Early motion and directed exercise (EMADE) versus usual care post ankle fracture fixation: study protocol for a pragmatic randomised controlled trial

Early motion and directed exercise (EMADE) versus usual care post ankle fracture fixation: study... Background: Following surgical fixation of ankle fractures, the traditional management has included immobilisation for 6 weeks in a below-knee cast. However, this can lead to disuse atrophy of the affected leg and joint stiffness. While early rehabilitation from 2 weeks post surgery is viewed as safe, controversy remains regarding its benefits. We will compare the effectiveness of early motion and directed exercise (EMADE) ankle rehabilitation, against usual care, i.e. 6 weeks’ immobilisation in a below-knee cast. Method/design: We have designed a pragmatic randomised controlled trial (p-RCT) to compare the EMADE intervention against usual care. We will recruit 144 independently living adult participants, absent of tissue-healing comorbidities, who have undergone surgical stabilisation of isolated Weber B ankle fractures. The EMADE intervention consists of a non-weight-bearing progressive home exercise programme, complemented with manual therapy and education. Usual care consists of immobilisation in a non-weight-bearing below-knee cast. The intervention period is between week 2 and week 6 post surgery. The primary outcome is the Olerud and Molander Ankle Score (OMAS) patient-reported outcome measure (PROM) at 12 weeks post surgery. Secondary PROMs include the EQ-5D-5 L questionnaire, return to work and return to driving, with objective outcomes including ankle range of motion. Analysis will be on an intention-to-treat basis. An economic evaluation will be included. Discussion: The EMADE intervention is a package of care designed to address the detrimental effects of disuse atrophy and joint stiffness. An advantage of the OMAS is the potential of meta-analysis with other designs. Within the economic evaluation, the cost-utility analysis, may be used by commissioners, while the use of patient-relevant outcomes, such as return to work and driving, will ensure that the study remains pertinent to patients and their families. As it is being conducted in the clinical environment, this p-RCT has high external validity. Accordingly, if significant clinical benefits and cost-effectiveness are demonstrated, EMADE should become a worthwhile treatment option. A larger-scale, multicentre trial may be required to influence national guidelines. Trial registration: ISRCTN, ID: ISRCTN11212729. Registered retrospectively on 20 March 2017. Keywords: Ankle, Fracture, Early rehabilitation, Exercise, Physiotherapy, Health economics * Correspondence: B.Scammell@nottingham.ac.uk Academic Orthopaedics, Trauma and Sports Medicine, Division of Rheumatology, Orthopaedics and Sports Medicine, University of Nottingham, Nottingham NG7 2UH, UK Nottingham University Hospitals NHS Trust, Arthritis Research UK Centre for Sport, Exercise and Osteoarthritis, Nottingham NG7 2UH, UK Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Matthews et al. Trials (2018) 19:304 Page 2 of 10 Background We propose that an effective way to address the multi- Background and rationale factorial condition of cast disease is the application of a Ankle fractures are extremely common, accounting for multifactorial physiotherapy intervention. Developed over 20% of all lower-limb fractures [1].TheAO through expert consensus this intervention is based on (Arbeitsgemeinschaft für Osteosynthesefragen) system of early motion and directed exercises (EMADE). To deter- open reduction and internal fixation (ORIF) technique, mine if the EMADE intervention is effective, it is being has become the accepted treatment for unstable ankle assessed against the current usual care for this condition. fractures [2]. The traditional post-surgery management The EMADE protocol is presented in accordance with has been based on 6 weeks’ non-weight-bearing, with Standard Protocol Items: Recommendations for Inter- the ankle immobilised in a below-knee cast. ventional Trials (SPIRIT) and Template for Intervention Detrimental sequelae of this traditional regimen are a Description and Replication (TIDieR) guidelines (see combination of joint stiffness, reduced range of motion Additional files 1 and 2, respectively). (ROM), pain, reduced circulation, oedema and muscle atrophy [3–6]. This presentation has been termed ‘fracture disease’ [2, 7, 8]and ‘cast disease’ [7, 9–12]; the term ‘cast Methods/design disease’ is used through the remainder of this protocol. Aim Attempts to address cast disease can necessitate extended We aim to establish if, for Weber B ankle fracture patients rehabilitation, but even so, not all patients obtain the who have undergone open reduction and internal fixation, desired recovery [13]. The necessity of delaying rehabilita- whether the EMADE intervention is more effective in re- tion for 6 weeks is being increasingly questioned. ducing symptoms and restoring function than usual care. Systematic reviews of previous randomised control trials (RCTs) conclude that early rehabilitation is safe, citing no statistical difference between early rehabilitation and Primary objective control groups in terms of fixation failure, delayed and The primary objective of this study is to test the hypoth- non-union and rates of infections. [13–20]. An exception esis that the early motion and directed exercise (EMADE) has been where rehabilitation was started immediately after physiotherapy intervention, applied in the clinical setting, surgery [21], yielding an unacceptable wound infection rate will perform better than usual care at 12 weeks following of 66%, in comparison to 16% in the control group. In operative fixation for Weber B fracture as measured by contrast, delaying rehabilitation until at least 10 days post the Olerud and Molander Score (OMAS) [26]. surgery resulted in a wound infection rate of just 9% [22]. While timing appears to be the single biggest risk factor for iatrogenic wound infections, the reviews identify ambi- Secondary objectives include guity surrounding the evidence supporting effectiveness of early rehabilitation due to risk of methodological bias. For 1. A key secondary objective is to determine whether, example, underpowered sample sizes and inadequacies in in this patient group, EMADE will perform better reporting of interventions and results [13–20]. The than usual care in the short term (12 weeks post Cochrane reviewers concluded that while early rehabilita- surgery) as measured by the EQ-5D-5 L quality of tion is mostly safe, there is only ‘limited evidence’ on its life measure and the Ankle-Fracture Outcome of effectiveness [13]. Rehabilitation Measure (A-FORM) Early interventions can be classed broadly as early 2. To determine whether, in this patient group, weight-bearing, early exercises or a combination of both. EMADE will perform better than usual care, in While NICE [23] recommend further research on early the medium- and long-term (24 and 52 weeks post weight-bearing, the impact of early exercise remains an surgery, respectively), as measured by the OMAS, important and under-investigated regimen. Where there EQ-5D-5 L and A-FORM has been a focus on exercise as the intervention, it has 3. To explore the cost-effectiveness of EMADE mostly been limited to range of motion. A comprehensive training programme [24] has shown some benefit over a minimal programme, while in contrast, no supporting Trial design and study setting evidence was identified by Moseley et al. [4] for the This is a prospective, pragmatic randomised controlled addition of stretches and no supporting evidence for the trial (p-RCT) of superiority design, with participants allo- addition of manual therapy by Lin et al. [25]. However, cated in a 1:1 ratio to either of two parallel groups. The interventions for these studies commenced after the trial is based in the fracture clinic of the Queen’sMedical 6-week period, by which time cast disease would have Centre, Nottingham University Hospitals, Nottingham, been established. UK, with other sites being considered. Matthews et al. Trials (2018) 19:304 Page 3 of 10 Participants, interventions and outcomes during the 2-week review (10 to 19 days post surgery). All Recruitment participants are non-weight-bearing throughout the study The clinical care team will identify potential participants until the 6-week point. from hospital consultant and theatre lists and notify the The EMADE intervention is a progressive home exer- researchers of those patients willing to be approached. A cise programme that includes range-of-motion (ROM) researcher will approach the potential participant and in- and strengthening exercises, and is conducted by the par- form them of all aspects of the study and provide a written ticipant up to six times a day. To be able to conduct the information sheet (available via http://www.isrctn.com/ exercises, at the 2-week fracture clinic review, those in the ISRCTN11212729). This states that entry is voluntary and EMADE intervention group are fitted with a removable that they are free to withdraw at any time without effect below-knee cast with Velcro retaining straps. on subsequent care. If appropriate, following screening The EMADE programme starts with light intensity and and following the opportunity to make an informed deci- low daily repetitions, and as the weeks progress, becomes