Search

Abstract Background Late-phase platform protocols (including basket, umbrella, multi-arm multi-stage (MAMS), and master protocols) are generally agreed to be more efficient than traditional two-arm clinical trial designs but are not extensively used. We have gathered the experience of running a number of successful platform protocols together to present some operational recommendations. Methods Representatives of six UK clinical trials units with experience in running late-phase platform protocols attended a 1-day meeting structured to discuss various practical aspects of running these trials. We report and give guidance on operational aspects which are either harder to implement compared to a traditional late-phase trial or are specific to platform protocols. Results We present a list of practical recommendations for trialists intending to design and conduct late-phase platform protocols. Our recommendations cover the entire life cycle of a platform trial: from protocol development, obtaining funding, and trial set-up, to a wide range of operational and regulatory aspects such as staffing, oversight, data handling, and data management, to the reporting of results, with a particular focus on communication with trial participants and stakeholders as well as public and patient involvement. Discussion Platform protocols enable many questions to be answered efficiently to the benefit of patients. Our practical lessons from running platform trials will support trial teams in learning how to run these trials more effectively and efficiently.

Category: Ankle Arthritis; Ankle; Other Introduction/Purpose: Both ankle replacement and ankle arthrodesis are offered as treatments to patients with end stage ankle osteoarthritis. Systematic reviews have confirmed that both procedures are effective but there has never been a robust randomised multicentre level I study comparing the two treatments. Our objective was to investigate and compare the clinical and cost effectiveness and complication rates of ankle replacement against ankle arthrodesis in the treatment of end-stage ankle osteoarthritis in patients aged 50-85 years. Methods: 17 NHS centres and 35 surgeons across the United Kingdom participated. Formal Ethics committee approvals were obtained. A Trial Management Group was overseen by a Trial Steering Committee, and an Independent Data Monitoring Committee. Randomisation was carried out using a secure on-line service and was stratified by surgeon and the presence or absence of adjacent joint OA (based on an independently reviewed preoperative MRI scan). Participants were randomised 1:1 to either TAR or ankle fusion. The primary outcome was the change in the Manchester Oxford Foot & Ankle Questionnaire (MOXFQ) walking/standing domain scores between pre-operation and 52 weeks post-operation. Secondary outcomes measures included FAAM; FAAM (ADL); and Sport subscale scores. Quality of life was measured using the EQ-5D-5L. Total range of motion was measured using a validated method. Radiological parameters and adverse events were captured. Health economic analysis used mean incremental cost per quality-adjusted life years (QALY) gained. Results: 1600 patients were screened for eligibility. 330 participants were consented and 303 were randomised; 282 underwent surgery and attended follow-up visits. Mean age was 68 years (71% male). The aetiology of OA was post-trauma in 60%, with 6% patients having inflammatory OA. 42% had MRI evidence of OA in the adjacent joints. The groups were well balanced at baseline on all other parameters including deformity, range of motion and baseline clinical and quality of life scores.42% had MRI evidence of OA in the adjacent joints. 54% TARs used were fixed bearing; 46% were mobile bearing. 61% of fusions were performed arthroscopically. We present all outcomes including adverse effects (death; thromboembolic events; reoperation and revision); radiological findings; and range of motion. We also present subgroup analyses looking at the performance of fixed versus mobile bearing implants; differences by age; and by the presence or absence of adjacent joint OA. Conclusion: This is the first publicly funded, multicentre, prospective, randomised clinical trial comparing the clinical and cost effectiveness of ankle replacement against ankle fusion. It is also the first study in surgery to have detailed prospectively captured health economic data to be able to feed into the reimbursement discussions on these life transforming treatments. Due to contractual requirements of the funders the formal results cannot be released until the final report has been submitted for peer review which will not happen until the end of April 2021. The paper is submitted on behalf of the TARVA Study Group.

Abstract Background There is limited research and literature on the data management challenges encountered in multi-arm, multi-stage platform and umbrella protocols. These trial designs allow both (1) seamless addition of new research comparisons and (2) early stopping of accrual to individual comparisons that do not show sufficient activity. FOCUS4 (colorectal cancer) and STAMPEDE (prostate cancer), run from the Medical Research Council Clinical Trials Unit (CTU) at UCL, are two leading UK examples of clinical trials implementing adaptive platform protocol designs. To date, STAMPEDE has added five new research comparisons, closed two research comparisons following pre-planned interim analysis (lack of benefit), adapted the control arm following results from STAMPEDE and other relevant trials, and completed recruitment to six research comparisons. FOCUS4 has closed one research comparison following pre-planned interim analysis (lack of benefit) and added one new research comparison, with a number of further comparisons in the pipeline. We share our experiences from the operational aspects of running these adaptive trials, focusing on data management. Methods We held discussion groups with STAMPEDE and FOCUS4 CTU data management staff to identify data management challenges specific to adaptive platform protocols. We collated data on a number of case report form (CRF) changes, database amendments and database growth since each trial began. Discussion We found similar adaptive protocol-specific challenges in both trials. Adding comparisons to and removing them from open trials provides extra layers of complexity to CRF and database development. At the start of an adaptive trial, CRFs and databases must be designed to be flexible and scalable in order to cope with the continuous changes, ensuring future data requirements are considered where possible. When adding or stopping a comparison, the challenge is to incorporate new data requirements while ensuring data collection within ongoing comparisons is unaffected. Some changes may apply to all comparisons; others may be comparison-specific or applicable only to patients recruited during a specific time period. We discuss the advantages and disadvantages of the different approaches to CRF and database design we implemented in these trials, particularly in relation to use and maintenance of generic versus comparison-specific CRFs and databases. The work required to add or remove a comparison, including the development and testing of changes, updating of documentation, and training of sites, must be undertaken alongside data management of ongoing comparisons. Adequate resource is required for these competing data management tasks, especially in trials with long follow-up. A plan is needed for regular and pre-analysis data cleaning for multiple comparisons that could recruit at different rates and periods of time. Data-cleaning activities may need to be split and prioritised, especially if analyses for different comparisons overlap in time. Conclusions Adaptive trials offer an efficient model to run randomised controlled trials, but setting up and conducting the data management activities in these trials can be operationally challenging. Trialists and funders must plan for scalability in data collection and the resource required to cope with additional competing data management tasks.