Is post-operative non-weight-bearing necessary? Study protocol for a pragmatic randomised multicentre trial of operatively treated ankle fracture (DoWeCAST?).

Background Post-operative management regimes vary following open reduction and internal fixation (ORIF) of unstable ankle fractures. There is an evolving understanding that extended periods of immobilisation and limitation of weight-bearing may lead to poorer clinical outcomes. Traditional non-weight bearing cast immobilisation may prevent loss of fixation, and this practice continues in many centres. The purpose of this trial is to investigate the safety and efficacy of immediate weight-bearing (IWB) and range of motion (ROM) exercise regimes following ORIF of unstable ankle fractures with a particular focus on functional outcomes and complication rate. Methods A pragmatic randomised controlled multi-centre trial, comparing IWB in a walking boot and ROM within 24 hours versus non-weight bearing (NWB) and immobilisation in a cast for six weeks, following ORIF of all types of unstable adult ankle fractures (lateral malleolar, bimalleolar, trimalleolar with or without syndesmotic injury) is proposed. All patients presenting to three trauma units will be included. Exclusion criteria will be skeletal immaturity and tibial plafond fractures. The three institutional review boards have granted ethical approval. The primary outcome measure will be the functional Olerud-Molander Ankle Score (OMAS). Secondary outcomes include; Wound infection (deep and superficial), displacement of osteosynthesis, total arc of ankle motion (plantar flexion and dorsal-flection), RAND 36-Item Short Form Survey (SF-36) scoring, time to return to work and postoperative hospital length of stay. The trial will be reported in accordance with the CONSORT statement for reporting a pragmatic trial and this protocol follow the SPIRIT guidance. Is post-operative non-weight-bearing necessary? A pragmatic randomised multicentre trial of operatively treated ankle fracture (DoWeCAST?).


Background
Post-operative management regimes vary following open reduction and internal fixation (ORIF) of unstable ankle fractures. There is an evolving understanding that extended periods of immobilisation and limitation of weight-bearing may lead to poorer clinical outcomes. Traditional non-weight bearing cast immobilisation may prevent loss of fixation, and this practice continues in many centres. The purpose of this trial is to investigate the safety and efficacy of immediate weight-bearing (IWB) and range of motion (ROM) exercise regimes following ORIF of unstable ankle fractures with a particular focus on functional outcomes and complication rate.

Methods
A pragmatic randomised controlled multi-centre trial, comparing IWB in a walking boot and ROM within 24 hours versus non-weight bearing (NWB) and immobilisation in a cast for six weeks, following ORIF of all types of unstable adult ankle fractures (lateral malleolar, bimalleolar, trimalleolar with or without syndesmotic injury) is proposed. All patients presenting to three trauma units will be included.
Exclusion criteria will be skeletal immaturity and tibial plafond fractures. The three institutional review boards have granted ethical approval. The primary outcome measure will be the functional Olerud-Molander Ankle Score (OMAS). Secondary outcomes include; Wound infection (deep and superficial), displacement of osteosynthesis, total arc of ankle motion (plantar flexion and dorsal-flection), RAND 36-Item Short Form Survey (SF-36) scoring, time to return to work and postoperative hospital length of stay. The trial will be reported in accordance with the CONSORT statement for reporting a pragmatic trial and this protocol follow the SPIRIT guidance.

Discussion
Traditional management of operatively treated ankle fractures includes an extended period of nonweight bearing. There is emerging evidence that earlier weight-bearing may have equivocal outcomes and favourable patient satisfaction but with higher wound-related complications. These studies often preclude more complicated fracture patterns or patient-related factors. To our knowledge, immediate weight-bearing (IWB) following ORIF of all types of unstable ankle fractures has not been investigated in a controlled prospective manner. This pragmatic randomised-controlled multi-centre trial will investigate immediate weight-bearing following ORIF of all ankle fractures pattern in the usual condition of care. It is hoped that these results will contribute towards the modern management of ankle fractures.

Administrative Information
Note the numbers in curly brackets in this protocol refer to SPIRIT checklist item numbers. The order of the items has been modified to similar group items (see http://www.equator-network.org/reportingguidelines/spirit-2013-statement-defining-standard-protocol-items-for-clinical-trials/).

