An interactive web randomisation system will be used by a member of the research team who is not blinded to the intervention. Participants will be randomly assigned to either control or experimental group with a 1:1 allocation as per a computer-generated randomisation schedule. Randomisation will occur after the completion of all baseline tests. This will take place four days (+/- three days) prior to the operation to allow the correct TKR to be made available. Randomisation will be stratified by; (a) site (i.e. hospital where surgery is to take place); and (b) age (<60 years = younger; equal or 60+ years = older) (Merle-Vincent et al 2011; Singh et al 2010).
It is not possible to blind the surgeon to the trial treatment. However, the participants, the physiotherapists, and all staff involved in assessing outcomes will be blinded. Processes will be in place to maintain blinding. These will include concealment in a sealed envelope, of the surgery notes mentioning the prosthesis implanted in the patient file.
In the unlikely event of a research nurse accidentally becoming unmasked, the contacts, assessments, and data entry for that participant will be undertaken by another member of the research team for the remaining period of this participant in the trial. Accidental unmasking will be logged and monitored to ensure that appropriate steps are taken to prevent this from reoccurring.
The clinical staff providing usual care will also be blinded, and thus the decision to unmasking a single case will be made when knowledge of an individual’s allocated treatment is required to enable treatment of a serious adverse event which is likely to be caused by the type of device implanted.
Where possible, requests for emergency unmasking of individuals will be made via the trial manager and agreement of the Clinical Chief Investigator will then be sought. However, in circumstances where there is insufficient time to make this request or for agreement to be sought, the treating clinician can make the decision to unmask immediately. This can be done via the trial database.
Methods: Data management and analysis
Each participant will be given a unique trial Participant Identification Number (PIN). Data will be entered under the participants PIN number onto the central database stored on the servers based at NCTU. Access to the database will be via unique, individually assigned (i.e. not generic) usernames and passwords, and only accessible to members of the CAPAbility trial team at NCTU, and external regulators if requested. The servers are protected by firewalls and are patched and maintained according to best practice. The physical location of the servers is protected physically and environmentally in accordance with UEA’s General Information Security Policy 3 (GISP3: Physical and environmental security).
The database and associated code have been developed by NCTU Data Management, in conjunction with the CAPAbility trial team. The database software provides a number of features to help maintain data quality, including; maintaining an audit trail, allowing custom validations on all data, allowing users to raise data query requests, and search facilities to identify validation failure/ missing data. After completion of the trial the database will be retained on the servers of NCTU for on-going analysis of secondary outcomes.
The identification, screening and enrolment logs, linking participant identifiable data to the pseudoanonymised PIN, will be held locally by the trial site. This will either be held in written form in a locked filing cabinet or electronically in password protected form on hospital computers. After completion of the trial the identification, screening and enrolment logs will be stored securely by the sites for 15 years unless otherwise advised by NCTU. The consent form will explain that if a participant wishes to withdraw from the study the data acquired prior to that point will be retained. Reason for withdrawal will be recorded, if given, as will loss to follow up.
A full Statistical Analysis Plan (SAP) will be developed between the trial statistician and Chief Investigators and agreed with the trial’s governance committees. All analysis will be based on the intention-to-treat principle in which all participants will be analysed according to the group they were allocated regardless of compliance.
Baseline factors will be summarised by group. All continuous variables will be summarised by the mean and standard deviation, or if appropriate, the median and interquartile range. Categorical variables will be summarised with the number, and percentage, in each category.
The primary comparison for OKS will be made using a general linear model with the stratification factors included as fixed effects. The difference between arms will be summarised using the mean difference and 95% confidence intervals will be presented. A similar analysis will be undertaken for all other outcome measures.
For the temporal gait parameters and kinematic outcomes, each participants 'closeness' to age-matched normative data will be calculated. This will then be compared between groups using a general linear model with the stratification factors included as fixed effects. This data will also be presented graphically via scatter and distributional graphs to describe the deviations from the normative data.
For all the measures of movement listed, a general linear model with the stratification factors included as fixed effects will be used to assess for differences between the groups. If appropriate adjusted analysis will be undertaken by including baseline factors and fixed effects in the above models.
