WAX: Weight Bearing in Ankle Fractures. A randomised clinical trial of weight-bearing following operatively treated ankle fracture.

The University of Oxford requires access to NHS Digital data for the purpose of the following research project: WAX: Weight Bearing in Ankle Fractures. A randomised clinical trial of weight-bearing following operatively treated ankle fracture.

The study aims to determine whether functional outcomes after early weight-bearing in patients with operatively treated unstable ankle fractures are not worse than adopting a delayed weight-bearing regime which is usual care.

University of Oxford will analyse the dataset to:

1. Investigate the difference in risk of adverse events between the trial treatment groups in the first 12 months post-surgery.

2. Investigate the resource use, costs and comparative cost utility between the trial treatment groups in the first 12 months post- surgery.

This study is a randomised clinical trial, which is the best method to compare treatments to guide the care of patients. Randomisation will be used to produce two groups of patients: those given advice to walk on their operated ankle 2 weeks after surgery, and those who wait until 6 weeks. Patient follow-up will extend to 12 months.

It is funded by the National Institute for Health Research (NIHR) Research for Patient Benefit (RfPB) programme, reference number PB-PG-1217-20029. There will be a report submitted to the funder currently planned for the end of February 2023. The study cohort will go through a one-year follow up in January 2023. The data has been requested until 2025 to allow peer review of submitted manuscripts and/or responses to readers, as there may be a need for additional analyses.

The University of Oxford relies on GDPR Article 6(1)(e) as the lawful basis for processing the data within this application. There is public interest for patients, healthcare staff and the NHS, as this research will decrease uncertainty and allow standardisation of care and promotion of development of pathways for more efficient and cost-effective care.

The study requires processing of special category data and relies on Article 9(2)(j) as a lawful basis for processing data.

Data for this project has been minimised to ensure researchers only have access to the data they require to carry out the statistical and scientific processing of the data and to meet the purpose of the project for which there is a public interest.

NHS Research Ethics Approval has been granted for this study and all participants have prospectively consented to share their data in line with the processing described in this agreement.

The project is not part of a wider project, collaboration, or associated work.

The data subjects will be the trial participant cohort who fulfil all eligibility criteria as defined in the project Protocol. Every participant has provided prospective consent to access their personal data.

The cohort will include adults (18 years+) undergoing surgery for an ankle fracture. All participants will be treated non-weight-bearing until their two-week postoperative follow-up visit. They will then be instructed to either begin weight-bearing on the injured leg or remain non-weight-bearing for an additional 4 weeks. The decision on which instruction they are given will be made by chance using a process called randomisation so that neither patients nor surgeons can influence the choice. All other care will be as per usual treatment. Participants will report how well their ankle is healing and working, and their quality of life using questionnaires at intervals over the first year following surgery. Differences in healthcare costs will also be compared as another element of this research.

The University of Oxford recruited 562 participants over a 21-month period (between 13th January 2020 and 29th October 2021), from more than 20 hospitals. At least 436 participants were required in this study. This number was calculated based on previous scientific research to ensure that the study was large enough to reach a firm conclusion about its aims. The published results will inform NICE recommendations and will influence clinical practice.

The participant population for this study consisted of adult patients with an operatively treated ankle fracture:

Inclusion Criteria

• Age 18 years and above.

• The patient has undergone operative fixation for an unstable ankle fracture.

• Surgery was performed within 14 days of the injury.

• In the opinion of the treating surgeon, the participant might benefit from early weight-bearing.

• Able and willing to give informed consent.

Exclusion Criteria

The participant may not enter the study if ANY of the following apply:

• A lack of protective sensation (e.g. peripheral neuropathy).

• Inability to adhere to trial procedures.

• Bilateral operatively treated ankle fractures.

• Already in a trial for ankle fracture.

• Patient has received a hindfoot nail to treat index fracture.

There are around 170 ankle fractures each day in the UK. Many of these injuries heal with support in a plaster cast or splint, but some require surgery to restore the natural alignment of the bones and fix them in place with screws and plates. This improves how the ankle works once the fracture has healed.

Following surgery for an ankle fracture, patients are commonly told not to walk on the affected leg for six weeks in order to allow the bones to heal. Restricting the weight put through the affected leg may reduce the chance of surgical complications such as infection, breakage of the plates and screws, and loss of alignment requiring revision surgery. However, this restriction has been associated with problems such as blood clots, muscle weakness, stiffness, and poor recovery. It is unclear that the traditional six weeks period of limited walking is of any benefit. A recent national review found that surgeons gave patients very varied instructions following ankle fracture surgery, indicating that overall, UK surgeons have differing opinions about the best extended treatment pathway.

