Study design and setting
A single-centre RCT. All patients will be recruited and included at the Orthopaedics Department of the Canisius Wilhelmina Hospital (CWZ), Nijmegen, the Netherlands. Eligible patients are randomized into two equal groups:
- The TTT group: 20 PFP patients who will be treated with TTT at the hospital of randomisation, followed by a 12-week supervised PT protocol;
- The PT group: 20 PFP patients who will be treated with the same 12-week supervised PT protocol.
This study will be conducted according to the principles of the Declaration of Helsinki (19) and in accordance with the Medical Research Involving Human Subjects Act (WMO), Good Clinical Practice (GCP) and the General Data Protection Regulation. The study will also be carried out in accordance with local legal requirements. This study was approved by the independent Ethical Committee METC Oost-Nederland (protocol number NL80956.091.22) and was registered on ClinicalTrials.gov (study identifier NCT06227806). Written informed consent will be provided by each participant before the start of the study assessments or the intervention. This protocol adheres to the SPIRIT checklist items.
Participants
Participants between 18 and 35 years of age with at least 12 months of PFP and a tibial tubercle trochlear groove (TT-TG) distance ≥15 mm on CT or MRI will be recruited at the CWZ hospital in Nijmegen, The Netherlands. PFP is defined as:
- Pain around or behind the patella aggravated by at least one activity that loads the patellofemoral joint (e.g., squatting, running, or jumping);
- Pain during daily life activities, such as: standing for an extended period, walking, or walking upstairs or downstairs.
Participants will be excluded when one or more of the following exclusion criteria are met:
- Previous knee surgery;
- Reported ligamentous or meniscal injuries of the knee;
- A history of patellar dislocation; however, subjects with patellar subluxation are included in the study;
- Malrotational deformity of the lower extremity evident from physical examination;
- Disabling general illness;
- Other diagnosed knee injuries, either clinically (such as jumper's knee) or radiologically (such as osteochondritis dissecans);
- Patients who cannot undergo surgery;
- Pregnancy;
- Patients with inability to complete follow-up or with limited understanding of the Dutch language.
Patient recruitment
All eligible patients will be approached by their treating physician at the orthopaedic department of the CWZ, provided with adequate patient information, and handed out a patient information file (PIF). They will be instructed about the TTT, PT, and possibility to crossover after 12 weeks of the PT. After having had sufficient time (>24 h) to reconsider participation, they will be contacted by a researcher to obtain approval and plan a baseline visit where participants will sign informed consent. Patients will also be asked for permission to approach them for future related research. A list of all eligible patients will be recorded in a screening log, including those that do not wish to participate, as well as the reason if provided.
Randomisation
Patients will be enrolled in the study by the study coordinator in the orthopaedic department. All patients who consent to participate in the study and meet the inclusion criteria will be randomized. Patients will be randomised to the TTT + PT: PT only in a 1:1 ratio. The randomisation process will be carried out using a computer-generated randomisation method in the Castor electronic data capture (EDC) system (20), in random blocks of 4. The exact randomisation algorithm is unknown to any of the investigators; hence, concealment of allocation is successful in all patients.
Blinding
Neither the treatment providers nor the study coordinator will be blinded due to the study design (with a blatant intervention).
Interventions
Tibial Tubercle Transfer (TTT)
The TTT is a surgical procedure that realigns the patella and, as a result, improves patellar tracking in the trochlear groove. TTT is a relatively safe procedure with a low complication rate (<1% for all major complications) (17, 18). The TTT will be scheduled as soon as possible after randomisation, with a target of <2 weeks. All surgeries will be carried out by either SK or Dr. S. Tigchelaar, both of whom have extensive experience in treating patellofemoral knee disorders. The operative technique used is described previously (21). Patients will be discharged the same day after surgery. Then, a splint phase is started for 4-6 weeks. The physiotherapist will be instructed to contact the study coordinator when the PT begins (see below). After 6 weeks, an outpatient visit with the orthopaedic surgeon is scheduled for a check-up following regular care. At 6 months, there will be an outpatient visit following regular care for evaluation of possible symptoms caused by the hardware. Consequently, removal of hardware (ROH) can be performed if the patient experiences pain derived from the hardware and if complete bone healing is observed on radiographs.