sion, written consent will be obtained from those willing progressively more intensive and repetitive. For example, to be recruited to the study. Consent will be re-confirmed exercises start resistance-free, and are followed by verbally at each stage of the study. elastic-exercise-band resistance; while the daily repetitions start twice daily and build up to six times daily. These pro- Eligibility gressions are taught during weekly face-to-face sessions Inclusion criteria between the week-2 and week-6 fracture clinic reviews. During the physiotherapy sessions, participants receive 1. Patients with isolated, closed Weber B fractures manual therapy consisting of 5 to 10 min of joint and (AO44-B1, -B2 or -B3) which are stable following soft-tissue manipulation to the ankle complex. Advice and open reduction and internal fixation. This includes education is on-going and includes; healing processes, those requiring syndesmosis stabilisation control of pain and swelling, and expectations of fluctu- 2. Patients aged 18 years and over ation of pain and swelling. These sessions take part in the 3. Independently living recruiting hospital, and are provided by an experienced 4. Capable of independently reading and completing physiotherapist trained in the application of the EMADE the study paperwork in English intervention. To encourage compliance with the EMADE home Exclusion criteria exercise programme, participants are provided with writ- ten and pictorial exercise sheets. These were developed 1. Inability to provide informed consent, or declining through patient input and include diary sheets, although participation completion of the diary sheets is neither mandatory nor 2. Comorbidities: diabetes requiring prescription used in data collection. Participants are not paid to at- drugs, non-healing leg/foot ulcers, oral or tend, but a basic travel allowance is offered to attend the intravenously administered steroid users, additional sessions for the study, but not for usual NHS pre-existing ankle arthritis and concurrent or care. Participants in the usual care group are treated in a history of significant ipsilateral or contralateral below-knee cast and remain non-weight-bearing until lower limb injury/condition, e.g. prosthesis in the 6-week point. lower-limb joints, or neurological disorders From the 6-week review, all study participants receive 3. At the 2-week clinic visit a patient may be excluded the same standard care. This includes removal of cast and, if, based on individual clinical decision, there is if appropriate following x-ray, weight-bearing as tolerated notable risk that early wound movement will may commence, along with physiotherapy as required. impede satisfactory healing. Protocol deviations will be as per standard care, being 4. Those unable to commit to weekly clinic visits, based on individual clinical decisions. if assigned to the EMADE intervention group Outcome measures Interventions Primary outcome measure Pre-operatively and, during the first two post-operative Theprimary outcomemeasure is theOlerudand Molander weeks, participants receive identical care consisting of Ankle Score (OMAS) [26] reported at 12 weeks following admission to hospital and consultant supervised surgery surgery. The OMAS is a validated ankle-fracture PROM including management on a standard care pathway. [27, 28] consisting of nine Likert-styled questions; three Participants are discharged home in a cast and reviewed 2 symptom- and six function-focussed questions. It is scored weeks following surgery. All participants undergo x-ray 0–100; poorest to best, respectively, and has been treated as post surgery and wound inspection following cast removal a continuous scale in the Cochrane ankle fracture review Matthews et al. Trials (2018) 19:304 Page 4 of 10 [13] and has been recommended by both Cochrane re- Human Physiology Unit, Medical School, University of viewers [13]and NICE [23]. Nottingham, UK. Secondary outcome measures Allocation and Blinding Secondary outcomes including the OMAS collected at 2 and An online computer service, www.sealedenvelope.com is 6 weeks post surgery, as baseline and end-of-intervention used for randomisation. This facility generated the codes measures, respectively and at 24 and 52 weeks post surgery, concealed from the research team, on a 1:1 allocation as medium- and long-term follow-ups. Other secondary out- basis to either group, with random order of permuted comes include: the Ankle-Fracture Outcome of Rehabilita- blocks (sizes of 4, 6 and 8). Over the duration of the tion Measure (A-FORM) [29]and theEQ-5D-5 L[30] trial, there is greater potential that those with syndes- PROMs, which are collected at the same time points as the mosis screw(s) may require further surgery. To mitigate OMAS. Other function-focussed outcomes include the Phys- against risk of allocation imbalance, stratification of this ical Activity Record Scale (PARS) [31], the Clinical Physical sub-group will be designed into the randomisation. Activity Questionnaire (CPAQ) [32], the use of walking aids, return to work and return to driving. X-ray findings and Blinding (masking) adverse events are also recorded. It is not possible to blind the participant nor the therapist When answering Likert-styled questions within the from the treatment allocation. PROMs, if a participant is unsure which Likert option to However, to reduce risk of bias, 12-, 24- and 52-week select, they are advised to select the poorer outcome. This paper PROMs are completed by participants, concealed approach is particularly pertinent at the 2-week and 6-week from the researchers and stored in sealed opaque enve- time points, when answering function-related questions lopes. A third party, blinded to the intervention group in- such as walking, as post-operative clinical instructions puts the data. The electronic PROMs are web-based, held would have been to remain non-weight-bearing. This is not by Bristol Online Survey (BOS), www.onlinesurveys.ac.uk. an anticipated concern for the primary outcome, being at Via this system at the appropriate time points, participants 12 weeks, nor the subsequent follow-ups. are e-mailed a single-use link to their e-PROM. Objective measures are included at the 2-week and 6-week time points: non-weight-bearing dorsiflexion and Sample size, data processing and statistical plantar flexion ROM and, ankle (figure-of-8) and calf methods (circumference) measures. Participants will be invited to Sample size calculations attend for repeated outcome assessments at 12 weeks, 24 It was estimated that a total of 120 participants will be weeks and 52 weeks, with the additions of weight-bearing required based on a minimal clinical important difference dorsiflexion, walking speed, balance and isokinetic of 10 points on the OMAS, with a standard deviation of plantar-flexion strength. Those declining will be encour- 19.5, significance level of 5% and powered at 80%. aged to complete and return the appropriate PROMs Allowance for attrition was set initially at 20% but, due to questionnaires. higher-than-expected dropout rates, this was increased to 30%, yielding a target of 156 to enter the study at Participant timeline randomisation. Recruitment and consent may take place from the in-patient stay until and including the 2-week Data processing post-surgery outpatient review. Only after all baseline PROM data collection is paper based, with participant outcome measures are recorded, does randomisation number 55 onwards being offered the option of complet- take place, see Figs. 1 and 2. ing PROMs online. Once paper-based 12-week, 24-week The data collection time points (post surgery) are: base- and 52-week PROMs are completed the participant seals line at 2 weeks, end of intervention at 6 weeks, and at them in a windowless opaque envelop and returns them three research follow-up time points; 12 weeks and 24 to the researchers (postage pre-paid). These are securely weeks as short- and mid-term follow-ups, respectively, stored and subsequently opened in batches by an and at 52 weeks as a long-term follow-up and the trial end individual blinded to group allocation, who inputs the point. For participant’s convenience, the 2-week and data into a holding database for subsequent transfer into 6-week EMADE sessions are combined with the ortho- SPSS for reporting and statistical analysis. For audit paedic 2-week and 6-week reviews. The 12-week, 24-week purpose, after inputting each batch, a ‘read-only’ copy is and 52-week PROMs data may be collected via either stored in a separate protected folder. A separate copy is return post (postage pre-paid), electronically or in person used for data screening and cleaning, guided by good according to participant choice. Participants undergoing practice [33] and may include self-evident corrections objective assessment will attend the David Greenfield [34] where appropriate. While filters and error alerts will Matthews et al. Trials (2018) 19:304 Page 5 of 10 Fig. 1 Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) Figure of enrolment, interventions and assessments. Key: EMADE early motion and directed exercise, PROMs Patient-reported outcome measures. *Study PROMs: Olerud Molander Ankle Score (OMAS), Ankle-Fracture Outcome of Rehabilitation Measure (A-FORM), EQ-5D-5 L, work and leisure activities, walking aid use and return to driving. **Option for patients to attend for Laboratory-based objective