There has been little high-quality research in this area. The National Institute for Health and Care Excellence (NICE) and the James Lind Alliance (JLA) Priority Settings Partnerships have identified this question as one of their top priorities for research in trauma.

The objectives that are addressed through this data processing are:

1. Investigate the difference in risk of adverse events between the trial treatment groups in the first 12 months post-surgery.

2. Investigate the resource use, costs, and comparative cost utility between the trial treatment groups in the first 12 months post- surgery.

Emergency Care Data set (ECDS), Hospital Episode Statistics (HES) Admitted Patient Care and Outpatient datasets will be used.

Each of the requested datasets provide distinct data that are not available elsewhere and are required to adjust for between-participant variation and to determine outcomes necessary to answer the research questions described in the objectives.

Data will be required at the level of the participant in order to construct an adequately explanatory statistical model to address the research questions; all data will be de-identified prior to transfer to University of Oxford.

Only 4 years of data for each participant is required in order to fully describe important characteristics of the participants to determine between-participant variation. This includes the one-year follow-up data to determine any adverse events that required treatment and the associated costs.

Only consented trial participants in England will be included in the requested cohort. The team carried out a multicentre trial in order that the results are generalisable to NHS practice (for a better comparison) and therefore require data from participants across England.

In planning the study with patient representatives and gaining NHS Research Ethics approval, the team explored alternatives means to address these objectives and this approach was considered both proportionate and appropriate.

The research team is minimising data requested to only the trial participant cohort; data for each participant in the cohort will be requested for the period of time that they are involved in the trial follow-up.

University of Oxford is the sole data controller and processor for these data. No other third-party organisations are involved in this study. The study team plan, and have ethical approval to, archive the de-identified data required for the study for 3 years beyond the end of the study. It is usual to do this in this type of clinical trial so that if there are queries around the study, the interpretation or the statistical methods used can be answered fully and if necessary with reference to the original data.

A file of unique identifiers and patient-level identifiers (NHS number, date of birth, sex, and postcode) will be sent from the University of Oxford to NHS Digital. The cohort includes 562 participants.

NHS Digital will link HES data for each patient identified in the cohort using the matching data file (containing NHS number, date of birth, gender, and postcode) to the unique identifier. The HES data will be at patient level and de-identified. NHS Digital will destroy the linkage file once linkage is achieved. The de-identified HES data, which will include special category health data, with the linked ID will be sent to the University of Oxford.

There will be no subsequent flows of data.

The processing organisation is University of Oxford. Two processing/storage sites will be used: Botnar Research Centre and Nuffield Department of Primary Care Health Sciences.

The trial team will initially prepare the linkage file as described above. On receipt of the linked, de-identified data from NHS Digital the trial team will carry out a prospective economic evaluation, conducted from an NHS and personal social services perspective, using the data provided by NHS Digital, augmented with participants’ self-reports. The economic evaluation will estimate the difference in the cost of resource inputs used by participants in the two arms of the trial, allowing comparisons to be made between the two weight-bearing strategies following ankle fracture fixation and enabling costs and consequences to be compared. Resource utilisation will be captured through the data provided by NHS Digital. The costs of the treatment options, including supplementary interventions (e.g., revision surgery) and rehabilitation inputs will be estimated using NHS reference costs and standardised to current prices. Health-related quality of life will be collected from participants’ self-report at randomisation, and at 6 weeks, 4- and 12-months post- randomisation using the EuroQol EQ-5D-5L measure; responses will be used to generate quality adjusted life-years (QALYs). The economic evaluation will be framed as a cost-utility analysis with results expressed in terms of incremental cost per QALY gained. The team will use non-parametric bootstrap estimation to derive 95% Confidence Intervals (CIs) for mean cost differences between the trial groups and to calculate 95% CIs for incremental cost- effectiveness ratios. The magnitude and significance of the coefficients on the interactions between the covariates and the intervention variable will provide estimates of the cost-effectiveness of the treatment options by participant subgroup.

The data will not be linked to any other data and only the linkages described are permitted under this Agreement.

Routine statistical procedures to suppress small cell numbers (less than 5) will be used to reduce the risk of re-identification. No attempt will be made in the processing to re-identify individuals.

Data processing will only be carried out by substantive employees of the University of Oxford who have been appropriately trained in data protection and confidentiality.

