Explanation for the choice of comparators

The comparator chosen is usual care as the aim of the study is to investigate the effects of the resistance exercise intervention in addition to usual care. Clinical management of patients following COVID-19 in the NHS will generally align with practice guidelines from the British Thoracic Society and other key stakeholders such as NICE, RCPGP and SIGN. Local practice may vary according to circumstances. In NHS Greater Glasgow and Clyde (NHSGGC) health board, patients who have been admitted with radiological and/or virology confirmed COVID-19 would be invited for a chest X-ray 12 weeks post-discharge and if there are persisting abnormalities on the X-ray, the patient would be invited to further assessment, predominantly via telephone consultation. Options for the evaluation of post-hospitalisation patients with persisting symptoms include provision of an oxygen saturation monitor, a functional assessment of physical capacity, thoracic imaging, pulmonary rehabilitation, and/or an invitation to attend an out-patient clinic according to clinical need and logistical considerations.

Intervention description Resistance exercise training

The exercise programme pack is provided to participants in a single document. There are 3 categories within the pack with exercise for those that are (1) bed-bound, (2) up-to-sit and (3) ambulatory, and within each category, the exercises have different levels of difficulty to allow progression or regression, as appropriate.

Participants will be asked to train daily. Patients will be invited to perform the number of repetitions that leads to a validated resistance exercise specific Rating of Perceived Exertion (RPE) of 8–10 [20]. The use of RPE to prescribe and progress resistance exercise has been shown to be as efficacious as other more complex methods but reported to be the most tolerable and enjoyable method [21]. Once patients can reach 10–20 repetitions of each exercise they will be advised to move to the next level within each category and once able to do this for the top level within the category, to move to the next category. Similarly, if patients are not able to manage 5 repetitions of each exercise they will move down a level and, if at the bottom level within a category, down a category. Exercises are as follows:

Bed-bound, lying chest-press, lying row, lying plantar flexion, lying leg press and bridging

Up-to-sit, seated chest-press, seated row, seated lateral raises, seated leg extension, seated plantar flexion, squats

Ambulatory, press-ups, standing lateral raises, seated rows, lunges, calf-raises, squats

A training package will be provided to the site research staff (research nurses, fellows). The pack will be given to patients during an initial face-to-face session where the nurse/therapist will help to select the most suitable category and level of exercise for the patient, and to demonstrate these and ensure patients are comfortable performing the exercises. Every 2 weeks a member of the research team will contact the patients to ensure they are happy with the exercises and to help overcome any issues that have arisen. If the patient is in hospital, the contact may be daily, as needed.

The instructional pack (with video links and pictures) and an exercise log will be provided to empower each patient. The pack was reviewed by our Patient and Public Involvement (PPI) group (4 November 2020) and feedback incorporated to reflect co-design of the programme. Based on our experience in the CISCO-19 study [6], we believe the exercise intervention will be feasible for most patients who have the capacity to follow and adhere to verbal and/or written instructions. We aim for a widely generalisable intervention that can be taken up by most post-COVID-19 patients. The programme is designed to ensure simplicity and safety and remove barriers to implementation, household objects, e.g. a bottle of water and a tin of food, which would be available to all participants, or exercise resistance bands are also an option, according to patient preference.

Criteria for discontinuing or modifying allocated interventions

In accordance with the Declaration of Helsinki, participants can withdraw from the trial at any time for any reason. Withdrawal criteria: A participant may withdraw from the study at any time. There are no specific withdrawal criteria, although clinicians can withdraw patients as appropriate and record the reasons. All patients will be followed up for clinical outcomes unless consent is specifically withdrawn.

Pregnancy is an exclusion criterion. If after enrolment the participant becomes pregnant, this is not considered an adverse event (AE) or serious adverse event (SAE) in this trial unless a negative or consequential outcome is recorded for the mother or child/foetus. However, the patient would then be invited to withdraw from the study.

Strategies to improve adherence to interventions

Every 2 weeks, a member of the research team will contact the patient to ensure they are doing the exercises, checking there are no ill effects to provide encouragement and motivation and answer questions and help overcome any issues that have arisen. If the patient is in hospital, the contact may be daily, as needed. An exercise log will be provided to empower each patient. This log will not only record adherence to the exercise but also capture any post-exercise issues such as fatigue, dizziness and soreness.

Relevant concomitant care permitted or prohibited during the trial

All aspects of clinical care will be permitted, and episodes of care recorded in the electronic case report form (eCRF).

Provisions for post-trial care

At the end of the trial, participants will be returned to usual care as defined by local and national guidelines at that time.

Outcomes Primary outcome

Incremental shuttle walk test (ISWT) at 3 months.

The ISWT [20]. This is a validated measure of functional capacity, with good test-retest reliability and evidence of being responsive to rehabilitation interventions. The ISWT is used as a Tier 2 evaluation in the post-hospitalisation COVID-19 (PHOSP-COVID) study [18]. By adopting the ISWT as the primary outcome measure, our study will complement PHOSP-COVID, align with the protocol (for those patients who have been enrolled), and potentially, enhance co-enrolment into this observational study.