measures reduce inputting errors, 20% of entries will be prior to randomisation will be reported, but not carried cross-checked against the paper PROMs for discrepan- into the main analysis. Descriptive statistics will be pro- cies. Data changes will be recorded for blinded adjudica- duced, within and between each intervention group(s) tion. For audit purposes a copy of the cleaned and for demographics and outcomes at all data time points. checked data will also be saved as a ‘read-only’ copy and Continuous data will be summarised as mean and stand- stored separately. The design of the e-PROMs does not ard deviation and confidence intervals (CI) (95% CI and permit questions to be left unanswered, mitigating p value threshold ≤ 0.05) for the PROM outcome data. against problems of incomplete data and once the Median and interquartile ranges will be used where participant completes their PROM the original dataset is appropriate statistical assumptions are not met, whereas locked against further alterations. The system permits categorical data will be presented as frequencies and data transfer into SPSS. proportions and analysed using either chi-square or The research team and statistician will conduct the Fisher’s exact test as indicated (p value of ≤ 0.05). analysis. The statistician will conduct the primary Non-parametric tests will be employed where appropri- outcome analysis independently and is blinded to group ate. Analysis will be conducted on the intention-to-treat allocation. Data and reason for any patient excluded (ITT) basis. Matthews et al. Trials (2018) 19:304 Page 6 of 10 Fig. 2 A schematic diagram of the patient’s journey through the early motion and directed exercises (EMADE) ankle study. Key: EMADE early motion and directed exercise, PROMs patient-reported outcome measures To test the primary outcome measure hypothesis that 1. If missing data is 5% or less, conduct analysis based the EMADE physiotherapy intervention, as described on complete-case analysis will perform better than usual care, the difference in 2. If missing data is greater than 5% and up to 10%: group means of the primary outcome, OMAS values at (a) Conduct analysis based on pairwise 12 weeks post surgery, will be statistically compared. deletion (assuming missing at random This will be through applying an independent t test with (MAR)) and then significance taken as p value of ≤ 0.05 and the inclusion (b) Conduct multiple imputation analysis of confidence intervals (CI at 95% CI and p value of ≤ (c) If these two analyses yield comparable results, 0.05 threshold). Where data is not found to be normally then it will be assumed that the missing data distributed such that parametric tests cannot be utilised, has not influenced the outcome of the trial the non-parametric Mann-Whitney U test will be (d) If the two analyses yield notable differences, employed (p value ≤ 0.05). to accommodate for the missing data, There is a lack of consensus in the academic literature sensitivity analysis will be conducted based on how to handle missing data [35, 36]. However, based on the statistician’s advice on the 120 sample size, the following sequential approach 3. If missing data exceeds 10%, detailed discussions will be applied for the primary outcome: will be held with the study statistician Matthews et al. Trials (2018) 19:304 Page 7 of 10 Interpretation of secondary outcome and sub-group Governance analysis will require caution due to risks of type II errors Governance procedures were developed following Good and, because of where post hoc analysis may demonstrate Clinical Practice (GCP) guidelines (non-CTIMP) [37] association, causation may not be supported. Secondary with agreements from the local sponsors and the Ethics analyses will be performed for hypothesis generation. The Committee. This includes reporting procedures for ad- difference in group mean scores for the secondary out- verse and serious adverse events. The governance proce- comes; EQ-5D-5 L and A-FORM at 12 weeks post surgery dures for this trial has been independently audited by will be analysed in a similar manner to the primary out- the Quality Assurance and Good Clinical Practice Audit come. The one-way analysis of covariance (ANCOVA), in- Office, Nottingham Health Science Partnership, with a cluding follow-up time as a covariance, will be applied to favourable outcome. assess these outcomes across the complete study period. Due to the size of the trial it was considered unneces- Adjustment for baseline scores, through analysis of sary to form a data monitoring committee. This study will covariance, will be conducted for OMAS, EQ-5D-5 L comply with the requirements of the UK Data Protection and A-FORM and compared with unadjusted scores. Act 1998 with regards to the collection, storage, process- Impact of covariates will be further explored through ing and disclosure of personal information and will uphold regression analysis. Initial analysis for co-variates where the Act’s core principles. Access to collated participant significance is nearly reached (p > 0.10) will be taken for- data will be restricted to the research study staff. Alloca- ward into a statistical model. Due to the bimodal impact tion of a unique code to each participant will help to en- of age and sex, these will be included in this analysis. sure confidentiality and anonymity. These identifiers will Other exploratory analysis for potential covariates may be used in all data, study material and reporting. Published include impact of smoking, previous level of physical results will not contain any personal data that could allow activity, type of fracture (AO classification), complexity identification of individual participants. All electronic data of surgical repair and any subsequent removal of metal will be stored on host NHS and University computers, work; most notably removal of syndesmosis screw(s) for with limited access under username and password protec- which stratification was applied at randomisation. tion system, as per host NHS and University ICT policies. Analysis will also be conducted using modified ITT by Paper-based data will be stored in a locked filing cabinet excluding those participants who attend only one session in a key-coded room. or less of EMADE sessions. Sub-groups will include return to work for those Ethics approval and amendments unable to work due to their ankle fracture at the time of NRES Committee East Midlands – Nottingham 2, randomisation, and similarly, return to driving for those reviewed and approved this study on 4 November 2014 unable to drive due to their ankle fracture at the time of (14/EM/1213). The Ethics Committee and sponsors have randomisation. Frequency of complications will be been informed of important protocol changes and described but, based on the published literature, it is events. Amendments have focussed on an embedded anticipated that frequency will be sufficiently low not to study, which has subsequently been removed from the warrant statistical analysis. trial; only two participants were recruited to this embed- ded study and both participants withdrew from the trial during their in-patient stay and did not reach random- Health economics isation. Other amendments include: (1) expanding the Health economic evaluations will be conducted from a recruitment period from the in-patient period, up to and societal perspective and from the service commis- including the 2-week clinical visit and (2) reducing the sioner’s perspective. The societal perspective will be burden on the participant by decreasing the number of limited to incremental cost-effectiveness ratio (ICER) of PROMs and permitting PROM completion online. The the natural units of; return to work and return to time point of randomisation, the intervention, and the driving (sub-groups as described earlier). Based on the primary and core outcome measures, have all remained EQ-5D-5 L PROM data, a cost-utility analysis (costs unchanged since the start of recruitment. per quality-adjusted life year; QALY) will be performed from the local commission’s perspective. Sensitivity Dissemination analysis will include the variability of the additional Routes of dissemination will include: EMADE physiotherapy service costs; for example, £18 to £25 per session (2016 rates) and frequency of 1. Medical and associated, conferences, meetings and post-6-week physiotherapy sessions. The final methods journals for health economic evaluations will be guided by dis- 2. Patient participation seminars and meetings, such cussion with a health economist. as those organised by Arthritis Research UK Matthews et al. Trials (2018) 19:304 Page 8 of 10 3. Further data-sharing plans for the current study are The primary objective of this study is to test whether unknown and will be made available at a later date the EMADE intervention is effective in the clinical set- ting. Therefore, it is appropriate to assess effectiveness Decisions on authorship will be directed by guide- of EMADE against usual care in the clinical setting, lines from International Committee of Medical Jour- through a p-RCT. If significant clinical benefits and nal Editors [38]. cost-effectiveness are demonstrated, EMADE should be- come a viable treatment option. A larger-scale, multicen- tre trial may be required to influence national guidelines. Discussion The aim of this trial is to determine if EMADE is more Trial status effective than usual care