This protocol follows guidance from Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) [18]. A SPIRIT schedule of enrolment, interventions and assessment is provided in Table 1 and a SPIRIT checklist is provided in additional file 1.
Aims and objectives
The aim of the study is to determine the feasibility of conducting a RCT to evaluate the clinical and cost-effectiveness of pre-operative protein supplementation and structured exercise in frail individuals waiting for a THR or TKR. Specific objectives include to determine eligibility, recruitment and retention rates, adherence to and acceptability of the trial, data completion rates, and to obtain information to calculate the sample size for a RCT.
Design
Joint PRehabilitation with Exercise and Protein (Joint PREP) is a feasibility study for a multicentre, two-arm, parallel group, pragmatic, RCT. The study will be conducted at 2 to 3 NHS elective orthopaedic centres. Embedded qualitative research with patients will explore their motivation to take part and experiences of participating, reasons for non-participation and/or reasons for withdrawal or treatment discontinuation. Group discussions with site staff will elicit views on organisational barriers or facilitators for the RCT and explore positions of equipoise and acceptability of the study.
Regulatory approvals
Ethics approval
was obtained from the East of Scotland NHS Research Ethics Committee 2 on 30th August 2022 (reference 22/ES/0033) and Health Research Authority (HRA) approval on 6th September 2022. The study is registered on the International Standard Randomised Controlled Trial Number registry (ISRCTN, reference: ISRCTN11121506). Any protocol amendments will be submitted to the HRA for approval prior to implementation and updated on the ISRCTN registry. All patients will provide informed, written consent prior to study participation.
Patient and public involvement in study design
This study was designed in collaboration with a patient and public involvement (PPI) group, called the Patient Experience Partnership in Research group. The group consists of patients with experience of osteoarthritis and joint replacement. Through group meetings, patient representatives have worked with the research team to co-design the intervention and study, including testing protein supplements, providing feedback on the exercise component and documents, preparing patient-facing study documents, and developing the patient interview topic guide. The research team and PPI group will continue to work together during the study to interpret study findings, develop strategies and outputs for public dissemination, and plan a grant application for a RCT if this study demonstrates that a trial is feasible.
Patient recruitment
An overview of participant flow is provided in Fig. 1.
Eligibility criteria
Inclusion criteria are patients scheduled for primary THR or TKR, ≥ 12 weeks until intended date of operation, ≥ 65 years of age, and frail according to self-reported Groningen Frailty Indicator (score of ≥ 4) (29). Exclusion criteria include contraindications to following study treatments (e.g., following a low protein diet or co-morbidities which preclude participation in exercise), participating in another study that may affect the outcomes of this feasibility study or that does not permit co-enrollment in another study or where co-enrollment would be burdensome to the patient, or unable or unwilling to provide informed consent.
Screening and recruitment
NHS patients on waiting lists for a THR or TKR who are aged ≥ 65 years and within an appropriate window prior to their anticipated date of surgery (i.e., as close to 12 weeks prior to surgery as possible), will be identified by the clinical care team and sent a study information pack and screening questionnaire. The screening questionnaire includes demographic questions, the Groningen Frailty Indicator [19], the self-reported version of the Clinical Frailty Scale [20], and questions about ability to participate in exercise, consume extra protein and participation in other studies. Interested patients are asked to complete and return the screening questionnaire and consent form in a pre-paid self-addressed envelope. One reminder pack will be sent if no response is received within 1 to 2 weeks, followed by a telephone call to ask if they would like any additional support to participate, such as completing the questionnaire over the telephone. Patients who return a screening questionnaire and consent form and meet the eligibility criteria will then be telephoned by the local research team to confirm that they fully understand what participation involves, answer any questions, and explain what will happen during the study. Participants will then be sent a baseline questionnaire to complete. All patients meeting the eligibility criteria will be invited to consider participation in a telephone/online semi-structured interview.