Assumptions and sensitivity analysis
All the assumptions will be checked via distribution graphs and tests. If the assumptions are not valid then transformation will be considered if none are found then a non-parametric approach will be used. The pattern of missing or incomplete data will be assessed and, if appropriate, then missing data will be imputed. The baseline comparability of the groups will be assessed and if appropriate any factor found to be imbalanced and important will be adjusted for in the analysis.
Exploratory subgroup analysis will be undertaken by including an interaction in the model to assess if the effectiveness of the prosthesis is dependent on age or gender.
All analysis will be conducted using Stata and the full SAP will be produced, and approved, before any comparative analysis is undertaken.
Additional Analyses – CT Scans
All Rotational profile measurements will be performed at NNUH under standard operating procedure on a full diagnostic workstation (Synapse DICOM viewer, Fujifilm, Japan, High resolution 2K monitors, Radiforce RX340 Eizo, Germany) in the BioImaging Laboratory and under the supervision of Prof Andoni Toms.
Inter-rater reliability will be assessed using intra-class correlation coefficients and 95% limits of agreement derived from Bland-Altman plots.
TKR alignment versus native landmarks
The difference between the post-operative component rotational alignment and the pre-operative native landmarks will be assessed using Bland-Altman plots.
Correlation with PROMS
The correlation between the PROMS and the difference between the post-operative component rotational alignment and the pre-operative native landmarks will be assessed using a correlation coefficient. A regression model will also be fitted including the randomisation group to allow for a potential difference in PROMS between these groups.
Correlation with movement analysis
A similar analysis will be undertaken for the correlation between movement analysis and the difference between the post-operative component alignment and the pre-operative native landmarks.
Additional Analyses – Qualitative Study
Interview transcripts will be organised using NVivo qualitative data management software (http://www.qsrinternational.com/nvivo-product). Analysis will follow qualitative content analysis procedures (Graneheim et al 2004). Coding and thematic analysis will be carried out independently by two experienced qualitative researchers. Trustworthiness strategies (Lincoln et al 1985) will be used to increase the credibility, dependability and transferability of analysis and interpretation, including cross-checking and review of codes and themes; constant comparative method (hypothesis testing within and across the data set) and deviant case analysis (the use of ‘outliers’ as a resource for understanding and interpretation of data) (Silverman 2000).
Analysis Population and Missing Data
The analyses population are defined as:
a) intention-to-treat: all randomised individuals
b) per-protocol: all randomised individuals who do not have an alternative knee replacement during the follow-up period. Individuals will be included up to the point of the alternative knee replacement.
c) safety population: all randomised individuals who receive the replacement knee.
Missing outcomes data will be multiply imputed to increase precision of the treatment effect estimates. Sensitivity analyses will be conducted to assess the impact of the multiple imputations and a complete case analysis will also be conducted. All imputations will be examined to ensure sensible values are being generated. Imputation models will contain baseline measures, outcome measures and factors predictive of missing data.
No Interim analysis is planned for this study.
A TMG has been convened to assist with developing the design, co-ordination and strategic management of the trial. A Safety Committee will review safety data and act in place of a Data Monitoring Committee (DMC). Monitoring activities will be undertaken both centrally and on-site. The frequency, type and intensity of routine and triggered monitoring are detailed in the Quality Management and Monitoring Plan (QMMP). Ongoing central monitoring will ensure quality and consistency of data thorough the trial. Details about data collection and cleaning are described in the Data Management Plan (DMP)
Definitions of harm of the EU Directive 2001/20/EC Article 2 based on the principles of International Council for Harmonisation (ICH) guideline for good clinical practice (GCP) apply to this trial. A record of all study related serious adverse events (SAEs), including details of the nature, onset, duration, severity, relationship to the device, relationship to the operative procedure, outcome and expectedness will be made on the relevant section(s) of the trial specific SAE Form to be sent to the trial manager for onward reporting where required. SAEs resulting from surgery or arthroplasty complications (clinical and safety outcomes) will be reported in the relevant section of the CRF.
All non-serious adverse events (AEs) and adverse drug events (ADEs), whether expected or not, should be recorded in the participant’s medical notes and also reported in the relevant section of the CRF.
Adverse events do NOT include:
- Readmissions for revision surgery
- Mild (i.e. not lasting more than 5 days) anaesthetics related complications: Nausea, vomiting, dizziness, drowsiness, vaso-vagal drop, hypotension and constipation.