Title
Is post-operative non-weight-bearing necessary? A pragmatic randomised multicentre trial of operatively treated ankle fracture (DoWeCAST? There is emerging evidence that extended periods of immobilisation and limitation of weight-bearing may lead to poorer outcomes (2). Traditional non-weight bearing (NWB) cast immobilisation periods of six or more weeks were used to protect soft tissue envelope and osteosynthesis (3). Newer trends in earlier mobilisation compete with traditional NWB doctrine and poor consensus exists as to the best post-operative strategy (4,5). This could be explained by the contradicting literature when it comes to the assessment of weight-bearing regimens following ankle fracture fixation (2,(6)(7)(8)(9)(10)(11)(12).

Objectives
The research question underpins the objective of this randomised controlled trial: Is it necessary to completely immobilise patients and prevent them from weight-bearing for six or more weeks following

Trial design
The study will be a prospective, pragmatic randomised controlled trial (p-RCT), un-blinded with participants allocated in a 1:1 ratio to one of two parallel groups. Patients will be randomised using computerised block randomisation (twenty patients per block). The study is multi-centre and will include three major orthopaedic centres in Ireland.

Methods: Participants, Interventions And Outcomes Study Setting
This pRCT will be conducted at three academic trauma units at three different urban centres in Ireland. Each centre serves a referral population of > 500,000 and receives all grades of trauma from both urban and rural environments on a 24-hour basis. A trauma team is on call daily and includes two trainee surgeons and a consultant orthopaedic surgeon. Surgeries are performed by in part, in total or supervised by consultant orthopaedic surgeons. Regional and general anaesthesia is used at the discretion of the anaesthetist. Ankle fracture surgery is conducted on both a day case or overnight basis. Ward based physiotherapy is provided daily to facilitate early discharges. All hospital personnel contributing towards recruitment and patient pathway in this trial will undergo training in the objectives and methodology of the study.
Patient recruitment and consent: All patients admitted to the hospital with ankle fracture (AO/OTA 44A1.3 to 44A3.3, 44B and 44C ) deemed appropriate for surgical intervention will be asked to participate in the trial and provided with a patient information leaflet (Appendix 1), given time to read the document and ask questions. If the patient agrees to enter the trial, they will sign the consent form in the presence of the admitting doctor on the morning of or the night before their surgery.
Randomisation process: Randomisation will occur upon skin closure. The circulating theatre nurse will consult the randomised block database and inform the surgical team that a walking boot (Group A) or a cast (Group B) is to be applied. The patient's details will be entered into the database and they will be assigned a trial number. Intervention: In accordance with a pragmatic study, surgical approach and choice of implant will be at the surgeon's discretion. Surgeons may or may not be authors in the study. Surgical practice at the three institutions is to achieve anatomical reduction and rigid fixation. The commonly used osteosynthesis systems for fixation is the Small Fragment System, with One-Third Tubular plate commonly used. The use of locking mode is not routinely used. Other systems are also available. All patients will be assessed by a physiotherapist for gait stability and provided with walking aids according to randomisation. Patients in the walking boot group (Group A) will be instructed to weight-bear as tolerated immediately with or without walking aids for balance. Patients in the NWB group (Group B) will be instructed to strictly non-weight bear using crutches or frame for a total of six weeks. Group A will be instructed to remove the walking boot four times a day at minimum to perform ankle range of motion exercises until they attend outpatient physiotherapy following their first post-operative visit.
All patients will receive a post-operative care information sheet according to their grouping (Appendix 2 and 3).
Follow up: Patients will be followed up in an outpatient setting at two weeks, six weeks, twelve weeks, six months and one year postoperatively. At each visit, the OMAS and SF-36 Health questionnaire will be collected by one of two study investigators. Surgeons that may or may not be authors in the study reviewing patients in either group will also record surgical site assessment, x-ray evaluation, ankle ROM (using goniometry), information regarding return to work, confirmation of physiotherapy referral and confirmation of collection of OMAS and SF-36 questionnaire according to a Case Report Form (Appendix 4).

Inclusion Criteria
All skeletally mature, acute ankle fractures treated with anatomical reduction and stable internal The admitting trainee or consultant surgeon will obtain consent after providing appropriate information and patient information leaflet (Appendix 1).
Additional consent provisions for collection and use of participant data and biological specimens Not applicable as no biological specimens were collected as part of this trial.

Interventions Explanation for the choice of comparators
The traditional non-weight bearing (NWB) cast immobilisation is a common practice in many centres, and this protocol could be not necessary.

