty-four participants with debilitating PSF were randomised to RIC (n=12) or sham cuff inflation (n=12), delivered as 4 cycles, 3 times per week for 6 weeks. Half of the participants self-delivered the intervention at home because of the COVID-19 pandemic. RIC was safe and well tolerated, with excellent adherence (91% of sessions completed).

Although the pilot was not powered to detect differences in fatigue, fatigue scores were lower in the RIC group than in the sham group at 6 weeks (adjusted between-group mean difference in FSS-7 -0.7, 95% CI -2.0 to 0.6), and the difference persisted at 6 months (-0.9, 95% CI -2.0 to 0.2). These differences are of similar magnitude to the clinically important difference for the Fatigue Severity Scale reported across clinical populations, including stroke (0.5 to 1.2). Between-group differences in 6-minute walk distance (+43.8 m, 95% CI -6.0 to 93.6) and in ventilatory anaerobic threshold favoured RIC, potentially indicating an increased capacity for aerobic adenosine triphosphate (ATP) metabolism. Phosphorus-31 magnetic resonance spectroscopy (31P-MRS) of tibialis anterior in 8 participants (4 RIC, 4 sham) showed increased resting ATP in all RIC participants, whereas resting ATP fell in sham participants.

It is not yet known whether more frequent or longer courses of RIC can be self-delivered at home by people with PSF, or whether they produce greater or more sustained benefit. RICFAST 2 addresses these questions and explores mechanisms of action.

Research question

Are more intense and longer RIC interventions feasible for people with PSF, and do they appear to be promising treatments for PSF?

Aim, objectives and hypotheses

The aim is to investigate the safety, tolerability and feasibility of differing treatment schedules of RIC in PSF and to understand its mechanisms of action.

Primary objective

1. To determine whether RIC self-delivered at home is feasible at a frequency of 3 times weekly for 6 weeks, 5 times weekly for 6 weeks, or 3 times weekly for 12 weeks. Hypothesis: participants in all treatment groups will find self-delivery of the intervention at home feasible.

   Secondary objectives

2. To determine whether an increased dose of RIC (frequency or duration of therapy) results in greater and more sustained improvement in PSF. Hypothesis: participants who undergo more intense or longer RIC will experience greater improvements in fatigue severity than those in the control or regular RIC groups.

3. To determine whether any benefits of RIC on fatigue are sustained beyond the end of treatment. Hypothesis: beneficial effects will be sustained at 24 weeks from the start of treatment, particularly in the long (12-week) RIC group.

4. To determine whether the effects of RIC occur through alterations in tissue ATP metabolism and improved anaerobic endurance. Hypothesis: RIC will increase resting skeletal muscle ATP, measured by 31P-MRS, and ventilatory anaerobic threshold, measured by cardiopulmonary exercise testing.

5. To determine whether people with PSF have a predominant fatigue phenotype or symptom profile using fatigue screening tools. Hypothesis: people with PSF differ in symptom characteristics, with some experiencing predominantly physical, cognitive or psychosocial symptoms.

6. To understand how PSF affects markers of physical activity measured with smart wearable devices. Hypothesis: people with more severe fatigue have lower levels of physical activity (e.g., step count).

Trial design

RICFAST 2 is a phase 2, four-arm, parallel-group, randomised controlled feasibility trial with participant blinding to cuff pressure and blinded outcome assessment. Sixty participants will be randomised 1:1:1:1 to one of four groups (15 per group). The trial includes an embedded mechanistic sub-study (30 participants: 10 from each of Groups A, B and C) and a qualitative interview study. The sponsor is Sheffield Teaching Hospitals NHS Foundation Trust, and the trial is funded by the Stroke Association.

Setting and participant identification

Participants are recruited through Sheffield Teaching Hospitals NHS Foundation Trust, with referrals from across South Yorkshire (Sheffield, Doncaster, Rotherham and Barnsley). Several identification routes are used so that the recruited population is inclusive and diverse:

• Community stroke rehabilitation teams share study information with people reporting significant fatigue after stroke, including people who have finished rehabilitation or never received it.
• The trial is promoted through the Stroke Association, posters in community care settings (such as the Sheffield Assessment and Rehabilitation Centre), regional Integrated Stroke Delivery Networks, and local and social media. The research team also runs information sessions with community groups that serve under-represented populations.
• Secondary care stroke databases are searched for people who had a stroke within the last 3 years and have agreed to be contacted about research. Invitations are prioritised towards areas with higher deprivation and larger ethnic minority populations. They are sent in waves, and targets are adjusted according to the characteristics of the people recruited so far.
• GP practices acting as participant identification centres search their records and send invitation text messages or emails, with a single reminder after 4 weeks.