Data will only be accessible to these employees in a designated, locked, secure data processing office with standalone computers in accordance with the data security policies of the University of Oxford, Big Health Data Group (NDORMS), and Nuffield Department of Primary Care Health Sciences.

At the conclusion of this study, it is hoped that the University of Oxford will have provided the most robust evidence available to infer whether patients who have had surgery for an ankle fracture should wait 6 weeks before walking on the operated leg or walk on their operated leg sooner following surgery. Patients and members of the public will help design a publicity strategy so that the results of the study are distributed outside of the routine scientific literature.

A report will be produced, which will inform the full update to the National Institute for Health and Care Excellence (NICE) Guidance NG38 (Fractures (non-complex): assessment and management) in 2024. Plain English outputs will include papers and web and blog media. A major international free-to-access publication is planned, alongside two national and two international presentations.

The University of Oxford have worked with members of the public who have personal experience of lower limb fractures and have knowledge of how weight-bearing advice can affect patients’ lives. A Patient and Public Involvement (PPI) member has access to the wider pool of experienced representatives who make up the Oxford Trauma and Emergency Care Patient and Public Involvement Group (the study's own PPI group). This group provides wider review of materials and provides input in reviewing plain language literature prior to dissemination, giving a broader forum for review, and providing efficient utilisation of the Patient and Public Involvement member. Using the INVOLVE guidance, the University of Oxford have given the members information on how they can be involved in the research and the type of support and training available to them.

Patients sit on the trial management and steering committees and have a key role in drafting trial documents for participants, attending conferences and assisting with the publication of the results. A Patient and Public Involvement member and a clinical expert led on the final drafting of the patient written intervention instructions.

For wider dissemination, the patient representatives will lead dissemination to the patients and carers directly through their extensive network of patient advocacy organisations which include the ARUK Centre for Epidemiology, Wales Centre for Primary and Emergency Care (Including Unscheduled) Care research (PRIME) and the Oxford Link and other local interface organisations.

They have already helped to generate a plain language summary for patients and the public. This document is available in paper copy, podcast and as a blog. An abstract will be submitted to the biannual NIHR INVOLVE Conference (https://www.invo.org.uk/current-work/) and a PPI member will give a presentation. Posters will also be prepared with the PPI team for inclusion at any workshop or conference where relevant PPI is being discussed.

In addition, to disseminate directly to study participants, findings will be more widely available locally through posters in appropriate outpatient rooms and liaising with identified service user groups.

All outputs will be aggregated with small numbers suppressed in line with the HES analysis guide. Data will be aggregated and presented at the level of the randomised treatment arm. If applicable data within cells will be suppressed if they are small values to reduce the risk of re-identification.

No participant-level data falling under this agreement will be shared with any third-party.

The dissemination strategy will consist of three strands. The first will ensure that patients and the public are informed of the trial results; the second will engage practitioners and health-care providers, and the third will inform national guideline and policymakers.

Patients, patient advocacy groups, and members of the public:

Our patient representatives will lead dissemination to the patients and carers directly through their extensive network of patient advocacy organisations which include the ARUK Centre for Epidemiology, Wales Centre for Primary and Emergency Care (Including Unscheduled) Care Research (PRIME) and the Oxford Link and other local interface organisations.

They will help generate a plain language summary for patients and the public. This document will be available in paper copy, podcast and as a blog. An abstract will be submitted to the biannual INVOLVE Conference and a Patient and Public Involvement member will give a presentation. Posters will also be prepared with the PPI team for inclusion at any workshop or conference where relevant PPI is being discussed. In addition, to disseminate directly to study participants, findings will be more widely available locally through posters in appropriate outpatient rooms and liaising with identified service user groups.

Health care providers:

The trial team will work with the Oxford NIHR Biomedical Research Centre (BRC) and Collaborations for Leadership in Applied Health Research and Care (CLARHC) media teams to maximise the reach of the press and publicity outputs from this study. The team has costed the application to include one free-to-access publication in the mainstream literature. The final results will be submitted for presentations at annual meetings of the British Orthopaedic Association (BOA) and the Orthopaedic Trauma Society (OTS). The findings will be presented to the entire NHS via the NHS national electronic Library for Health (NHS Evidence). International ‘reach’ of the published research findings will be supplemented by presentations at high visibility meetings such as the Orthopaedic Trauma Association (OTA) Annual Meeting (US) and European Federation of National Associations of Orthopaedics and Traumatology (EFORT) Annual Congress (Europe).