Randomisation
Participants will be randomised by a member of the local research team using a computer-based tool (REDCap), stratified by study site and operation type (THR/TKR), with full allocation concealment. Randomisation will be conducted as soon as possible after the research team receive a completed baseline questionnaire. Participants will be informed of their treatment allocation by letter, followed by a telephone call for participants randomised to the intervention group to discuss arrangements for the intervention. Blinding of study participants will not be possible due to the nature of this intervention. After participants have been randomised, a letter will be sent to their GP to inform them of their participation in the Joint PREP study and their treatment allocation.
Usual care
All participants in the study will receive their usual care. Participants randomised to the usual care group will not receive any additional advice or treatment to that provided routinely by their healthcare team. Usual care can vary between NHS Trusts, but may involve education classes, physiotherapy, group exercise, occupational therapy, and surgeon review before and after joint replacement. We will capture what constitutes usual care at each study site and will record details of any other pre-operative exercise or nutrition programme(s) the participant is following as part of their usual care.
Intervention
Participants randomised to the intervention arm will undertake 12 weeks of a pre-operative exercise and protein intervention. The intervention was designed as a personalised and home-based programme with regular contact and support to maximise success [21]. An intervention duration of 12 weeks was informed by previous research that at least this duration of exercise is required to have benefits relevant to frailty [17]. Reporting of the intervention follows guidance from the template for intervention description and replication (TIDieR) [22] and a TIDieR checklist is provided in additional file 2.
Exercise
Participants will have an initial 1:1 appointment with a trained physiotherapist (either in person at the hospital or virtually via a secure video platform) to introduce the intervention and develop a 12-week individualised home-based exercise programme. A risk assessment will be carried out and will inform adaptation of exercises and progression schedule to ensure they are tailored to individual physical capabilities and to minimise risk. Appropriate progressions (difficulty and number of repetitions) will be agreed, and participants will be supported with telephone calls every two weeks to gradually increase their levels of moderate physical activity throughout the intervention period. The exercises and resources are based on the NEMEX-TJR programme (https://nemex.trekeducation.org) and have been adapted for home use with permission from the Translating Research Evidence and Knowledge programme at La Trobe University, Australia (https://trekeducation.org). The exercises include a warmup, pelvic lifts, sit-ups, lunges, sideway lunges, knee flexion and extension, hip abduction and adduction, chair stands, step ups and a cool down. Participants will be provided with two booklets to assist them with completing the exercises. One booklet will have instructions and illustrations for each of the exercises and the other will have more general information about maintaining exercise, goal setting, pacing, and how best to deal with setbacks. Participants will also be offered the option of signing up to an online platform to support the home-exercise programme. All participants will be issued with therabands (of varying resistance) for the knee and hip exercises and where appropriate, participants will be issued with an exercise step and/or gym ball.
Protein
Participants will be asked to consume 20g of additional protein in the form of one pot of jelly (118ml) each day for 12 weeks prior to their surgery (ProSource jelly from Nutrinovo, Wiltshire, UK). Participants who do not eat gelatine will be offered an alternative product vanilla flavoured whey or fava bean protein powder or chocolate pea protein powder (Pulsin, Gloucester, UK) that does not contain gelatine. Participants will be asked to consume the protein within three hours after exercise as muscle protein synthesis peaks during this time [23]. They will also be advised to consume the protein between meals to minimise any effect on appetite. Participants will be provided with instructions for eating the jelly pots or making up and drinking the powder shakes. Batches of jelly pots/protein powder will be posted to participants at regular intervals to avoid the need to store large quantities in their home. Provision of protein supplements will cease after 12 weeks, however participants will have the option to continuing to purchase their own protein supplements after this time period.
Telephone follow-up calls
Participants will be telephoned by a physiotherapist six times over the 12-week intervention period, at approximately 1, 2, 4, 6, 8 and 10 weeks. The purpose of the telephone calls will be to check that participants are coping with the exercises and the additional protein, review and consider appropriate progression of exercises and to address any problems or concerns participants may have. In the final telephone call, continuation of the home exercise programme until the time of surgery (if relevant) will be discussed.
Intervention training
Physiotherapists delivering the intervention will have attended a half-day training session from the study team nutritionist and physiotherapist and will have been provided with an intervention training manual. They will have experience of working clinically with patients undergoing joint replacement.