- Medical or surgical procedures; the condition that led to the procedure is the adverse event
- Pre-existing disease or a condition present that was diagnosed before trial entry and does not worsen
- Hospitalisation where no untoward or unintended response has occurred e.g. elective surgery, social admissions
The Safety Committee will be provided with safety data for each treatment arm including related AEs. The committee will advise on the continuation or early stoppage of the trial in the unlikely event that there are concerns over harm to participants.
The Quality Assurance (QA) and Quality Control (QC) considerations for the CAPAbility trial are based on the standard NCTU Quality Management Policy that includes a formal risk assessment, and that acknowledges the risks associated with the conduct of the trial and proposals of how to mitigate them through appropriate QA and QC processes. Risks are defined in terms of their impact on: the rights and safety of participants; project concept including trial design, reliability of results and institutional risk; project management; and other considerations.
NCTU staff will review CRF data for errors and missing key data points. The trial database will also be programmed to generate reports on errors and error rates. Essential trial issues, events and outputs, including defined key data points, will be detailed in the trial DMP. The frequency, type and intensity of routine and triggered on-site monitoring will be detailed in the QMMP. The QMMP will also detail the procedures for review and sign-off of monitoring reports. In the event of a request for a trial site inspection by any regulatory authority, NCTU must be notified as soon as possible.
Ethics and dissemination
Research Ethics Approval
The trial is being conducted in accordance with CODEX rules and guidelines for research and the Helsinki Declaration as well as the ICH Guideline for GCP. The study protocol was approved by the East of England - Cambridge Central Research Ethics Committee (reference 17/EE/0230) prior to the start of the trial. The trial is registered on the International Standard Randomised Controlled Trials Number (ISRCTN) registry (reference ISRCTN32315753). Approval was granted by the Health Research Authority (HRA) and Confirmation of Capacity and Capability to conduct the trial has been provided by the NNUH R&D office.
The NNUH is the trial sponsor and has delegated responsibility for the overall management of the trial to the Co-CIs and NCTU including the trial design, coordination, monitoring and analysis and reporting of results. The standard procedures and policies at NCTU, a UK Clinical Research Collaboration (UKCRC)-registered trial unit and the study’s QMMP are followed. A TMG, including lay membership, has been set up to assist with the design, coordination and strategic management of the trial. An independent Safety Committee has also been set up to provide oversight on the trial and to safeguard the interests of the participants
The protocol was amended in August 2017 (before trial start at sites) to improve consistency and clarity. To that effect, an additional inclusion criterion was added to match the consent form requiring participants to agree to any incidental findings to be reported to their GP. The exclusion criteria relating to the use of the Warfarin was also improved by the addition of novel anti-coagulants therapies which are increasingly used. As part of this amendment we also changed the stratification criteria from ASA grade and age to site and age as we became aware that ASA grading is highly subjective and has poor inter-rater reliability. We added the UCLA Activity Score as a secondary outcome measure to provide valuable information on the participant activity levels pre-and post-operatively. The HADS was also added to be taken at baseline as part of the embedded qualitative study. The embedded qualitative study was also simplified by the removal of the physiotherapists’ interview after agreeing that these would not add relevant information towards the outcome measure due to recall biases that would be introduced by practical aspects of running these interviews.
Further changes were made in June 2018 allowing further clarifications. This was done following the removal of the BMI requirement enforced by one of our surgery sites. The associated exclusion criteria could therefore be removed opening the recruitment to a wider population and thus improving the representativeness of the study sample as many patients have a BMI greater than 35. In addition to this, the criteria excluding prior knee surgery was refined to exclude only previous surgery of the collateral ligaments of the knee as previous surgery on the cruciate ligaments would not affect the trial outcome as these ligaments are to be removed during surgery. The clarification of this exclusion criteria also permitted for previous non-intra-articular knee surgery (e.g. minor procedures around the knee) which were excluded despite not affecting the trial outcome. The visit windows were also reviewed as part of these changes to increase the baseline window from - 21 days to - 42 days up to surgery and to change the six month visit timeframe from +/- two weeks to + four weeks. The former ensuring enough time for the assessments to take place before randomisation and the latter that all participants would have a full six months rehabilitation period before undertaking the last follow-up visits. Additional changes included the addition of the learning curve details for surgeon training to perform the intervention, the addition of the process for participants to be informed of their knee allocation at the end of the trial as part of the result dissemination, the clarification of the non-adherence and non-retention section to confirm that any data collected up to a participant withdrawal will be retained and the clarification of the safety reporting period and responsibilities. This amendment also allowed us to update the compliance section to add the General Data Protection Regulation (GDPR).