in reducing symptoms and restor- At the time of manuscript submission 111 participants ing function in those who have undergone open reduction had joined the trial. and internal fixation following a Weber B ankle fracture. While EMADE does not contain novel modalities, what is Protocol version distinctive for this trial is EMADE’s early clinical applica- Version 2.2, 18 April 2017. First recruit June 2015, last tion of a progressive ankle rehabilitation programme, expected mid 2018. being at 2 weeks post ankle surgery versus the traditional of starting after 6 weeks of immobilisation. Additional files We do not anticipate significant bias from known con- founders, such as age and sex, and unknown confounders, Additional file 1: Early motion and directed exercises (EMADE) Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) due to the limiting effect on bias from random allocation. Checklist. (DOCX 53 kb) However, as a pragmatic study, there is no control nor Additional file 2: Early motion and directed exercises (EMADE) and influence over the quality and volume of care, including Template for Intervention Description and Replication (TIDieR) Checklist. physiotherapy, after the end of the intervention at 6 weeks (DOCX 30 kb) post surgery. While compliance with the EMADE home exercise Abbreviations A-FORM: Ankle-Fracture Outcome of Rehabilitation; AO: Arbeitsgemeinschaft programmewillbeencouraged through theweekly für Osteosynthesefragen; ARUK: Arthritis Research UK; CPAQ: Clinical Physical face-to-face reviews and the written and pictorial exercise Activity Questionnaire; EMADE: Early motion and directed exercises; EQ-5D- sheets, compliance will still be a potential confounder. 5 L: EuroQol 5 Dimension 5-Level Questionnaire; ICER: Incremental cost- effectiveness ratio; OMAS: Olerud and Molander Ankle Score.; ORIF: Open However, as a pragmatic trial, this level of encouragement reduction and internal fixation; p-RCT: Pragmatic randomised controlled trial; and supervision was felt to be appropriate, as it reflects PROM: Patient-reported outcome measure; ROM: Range of motion current physiotherapy clinical practice. Acknowledgements It may be argued that starting physiotherapy early with Acknowledgement is made to both Arthritis Research UK, Centre of EMADE will reduce the number of sessions subsequently Sports, Exercise Osteoarthritis and AO-UK for their support and funding, required and, thus, the overall number of sessions may and to staff of both the Arthritis Research UK, Centre for Sports Exercise and Osteoarthritis and of the David Greenfield Physiology Laboratory, not be significantly different from usual care. However, University of Nottingham. while this remains unproven it is pertinent to assume that EMADE is more expensive (approximately £54 to £75) Funding This work is supported by the Arthritis Research UK (grant number 20194), and, therefore a cost-utility analysis in QALYs is required the funding covers provision for researcher salaries, stipends and experimental from the commissioner’s perspective to determine if running and analytical costs. In addition, AO-UK is part funding the study. The EMADE is value for money. Also, while QALY units will funders did not influence the design nor the implementation of the study and will not influence the analyses and decisions surrounding publication and be valued by commissioners, the use of natural units; dissemination of the findings. Views expressed are those of the authors and return to driving and return to work will be tangible to do not necessarily reflect the view of the funders. patients and their families. Availability of data and material As this intervention requires no specialist equipment, it Beyond the previously described plans for dissemination, further data-sharing is suitable for provision in both primary and secondary plans are currently unknown and will be made available at a later date. care-based physiotherapy departments and, therefore, has potential for broad clinical impact. The trial design limits Trial sponsor Dr. Maria Koufali. bias where possible, including during the collection, pro- Research and Innovation, cessing and analysis of PROM data. Objective outcomes Nottingham Integrated Clinical Research Centre, will be recorded unblinded; however, being secondary C Floor, South Block, Queen’s Medical Centre Campus, outcomes and analysed separately from the PROM data, Nottingham University Hospitals NHS Trust, the potential impact of bias from objective data will have Nottingham, NG7 2UH. limited impact on the overall quality of the study. Telephone: 0115 9249924 Matthews et al. Trials (2018) 19:304 Page 9 of 10 Authors’ contributions 10. Tisherman SA, Forsythe RM. Trauma intensive care. New York: Oxford BES conceived this study, participated in the design detail and writing University Press; 2013 of the manuscript. PAM conceived this study, participated in the design 11. Coughlin MJ, Saltzman CL, Mann RA. Mann's surgery of the foot and ankle detail, writing of the manuscript and participated in recruiting and E-Book: Expert Consult-Online. Philadelphia: Elsevier Health Sciences; 2013. enrolling patients for this study. BJO conceived this study, participated in 12. Safran MR, McKeag D, Van Camp SP. Manual of sports medicine. the design detail, writing of the manuscript, and participated in recruiting Philadelphia: Lippincott Williams & Wilkins; 1998. and enrolling patients for this study. AA participated in the design, and 13. Lin CW, Donkers NA, Refshauge KM, Beckenkamp PR, Khera K, Moseley AM. participated in recruiting and enrolling patients for this study. JN Rehabilitation for ankle fractures in adults. Cochrane Database Syst Rev. participated in recruiting and enrolling patients for this study. TC 2012;11:CD005595. participated in recruiting and enrolling patients for this study. TK 14. Beckenkamp PR, Lin C-WC, Chagpar S, Herbert RD, van der Ploeg HP, participated in recruiting and enrolling patients for this study. Moseley AM. Prognosis of physical function following ankle fracture: a All authors read and approved the final version of the manuscript. systematic review with meta-analysis. J Orthop Sports Phys Ther. 2014; 44(11):841–51. Ethics approval and consent to participate 15. Black JDJ, Bhavikatti M, Al-Hadithy N, Hakmi A, Kitson J. Early weight-bearing Ethical approval was granted by NRES Committee East Midlands – Nottingham in operatively fixed ankle fractures: a systematic review. Foot. 2013;23(2):78-85. 2, reviewed on 4 November 2014 (14/EM/1213). Before participation, all 16. Del Buono A, Smith R, Coco M, Woolley L, Denaro V, Maffulli N. Return participants are required to provide their written informed consent, which to sports after ankle fractures: a systematic review. Br Med Bull. 2013; was verbally re-confirmed at each stage by the research team. 106(1):179–91. 17. Keene DJ, Williamson E, Bruce J, Willett K, Lamb SE. Early ankle movement Consent for publication versus immobilization in the postoperative management of ankle fracture in Consent to publish anonymised data, was explicit within the initial adults: a systematic review and meta-analysis. J Orthop Sports Phys Ther. consenting process. 2014;44(9):690–C7. 18. Smeeing DPJ, Houwert RM, Briet JP, Kelder JC, Segers MJM, Verleisdonk Competing interests EJMM, Leenen LPH, Hietbrink F. Weight-bearing and mobilization in the The authors declare that they have no competing interests. postoperative care of ankle fractures: a systematic review and meta- analysis of randomized controlled trials and cohort studies. PLoS One. 2015;10(2):e0118320. Publisher’sNote 19. Thomas G, Whalley H, Modi C. Early mobilization of operatively fixed ankle Springer Nature remains neutral with regard to jurisdictional claims in fractures: a systematic review. Foot Ankle Int. 2009;30(7):666–74. published maps and institutional affiliations. 20. van Son MA, De Vries J, Roukema JA, Den Oudsten BL. Health status, health- related quality of life, and quality of life following ankle fractures: a Author details systematic review. Injury. 2013;44(11):1391–402. Academic Orthopaedics, Trauma and Sports Medicine, Division of 21. Lehtonen H, Jarvinen TL, Honkonen S, Nyman M, Vihtonen K. Jarvinen M. J. Rheumatology, Orthopaedics and Sports Medicine, University of Nottingham, 2 Use of a cast compared with a functional ankle brace after operative Nottingham NG7 2UH, UK. Nottingham University Hospitals NHS Trust, treatment of an ankle fracture. A prospective, randomized study. J Bone Arthritis Research UK Centre for Sport, Exercise and Osteoarthritis, 3 Joint Surg (Am Vol). 2003;85(2):205–11. 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Epidemiology of lower limb fractures in general practice in addition to physiotherapy does not improve clinical or economic outcomes the United Kingdom. Injury Prevention. 2004;10(6):368–74. after ankle fracture. J Rehabil Med. 2008;40(6):433–9. 2. Müller ME, Allgöwer M, Perren SM. Manual of internal fixation: 26. Olerud C, Molander H. A scoring scale for symptom evaluation after ankle techniques recommended by the AO-ASIF group: Springer Science & fracture. Arch Orthop Trauma Surg. 1984;103(3):190–4. Business Media; 1991. 