Oxygen saturation, heart rate and respiratory rate will be measured at the start and end of the ISWT. They will be exploratory outcomes.

Secondary outcomes at 3 months (unless stated otherwise) 1.

Spirometry: we will record peak expiatory flow rate, forced vital capacity and forced expiratory volume in 1 s.

2.

Handgrip strength: we will measure handgrip strength using a Jamar dynamometer 3 times in the dominant hand.

3.

Short Physical Performance Battery (SPPB): we will record the time taken to walk 4 m, time to perform 5 chair rises, and side-by-side, semi-tandem and tandem stands balanced stands with participants asked to hold each for 10 seconds [22]

4.

Euroqol-5 dimension (EQ5D) [23]

5.

Patient health questionnaire-4 (PHQ) [24]

6.

Illness perception (Brief IPQ) [25]

7.

Duke Activity Status Index (DASI) [26]

8.

International Physical Activity Questionnaire (IPAQ-SF) short-form [27]

9.

Fatigue severity scale [28]

10.

Medical Research Council (MRC) dyspnoea score [29]

11.

Frailty assessed using 1) Fried frailty phenotype: five criteria: weight loss; exhaustion; grip strength; low physical activity; and slow walking pace [30]; 2) Clinical Frailty Scale [31]

12.

Episodes of care will be recorded with the following recorded based on the previous 3 months: number of visits/appointments and average duration of contact with GP, GP practice nurses, community assessment centre, physiotherapy, rehabilitation service, accident and emergency, acute medical receiving unit, coronary care unit, ICU, medicine, care of elderly and surgery.

13.

Hospitalisation for any reason over the previous 3 months will be recorded.

14.

At 1 and 10 years we will also use E-linkage to hospital records to record episodes of care and death (and their causes) and medication use.

The secondary outcomes are intended to align with the post-hospitalisation COVID-19 study (PHOSP-COVID; ISRCTN10980107) assessments at 3-months.

Exploratory outcomes at 3 months 1)

Exercise dose achieved (1) daily log, (2) level attained and within-subject change from baseline

2)

Post-exertional malaise questionnaire [32]

3)

Vital parameters of cardio-respiratory function, e.g. oxygen saturation, heart rate, respiratory rate at baseline and during follow-up

4)

Accelerometery to measure time spent in light, moderate and vigorous physical activity [33] (Glasgow site)

5)

Biobank tissues samples for future biomedical research

6)

Observational sub-study of small vessel function using myography in arterioles isolated from gluteal skin biopsies and laboratory analysis of adipose tissue, cells and molecules from the biopsy

Research blood samples: Exploratory analyses may include - Haemostasis - Claus Fibrinogen, D-Dimer, factor VIII (one stage), von Willebrand factor (VWF) antigen, VWF:glycoprotein-1ba, Antithrombin activity, Protein C activity, Free protein S; Cardiac - N-terminal pro-brain natriuretic peptide, hs-troponin; Vascular cytokines – endothelin-1, intracellular adhesion molecule, vascular cell adhesion molecule, p-selectin, interleukin-6, VWF, Nicotinamide adenine dinucleotide phosphate oxidase 3; Vascular cells and microparticles; Metabolic status – glycated haemoglobin, lipids; Blood ribonucleic acid (RNA) (Tempus™ or PAXgene®) including for Real Time-PCR of SARS-CoV-2 and RNA for vascular biology; Inflammation – hs-CRP, ST2; Immune response antibodies; Collagen metabolites; Deoxyribonucleic acid (DNA) - The buffy coat will be stored for DNA analysis e.g. candidate gene single nucleotide polymorphisms, other variants. Residual blood will be saved for future analyses of interest.

Participant timeline

The participant timeline is shown in Table 2.

Table 2 Schedule of enrolment, interventions and assessmentsSample size

The minimum clinically important between-group difference in the ISWT at follow-up (3 months) = 46 m, SD=105, sample size for 80% power, 5% significance, no loss to follow-up (LTFU) = a minimum of 85/group; allowing for LTFU and incomplete data, the sample size is n=110/group (n=220 total).

Recruitment

All patients presenting at participating acute hospitals in Glasgow and Dundee and Primary Care settings, e.g. General Practice, community assessment centres, Community Health Centres or Community Test Centres, with COVID-19 can be considered for inclusion. A screening log with the reasons for not being enrolled will be prospectively completed.

We estimate recruiting participants from existing networks (e.g. Long COVID Scotland groups) from primary care. Recruitment from General Practice will be facilitated by providing information about the study i.e. poster, patient information sheet, consent form, and NRS Primary Care Network using: electronic records search; mail/text invitations; alerts for prospective/opportunistic identification.

Healthcare staff who participate in this study will adopt a consecutive approach to enrolment in order to minimise selection bias and provide a study cohort that is representative of patients treated during usual care. The results are intended to have external relevance and be transferable to clinical practice. This approach will also facilitate timely delivery of the trial.