Intervention Description
Patients will be allocated randomly to one of two groups;

Group A:
Will receive a walking boot orthosis postoperatively in theatre and allowed weight bearing as tolerated and range of motion (ROM) exercises immediately.
Will be encouraged to elevate the affected foot in the first two weeks to reduce swelling. The first follow up appointment will be after two weeks. This visit is for surgical site inspection, removal of sutures, check x-ray and referred to physiotherapy to continue ROM exercises and weight-bearing as tolerated progressing to full weight-bearing.

Group B:
Will receive full below-knee cast postoperatively in theatre and prevented from weight-bearing with for six weeks.
Will be encouraged to elevate the foot in the first two weeks to reduce swelling.
The first follow up appointment is after two weeks. This visit is for surgical site inspection, removal of sutures, check x-ray and re-application of a full below-knee cast.
The second follow up is after six weeks, for removal of cast and referral to physiotherapy to commence ankle ROM exercises and weight-bearing as tolerated progressing to full weight-bearing.

Criteria For Discontinuing Or Modifying Allocated Interventions
The trial will be terminated early if 20% complication rate detected in either of the treatment groups (10,13).
Strategies To Improve Adherence To Interventions Surgeon: As the intervention is visible and the trail could not be blinded, the operating surgeon will not be informed with the randomisation sequence until after the end of surgical fixation.
A regular internal audit process is established to ensure adherent to the ankle trial protocol and increase compliance with recruitment process; this will provide detailed information about all patients with an ankle fracture that is admitted to hospital (included or excluded from the trail).

Participant:
In the post-operative setting on the ward and before discharge, a physiotherapist will reinforce the patient's role in the trial and provide them with information leaflet appropriate to their grouping. At subsequent outpatient follow up attendances, patients will be reminded of the trial. The trial Case Report Form (Appendix 4) will record if the patients have received outpatient physiotherapy.

Relevant concomitant care permitted or prohibited during the trial
The choice of and duration of DVT prophylaxis will be at the surgeon's discretion.

Provisions For Post-trial Care
None.

Outcomes
The primary outcome measure is the functional Olerud-Molander Ankle Score (OMAS). This score ranges from 0 to 100, with 100 representing the normal ankle function (14).

Recruitment
Please see the recruitment above. As this is a multi-centre pragmatic trial examining a common fracture, the target number is achievable.

Assignment Of Interventions: Allocation
Sequence generation An online computer-generated block randomisation list (20 patients per block) will be created at the start of the trial via the website http://www.randomization.com.

Concealment mechanism
Circulating theatre nurse will check the randomisation sequence by accessing the trial excel sheet and inform the surgeon upon skin closure surgery and enter the patient's details in randomisation slot.

Implementation
Who will generate the allocation sequence: The Principal investigator.
Who will enrol participants: admitting trainee surgeon.
Who will assign participants to interventions: Circulating theatre nurse.

Assignment of interventions: Blinding Who will be blinded
It is not possible to blind the intervention from the participant nor the surgeons as it is external and visible (cast or boot). However, to reduce the risk of bias, the surgeon will be blinded with the sequence of randomisation until the surgery is completed.

Procedure For Unblinding If Needed
It is not possible to blind the intervention.

Data collection and management Plans For Assessment And Collection Of Outcomes
At each follow-up visit, the OMAS and SF-36 Health questionnaire will be collected from the participants by outpatient clinic nurse. The attending orthopaedic consultant or NCHD fills up a case report form, and this includes documentation of the following information; surgical site assessment, xray evaluation, ankle total arc measure (goniometry), information regarding return to work, confirmation of physiotherapy referral and confirmation of collection of OMAS and RAND SF-36 Health survey.

Plans To Promote Participant Retention And Complete Follow-up
We have developed a patients tracking system to allow the researchers to monitor follow up carefully.
As part of this system, a weekly list of expected patients is provided to the research nurse in the OPD, and this list is reviewed on a daily bases to record attendance. In case of a patient being absent from the clinic, another appointment for the following week will be arranged, the RAND SF-36 and the OMAS score will be posted to the patients with pre-paid envelope enclosed and the patient will be contacted to encourage follow up.