Physiotherapy (PT) program
This will start as soon as possible in the PT group and after the splint phase in the TTT group. The PT will consist of three levels and will be supervised by a physiotherapist. According to predefined criteria, the physiotherapist decides whether a patient can step onto the next level within the PT. The PT consists of flexibility, neuromuscular coordination, and strength exercises for the quadriceps and hip muscles. The PT is developed by a team of experienced physiotherapists who are specialized in treating patients with PFP and based upon the most recent physiotherapeutic insights (7). In addition to training, education about PFP is incorporated into the PT according to the most recent insights regarding pain mechanisms (22, 23). Physiotherapists who participate as self-chosen treating health care professionals by patients will be requested to follow the instructional video developed by the REVITALISE study team. Additionally, the three levels of exercise of the PT program are available on the Physitrack® tool for both participating physiotherapists and patients with PFP to improve exercise adherence and support clinical decision-making. In total, there will be 12 sessions with the physiotherapist. In the first three weeks of the PT, patients visit the physiotherapist twice a week. This will occur once a week from week 3 to week 6. This will occur every other week from week 6 to week 12. However, the treating physiotherapist may increase or decrease the number of appointments if needed. The PT is included in the Supplementary file, which contains more detailed information and instructions.
TTT and PT versus PT only
The study involves four outpatient visits (at inclusion/randomisation, 6 weeks after the start of the intervention, after 12 (PT group)/18 weeks (surgery + PT group), and after 26 weeks in both groups). A physical examination will take place at every outpatient visit, with the addition of the decline step-down test (DSDT) at baseline and 12/18 weeks after randomisation. Patients will complete online questionnaires at every outpatient visit and 12 months after randomisation.
After randomisation, patients will either have a TTT (treatment group) or start with the PT (control group). From 12 weeks, there will be the possibility to crossover from the PT group to surgery if the symptoms do not improve. Surgery will then be performed within 2 weeks. Participants will then follow the same protocol as the TTT group, including the PT program, surveys, and physical measurements.
Criteria for discontinuing or modifying allocated interventions
Subjects can leave the study at any time for any reason if they wish to do so without any consequences. The investigator can decide to withdraw a subject from the study for urgent medical reasons. There will be no follow-up of patients who withdraw from the study, but reasons for withdrawal will be recorded. Patients who withdraw from the study will not be replaced.
Strategies to improve adherence to interventions
To improve adherence, patients will receive the PT in text and with visual instructions on the Physitrack app if possible. They will also receive a weekly questionnaire to register the amount of exercising with the physiotherapist and at home, as well as their VAS score during the 12-week PT.
Relevant concomitant care permitted or prohibited during the trial
Patients are permitted to take any medication such as paracetamol or other prescribed pain killers. The use of other interventions, such as braces or insoles, is not restricted.
Provisions for post-trial care
Post-trial care will follow standard care, especially for the surgery group. Therefore, we do not expect post-trial harm from participation in this study. There are no specific provisions for post-trial care.
Outcomes
Primary outcome
The main study parameter will be the between-group difference in activity-related knee pain at 10-12 weeks after PT in both groups (week 16-18 in TTT group, week 10-12 in PT group), measured with the 10cm VAS-scale. In this period, an expected plateau phase of pain will be reached. The mean from the three scores (week 10, 11, and 12) will be used to account for variance in pain levels. Participants will assess the maximum pain they had felt during the previous 7 days when participating in activities of daily living such as ascending stairs, descending stairs and standing up from a sitting position. The 10-cm VAS is a valid and responsive tool for evaluating overall pain in patients with PFP (24). A minimal clinically important difference (MCID) of 2 cm or 20% has been reported to reflect real changes in a patient’s symptoms (24).
Secondary outcomes
Secondary outcomes are between-group difference in: pain during the intervention (VAS); functional outcomes (Kujala score, IKDC), activity level (Tegner score), quality of life (EQ-5D-5L), and functional ROM (DSDT) at 12/18 weeks follow-up, as well as the change over time from baseline to 12 months follow-up. Furthermore, this study will provide a global overview of the direct medical costs of surgery + PT compared to PT only treatment.
VAS
Difference in participants’ assessment of pain during the intervention (TTT + PT or PT only) is measured by the VAS pain score in the weekly questionnaires during the PT, and at 6 and 12 months follow-up.
Functional outcomes
The Kujala score is a 13-item questionnaire used to evaluate subjective symptoms and functional limitations in patients with PFP (25). Kujala grade ranges from 0-100, with 100 reflecting no signs of PFP. This index shows high validity and is responsive to change (24). To detect improvement, a change of 8-10 points is required (24).