27. Lash N, Horne G, Fielden J, Devane P. Ankle fractures: functional and 3. Lin C-WC, Moseley AM, Herbert RD, Refshauge KM. Pain and dorsiflexion lifestyle outcomes at 2 years. ANZ J Surg. 2002;72(10):724–30. range of motion predict short- and medium-term activity limitation in 28. Nilsson GM, Eneroth M, Ekdahl CS. The Swedish version of OMAS is a people receiving physiotherapy intervention after ankle fracture: an reliable and valid outcome measure for patients with ankle fractures. BMC observational study. Aust J Physiother. 2009;55(1):31–7. Musculoskelet Disord. 2013;14(1):109. 4. Moseley A, Herbert R, Nightingale E, Taylor D, Evans T, Robertson G, Gupta 29. McPhail SM, Williams CM, Schuetz M, Baxter B, Tonks P, Haines TP. S, Penn J. Passive stretching does not enhance outcomes in patients with Development and validation of the ankle fracture outcome of rehabilitation plantarflexion contracture after cast immobilization for ankle fracture: a measure (A-FORM). J Orthop Sports Phys Ther. 2014;44(7):488–99. B481-482 randomized controlled trial. Arch Phys Med Rehabil. 2005;86(6):1118–26. 30. Mandy vR, Bas J. EQ-5D-5L user guide basic information on how to use the 5. Vandenborne K, Elliott MA, Walter GA, Abdus S, Okereke E, Shaffer M, EQ-5D-5L instrument v2.1. 2015. Tahernia D, Esterhai JL. 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Aust N Z J Public Health. 2001;25(5):464–9. 37. CRN. Introduction to Good Clinical Practice (GCP). A practical guide to ethical and scientific quality standards in clinicl research. Leeds: Development NCW; 2013. 38. Defining the role of authors and contributors. http://www.icmje.org/. Accessed 1 May 2017. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Trials Springer Journals

Early motion and directed exercise (EMADE) versus usual care post ankle fracture fixation: study protocol for a pragmatic randomised controlled trial

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Medicine & Public Health; Medicine/Public Health, general; Biomedicine, general; Statistics for Life Sciences, Medicine, Health Sciences
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Abstract

Background: Following surgical fixation of ankle fractures, the traditional management has included immobilisation for 6 weeks in a below-knee cast. However, this can lead to disuse atrophy of the affected leg and joint stiffness. While early rehabilitation from 2 weeks post surgery is viewed as safe, controversy remains regarding its benefits. We will compare the effectiveness of early motion and directed exercise (EMADE) ankle rehabilitation, against usual care, i.e. 6 weeks’ immobilisation in a below-knee cast. Method/design: We have designed a pragmatic randomised controlled trial (p-RCT) to compare the EMADE intervention against usual care. We will recruit 144 independently living adult participants, absent of tissue-healing comorbidities, who have undergone surgical stabilisation of isolated Weber B ankle fractures. The EMADE intervention consists of a non-weight-bearing progressive home exercise programme, complemented with manual therapy and education. Usual care consists of immobilisation in a non-weight-bearing below-knee cast. The intervention period is between week 2 and week 6 post surgery. The primary outcome is the Olerud and Molander Ankle Score (OMAS) patient-reported outcome measure (PROM) at 12 weeks post surgery. Secondary PROMs include the EQ-5D-5 L questionnaire, return to work and return to driving, with objective outcomes including ankle range of motion. Analysis will be on an intention-to-treat basis. An economic evaluation will be included. Discussion: The EMADE intervention is a package of care designed to address the detrimental effects of disuse atrophy and joint stiffness. An advantage of the OMAS is the potential of meta-analysis with other designs. Within the economic evaluation, the cost-utility analysis, may be used by commissioners, while the use of patient-relevant outcomes, such as return to work and driving, will ensure that the study remains pertinent to patients and their families. As it is being conducted in the clinical environment, this p-RCT has high external validity. Accordingly, if significant clinical benefits and cost-effectiveness are demonstrated, EMADE should become a worthwhile treatment option. A larger-scale, multicentre trial may be required to influence national guidelines. Trial registration: ISRCTN, ID: ISRCTN11212729. Registered retrospectively on 20 March 2017. Keywords: Ankle, Fracture, Early rehabilitation, Exercise, Physiotherapy, Health economics * Correspondence: B.Scammell@nottingham.ac.uk Academic Orthopaedics, Trauma and Sports Medicine, Division of Rheumatology, Orthopaedics and Sports Medicine, University of Nottingham, Nottingham NG7 2UH, UK Nottingham University Hospitals NHS Trust, Arthritis Research UK Centre for Sport, Exercise and Osteoarthritis, Nottingham NG7 2UH, UK Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Matthews et al. Trials (2018) 19:304 Page 2 of 10 Background We propose that an effective way to address the multi- Background and rationale factorial condition of cast disease is the application of a Ankle fractures are extremely common, accounting for multifactorial physiotherapy intervention. Developed over 20% of all lower-limb fractures [1].TheAO through expert consensus this intervention is based on (Arbeitsgemeinschaft für Osteosynthesefragen) system of early motion and directed exercises (EMADE). To deter- open reduction and internal fixation (ORIF) technique, mine if the EMADE intervention is effective, it is being has become the accepted treatment for unstable ankle assessed against the current usual care for this condition. fractures [2]. The traditional post-surgery management The EMADE protocol is presented in accordance with has been based on 6 weeks’ non-weight-bearing, with Standard Protocol Items: Recommendations for Inter- the ankle immobilised in a below-knee cast. ventional Trials (SPIRIT) and Template for Intervention Detrimental sequelae of this traditional regimen are a Description and Replication (TIDieR) guidelines (see combination of joint stiffness, reduced range of motion Additional files 1 and 2, respectively). (ROM), pain, reduced circulation, oedema and muscle atrophy [3–6]. This presentation has been termed ‘fracture disease’ [2, 7, 8]and ‘cast disease’ [7, 9–12]; the term ‘cast Methods/design disease’ is used through the remainder of this protocol. Aim Attempts to address cast disease can necessitate extended We aim to establish if, for Weber B ankle fracture patients rehabilitation, but even so, not all patients obtain the who have undergone open reduction and internal fixation, desired recovery [13]. The necessity of delaying rehabilita- whether the EMADE intervention is more effective in re- tion for 6 weeks is being increasingly questioned. ducing symptoms and restoring function than usual care. Systematic reviews of previous randomised control trials (RCTs) conclude that early rehabilitation is safe, citing no statistical difference between early rehabilitation and Primary objective control groups in terms of fixation failure, delayed and The primary objective of this study is to test the hypoth- non-union and rates of infections. [13–20]. An exception esis that the early motion and directed exercise (EMADE) has been where rehabilitation was started immediately after physiotherapy intervention, applied in the clinical setting, surgery [21], yielding an unacceptable wound infection rate will perform better than usual care at 12 weeks following of 66%, in comparison to 16% in the control group. In operative fixation for Weber B fracture as measured by contrast, delaying rehabilitation until at least 10 days post the Olerud and Molander Score (OMAS) [26]. surgery resulted in a wound infection rate of just 9% [22]. While timing appears to be the single biggest risk factor for iatrogenic wound infections, the reviews identify ambi- Secondary objectives include guity surrounding the evidence supporting effectiveness of early rehabilitation due to risk of methodological bias. For 1. A key secondary objective is to determine whether, example, underpowered sample sizes and inadequacies in in this patient group, EMADE will perform better reporting of interventions and results [13–20]. The than usual care in the short term (12 weeks post Cochrane reviewers concluded that while early rehabilita- surgery) as measured by the EQ-5D-5 L quality of tion is mostly safe, there is only ‘limited evidence’ on its life measure and the Ankle-Fracture Outcome of effectiveness [13]. Rehabilitation Measure (A-FORM) Early interventions can be classed broadly as early 2. To determine whether, in this patient group, weight-bearing, early exercises or a combination of both. EMADE will perform better than usual care, in While NICE [23] recommend further research on early the medium- and long-term (24 and 52 weeks post weight-bearing, the impact of early exercise remains an surgery, respectively), as measured by the OMAS, important and under-investigated regimen. Where there EQ-5D-5 L and A-FORM has been a focus on exercise as the intervention, it has 3. To explore the cost-effectiveness of EMADE mostly been limited to range of motion. A comprehensive training programme [24] has shown some benefit over a minimal programme, while in contrast, no supporting Trial design and study setting evidence was identified by Moseley et al. [4] for the This is a prospective, pragmatic randomised controlled addition of stretches and no supporting evidence for the trial (p-RCT) of superiority design, with participants allo- addition of manual therapy by Lin et