In addition, the team is developing complementary systems incorporating non-traditional media. The Chief Investigator has been developing an enhanced web presence through blogging on the leading UK trauma and orthopaedic websites. These blogs engage both trauma and research communities. They have been very successful and have provided a means for rapid dissemination. The team plans to expand this activity into additional subject-specific and general blogs such as the British Medical Journal (BMJ).

National guidelines:

The research team will use their established network involvement to disseminate these research findings. These include the NIHR Clinical Research Network, and specialist interest groups (British Orthopaedic Association, Orthopaedic Trauma Society, Orthopaedic Trauma Association and The European Federation of National Associations of Orthopaedics and Traumatology).

The team will alert the relevant NICE standing committee to the results of the trial by notifying their surveillance team.

The study team is due to report in March 2023 and inform the full update to NICE Guidance NG38 in 2024. Progress in the work has been successful despite COVID and they are confident of hitting this timeline. De-identified data will be stored securely for a period of 3 years by University of Oxford following the final report to respond to any queries regarding the study.

Each day approximately 170 patients sustain an ankle fracture in the UK. This rate is predicted to rise, reflecting an ageing population. There is a bimodal age distribution for these fractures with one peak in young men sustaining high energy injuries through sports and leisure activities, and another peak in older women sustaining fragility fractures after simple twists or falls. Immediate effects include pain, swelling and physical impairment. Some symptoms, most notably pain and functional deficits can persist. This can lead to prolonged work absence and in the long-term, to post-traumatic arthritis and psychological consequences. Ankle fractures are grouped into those in which the bones remain aligned (stable) and those in which they do not (unstable). Stable injuries are relatively benign; the unstable injury pattern reflects a more severe injury with greater bone and ligament damage. These fractures often require surgery to correct and then stabilise the alignment of the ankle bones to ensure good function once the fracture has healed. Unstable ankle fractures represent a substantial burden of disease, with an average length of hospital stay of nine days and an associated mean cost of £4,491 per patient. In patients over sixty, this increases to a mean NHS cost of £6,648 and mean societal cost of £7,684 per patient. Ankle fracture surgery is a commonly carried out operation within the NHS with over 9,000 of these procedures performed per year in the UK. The operation is well established and standardised. However, post- operative mobilisation strategies are variable. Historically surgeons restricted patients’ weight-bearing due to a fear that excessive loading of the bone and metal implants could lead to an early loss of alignment, soft tissue compromise, poor functional outcomes and revision surgery. This weight-bearing restriction, however, has a major impact on patients and health services. The patient experiences inconvenience, with an enforced use of crutches or other aids that can translate into increased dependency on social care services and/or longer hospital stays. Patients also report a later return to work with the consequent personal and societal cost impact. It is reasonable that given no risk of harm, many patients would prefer to be free to walk without an instruction to restrict their weight bearing. High-quality systematic reviews conducted by Cochrane and NICE have found no credible evidence of harm associated with an early weight-bearing strategy. The weight-bearing restriction that has become established historically, and is now part of surgical dogma, has significant implications for patients and health services and may yield worse functional outcomes for patients. There is a pressing need to definitively test the appropriateness of this component of the surgical treatment of ankle fractures.

There is increasing recognition that high-quality evidence is required to determine whether the drawbacks of early weight-bearing are balanced by improved functional outcomes. The clinical and cost-effectiveness of different weight-bearing strategies in unstable ankle fractures is a top 5 research recommendation in the recent NICE guidance. Furthermore, a 2017 Arthritis UK workshop identified weight-bearing strategies as a priority. Finally, weight-bearing after ankle fracture was one of the Top 10 research priorities in the 2018 James Lind Alliance Partnership.

The outcomes of the study could directly benefit patients, healthcare staff and the NHS by decreasing uncertainty, allowing standardisation of care, and promoting the development of pathways for more efficient and cost-effective care.

This trial is highly likely to be the only definitive trial addressing the research question and it is expected that it will therefore directly influence national clinical practice within five years.

It is hoped that the outcomes of this project are also expected to lead to updating NICE guidance on non-complex fractures.

The University of Oxford hopes to also be able to provide evidence for standardising the care pathway for patients recovering from an operatively treated ankle fracture, generating high impact research findings from this dataset.

The realisation of benefits will begin immediately once the outputs are delivered.

The study is not in support of a PhD/post graduate research study.

Yielded Benefits is not a requirement for new applications.