Title: TARVA (Total Ankle Replacement Versus Arthrodesis Trial) A randomised, multi-centre, non-blinded, prospective, parallel group trial of total ankle replacement versus ankle arthrodesis in the treatment of patients with end stage ankle osteoarthritis, comparing clinical outcomes and cost-effectiveness
Funder: Department of Health and Social Care

Abstract: DESIGN: A multi-centre randomized pragmatic open trial of total ankle replacement (TAR) versus ankle arthrodesis with an internal feasibility phase in patients with end-stage ankle osteoarthritis (OA). Randomisation will use a minimisation algorithm incorporating a random element, stratifying by surgeon and presence of OA in the 2 joints adjacent to the ankle (subtalar and talonavicular) – as determined by a preoperative MRI scan. SETTING: 12 committed NHS hospitals including district general hospitals, University teaching hospitals and Specialist centres. TARGET POPULATION: Patients aged 50-85 with end-stage ankle OA not meeting the exclusion criteria. HEALTH TECHNOLOGIES BEING ASSESSED: TAR is being compared to ankle arthrodesis, the two main surgical treatments for end-stage Ankle OA. We aim to run a pragmatic trial comparing two existing NHS surgical treatment options. There is marked variation in practice nationally. To ensure treatment homogeneity for TAR we will only use third generation (mobile bearing) CE marked implants with an agreed post-operative protocol. Ankle arthrodesis will be by the surgeon’s usual technique, again with a similar post-operative protocol. Surgical trials that specify a single type of implant are notoriously difficult to conduct and we do not believe such a design could recruit surgeons, nor would the outputs be generalizable across the NHS. MEASUREMENT OF COSTS AND OUTCOMES: The primary outcome measure is the change in Manchester Oxford Foot & Ankle Questionnaire (MOXFQ) walking/standing domain scores from pre-op to 1 year post-op. MOXFQ is a validated clinical score, and the most published patient reported measure for foot and ankle conditions. A search of www.comet-initiative.org has not identified other established relevant Core Outcomes. Secondary outcome measures include MOXFQ pain and social interaction domains, EQ-5D, AOFAS score, revision surgery, other reoperation, complications, and resource utilisation. The incremental cost and cost-effectiveness of both treatments from the NHS and societal perspectives will be compared in terms of quality-adjusted life years, based on the EQ-5D. Resource use will be collected directly from patient notes and patient diaries. INCLUSION CRITERIA: Patients with end-stage ankle OA; age 50-85 inclusive; fit for an anaesthetic; no exclusion criteria. EXCLUSION CRITERIA: Deformity greater than 25 degrees at Tibiotalar joint (on standing films); Complete ligamentous disruption and clinical instability; poorly controlled diabetes (HbA1C level of over 9% or as advised by the diabetologist); moderate to severe avascular necrosis of the talus (more than 15% talus affected on plain x- ray); history of infection in ipsilateral ankle/foot; more than 3 lower limb joints previously fused (ipsilateral) and/or more than 4 bilateral; patient has had concomitant ipsilateral subtalar or talonavicular fusion or where this is planned; poor vascular supply (established critical limb ischaemia or active leg ulceration); serious concomitant disease (metastatic disease or terminal illness); severe osteoporosis (T Score of less than -2.5) with recent fracture (within last 12 months); pregnancy; unable to give informed consent – cognitive impairment demonstrated by Mini-Mental State Exam (MMSE) of under 16/30; patient unwilling to give informed consent. SAMPLE SIZE: To detect a difference of 12 (the minimum clinically important detectable change) in the post-operative change in MOXFQ walking/standing domain score (primary outcome) between the two treatment groups assuming a standard deviation of 27, a significance level of 5%, and power of 90%, a sample size of 214 participants is required. To account for clustering by surgeon, assuming an average cluster size of 14 (participants/surgeon) and an Intra-class correlation coefficient (ICC) of 0.03 (estimated from the median of 10 previous surgical studies) an adjusted sample size of 298 is required. After taking into account an anticipated 10% dropout rate (attrition in other orthopaedic RCTs has been 5-7%), the total sample size required is 328 patients (164 per arm). As the ICC used in the sample size calculation is an estimate, blinded data will be used to provide a more accurate value to re-estimate the required sample size before recruitment closes, as advised by our Independent Data Monitoring Committee (IDMC). STRATEGY FOR REVIEWING LITERATURE: A systematic review and meta-analysis of the outcomes of 7,942 TARs was performed by our group (Zaidi et al 2013. BJJ 95-B). No randomised trial (RCT) comparing TAR and ankle arthrodesis (fusion) has been identified although there has been a systematic review comparing ankle replacement with ankle fusion (Haddad et at 2007, JBJSA 89(9)). A recently NIH funded RCT in the USA (NCT01620541) is comparing TAR to arthrodesis, but is using different types of implants for TAR not used in the UK. The annual reports of the National Joint Register for ankle replacements have been read and all grey literature has been reviewed through Google searches. PROJECT TIMETABLES INCLUDING RECRUITMENT RATE: The trial will include a feasibility phase and consequently will be delivered in two stages. Stage 1 will follow set-up, to establish feasibility of recruitment and randomisation and run from months 12 when the first patient is randomised to 17. This would provide 6 months information on randomisation rates and at least 4 months information on whether study participants change their mind between randomisation and surgery. Surgeons’ willingness to randomise and patients’ willingness to be randomised will be closely monitored through monthly reviews of each centre and quarterly Trial Management Group (TMG) meetings, together with regular investigator meetings. Each centre sees over 80 potentially eligible patients per year, and we estimate a total of 24 months (consisting of a 6 month internal feasibility phase in 4 centres and a further recruitment period of 18 months in all 12 centres) to randomise 328 patients in 12 centres (assuming a randomisation rate of 1.37 per centre per month), a rate comparable to other surgical trials. After 24 centre months of randomisation from a 6-month internal feasibility phase in 4 centres, we should have randomised 33 patients. Failure to meet this target will trigger submission of a plan to HTA outlining the actions to be implemented to improve recruitment to ensure the target is met. STUDY TIMELINE: Site set-up 9 months; recruitment 24 months (months 10-33) with a 6-month built-in feasibility phase; MRI, randomisation within 2 months of recruitment and surgery within 3 months of recruitment; Follow up 12 months; Site close down, analysis, report 6 months. EXPERTISE IN TEAM: The team has relevant expertise in clinical trial management, health economics; statistics; clinical trial methodology; surgery and radiology. We will set up a TMG, Trial Steering Committee (TSC) and IDMC for trial oversight.