al. [25]. However, cated in a 1:1 ratio to either of two parallel groups. The interventions for these studies commenced after the trial is based in the fracture clinic of the Queen’sMedical 6-week period, by which time cast disease would have Centre, Nottingham University Hospitals, Nottingham, been established. UK, with other sites being considered. Matthews et al. Trials (2018) 19:304 Page 3 of 10 Participants, interventions and outcomes during the 2-week review (10 to 19 days post surgery). All Recruitment participants are non-weight-bearing throughout the study The clinical care team will identify potential participants until the 6-week point. from hospital consultant and theatre lists and notify the The EMADE intervention is a progressive home exer- researchers of those patients willing to be approached. A cise programme that includes range-of-motion (ROM) researcher will approach the potential participant and in- and strengthening exercises, and is conducted by the par- form them of all aspects of the study and provide a written ticipant up to six times a day. To be able to conduct the information sheet (available via http://www.isrctn.com/ exercises, at the 2-week fracture clinic review, those in the ISRCTN11212729). This states that entry is voluntary and EMADE intervention group are fitted with a removable that they are free to withdraw at any time without effect below-knee cast with Velcro retaining straps. on subsequent care. If appropriate, following screening The EMADE programme starts with light intensity and and following the opportunity to make an informed deci- low daily repetitions, and as the weeks progress, becomes sion, written consent will be obtained from those willing progressively more intensive and repetitive. For example, to be recruited to the study. Consent will be re-confirmed exercises start resistance-free, and are followed by verbally at each stage of the study. elastic-exercise-band resistance; while the daily repetitions start twice daily and build up to six times daily. These pro- Eligibility gressions are taught during weekly face-to-face sessions Inclusion criteria between the week-2 and week-6 fracture clinic reviews. During the physiotherapy sessions, participants receive 1. Patients with isolated, closed Weber B fractures manual therapy consisting of 5 to 10 min of joint and (AO44-B1, -B2 or -B3) which are stable following soft-tissue manipulation to the ankle complex. Advice and open reduction and internal fixation. This includes education is on-going and includes; healing processes, those requiring syndesmosis stabilisation control of pain and swelling, and expectations of fluctu- 2. Patients aged 18 years and over ation of pain and swelling. These sessions take part in the 3. Independently living recruiting hospital, and are provided by an experienced 4. Capable of independently reading and completing physiotherapist trained in the application of the EMADE the study paperwork in English intervention. To encourage compliance with the EMADE home Exclusion criteria exercise programme, participants are provided with writ- ten and pictorial exercise sheets. These were developed 1. Inability to provide informed consent, or declining through patient input and include diary sheets, although participation completion of the diary sheets is neither mandatory nor 2. Comorbidities: diabetes requiring prescription used in data collection. Participants are not paid to at- drugs, non-healing leg/foot ulcers, oral or tend, but a basic travel allowance is offered to attend the intravenously administered steroid users, additional sessions for the study, but not for usual NHS pre-existing ankle arthritis and concurrent or care. Participants in the usual care group are treated in a history of significant ipsilateral or contralateral below-knee cast and remain non-weight-bearing until lower limb injury/condition, e.g. prosthesis in the 6-week point. lower-limb joints, or neurological disorders From the 6-week review, all study participants receive 3. At the 2-week clinic visit a patient may be excluded the same standard care. This includes removal of cast and, if, based on individual clinical decision, there is if appropriate following x-ray, weight-bearing as tolerated notable risk that early wound movement will may commence, along with physiotherapy as required. impede satisfactory healing. Protocol deviations will be as per standard care, being 4. Those unable to commit to weekly clinic visits, based on individual clinical decisions. if assigned to the EMADE intervention group Outcome measures Interventions Primary outcome measure Pre-operatively and, during the first two post-operative Theprimary outcomemeasure is theOlerudand Molander weeks, participants receive identical care consisting of Ankle Score (OMAS) [26] reported at 12 weeks following admission to hospital and consultant supervised surgery surgery. The OMAS is a validated ankle-fracture PROM including management on a standard care pathway. [27, 28] consisting of nine Likert-styled questions; three Participants are discharged home in a cast and reviewed 2 symptom- and six function-focussed questions. It is scored weeks following surgery. All participants undergo x-ray 0–100; poorest to best, respectively, and has been treated as post surgery and wound inspection following cast removal a continuous scale in the Cochrane ankle fracture review Matthews et al. Trials (2018) 19:304 Page 4 of 10 [13] and has been recommended by both Cochrane re- Human Physiology Unit, Medical School, University of viewers [13]and NICE [23]. Nottingham, UK. Secondary outcome measures Allocation and Blinding Secondary outcomes including the OMAS collected at 2 and An online computer service, www.sealedenvelope.com is 6 weeks post surgery, as baseline and end-of-intervention used for randomisation. This facility generated the codes measures, respectively and at 24 and 52 weeks post surgery, concealed from the research team, on a 1:1 allocation as medium- and long-term follow-ups. Other secondary out- basis to either group, with random order of permuted comes include: the Ankle-Fracture Outcome of Rehabilita- blocks (sizes of 4, 6 and 8). Over the duration of the tion Measure (A-FORM) [29]and theEQ-5D-5 L[30] trial, there is greater potential that those with syndes- PROMs, which are collected at the same time points as the mosis screw(s) may require further surgery. To mitigate OMAS. Other function-focussed outcomes include the Phys- against risk of allocation imbalance, stratification of this ical Activity Record Scale (PARS) [31], the Clinical Physical sub-group will be designed into the randomisation. Activity Questionnaire (CPAQ) [32], the use of walking aids, return to work and return to driving. X-ray findings and Blinding (masking) adverse events are also recorded. It is not possible to blind the participant nor the therapist When answering Likert-styled questions within the from the treatment allocation. PROMs, if a participant is unsure which Likert option to However, to reduce risk of bias, 12-, 24- and 52-week select, they are advised to select the poorer outcome. This paper PROMs are completed by participants, concealed approach is particularly pertinent at the 2-week and 6-week from the researchers and stored in sealed opaque enve- time points, when answering function-related questions lopes. A third party, blinded to the intervention group in- such as walking, as post-operative clinical instructions puts the data. The electronic PROMs are web-based, held would have been to remain non-weight-bearing. This is not by Bristol Online Survey (BOS), www.onlinesurveys.ac.uk. an anticipated concern for the primary outcome, being at Via this system at the appropriate time points, participants 12 weeks, nor the subsequent follow-ups. are e-mailed a single-use link to their e-PROM. Objective measures are included at the 2-week and 6-week time points: non-weight-bearing dorsiflexion and Sample size, data processing and statistical plantar flexion ROM and, ankle (figure-of-8) and calf methods (circumference) measures. Participants will be invited to Sample size calculations attend for repeated outcome assessments at 12 weeks, 24 It was estimated that a total of 120 participants will be weeks and 52 weeks, with the additions of weight-bearing required based on a minimal clinical important difference dorsiflexion, walking speed, balance and isokinetic of 10 points on the OMAS, with a standard deviation of plantar-flexion strength. Those declining will be encour- 19.5, significance level of 5% and powered at 80%. aged to complete and return the appropriate PROMs Allowance for attrition was set initially at 20% but, due to questionnaires. higher-than-expected dropout rates, this was increased to 30%, yielding a target of 156 to enter the study at Participant timeline randomisation. Recruitment and consent may take place from the in-patient stay until and including the 2-week Data processing post-surgery outpatient review. Only after all baseline PROM data collection is paper based, with participant outcome measures are recorded, does randomisation number 55 onwards being offered the option of complet- take place, see Figs. 1 and 2. ing PROMs online. Once paper-based 12-week, 24-week The data collection time points (post surgery) are: base- and 52-week PROMs are completed the participant seals line at 2 weeks, end of intervention at 6 weeks, and at them in