People who do not respond to an invitation are contacted at least once more, so that those who find it difficult to initiate contact are not excluded.

Screening and consent

Interested people have a telephone or video screening call. The call includes a fatigue assessment and a clear explanation of the number of visits and assessments involved, to reduce missed visits and missing data later in the trial. Everyone screened is recorded on an anonymised screening log to inform the CONSORT flow diagram.

Written informed consent is taken face to face at Sheffield Teaching Hospitals by the principal investigator or a delegated, trained member of the research team, after at least 24 hours to consider the information. For people with aphasia, Part A of the Consent Support Tool is used to assess comprehension. Those who understand at least two key written and spoken words in a sentence receive an accessible, aphasia-friendly information sheet and consent form, developed in line with Stroke Association accessible information guidelines. Audio versions of the information sheet are available for people with reading difficulties, and an independent witness can countersign the consent form if a participant cannot sign because of arm impairment.

Eligibility is confirmed after consent at the baseline visit, including a mean FSS-7 score of 4 or more, and people of childbearing potential have a pregnancy test. Where possible, consent, eligibility confirmation, baseline assessment and randomisation take place in a single visit; they can be split across visits if the participant becomes fatigued. Consent is reconfirmed verbally at each visit, and participants' GPs are informed of their participation.

Interventions

All participants are trained face to face, with access to video explainers, to self-deliver the intervention at home in addition to usual care. Each session consists of placing a manual blood pressure cuff (Accoson) around the upper arm, inflating it to the allocated pressure for 5 minutes and deflating it for 5 minutes, repeated for 4 cycles (approximately 40 minutes). Participants inflate the cuff to a sticker marked on the pressure gauge and can complete sessions at any time of day. The four groups are:

• Group A (control): cuff inflated to Pressure 1, 3 times per week for 6 weeks (18 sessions)
• Group B (regular RIC): cuff inflated to Pressure 2, 3 times per week for 6 weeks (18 sessions)
• Group C (intense RIC): cuff inflated to Pressure 2, 5 times per week for 6 weeks (30 sessions)
• Group D (long RIC): cuff inflated to Pressure 2, 3 times per week for 12 weeks (36 sessions)

The control procedure uses the same cuff, cycle timing, training and support as active RIC. A comparable control protocol has been shown to maintain participant blinding in a previous RIC trial.

Participants complete a weekly treatment log and symptom diary. These record the sessions completed, any symptoms related to the intervention (rated on a 5-point scale) and any other therapies received. This approach to home delivery and fidelity monitoring was piloted successfully in RICFAST. Research staff phone or video call every participant each week to review adverse events, solve problems with treatment, and encourage adherence and log completion; all groups receive equal attention. If a problem with the intervention is identified, an unscheduled visit is arranged, which may include retraining, and the reason and any action taken are recorded.

Participants remain free to undertake other therapies, such as stroke rehabilitation, exercise or psychological therapies. Participants or clinicians may stop the intervention at any time. The reason is recorded, the participant reverts to usual care, and follow-up continues unless the participant withdraws from the trial.

Randomisation

After eligibility and consent are confirmed and baseline assessments are complete, participants are block randomised (1:1:1:1) by an independent researcher using an online system (Sealed Envelope Ltd). Randomisation is stratified by baseline modified Rankin Scale score (0-2 vs 3-4) and baseline FSS-7 score. Participants in the mechanistic sub-study complete their baseline cardiopulmonary exercise test and MRI scan before randomisation and the start of treatment.

Blinding

Participants are told that they will receive one of four treatment allocations, but not which one. All procedures produce a sensation of pressure in the upper arm, and participants are not told which cuff pressure is expected to be therapeutically active. Participants cannot be blinded to the frequency or duration of their treatment.

Follow-up assessments are carried out by a researcher blinded to treatment allocation, and 31P-MRS data are processed by a researcher blinded to group. Staff who train participants and make the weekly calls are aware of allocation. At the final follow-up visit, participants are asked which group they believe they were in, to assess the success of blinding.

