The FJS, EQ5D-5L, OKS, VAS Pain, Likert scale, KOOS JR and Kujala anterior knee pain scores are validated tools for the clinical assessment of patients after knee arthroplasty (31,32). Each of these scores is completed preoperatively and then at regular intervals during follow-up (section 13).
Routine clinical measures of height, weight, range of movement and pain description will be taken. To test endurance and strength, a 30 sec Sit to Stand test will be measured. This test asks the participant to stand up / sit down from a standardised chair height within 30 seconds. To measure the AP stability of the knee(33), a lachmeter reading will also be recorded at the post-operative intervals and to measure strength, a dynamometer test will also be performed(34-36). More detail of these tests can be found in additional file 1.
Participant timeline {13}
Patients will be recruited from the private rooms at Perth Hip & Knee clinic. Based on the volume of TKAs performed and recruitment rates from previous studies within clinic, patients are expected to be recruited at a rate of 10 patients per month. The recruitment process will therefore take approximately 10-12 months from the start of the study. From the date of the operation, each patient will be followed-up for 24 months. A further six months will be required for data collection, analysis and dissemination of findings. The total duration of the study will therefore be 40 months. Recruitment is planned to begin in April 2021.
Sample size {14}
In total, 100 patients will be enrolled in a 1:1 ratio between the two treatment groups. This will ensure that the minimum of 90 patients required to answer the study question are followed up for the duration of the study. The enrolment goal is to have at least 45 patients in each of the two treatment groups completing the study.
Power / Sample size calculation
Primary Outcome measure: Functional outcome as assessed using the FJS score at two years following Mako-arm assisted TKA. Using data from our initial cohort recording functional outcomes, the mean FJS score at 1 year in the MA TKA was 59 (SD 6) and in the FA TKA was 75 (SD 8). It is assumed that MA results will be no better than FA results. The study was powered to demonstrate a 12 point difference in the Forgotten Joint score, which is the minimal clinical important change in the score. Using a one tailed analysis (assuming superior results with the FA), an alpha value of 0.05 and power of 0.80, and accounting for expected drop-out rate of 10%, this study will need 100 patients to answer the study question. Note that a more careful assessment of power and sample size for linear mixed effects model requires assumptions on the other covariates in the model and simulations. Such modelling is expected not expected to provide any reduction in power, so we have chosen to avoid this at the moment.
Recruitment {15}
Refer to section 26a- informed consent
Assignment of interventions: allocation
Sequence generation {16a}
The system for randomisation will be the same throughout the study period and must be strictly adhered to. The following method will be used to allocate a trial patient to either the MA TKA (‘Control group’) or to the FA TKA (‘Investigation group’).
Randomisation will be carried out using a blocked effect. This method is designed to randomize subjects into two groups that result in equal sample sizes over time. The blocks will be small (n=4), and balanced within the predetermined group assignments, which will keep the number of subjects in each group similar at all times. There will be no stratification factors involved in the randomization as randomization will occur before the trial starts. Using a randomization website (www.random.org), a random number (between 1 and 100000) will be generated. This will form the “seed” number for the blocked randomization process. Using a randomization website (www.sealedenvelope.com) the randomization list will be created. Patients will be allocated in a sequential order of consent, strictly adhering to the allocation of groups. Screen shots of the randomization process and seed number will be taken throughout, and held from the CI to minimize randomization bias.
Concealment mechanism {16b}
The orthopaedic fellow will then privately communicate to the CI the allocated group, to enable alignment and templating planning to be performed using the MAKO software. All patients and clinical staff recording the post-operative clinical outcomes of interest will remain blinded to minimize performance and detection bias.
Implementation {16c}
Randomisation and allocation to groups will be performed by the orthopaedic fellow. They will be responsible for communicating the group allocation to the investigating surgeons just prior to surgery for surgical planning.
Assignment of interventions: Blinding
Who will be blinded {17a}
The participants and physiotherapists collecting outcome measures both before and after surgery will be blinded to the treatment group allocation. The investigators will be unblinded prior to surgery in order for an appropriate treatment plan to be implemented.
Procedure for unblinding if needed {17b}
There should be no reason during the study in which unblinding is required. There is no increased risk of harm associated with either group allocation to the patient, which will necessitate unblinding to occur.
Data collection and management
Plans for assessment and collection of outcomes {18a}
Clinical assessments and outcomes will undertaken as the patient timeline (section 13). All investigators will undertake training in the clinical assessment to ensure standardisation of assessments.
Plans to promote participant retention and complete follow-up {18b}
The study will use participants who live locally and under the age of under 76 will aid in the participant retention. All participants will be aware of the 2 year follow up prior to agreeing to participate in the study, therefore decreasing the likelihood of dropout.