Following on the previous amendment additional modifications were made in August 2018 after the agreement that the recruitment of patients with previous TKR could be allowed as long as they are over a year old at the time of the consultation and painless, mildly or moderately painful. This was agreed to create a more representative data set while ensuring that these participants’ mobility won’t be affected by contralateral pain.
Additional changes were made in December 2018 to include the MVIC of the hamstring and quadriceps muscles on both limbs to assess the known issue of muscle strength loss after TKR (Moon et al 2016). This biomechanical measure evaluates postoperative quadriceps and hamstring muscle strength loss and subsequent recovery in both the non-operative legs and healthy control legs for comparison. The inclusion criteria were also amended to remove “Patient willing to provide full informed consent to the trial, including consent for any incidental findings to be communicated to their GP”. This does not need to be an inclusion criteria as a potential participant would not be enrolled on the trial if the consent form, which includes a statement about communicating findings with the GP, was not initialled and signed. In addition the patient information was amended to clarify that baseline data collected for participants that may not progress to randomisation or surgery, for reasons other than withdrawal, will be retained and used as observational data.
Furthermore, the protocol was amended in March 2019 to extend the six to eight week visit window to six to ten weeks to ensure all participants can be seen within the appropriate window. An additional time point for collecting changes in pain medication was also added to the participant timeline at discharge from surgery. This will allow for a comparison between the participant reported pain medications at the Week 1 phone call and what was prescribed at discharge.
Consent or assent
Potential participants will be provided with a PIS and given time to read it fully. Following a discussion with a medical qualified investigator or suitable trained and authorised delegate, any questions will be satisfactorily answered and if the participant is willing to participate, written informed consent will be obtained. During the consent process it will be made clear that the participant is free to refuse to participate in all or any aspect of the trial, at any time and for any reason, affecting their treatment.
Potential participants who, in the opinion of the clinical team do not have capacity to consent will be ineligible for this study. If a participant loses capacity during the course of the trial, they will be withdrawn from the any further assessments but, the data which has already been collected will be retained.
Consent will be re-sought if new information becomes available that affects the participant’s consent in any-way. This will be documented in a revision to the patient information sheet and the participant will be asked to sign an updated consent form. These will be approved by the ethics committee prior to their use. A copy of the approved consent form is available from the NCTU trial team.
Any paper copies of personal trial data will be kept at the participating site in a secure location with restricted access. Following consent, identifiable data will be kept on the trial database to allow the MoveExLab staff to contact participants in order to arrange appointments. Only authorised trial team members will have password access to this part of the database.
Confidentiality of participant’s personal data is ensured by not collecting participant names on CRFs and limiting access to personal information held on the database at NCTU. At trial enrolment the participant will be issued a participant identification number and this will be the primary identifier for the participant, with secondary identifiers of month and year of birth and initials.
The participant's consent form will carry their name and signature. These will be kept at the trial site, and a copy sent to NCTU for monitoring purposes. They will not be kept with any additional participant data.
Declaration of interests
The investigators named on the protocol have no financial or other competing interests that impact on their responsibilities towards the scientific value or potential publishing activities associated with the trial.
Access to data
Requests for access to trial data will be considered, and approved in writing where appropriate, after formal application to the TMG. Considerations for approving access are documented in the TMG Terms of Reference. The Co-CIs and trial statistician at NCTU will have access to the full trial dataset.
The results of the trial will be disseminated regardless of the direction of effect and will be reported following the Consolidated Standards of Reporting Trials (CONSORT) Statement (Schulz et al 2010). Ownership of the data arising from the trial resides with the trial team. The publication policy will be in line with rules of the International Committee of Medical Journal Editors (ICMJE recommendations 2019). The TMG will decide on the dissemination strategy including presentations, publications and authorship.