Outcomes

The following characteristics will be retrieved from patient questionnaires, physical examination, the hospital information system or medical records: patient characteristics (ie, sex, age, height and weight); indication for surgery; American Society of Anesthesiologists classification; previous joint procedures or injury; present degree of deformity and degree of deformity before the index procedure; comorbidities; smoking and alcohol consumption and pain medication consumption.

We will also note arthroplasty-related characteristics such as anaesthesia method, type of arthroplasty, surgical approach, postoperative analgesic consumption and arthroplasty-related complications.

The primary outcome of the study will be the postoperative functional outcome as measured by the self-administered Knee Injury and Osteoarthritis Outcome Score (KOOS).25 ,26 The KOOS was developed in the 1990s to assess patients' opinions on the state of their knees after injury or surgery.26 ,27 The score also has sufficient sensitivity in the younger and more active patients with knee problems. In addition to questions about pain and stiffness, it examines knee function in daily life, sport and recreational activities and the quality of life.

Secondary outcomes of this study are:

• Joint awareness during various activities of daily living, as measured by the Forgotten Joint Score-12 (FJS-12).28 The FJS-12 is a recently published patient-reported outcome measure to assess joint awareness in hips and knees during various activities of daily living.28 It consists of 12 questions.29 The FJS-12 has a high internal consistency (Cronbach's α 0.95), a low ceiling effect and the instrument discriminates well between good, very good and excellent outcomes after total hip arthroplasty (THA) and TKA.29

• Patients' knees and functional abilities such as walking and stair climbing before and after TKA as assessed via the KSS, a simple, objective, globally recognised scoring system30 to track and report outcomes after total and partial knee arthroplasty.

• Conventional anteroposterior and lateral radiographs will be taken at designated time points. Postoperative radiographs will assess component position, alignment and the location and incidence of radiolucent lines using the Knee Society TKA radiographic evaluation system.31

• The incidence of adverse events (AEs) and adverse device effects.

Study population

For a patient to qualify for study enrolment, the CCK and the RTH design should be indicated. If one of the two designs prevails in the physician's reasonable medical judgement, the patient should receive the treatment deemed most suitable by the patient's physician.

Study participants will be recruited from eligible patients at the orthopaedic department of the Krankenhaus Märkisch Oderland GmbH BT, Wriezen, Germany scheduled for knee arthroplasty, and from three other clinical sites that have yet to be recruited. Eligible patients must require primary or revision surgery and must have an axial malalignment >18°, with one of the collateral ligaments (ie, medial collateral and/or lateral collateral ligament) being absent or incompetent.15

Indications are:32

• rheumatoid arthritis;

• post-traumatic arthritis, osteoarthritis or degenerative arthritis in older patients whose age, weight and activity levels are compatible with an adequate long-term result;

• failed osteotomies, unicompartmental replacement or total knee replacement.

In addition, the patient has to fulfil the following criteria to be eligible for the study:

• The patient is scheduled for elective primary or revision knee arthroplasty.

• The patient is 18 years or older. There are no upper age limits for the study, as long as the patient is healthy enough to undergo surgery.

• The patient is willing to provide informed consent.

The following exclusion criteria shall be used for the study:

• genu recurvatum;

• gross anteroposterior instability;

• the patient participates in another concurrent study;

• major psychiatric disease;

• patients who do not comprehend the German language (read and speak);

• pregnancy, lactation or childbearing potential without using adequate contraception;

• acute or chronic infections, local or systemic (or corresponding previous incidents);

• severe muscle, nerve or vascular diseases that endanger the extremity in question;

• lacking bone substance or possessing inadequate bone quality that endangers a stable seating of the prosthesis;

• extreme insufficiency of the knee extensor mechanism as this can lead to excessive joint distortion;

• adipositas permagna;

• local tumours;

• known hypersensitivity to the material.

Devices

The Legion Revision System (Smith and Nephew, Memphis, Tennessee, USA) was introduced in Europe in 2006, and good postoperative outcome has been reported with the system.33 The system is available with a variety of wedges and femoral and tibial stems with and without offset. It is indicated for use in total knee replacement to overcome severe ligamentous imbalance, laxity or in the presence of deformity in excess of 20°.

The RTH RT-Plus (Smith and Nephew) was introduced in Europe in 1997, and we previously reported good mid-term to long-term outcome with this device.15 The system is available with a variety of wedges and femoral and tibial stems. For the study, the device will be used within its indications for use while excluding severe ligamentous imbalances, ligamentous laxities or gross deformities in excess of 20°.