a windowless opaque envelop and returns them three research follow-up time points; 12 weeks and 24 to the researchers (postage pre-paid). These are securely weeks as short- and mid-term follow-ups, respectively, stored and subsequently opened in batches by an and at 52 weeks as a long-term follow-up and the trial end individual blinded to group allocation, who inputs the point. For participant’s convenience, the 2-week and data into a holding database for subsequent transfer into 6-week EMADE sessions are combined with the ortho- SPSS for reporting and statistical analysis. For audit paedic 2-week and 6-week reviews. The 12-week, 24-week purpose, after inputting each batch, a ‘read-only’ copy is and 52-week PROMs data may be collected via either stored in a separate protected folder. A separate copy is return post (postage pre-paid), electronically or in person used for data screening and cleaning, guided by good according to participant choice. Participants undergoing practice [33] and may include self-evident corrections objective assessment will attend the David Greenfield [34] where appropriate. While filters and error alerts will Matthews et al. Trials (2018) 19:304 Page 5 of 10 Fig. 1 Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) Figure of enrolment, interventions and assessments. Key: EMADE early motion and directed exercise, PROMs Patient-reported outcome measures. *Study PROMs: Olerud Molander Ankle Score (OMAS), Ankle-Fracture Outcome of Rehabilitation Measure (A-FORM), EQ-5D-5 L, work and leisure activities, walking aid use and return to driving. **Option for patients to attend for Laboratory-based objective measures reduce inputting errors, 20% of entries will be prior to randomisation will be reported, but not carried cross-checked against the paper PROMs for discrepan- into the main analysis. Descriptive statistics will be pro- cies. Data changes will be recorded for blinded adjudica- duced, within and between each intervention group(s) tion. For audit purposes a copy of the cleaned and for demographics and outcomes at all data time points. checked data will also be saved as a ‘read-only’ copy and Continuous data will be summarised as mean and stand- stored separately. The design of the e-PROMs does not ard deviation and confidence intervals (CI) (95% CI and permit questions to be left unanswered, mitigating p value threshold ≤ 0.05) for the PROM outcome data. against problems of incomplete data and once the Median and interquartile ranges will be used where participant completes their PROM the original dataset is appropriate statistical assumptions are not met, whereas locked against further alterations. The system permits categorical data will be presented as frequencies and data transfer into SPSS. proportions and analysed using either chi-square or The research team and statistician will conduct the Fisher’s exact test as indicated (p value of ≤ 0.05). analysis. The statistician will conduct the primary Non-parametric tests will be employed where appropri- outcome analysis independently and is blinded to group ate. Analysis will be conducted on the intention-to-treat allocation. Data and reason for any patient excluded (ITT) basis. Matthews et al. Trials (2018) 19:304 Page 6 of 10 Fig. 2 A schematic diagram of the patient’s journey through the early motion and directed exercises (EMADE) ankle study. Key: EMADE early motion and directed exercise, PROMs patient-reported outcome measures To test the primary outcome measure hypothesis that 1. If missing data is 5% or less, conduct analysis based the EMADE physiotherapy intervention, as described on complete-case analysis will perform better than usual care, the difference in 2. If missing data is greater than 5% and up to 10%: group means of the primary outcome, OMAS values at (a) Conduct analysis based on pairwise 12 weeks post surgery, will be statistically compared. deletion (assuming missing at random This will be through applying an independent t test with (MAR)) and then significance taken as p value of ≤ 0.05 and the inclusion (b) Conduct multiple imputation analysis of confidence intervals (CI at 95% CI and p value of ≤ (c) If these two analyses yield comparable results, 0.05 threshold). Where data is not found to be normally then it will be assumed that the missing data distributed such that parametric tests cannot be utilised, has not influenced the outcome of the trial the non-parametric Mann-Whitney U test will be (d) If the two analyses yield notable differences, employed (p value ≤ 0.05). to accommodate for the missing data, There is a lack of consensus in the academic literature sensitivity analysis will be conducted based on how to handle missing data [35, 36]. However, based on the statistician’s advice on the 120 sample size, the following sequential approach 3. If missing data exceeds 10%, detailed discussions will be applied for the primary outcome: will be held with the study statistician Matthews et al. Trials (2018) 19:304 Page 7 of 10 Interpretation of secondary outcome and sub-group Governance analysis will require caution due to risks of type II errors Governance procedures were developed following Good and, because of where post hoc analysis may demonstrate Clinical Practice (GCP) guidelines (non-CTIMP) [37] association, causation may not be supported. Secondary with agreements from the local sponsors and the Ethics analyses will be performed for hypothesis generation. The Committee. This includes reporting procedures for ad- difference in group mean scores for the secondary out- verse and serious adverse events. The governance proce- comes; EQ-5D-5 L and A-FORM at 12 weeks post surgery dures for this trial has been independently audited by will be analysed in a similar manner to the primary out- the Quality Assurance and Good Clinical Practice Audit come. The one-way analysis of covariance (ANCOVA), in- Office, Nottingham Health Science Partnership, with a cluding follow-up time as a covariance, will be applied to favourable outcome. assess these outcomes across the complete study period. Due to the size of the trial it was considered unneces- Adjustment for baseline scores, through analysis of sary to form a data monitoring committee. This study will covariance, will be conducted for OMAS, EQ-5D-5 L comply with the requirements of the UK Data Protection and A-FORM and compared with unadjusted scores. Act 1998 with regards to the collection, storage, process- Impact of covariates will be further explored through ing and disclosure of personal information and will uphold regression analysis. Initial analysis for co-variates where the Act’s core principles. Access to collated participant significance is nearly reached (p > 0.10) will be taken for- data will be restricted to the research study staff. Alloca- ward into a statistical model. Due to the bimodal impact tion of a unique code to each participant will help to en- of age and sex, these will be included in this analysis. sure confidentiality and anonymity. These identifiers will Other exploratory analysis for potential covariates may be used in all data, study material and reporting. Published include impact of smoking, previous level of physical results will not contain any personal data that could allow activity, type of fracture (AO classification), complexity identification of individual participants. All electronic data of surgical repair and any subsequent removal of metal will be stored on host NHS and University computers, work; most notably removal of syndesmosis screw(s) for with limited access under username and password protec- which stratification was applied at randomisation. tion system, as per host NHS and University ICT policies. Analysis will also be conducted using modified ITT by Paper-based data will be stored in a locked filing cabinet excluding those participants who attend only one session in a key-coded room. or less of EMADE sessions. Sub-groups will include return to work for those Ethics approval and amendments unable to work due to their ankle fracture at the time of NRES Committee East Midlands – Nottingham 2, randomisation, and similarly, return to driving for those reviewed and approved this study on 4 November 2014 unable to drive due to their ankle fracture at the time of (14/EM/1213). The Ethics Committee and sponsors have randomisation. Frequency of complications will be been informed of important protocol changes and described but, based on the published literature, it is events. Amendments have focussed on an embedded anticipated that frequency will be sufficiently low not to study, which has subsequently been removed from the warrant statistical analysis. trial; only two participants were recruited to this embed- ded study and both participants withdrew from the trial during their in-patient stay and did not reach random- Health economics isation. Other amendments include: (1) expanding the Health economic evaluations will be conducted from a recruitment period from the in-patient period, up to and societal perspective and from the service commis- including the 2-week clinical visit and (2) reducing the sioner’s perspective. The societal perspective will be burden on the participant by decreasing the number of limited to incremental cost-effectiveness ratio (ICER) of PROMs and permitting PROM completion online. The the natural units of; return to work and return to time point of randomisation, the intervention, and the