Data management {19}
The principle of Good Clinical Practice will be adhered to throughout with the research team responsible for its own regular internal audit for quality, recruitment goals and results targets. This will be in the form of monthly research meetings for those involved in the trial. The investigator will designate one or more appropriately trained and qualified individuals to monitor the progress of the clinical study. As per section 2.1.1 of the NHMRC Code, all clinical trial research data will be retained for a minimum of 15 years from the date of publication or 5 years following the completion of the research.
The Chief Investigator will review and provide assurances of the training and experience of all staff working on this study. Appropriate training records will be maintained in the study files. All personnel working on this study will have completed the Guideline for Good Clinical Practice ICH E6(R2) Qualification.
All case report forms (CRFs) must be completed and signed by staff that are listed on the site staff delegation log and authorised by the CI/ PI to perform this duty. The CI/PI is responsible for the accuracy of all data reported in the CRF.
Data required according to this protocol are to be recorded on the CRFs as soon as possible. Patients will be identifiable with a unique study number. Only the research physiotherapist will have the key to identify individual patients. All CRFs must be legible and completed in black ink. Any necessary corrections are to be made by drawing a single line through the incorrect entry and writing in the revision, and must be initialed and dated by the investigator or his or her representative. Data are not to be obliterated by blacking out, using correction fluid or by erasing the original entry. Any documents related to the study must be archived directly at the study site. These documents include listings that identify study subjects, research group allocated to each study subject, consent forms, and all completed CRFs. All consent forms and CRFs will be stored by the CI/PI investigator in a locked filing cabinet in a dedicated locked research office. This office has key access with monitored security. Patient data will be logged electronically using each patient’s unique identification number with Socrates computer software on an encrypted, password-protected research computer on the Perth Hip and Knee Clinic network. This computer is located within a dedicated lockable research office within Perth Hip and Knee Clinic, Subiaco, Australia.
Confidentiality {27}
See Data Management (19)
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
There will be no specimens collected during this study.
Statistical methods
Statistical methods for primary and secondary outcomes {20a}
Primary Endpoint
The analysis of the per-protocol population will be considered the primary analysis. Data exploration (numerical and graphical) will precede statistical modelling. A linear mixed-effects statistical model will be fitted to the data with FJS score as response and the other variables (demographic, and treatment) to assess any difference in mean FJS score es between the MA TKA and FA TKA groups after adjusting for the effects of the other covariates. Note that several measurements will be made on each patient over time, so an appropriate correlation structure will also be fitted into the model.
Secondary Endpoints
An appropriate linear statistical model will be fitted to the secondary outcomes, depending on the outcome. For data with a longitudinal structure mixed effect linear model with an appropriate correction structure will be fitted(37).
Intention-to-treat population
The intention-to-treat (ITT) population is defined as all randomised patients assigned to either the MA TKA or FA TKA group, regardless of adherence with the entry criteria, regardless of the treatment they actually received, and regardless of subsequent withdrawal from treatment or deviations from the protocol. In the event that MA is converted to FA or vice versa intraoperatively, analysis will be performed using the ITT population and the treatment actually received by the patients. Intra-operative conversion from one method to another will however, be documented and presented/published as part of the study.
In the event that there are errors in the randomization assignment, the analysis will be performed using the assigned treatment, not the treatment that the patient actually received. Any patient terminated early from the clinical trial will be included in the ITT population. All attempts will be made to collect complete follow-up evaluations for these patients despite study exit. These patients will be included in the analysis as the statistical model will allow for missing data at some follow-up time points.
Per-protocol population
The per-protocol population is defined as all patients who are randomised to MA TKA or FA TKA and complete the study according to the protocol.
In the event that there are errors in the randomisation assignment, the analysis will be performed using the treatment that the patient actually received, not the assigned treatment. Patients will be considered protocol violators if they do not meet the eligibility criteria as outlined in the protocol. Other reasons to be considered a protocol violator include, but are not limited to, protocol violations, and any actions that compromise the effectiveness of the treatment, such as receiving a secondary treatment. Protocol violators will not be considered as part of the per-protocol population and will be listed separately with the reason for their exclusion from the per-protocol population.
Interim analyses {21b}
There will be no interim analysis undertaken.
Methods for additional analyses (e.g. subgroup analyses) {20b}
There will be a smaller subset within each group where a VERASENSE sensor (Orthosensor Inc, Florida, USA) will be used intraoperatively to assess for balance and also medial congruence.
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
See section 20a
Plans to give access to the full protocol, participant level-data and statistical code {31c}
The full protocol or collected data will not be granted to the public. Participants will be provided with a lay summary of the research findings after completion of the study.