Study withdrawal

In accordance with the Declaration of Helsinki and with local regulations, study subjects have the right to withdraw at any time from the study without providing a reason. The investigator or regulatory authority can discontinue a subject's participation in the study at any time if medically or otherwise necessary. Unless the subject wishes to withdraw from the study completely, all scheduled examinations will be performed as planned.

Study hypothesis

The current study will be designed as an equivalence trial, that is, a trial designed to show that the two interventions do not differ in either direction by more than a prespecified unimportant or insignificant amount.34 The amount of permissible difference is the margin that delineates the ‘zone of indifference’. Within this zone of indifference, the two groups are considered equivalent.35

The KOOS has a minimally clinically important difference (MCID) of 8 to 10 points, and the SD in a cohort of TKA patients is ∼15 points.26

The null hypothesis (of non-equivalence) of the study is that functional outcome at 2 years of follow-up in the RTH group is not equal to the functional outcome at 2 years of follow-up in the CCK group, or:versus the equivalence assumption that functional outcome at 2 years of follow-up in the RTH group is equivalent to the functional outcome at 2 years of follow-up in the CCK group, or:

Sample size calculation

With α=0.05 and β=0.10, a sample size between 49 (MCID=10) and 77 (MCID=8) will be required. Calculation is based on the following formula:36with:

Attrition and dropout rate at the 2-year follow-up is estimated to be 10%. To account for attrition and drop-out, a total of 2×85 patients will be enrolled.

Randomisation

Patients will be randomly allocated to the treatment or control group in a 1:1 ratio, using block randomisation with random block sizes. Stratification based on study site will be performed. Under all circumstances, subjects will not be randomised before they have provided informed consent. Randomisation in advance of surgery (by at least 24 hours) is required in order to allow proper preoperative planning of the surgery, alongside preparation of the instrument sets. The investigator will randomise the patient through the internet (http://www.randomisation.com) and document the treatment group in the patient's chart.

Blinding

Surgeon and patients will not be blinded for the assigned treatment. In order to preserve the blinding of the study, a minimum number of examiners will have access to the randomisation schedule before the study is complete. To reduce measurement bias, the preoperative and follow-up assessments will be performed by independent examiners blinded to group allocation (one examiner plus one back up at each centre, both trained and neither involved in surgery). Before each follow-up visit, subjects will be reminded not to disclose their allocation.

One independent single examiner will perform the radiographic assessments. Blinding of this examiner will not be possible.

One interim analysis is planned to investigate the safety and the primary outcome after half of the patients have been enrolled. The statistician will provide a summary of the AEs and an analysis of the primary outcome. Study groups will be blinded; the group assignments will not be revealed. These results will be presented to the Clinical Study Steering Committee (CSSC).

Based on the interim analysis, the CSSC will then decide whether to continue the study without adjustment, continue the study with adjustment(s) or to stop the study due to safety or efficacy concerns. The CSSC may request to reveal study arm assignments before coming to a definitive decision. Early termination of the study for efficacy at the interim analysis will be considered if the benefit of either one of the study groups is shown ‘beyond reasonable doubt.’ A nominal p value<0.003 (O'Brien Fleming α spending37) provides guidance in this instance but is not binding for this decision. As the products used in both study arms are CE-marked and are present in the market for <10 years, no formal criteria for early stopping for safety reasons have been defined. The CSSC's decision will be based on the statistical analysis and the clinical expertise of the board members.

The interim results will be confidential and strictly limited to the members of the CSSC. This confidentiality minimises the risk of interim-result bias on the remaining course of the trial.

All analyses will be performed primarily as an intention-to-treat-analysis, assessing all patients with available data for the outcomes according to the randomisation. For baseline characteristics, descriptive statistics will be used as appropriate. The primary hypothesis will be tested using the Westlake version of an equivalence test with known and fixed delta.38 Further exploration of the primary and secondary outcomes will be based on linear mixed models.39 Inferences on the random effect structures will be based on the restricted maximum likelihood and inferences for the fixed effect structure will be based on the standard maximum likelihood.

With the exception of the interim analysis of the primary outcome, two-sided significance tests with an α of 0.05 will be applied. Stata 12.1 (StataCorp, College Station, Texas, USA) will be used for the analysis.

Study procedures

Patients that are screened and deemed ineligible prior to study inclusion will be tracked on a screening log along with a detailed reason for exclusion.