Data Management
Three forms are collected at each follow-up visit and stored securely in the trial locker, two PROM forms, the RAND SF-36 and OMAS and the case report form. Periodically, all data is transferred to a temporal database located within the HSE computer system by two researchers, and a read-only copy is stored in a separate folder. This is then cross-checked before data is transferred to STATA16 and PRISM for statistical analysis and reporting by the research team and statistician.
RAND SF-36 is multiple steps analysis; this will be performed with oblique scoring rather than the orthogonal-factor analytic model (19). Normative data for the Irish population will be used as a reference (20).
Confidentiality Data management will be in accordance with the General Data Protection Regulation (GDPR) Health Service Executive (HSE) and Health Research regulations (21,22). Data will be kept anonymously in the database within the HSE local hospital computer system in protected folders to ensure confidentiality. Paperwork will be stored in the trail locker in a locked researcher office within the hospitals.
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use Statistical Methods Statistical methods for primary and secondary outcomes Unpaired t-test will be used for continuous data such as, OMAS, SF-36, total ankle arc, return to work (days), length of hospital stay (days). For categorical data such as rate of infection and other demographic data, Chi-squared test or Fisher's exact test will be used as indicated. Adjustment for strong predictors of the outcome, such as fracture complexity determined by fracture classification will be performed if necessary. Continuous data will be summarised as mean and standard deviation and confidence intervals (CI) (95% CI and p-value threshold ≤ 0.05) A p-value of < 0.05 will be considered significant. Categorical data will be presented as frequencies and proportions. STATA16 and PRISM software will be used for statistical analysis. Analysis will be conducted on the intention-totreat (ITT) basis.

Interim Analyses
No planned interim analysis.

Methods For Additional Analyses (e.g. Subgroup Analyses)
Additional subgroup analysis comparing the outcomes of different fracture complexity pattern will be performed.
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data Any protocol non-adherence will be disclosed and handled accordingly. Effort will be made to prevent missing of data as much as possible, and unavoidable missing data, such as withdrawals from the study or loss of follow up data will be analysed on an intention to treat basis including sensitivity analysis. Methods such as Observation carried forward (LOCF), or imputation will only be used when scientifically justified (23)(24)(25).
Plans to give access to the full protocol, participant level-data and statistical code The full protocol is available at the registry website and will be published in one of the trial protocols journals.
Oversight And Monitoring Composition of the coordinating centre and trial steering committee Four authors at the coordinating centre (University Hospital Waterford) take responsibility for the scientific validity of the study protocol, assessment of study quality and conduct, as well as, for the scientific quality of the final study report.
Composition of the data monitoring committee, its role and reporting structure The authors understand the composition for a data monitoring committee for this trial is not necessary and will not add much to the study. This non-funded trail does not involve the administration of medication and does not expose patients to significant harm; the composition of DMC may even be counterproductive (26).

Adverse Event Reporting And Harms
Collected case report forms are checked daily by the research team before stored in the trial locker; any adverse event or harm will be communicated with the study team.

Frequency And Plans For Auditing Trial Conduct
The trial conduct is continuously audited in the departmental audit meeting (three monthly).
Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) Any change to the trial protocol will be communicated with the ethical committees and trial registry.

Dissemination Plans
The result of this trial will be published in one of the medical journals.

Discussion
Some studies have investigated early weight-bearing (EWB) following fixation of ankle fractures, some of which reported favourable outcomes (2,6-10) and others raised concerns of increasing complication rate (9,11,12). The National Institute for Health and Care Excellence (NICE) has recommended the subject as worthy of further research (27), and this has been reinforced by a recent audit of the UK Practice (3).
To our knowledge, immediate weight-bearing (IWB) following ORIF of all types of unstable ankle fractures has not been investigated with a randomised controlled trial. This pragmatic randomisedcontrolled multi-centre trial will investigate the safety and efficacy of IWB following ORIF of all ankle fracture patterns in the usual condition of care and help in formulating a widely accepted guideline for postoperative management of ankle fractures.

Trial status
The recruitment has started on the 7th of January 2019 and expected to complete in July 2020. One

Declarations
No personal data will be available. The coded datasets used and analysed during this trial will be available from the corresponding author on reasonable request in accordance with the GDPR and Health Research Regulations 2018(21, 22).

Ethics approval and consent to participate {24}
The following Research Ethics Committees have approved the study: Informed consent will be obtained from all study participants.

Consent for publication {32}
Consent to publish anonymised data, was explicit within the consenting process. No identifiable personal data will be published.