Assessment of contamination
An estimate of protein adequacy in usual diet and usual physical activity data will be collected from all participants via study questionnaires to explore if participation in the study has influenced the behaviour of participants randomised to the usual care group. Participants in the usual care group will also be asked if they made any changes to their diet or physical activity over the 12-week intervention period.
Questionnaires
All participants will be asked to complete questionnaires at baseline (after recruitment and prior to randomisation) and 12 weeks after randomisation. Questionnaires will be administered on paper or online, depending on participant preference. Non responders will be followed up with a reminder questionnaire and then a telephone call from the local research team to offer the option of completing the outcome measures over the telephone.
A schedule of assessment is provided in Table 1. Pain and function will be assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) [24]. Health-related quality of life will be measured using the EQ-5D-5L [25] and capabilities with the ICECAP-O [26]. Other measures include the Groningen Frailty Indicator, Clinical Frailty Scale, Global Physical Activity Questionnaire [27], Exercise self-efficacy and beliefs questionnaire [28] and Protein screener 55+ [29]. Participants will be asked to self-report their height and weight to allow BMI to be calculated. Participants in the usual care group will be asked about any changes to usual diet or usual exercise/physical activity in the past 12 weeks, and if so, what these changes were. Participants in the intervention group will be asked questions on the acceptability of the intervention.
Outcome assessment and progression criteria
Primary outcome: feasibility of a RCT
The primary outcome is to determine the feasibility of a definitive RCT. This will involve evaluation of the key parameters of uncertainty for a RCT which are eligibility and recruitment rates, adherence to the intervention, and acceptability of the trial and the intervention. Eligibility and recruitment will be assessed by collecting detailed screening and recruitment records to allow review of the number of eligible, approached, and consented patients, alongside information on reasons for non-eligibility and non-participation. To assess adherence to the intervention, participants will be provided with a log form and asked to keep a daily record of whether they eat their protein and complete their exercises. Further details about reasons for non-adherence will be recorded on a proforma during the intervention telephone calls. Participants will be considered to have adhered to the intervention if they consumed the protein on at least 4 days per week for at least 10 weeks and/or completed the exercises at least 3 days per week for at least 10 weeks (or 80% of intervention duration if the time available for the intervention is shorter than 12 weeks e.g. if the participant is offered an operation date earlier than expected). Acceptability of the trial and intervention will be evaluated through qualitative interviews, questions in the study questionnaires, retention rates and reasons for withdrawal.
Secondary outcomes
The Clinical Frailty Scale will be completed by a healthcare professional when the patient attends the hospital for their routine pre-operative assessment appointment so that self-reported and clinician-assessed versions of the Clinical Frailty Scale can be compared. Data will be extracted from participants’ medical records on pre-operative comorbidities, indication for surgery, surgery details, length of hospital stay, discharge destination, pre-admission residence, post-operative mobilisation and post-operative complications up to 30 days after surgery (if surgery takes place within the study timeframe).Completion rates for questionnaires administered at baseline and 12 weeks after randomisation will be calculated. Data from the study questionnaires will be used to inform a sample size calculation for a full-scale RCT.
Progression criteria for a full-scale RCT
The key feasibility issues will be considered on a red (stop), amber (amend), green (proceed) traffic light system. The feasibility of a full trial will be determined by overall recruitment, retention, and adherence rates. Recruitment will be considered achievable if the rate observed is > 23% (lower limit of the 95% confidence interval for a 30% recruitment rate based on 200 screened). Similar criteria will be applied for retention: i.e., > 70%, for an 80% retention rate based on 60 participants, and for adherence: >37%, for a 50% adherence rate based on 60 participants. If all three elements fail to reach the threshold (i.e. recruitment is ≤ 23%, retention is ≤ 69% and adherence is ≤ 37%), a RCT will not be considered feasible. If one or two elements fail to reach the threshold, we will consider how the trial can be modified to address the shortfall. Examples may include modifying recruitment processes or study documents (recruitment), providing additional support/advice (retention and adherence), or offering alternative protein-rich products/exercises (retention and adherence). If all three elements are above the threshold the trial will be considered feasible.