The International Knee Documentation Committee (IKDC) ‘Subjective Knee Form’ is a tool containing 11 items: 7 on knee symptoms, 2 on function, and 2 on sports activities, resulting in a score ranging from 0-100, with 100 reflecting the highest level of pain and functional restrictions. The IKDC showed high internal consistency (0.92) and test-retest reliability (0.95), with a value change of 9 points indicating true change (26).
Activity level
The Tegner activity score consists of 1 item, which scores the level of work- and sport activities on a 10-point scale, with 10 reflecting a high level of activity (27).
Quality of life
The health-related quality of life (EQ-5D-5L) questionnaire consists of 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) that are scored on 5 levels (no problems, slight problems, moderate problems, severe problems, and extreme problems) (28). An index value will be calculated to reflect health status on a scale of 0 to 1, where 1 represents maximum quality of life.
Functional ROM
The maximum pain-free flexion angle (MPFFA) is measured by the DSDT. The DSDT is a reliable and valid performance test simulating stair descent with almost perfect intra- and interobserver reliability (ICC 0.83-0.85) and an average positive correlation between the DSDT score and the total AKPS score (rs= 0.31, p = .030) (29).
Other study parameters
This study will include items strongly recommended by the International Patellofemoral Research Network (iPFRN) in the REPORT-PFP consensus statement (30). These include demographics, such as age, biological sex, symptom duration, and unilateral/bilateral symptoms (30). Furthermore, physical examination data, such as height and weight (and hence BMI) will be recorded. To evaluate the adherence to the PT, patients will also receive a weekly email during the PT asking how often they have visited the physiotherapist and how often they have executed the PT at home.
Any adverse events (AEs) will be monitored, as explained in the ‘Adverse event reporting and harms’ section. The rate of ROH after surgery will be registered as a separate outcome.
Participant timeline
Figure 1 provides an overview of the study design and procedures.
Sample size
Our primary outcome is the between-group difference in overall knee pain 12 weeks after PT and 18 weeks after TTT and PT, measured with the VAS score. Our hypothesis is that the improvement in the TTT group will be greater than the improvement in the PT group.
To detect the superiority of the treat-to-target TTT with PT to PT alone, we calculated the required sample size for an independent samples t-test on the following assumptions: power (1-beta) 0.8, significance level (alpha) 0.05, two-sided testing, MCID mean VAS-pain in TTT + PT: mean 4.1, standard deviation (SD) 2.0, versus PT alone: mean 6.1, and SD 1.9. The SD was based on a study by Bayoumi et al., which compared different surgical techniques for patellar maltracking without instability (16). The MCID was based on a study by Crossley et al., who demonstrated that a change in the VAS score of two points or more is considered clinically relevant and worthwhile for performing surgery (24).
Based on these parameters, a sample size of 16 patients per group is needed. Anticipating on a loss to follow-up of 20%, 20 patients per group are needed.
Feasibility of recruitment
Given the >50 TTTs for patients with chronic PFP already performed annually in the CWZ, and accounting for patients who are not willing to participate, we expect to have sufficient numbers of patients for our inclusion within 12 months. The CWZ is a nationally recognized top clinical expertise centre in (patellofemoral) knee surgery and performs approximately 80% of patellofemoral surgeries in the Netherlands, including TTT (31).
Data collection methods
Plans for assessment and collection of outcomes
The clinical assessment data and PROMs data will be collected in CastorEDC. This data collection will be organized by the study coordinator.
Plans to promote participant retention and complete follow-up
Participants will be closely monitored by the study coordinator to ensure follow-up. To reduce patient burden, data collection will be web-based as often as possible.
Data management
We have created a data management plan in line with the General Data Protection Regulation, which can be viewed upon request. The data will be managed within the online CastorEDC system. This is a secure cloud-based platform that contains an audit trail, automatic range checks, and pseudomized study IDs for all data.
Confidentiality
The type of data that is collected is in line with the General Data Protection Regulation. Study IDs are pseudonymized in CastorEDC for all data. The key to the study ID is safely kept by the study coordinator. The data will be stored for 15 years.
Statistical methods for primary and secondary outcomes
In accordance with the international patellofemoral research network, the REPORT-PFP consensus statement outcome measure description will be adequate (30). The items described in the assessment will be in adequate detail to allow replication. We will report n (%), the mean (SD), and median (interquartile range; IQR) for categorical/descriptive, normally distributed continuous and non-normally distributed continuous data, respectively (30). Results over time will be visualized descriptively in spaghetti plots. The primary analyses will be performed following the intention-to-treat method.
Statistical analyses will be done using R software (R Foundation for Statistical Computing, Vienna, Austria).