Unblinding may take place if needed for participant safety or to assess the causality of serious or unexpected adverse events. Participants are offered unblinding at the end of the trial, once data entry and cleaning are complete and the final analysis plan has been signed off. Participants in the control group will not be offered active RIC after the trial, because its therapeutic benefit has not been established.

Assessments and follow-up

Follow-up time points are measured from the start of treatment, with a window of plus or minus 1 week:

• Baseline (face to face): sociodemographic and clinical data, medical history and examination, and measures of fatigue (FSS-7, MFIS), disability and independence (modified Rankin Scale, Barthel Index), mood (GAD-7, PHQ-9), stroke-specific and generic quality of life (Stroke Impact Scale, EQ-5D) and walking endurance (6-minute walk test). The activity tracker is also set up.
• Weekly during treatment (telephone or video, or face to face if needed): adverse events, adherence and troubleshooting.
• 6 weeks (face to face): end of treatment for Groups A-C. Baseline measures are repeated, adverse events and treatment logs are reviewed, and activity data are downloaded.
• 12 weeks (face to face): end of treatment for Group D. Baseline measures are repeated, adverse events and treatment logs are reviewed, and activity data are downloaded.
• 24 weeks (remote): questionnaire measures (no 6-minute walk test), adverse events, activity data download and participants' perceived allocation.

Assessments can be spread over more than one session to limit participant burden. Travel expenses of up to £20 per scheduled visit are reimbursed.

Wearable activity monitoring

Each participant receives a wrist-worn activity tracker (Fitbit Inspire 3) to wear throughout the 24 weeks of participation. People with hemiparesis wear it on the non-affected arm. Participants are asked to wear it as much as possible, including overnight, for at least 16 hours per day. Daily step count, sedentary time, distance moved, exercise time and total estimated sleep time per night are collected through a web API service, with project support from Google Health UK. To protect privacy, each device is linked to a generic research Google account that contains no personally identifiable information. Participants are advised that using the device means agreeing to the Google/Fitbit terms and conditions and privacy policy.

Mechanistic sub-study

Thirty participants (10 from each of Groups A, B and C) have additional assessments at baseline, before treatment starts, and at 6 weeks, the end of treatment for these groups.

Cardiopulmonary exercise testing (CPET) takes place at the Advanced Wellbeing Research Centre, Sheffield Hallam University, supervised by an exercise physiologist. Symptom-limited tests use an electronically braked upright cycle ergometer (Lode Corival) linked to MetaSoft Studio. Heart rate is monitored continuously (Polar H10) alongside blood pressure, and breath-by-breath respiratory data are collected through a Hans Rudolph face mask and a gas analyser (Cortex MetaLyzer 3B) calibrated before each test. Participants pedal unloaded for 3 minutes at a target cadence of 60 revolutions per minute. Work rate then increases by 10 W per minute until volitional exhaustion, symptom development (e.g., palpitations, faintness, pallor, confusion, loss of coordination or chest pain), or inability to maintain a cadence of 50 revolutions per minute. Outcomes are peak oxygen uptake (VO2peak), ventilatory anaerobic threshold (VAT, estimated by the V-slope method), the minute ventilation/carbon dioxide output (VE/VCO2) slope and the oxygen uptake efficiency slope.

31P-MRS takes place at the Academic Department of Radiology, University of Sheffield, at 3 Tesla using a 31P/1H dual-tuned coil (Rapid Biomedical). Resting spectra are acquired with a pulse-acquire sequence from the proximal ankle dorsiflexors of both legs, including tibialis anterior. Coil placement around the tibial tuberosity is cross-checked for each participant to ensure consistency. A researcher blinded to group processes the spectra. Phasing and the frequency shift of phosphocreatine to 0 ppm are checked visually, 12 resonances are fitted using the AMARES algorithm in jMRUI, and the resulting amplitudes are corrected for T1 relaxation and normalised to total phosphorus signal. A full MR safety screen is completed at the scan visit.

Serum and plasma samples are collected at baseline and 6 weeks, processed and stored at the Clinical Research Facility, Royal Hallamshire Hospital, and analysed together at University of Sheffield laboratories once the final sample has been collected. The samples are analysed for IL-1β, IL-6, IL-10, TNF-α, heat shock protein and GLP-1.