Safety
Data on adverse events and serious adverse events will be collected and monitored by the research team to ensure the ongoing safety of participants. All serious adverse events during the intervention period will be notified and reviewed by the study sponsor (North Bristol NHS Trust).
Withdrawal
Participants may choose to withdraw from the study at any time. Participants who withdraw will be invited to provide their reasons if they wish to do so and these will be recorded on a proforma to allow identification of barriers to participating and highlight measures to facilitate continued participation in a future RCT.
Embedded qualitative study
Patient interviews
Patients who are approached for the study will be invited to take part in a semi-structured face-face/telephone/online interview (according to preference) with a trained qualitative researcher. Interviews with patients who agree to be randomised in the feasibility study will explore their experiences of participating. For those who decline to be randomised or withdraw, interviews will explore reasons for non-participation and/or reasons for withdrawal or treatment discontinuation. Target numbers are around 15 to 20 patients who agree to be randomised, and 10 to 15 patients who decline to be randomised and/or are randomised but subsequently withdraw/discontinue treatment, with precise numbers of interviews being determined by principles of data saturation. Interviews will follow a topic guide, which covers experiences of randomisation, tolerability of the intervention, experience of participation and data collection methods and any barriers or enabling factors that participants experienced in adhering to the intervention. For patients who decline to participate in the feasibility study, the questions will focus on reasons for declining or withdrawing and any barriers to participation.
Local research delivery team discussion groups
Group discussions with members of the local research delivery team from each site will be held to elicit their acceptability of the study design, their preference, and margins of equipoise, and to understand any potential organisational barriers to RCT implementation and potential mitigation strategies. These will take place once the site has been open to recruitment for approximately 3–6 months to allow for reflection on the experiences of undertaking the study. The discussion groups will take place in person, at local sites, or online (guided by the preferences of the participants) and will be facilitated by the qualitative team. The group discussions will be recorded for the purposes of minute taking only, and the recording will then be deleted once the minutes have been written up. We will not seek consent as the purpose of the discussion is to inform the design of a future RCT rather than generate research data.
Sample size
As this is a feasibility study, we have based our sample size on recruitment rate. If we identify 200 eligible patients, we can estimate a recruitment rate of 30% (i.e., 60 participants) to within a 95% confidence interval of ± 6.35%.
Data management
Study data will be stored in the REDCap secure online data capture system. Data validation will be completed in REDCap and any data queries resolved with the site trial team. Participants’ personal data will be stored securely and will only be accessible to trial staff and authorised personnel. All study documents will be made available on request for monitoring and audit by the Sponsor or the Research Ethics Committee.
Statistical analysis
This study is not powered to look at differences in outcomes between the intervention and usual care group. Data on recruitment, retention, and adherence will be reported using frequencies and proportions with 95% confidence intervals. Sample characteristics and outcome data will be summarised by means and standard deviations, medians and inter-quartile ranges, or frequencies and proportions as appropriate.
Qualitative data analysis
Audio-recordings of interviews will be transcribed and anonymised. Data will be analysed using thematic analysis, guided by the constant comparison method utilised in the Qualitative Research Integrated within Trials (QuinteT) Recruitment Intervention [30]. A coding index, based on the interview topic guide, will be used to sort the data into themes. An inductive approach to analysis will be used, allowing emergent themes to alter the coding as the analysis progresses. Coding will be completed by a single researcher, then reviewed by a second researcher to ensure both consistency of coding and grounding in the original data. Any inconsistencies in themes or coding will be discussed and resolved between the two researchers. This process will take place in parallel with the data collection to allow any emerging themes to be further explored in subsequent interviews. Qualitative data analysis will be assisted by Nvivo software.
Dissemination plans
We will develop a comprehensive plan for dissemination in collaboration with our PPI group. We anticipate that findings will be disseminated via plain language summaries, conference presentations and publications in peer-reviewed journals. The main output from this study is data on whether a future RCT is feasible.
Study status
Recruitment for the study began in December 2022 and the study is anticipated to be complete by December 2023.