driving (sub-groups as described earlier). Based on the primary and core outcome measures, have all remained EQ-5D-5 L PROM data, a cost-utility analysis (costs unchanged since the start of recruitment. per quality-adjusted life year; QALY) will be performed from the local commission’s perspective. Sensitivity Dissemination analysis will include the variability of the additional Routes of dissemination will include: EMADE physiotherapy service costs; for example, £18 to £25 per session (2016 rates) and frequency of 1. Medical and associated, conferences, meetings and post-6-week physiotherapy sessions. The final methods journals for health economic evaluations will be guided by dis- 2. Patient participation seminars and meetings, such cussion with a health economist. as those organised by Arthritis Research UK Matthews et al. Trials (2018) 19:304 Page 8 of 10 3. Further data-sharing plans for the current study are The primary objective of this study is to test whether unknown and will be made available at a later date the EMADE intervention is effective in the clinical set- ting. Therefore, it is appropriate to assess effectiveness Decisions on authorship will be directed by guide- of EMADE against usual care in the clinical setting, lines from International Committee of Medical Jour- through a p-RCT. If significant clinical benefits and nal Editors [38]. cost-effectiveness are demonstrated, EMADE should be- come a viable treatment option. A larger-scale, multicen- tre trial may be required to influence national guidelines. Discussion The aim of this trial is to determine if EMADE is more Trial status effective than usual care in reducing symptoms and restor- At the time of manuscript submission 111 participants ing function in those who have undergone open reduction had joined the trial. and internal fixation following a Weber B ankle fracture. While EMADE does not contain novel modalities, what is Protocol version distinctive for this trial is EMADE’s early clinical applica- Version 2.2, 18 April 2017. First recruit June 2015, last tion of a progressive ankle rehabilitation programme, expected mid 2018. being at 2 weeks post ankle surgery versus the traditional of starting after 6 weeks of immobilisation. Additional files We do not anticipate significant bias from known con- founders, such as age and sex, and unknown confounders, Additional file 1: Early motion and directed exercises (EMADE) Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) due to the limiting effect on bias from random allocation. Checklist. (DOCX 53 kb) However, as a pragmatic study, there is no control nor Additional file 2: Early motion and directed exercises (EMADE) and influence over the quality and volume of care, including Template for Intervention Description and Replication (TIDieR) Checklist. physiotherapy, after the end of the intervention at 6 weeks (DOCX 30 kb) post surgery. While compliance with the EMADE home exercise Abbreviations A-FORM: Ankle-Fracture Outcome of Rehabilitation; AO: Arbeitsgemeinschaft programmewillbeencouraged through theweekly für Osteosynthesefragen; ARUK: Arthritis Research UK; CPAQ: Clinical Physical face-to-face reviews and the written and pictorial exercise Activity Questionnaire; EMADE: Early motion and directed exercises; EQ-5D- sheets, compliance will still be a potential confounder. 5 L: EuroQol 5 Dimension 5-Level Questionnaire; ICER: Incremental cost- effectiveness ratio; OMAS: Olerud and Molander Ankle Score.; ORIF: Open However, as a pragmatic trial, this level of encouragement reduction and internal fixation; p-RCT: Pragmatic randomised controlled trial; and supervision was felt to be appropriate, as it reflects PROM: Patient-reported outcome measure; ROM: Range of motion current physiotherapy clinical practice. Acknowledgements It may be argued that starting physiotherapy early with Acknowledgement is made to both Arthritis Research UK, Centre of EMADE will reduce the number of sessions subsequently Sports, Exercise Osteoarthritis and AO-UK for their support and funding, required and, thus, the overall number of sessions may and to staff of both the Arthritis Research UK, Centre for Sports Exercise and Osteoarthritis and of the David Greenfield Physiology Laboratory, not be significantly different from usual care. However, University of Nottingham. while this remains unproven it is pertinent to assume that EMADE is more expensive (approximately £54 to £75) Funding This work is supported by the Arthritis Research UK (grant number 20194), and, therefore a cost-utility analysis in QALYs is required the funding covers provision for researcher salaries, stipends and experimental from the commissioner’s perspective to determine if running and analytical costs. In addition, AO-UK is part funding the study. The EMADE is value for money. Also, while QALY units will funders did not influence the design nor the implementation of the study and will not influence the analyses and decisions surrounding publication and be valued by commissioners, the use of natural units; dissemination of the findings. Views expressed are those of the authors and return to driving and return to work will be tangible to do not necessarily reflect the view of the funders. patients and their families. Availability of data and material As this intervention requires no specialist equipment, it Beyond the previously described plans for dissemination, further data-sharing is suitable for provision in both primary and secondary plans are currently unknown and will be made available at a later date. care-based physiotherapy departments and, therefore, has potential for broad clinical impact. The trial design limits Trial sponsor Dr. Maria Koufali. bias where possible, including during the collection, pro- Research and Innovation, cessing and analysis of PROM data. Objective outcomes Nottingham Integrated Clinical Research Centre, will be recorded unblinded; however, being secondary C Floor, South Block, Queen’s Medical Centre Campus, outcomes and analysed separately from the PROM data, Nottingham University Hospitals NHS Trust, the potential impact of bias from objective data will have Nottingham, NG7 2UH. limited impact on the overall quality of the study. Telephone: 0115 9249924 Matthews et al. Trials (2018) 19:304 Page 9 of 10 Authors’ contributions 10. Tisherman SA, Forsythe RM. Trauma intensive care. New York: Oxford BES conceived this study, participated in the design detail and writing University Press; 2013 of the manuscript. PAM conceived this study, participated in the design 11. Coughlin MJ, Saltzman CL, Mann RA. Mann's surgery of the foot and ankle detail, writing of the manuscript and participated in recruiting and E-Book: Expert Consult-Online. Philadelphia: Elsevier Health Sciences; 2013. enrolling patients for this study. BJO conceived this study, participated in 12. Safran MR, McKeag D, Van Camp SP. Manual of sports medicine. the design detail, writing of the manuscript, and participated in recruiting Philadelphia: Lippincott Williams & Wilkins; 1998. and enrolling patients for this study. AA participated in the design, and 13. Lin CW, Donkers NA, Refshauge KM, Beckenkamp PR, Khera K, Moseley AM. participated in recruiting and enrolling patients for this study. JN Rehabilitation for ankle fractures in adults. Cochrane Database Syst Rev. participated in recruiting and enrolling patients for this study. TC 2012;11:CD005595. participated in recruiting and enrolling patients for this study. TK 14. Beckenkamp PR, Lin C-WC, Chagpar S, Herbert RD, van der Ploeg HP, participated in recruiting and enrolling patients for this study. Moseley AM. Prognosis of physical function following ankle fracture: a All authors read and approved the final version of the manuscript. systematic review with meta-analysis. J Orthop Sports Phys Ther. 2014; 44(11):841–51. Ethics approval and consent to participate 15. Black JDJ, Bhavikatti M, Al-Hadithy N, Hakmi A, Kitson J. Early weight-bearing Ethical approval was granted by NRES Committee East Midlands – Nottingham in operatively fixed ankle fractures: a systematic review. Foot. 2013;23(2):78-85. 2, reviewed on 4 November 2014 (14/EM/1213). Before participation, all 16. Del Buono A, Smith R, Coco M, Woolley L, Denaro V, Maffulli N. Return participants are required to provide their written informed consent, which to sports after ankle fractures: a systematic review. Br Med Bull. 2013; was verbally re-confirmed at each stage by the research team. 106(1):179–91. 17. Keene DJ, Williamson E, Bruce J, Willett K, Lamb SE. Early ankle movement Consent for publication versus immobilization in the postoperative management of ankle fracture in Consent to publish anonymised data, was explicit within the initial adults: a systematic review and meta-analysis. J Orthop Sports Phys Ther. consenting process. 2014;44(9):690–C7. 18. Smeeing DPJ, Houwert RM, Briet JP, Kelder JC, Segers MJM, Verleisdonk Competing interests EJMM, Leenen LPH, Hietbrink F. Weight-bearing and mobilization in the The authors declare that they have no competing interests. postoperative care of ankle fractures: a systematic review and meta- analysis of randomized controlled trials and cohort studies. PLoS One. 2015;10(2):e0118320. Publisher’sNote 19. Thomas G, Whalley H, Modi C. 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TrialsSpringer Journals

Published: May 31, 2018

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