Qualitative study

Semi-structured interviews with at least 12 participants explore their experiences of self-delivering the intervention at home and its acceptability, continuing until content saturation is reached. Interviews take place in a quiet, private room and are audio-recorded. Recordings are deleted once transcribed, and transcripts are anonymised. The transcripts are analysed thematically in five stages: familiarisation, keyword selection, coding, theme development, and conceptualisation of the themes in relation to the existing literature on stroke and RIC.

Safety

Adverse events (AEs), including device-related events, and serious adverse events (SAEs) are recorded from randomisation until the final follow-up. They are identified at weekly contacts and follow-up visits and can be reported by any member of the clinical or research team. All events are recorded in the case report form, and the principal investigator assesses seriousness and relatedness to the intervention. Additional detail on SAEs is recorded within one working day of identification.

Expected AEs related to the intervention are skin petechiae, headache, arm paraesthesia, arm numbness, arm discolouration, and new or increased upper limb pain. In the mechanistic sub-study, injury during MRI related to a pacemaker, medical implant or other metallic object (failure of MR safety screening) is listed as expected. Pregnancies are reported to the Chief Investigator and Sponsor within 24 hours. Participants who become pregnant stop the intervention but continue follow-up, and the outcome of the pregnancy is collected.

Withdrawal and loss to follow-up

Participants may stop the intervention and remain in follow-up, or withdraw consent for further data collection at any time without giving a reason. Data collected before withdrawal are retained and included in the analysis. Participants who miss the 12-week assessment are still approached at 24 weeks. A participant is defined as lost to follow-up only if the 24-week assessment is not completed after all attempts to make contact.

Sample size

Between 12 and 20 participants per arm are recommended to estimate feasibility parameters and the standard deviation of outcome measures for future sample size calculations. Fifteen participants per arm (60 in total) will therefore be recruited. The trial is not designed to detect between-group differences in clinical outcomes.

Statistical analysis

Intervention and trial feasibility outcomes will be analysed with descriptive statistics and assessed against the pre-specified criteria for safety, acceptability, compliance and recruitment rate. Exploratory between-group comparisons of secondary outcomes will use one-way analysis of covariance of change from baseline, adjusted for age, baseline score and baseline modified Rankin Scale score (≤2 vs >2), following the intention-to-treat principle. Adjusted mean differences with 95% confidence intervals will be reported for each time point.

Differences by fatigue type (predominantly physical, cognitive or psychosocial) will be explored using fractional polynomial models with an interaction term between treatment group and fatigue type. Associations between fatigue levels and physical activity data from the wearable devices will be examined with Pearson correlations. In the mechanistic sub-study, exploratory mediation analysis will examine whether changes in inflammatory markers mediate effects on fatigue.

Trial oversight and data management

The Chief Investigators have overall responsibility for the trial and supervise and review the data collected and the analyses performed. A trial management group meets approximately every 2 months, and at least monthly before key milestones. The funder has approved the membership of the oversight committees. All members of the research team have Good Clinical Practice training.

Data are recorded on paper case report forms identified only by a unique study number and are entered into an encrypted database on a password-protected Sheffield Teaching Hospitals research laptop. An enrolment log linking study numbers to identifiable information is kept separately, and study files are stored in a locked office at the Royal Hallamshire Hospital.

Patient and public involvement, equality, diversity and inclusion

The Sheffield Stroke Advisory Group has worked with the research team from the conception of the RICFAST pilot. The group helped develop this trial, including its design, recruitment predictions, outcome measures and use of wearable technology, and a lay representative is a co-investigator. On the group's advice, trial information will be available as explainer videos in the three most prevalent local languages (English, Punjabi and Urdu) and as easy-access materials for people with aphasia. The Consent Support Tool is used to tailor communication support to each participant throughout trial procedures.

The team works with Darnall Wellbeing, a community health organisation in an area of Sheffield with high ethnic diversity and socio-economic deprivation. Geographically targeted invitations are used to improve recruitment from under-served groups disproportionately affected by stroke, including people from Black and South Asian communities and people with lower socio-economic status. Participant engagement is supported by the HRA-endorsed Staying Connected toolkit. Lay members are supported in trial meetings through briefings, debriefings and a buddy system.

Dissemination

Results will be published in peer-reviewed journals, presented at clinical and academic conferences and submitted to the funder in a final report that will be made available online. Results will also be published on a freely accessible database within one year of trial completion, and progress summaries will be posted on the University of Sheffield website.