Lay abstract: BACKGROUND AND CLINICAL BENEFITS: Ankle osteoarthritis (OA) occurs when the cartilage lining the joints has become worn, causing pain and stiffness and major disability with a similar impact on quality of life as hip OA and congestive heart failure. The majority of ankle OA follows trauma or injury, although inflammation (such as rheumatoid arthritis) can also be a cause. Over 29,000 cases of symptomatic ankle OA are referred to specialist foot and ankle surgeons each year in the UK. The ankle is injured more than any other joint, indeed ankle sprains are one of the commonest reasons for attending Emergency Departments. The incidence of ankle fractures is increasing especially in young athletes and elderly females. After an unstable ankle fracture, radiographic ankle OA can occur in up to 66% of patients within 6 years. Many patients are afflicted in their sixth decade, during their working life. In the early stages of disease non-operative measures such as change in activity levels, weight loss, physiotherapy, pain killers and ankle braces should be used. We have defined “end stage OA as a combination of unrelenting symptoms sufficient to make the patient consider surgical intervention; radiological changes consistent with OA; and failure of at least 6 months of non-operative measures. Surgery is only considered when all non-operative measures have failed. The main surgical treatments for end-stage ankle OA are ankle fusion or total ankle replacement (TAR). Ankle fusion is the commonest surgical treatment but patients are increasingly requesting TAR and so the number of surgeons performing this procedure is also increasing. Approximately 3,000 patients undergo ankle fusion or TAR in the NHS each year, with much variation in practice across the country. Both treatments are available on the NHS, and both have been reported to have good results. Some studies suggest that TAR restores a more natural walking pattern than ankle fusion but other studies have suggested that the need for further surgery is higher with TAR than with fusion. Information on all TARs implanted in the NHS has been captured on the National Joint Registry since 2010, but no similar national registry exists for ankle fusion. There has never been a randomized trial directly comparing the two procedures and therefore it is difficult to recommend the best procedure for a patient. The TARVA trial will compare TAR with ankle fusion, using a patient reported walking/standing functional score as the primary outcome. The trial design will not restrict surgeons to a specific type of implant (although only third generation implants will be included) or a particular fusion surgical technique within each randomised intervention arm, providing a comparison of these two treatments that reflects usual clinical practice. The results will provide high quality evidence to help patients and their surgeons to choose between the two procedures, and inform commissioning decisions in the NHS. OBJECTIVES: Our main objectives are 1) to determine which treatment offers better pain free function and quality of life, fewer complications and best value for money; 2) to disseminate the trial findings to the public through the patient group involved with our research as well as through peer reviewed journals, conferences, seminars and meetings. We propose a built-in feasibility phase whose specific objectives are to review and adopt effective patient recruitment and retention strategies; and to recommend an increase in the number of surgeons and centres participating in the trial, if necessary. DESIGN AND METHODS: This will be a multi-centre trial involving 328 patients, aged between 50-85 with end-stage ankle OA, randomised to one of two surgical strategies, TAR or ankle fusion (164 patients per group). Patients will have clinical assessments and complete questionnaires preoperatively and at 6, 12, 26 and 52 weeks after surgery. The primary outcome is a patient reported outcome measure (the change in walking/standing domain of the MOXFQ, a validated clinical score) from before surgery to 12 months after surgery. Other outcomes include quality of life scores, complications, revision and other reoperation, and value for money. Beyond the end of the trial, patients will be sent questionnaires at 2, 5 and 10 years following surgery so that long term outcomes can be captured. TEAM: The team has a wealth of experience in running clinical trials and includes trial methodologists, health economists, statisticians, surgeons, and radiologists.

Research activity codes: 6.4 SURGERY;7.3 MANAGEMENT AND DECISION MAKING
Health categories: MUSCULOSKELETAL