Oversight and monitoring
Composition of the coordinating centre and trial steering committee {5d}
The study base will be Perth Hip and Knee Clinic, 1/1 Wexford St, Subiaco 6008, WA. All Patients will have surgery and their inpatient stay will be at St John of God Subiaco Hospital with recruitment and follow up at either Perth Hip and Knee Clinic, (Subiaco or Murdoch rooms) or Midland Orthopaedics (Suite 11 St John of God Midland Hospital, Clayton Rd. Midland). All confidential study information will be stored on designated-password protected research computers and assigned research offices at Perth Hip and Knee Clinic.
The trial steering committee will include The chief investigator, co-investigator, a research physiotherapist, orthopaedic clinical fellow for Perth Hip and Knee Clinic. They will meet on a fortnightly basis.
The study protocol has been reviewed by two external reviewers prior to HREC approval and trial registration.
Composition of the data monitoring committee, its role and reporting structure {21a}
No data analysis will not occur until completion of the study. However, an independent data safety monitor (IDSM) has been appointed for the study- Professor David Wood, University of Western Australia, Western Australia, Australia.
Adverse event reporting and harms {22}
All serious adverse events will be recorded in the medical records and the CRF, and the sites AE log. All serious adverse events (SAEs) must be recorded on a serious adverse event form. The Principal Investigator will complete the SAE form and the form will be emailed to the SJOG HREC Committee within 5 working days of becoming aware of the event. The Chief Investigator will respond to any SAE queries raised by the primary HREC as soon as possible. Where the event is unexpected and thought to be related to the procedure this must be reported by the Investigator to the Therapeutic Goods Administration via the Incident Reporting and Investigation Scheme within 15 days.
Reporting Incidents
Protocol deviations and notification of protocol violations
A deviation is usually an unintended departure from the expected conduct of the study protocol, which does not need to be reported to the TGA. The principal investigator will monitor protocol deviations.
A protocol violation is a breach which is likely to effect to a significant degree;
a) the safety or physical or mental integrity of the participants of the study; or
b) the scientific value of the study.
The Chief investigator and IDSM will be notified immediately of any case where the above definition applies during the study conduct phase.
Reporting Incidents involving a medical device
Adverse device effects (complications) are defined as any of the following:
a) Any device component failure (e.g. excessive migration of the implant or failure otherwise).
b) Local complications arising from use of the TKA implants to include osteolysis, inflammation, local tissue reaction, periprosthetic fracture.
c) Bone fracture during implantation
d) Nerve damage arising from implant placement (as evidenced immediate postoperative by motor and/or sensory deficit not present preoperatively).
e) Large vessel damage arising during surgery (with large blood loss, i.e. > 1500 ml).
f) Prosthetic joint infection
g) Surgical site infection
h) Loosening of prosthetic components
i) Other adverse events that are deemed device related and serious.
All serious adverse events, life-threatening problems, or deaths that occur during or following the use of the devices during the study should be fully documented in the research record by the Chief Investigator including the onset date, complete description of the event, severity, duration, action taken, and outcome. The event should be documented at the appropriate interval case report form. The Chief Investigator will be responsible for notifying the reviewing Research Ethics Committee, of any unanticipated adverse events according to local regulations. The Chief Investigator will record all non-serious adverse events on the appropriate case report form.
Some adverse events may lead to subsequent surgical intervention. The surgical intervention should be reported separately from the presentation of the other adverse event. For example, if the adverse event is reported at the 3 months visit and a revision subsequently occurs after the 3 months visit, the revision should be reported in the next follow-up visit.
In the short term, revisions will usually occur due to acute/chronic infection, instability, and/or subject experiencing severe pain due to various causes. This data will be used in combination with clinical assessment, target history / examination and further investigation to determine likelihood of requiring revision.
For all cases where revision was necessary, the investigator must record and forward a description of intraoperative findings including: presence of local reaction to implant, gross subsidence of implant, and any intraoperative findings relating to the device failure. This information will be recorded by the intra-operative product specialist, and information will be submitted to the TGA via the medical device incident reporting guide. Explant analysis will occur throughout the duration of this study.
Frequency and plans for auditing trial conduct {23}
On-site monitoring visits shall occur throughout the course of the clinical study by the Chief Investigator. The Chief Investigator shall permit and assist the IDSM (should they choose to monitor the study) to carry out verification of completed case report forms (CRFs) against data in the source documents, which shall occur as per the departmental policy for undertaking such activities.
All personnel involved with the conduct of the study must undertake to maintain the confidentiality of patients in the study. The requirements of the current Good Clinical Practice guidelines will be adhered to for data processing.
Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}
Annual reports with progress of the study will be submitted to the ethics committee. Any SAE will reported to the committee as per section 22. Any changes to the protocol will be approved by the St John of God HREC. If there are major changes to protocol, participants will be notified at their follow up appointment and re-consented to continue in the study.
Dissemination plans {31a}
The findings of this study will be published in peer-review journals. There are no terms or conditions to the funding that may impact upon publication and dissemination. Authorship will reflect the amount of time spent designing the study, collating the data and writing the manuscript.