Primary endpoint
The primary outcome parameter is the between-group difference in VAS score, at 10-12 weeks after start of the PT (week 16-18 for TTT group). For analysis of the primary parameter, the mean of the three VAS scores at 10, 11, and 12 weeks of the PT in the TTT group will be compared with that of the PT group. Baseline VAS score, biological sex, and treatment group will be included as covariates in a multivariable linear regression analysis.
Secondary endpoints
For the secondary parameters (functional outcomes on the Kujala and IKDC score, activity level on Tegner score, QoL on the EuroQol-5D-5L score, and functional ROM on the DSDT score) at 12 weeks after the start of the PT (week 18 for TTT group), the between-group difference will be assessed using multivariable linear regression analysis in the same manner as the primary endpoint.
To assess the longitudinal clinical effectiveness of both groups, linear mixed models for repeated measures (MMRM) will be used for the secondary outcomes and activity-related knee pain on VAS score during the PT from baseline to 12 months follow-up. MMRMs take the correlation of multiple measurements over time within one patient into account. In the MMRM, this secondary outcomes will be analysed as dependent variables. To evaluate the effect at different time points, the fixed effects will be patient, time, and the treatment group (TTT versus PT only). Time will be included as dummy variable, with baseline as reference.
The main effects for treatment will be reported as difference in means with 95% confidence intervals (CI).
Other study parameters
The economic aspect will be published based upon an estimation of the direct medical healthcare costs for TTT + PT and conservative care for PFP + PT, including costs for hospital visits, scans, surgery, physiotherapy, prescription medication, and possible readmission. The medical costs are based on resource costs. Furthermore, ROH and complications will be reported.
Methods for additional analyses (e.g. subgroup analyses)
Per-protocol analyses will be performed including only the patients that did not crossover from the PT to TTT group, for comparison with intention-to treat analysis.
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data
In the case of missing outcome values, data will be imputed before analysis using multiple imputation methods.
Plans to provide access to the full protocol, participant-level data and statistical code
The trial protocol is available from the corresponding author upon reasonable request. Data will be handled according to the FAIR principles (a guideline to improve the Findability, Accessibility, Interoperability, and Reusability of Digital Assets) (32). After completion of the study, metadata will be available upon request. For access to anonymised participant-level data and statistical code, an application can be submitted to the corresponding author.
Monitoring
Data monitoring
A data monitoring plan has been created and is available upon request. As both groups in this study are within the spectrum of regular care, no data safety monitoring board is installed. Furthermore, since this is a monocentre study, a coordinating centre and trial steering committee are not needed.
No interim analyses will be performed. As the treatments in both groups are within the range of usual care, we do not anticipate differences between the groups that could warrant early cessation of the study due to detrimental effects to the participant.
Adverse event reporting and harms
All AEs reported spontaneously by the subject or observed by the investigator or his staff will be recorded. The patient's general practitioner will receive a letter about the patient's participation in the study. To prevent underregistration of AEs, we will ask for this information during outpatient visits. AEs will be reported until 12 weeks for the PT group and 18 weeks for the surgery group.
Elective hospital admission will not be considered a serious adverse event (SAE). Prolongation of initial hospital stay after surgery due to pain or reduced mobility and the need for mobilization under sedation (hardly ever performed after TTT) will not be considered a serious adverse event. The investigator will report all SAEs to the sponsor without any delay after obtaining knowledge of the events. The sponsor will report the SAEs through the web portal ToetsingOnline to the accredited METC, which approved the protocol within 7 days of first knowledge for SAEs that result in death or are life threatening, followed by a period of a maximum of 8 days to complete the initial preliminary report. All other SAEs will be reported within a maximum of 15 days after the sponsor has first knowledge of the serious adverse events. SAEs will be reported until 12 weeks for the PT group and 18 weeks for the surgery group.
Auditing
Monitoring will be performed once per year. It will involve monitoring the investigator site file, informed consent, SAEs, in- and exclusion criteria, among others. Monitoring will be performed according to Nederlandse Federatie van Universitair Medische Centra (NFU) guidelines and a monitoring plan by a monitor from the CWZ academy.
Protocol amendments
All amendments will be reported to the ethical review committee that gave a favourable opinion. Non-substantial amendments will not be notified to the accredited ethical review committee or the competent authority but will be recorded and filed by the investigator.
Dissemination plans
Overall trial results will be communicated to participants, presented at (inter)national conferences, and reported in peer-reviewed journals. There are no publication restrictions. Medically relevant incidental findings will be shared with the study subject.