Patients who are deemed eligible but who are not included in the study will be tracked on a screening log along with the reason for exclusion.

Patients that are enrolled and are deemed ineligible during surgery will be tracked on a dedicated Termination Case Report Form along with the reason for exclusion.

Informed consent

Patients will be informed verbally by the investigator about the study objectives, design, risks, the study procedures and patient rights. Only patients who have signed the informed consent form 24 hours before surgery and meet all inclusion criteria and no exclusion criteria will be included in the trial. Patients will receive a copy of the signed informed consent form.

Study visit definitions

The screening date is defined as the date the informed consent is signed. The enrolment date is defined as the date of randomisation. Day 1 is defined as the surgery day. All on-study visits will be calculated from the initial day-1 visit. However, if a subject's visit is delayed, the subsequent visit date will be shifted.

Study visit windows will be ±7 days for all the visits of the treatment and observation period and ±14 days for follow-up visits at the 1-year and 2-year follow-ups. Study procedures for a specific visit may be completed on multiple days as long as all the procedures are completed within the visit window. The subject's medical history will be obtained prior to enrolment and recorded in an electronic data capturing system. Table 3 shows all the assessments and procedures performed during each visit.

Concomitant care

It is imperative that all study participants receive the best available care. This may lead to differences in concomitant care between the study groups. All concomitant medications and treatments will therefore be reported on a concomitant care case report form.

Dissemination

This clinical study will be conducted in accordance with the latest version of the World Medical Association Declaration of Helsinki, ISO14155, and German regulations. The study is registered at the German Clinical Trials Register (trial registration number DRKS00010539). The ethics committee will be notified should future amendments (ie, modifications that are likely to affect the safety or the scientific value of the trial) arise.

The results of the study will be published in international peer-reviewed scientific journals, independent from the outcome. Anonymous patient data will be made available on request of the journal. We will provide a copy of the protocol, including the statistical analysis plan, to the medical journal considering a submitted manuscript for publication, if requested by the journal.

Authorship

The International Committee of Medical Journal Editors (ICMJE) recommendations regarding authorship will be followed. The investigators will identify the individuals who accept direct responsibility for the publication. All authors must take responsibility for the manuscript. Publications from individual institutions participating in the study will not precede the primary manuscript. An external professional medical or scientific writer may be employed to assist in producing publications. Names, involvement and funding of the external writer will be acknowledged in the publication. We will not engage ghostwriters.

Study organisation

No data and safety monitoring board will be installed, as the safety and efficacy of the study devices have been documented. A CSSC has been installed consisting of the principal investigators of the four study sites and a statistician. The CSSC has the primary responsibility for designing the study, maintaining the quality of study conduct, the ongoing monitoring of safety and efficacy and writing the study publications. The committee will also assess whether the endpoints meet the criteria of equivalence. Except for the statistician, the committee will be masked to the assigned study arm when performing their assessments.

Data collection and monitoring

Patients will be hospitalised during the whole study (due to the RTKA procedure). Study participants will therefore be under steady monitoring by surgeons and regular hospital staff. Dedicated study physicians and study nurses will collect data from the patients' records. Study nurses will schedule patient follow-ups to the clinic and will oversee the physical and the radiographic assessments. Study nurses will also provide and collect the questionnaires from the patients and will provide assistance with completing the questionnaires if requested by the patient. The clinical data management system used for the study will be the 21 CFR Part 11 and GCP compliant, CDISC-certified electronic data capture system Marvin (XClinical GmbH, Munich, Germany). Patients will be coded and patient-identifiable information will not be stored in the clinical data management system.

Data entry comprises extensive data edit checks. The software will dynamically check and query illegal ranges and inconsistent entries. Data entry is recorded in an audit trail, and backup to a remote server is performed several times per day.

The sponsor has appointed an independent contract research organisation (CRO) to perform site/clinical monitoring of the study to assure high-quality trial conduct. A monitor appointed by the CRO will perform biannual ‘on site’ monitoring of individual case histories, assess adherence to the protocol, ensure the ongoing implementation of appropriate data entry and quality control procedures and, in general, assess adherence to good clinical practices.40 The study monitor will remain blinded to study arm assignment.

AEs and adverse device effects

All AEs and adverse device effects reported spontaneously by the study subject or observed by the investigators or staff will be recorded. In case of a serious adverse device effect (SADE), the principal investigator will report the SADE to the ethics committee and the authorities (Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM)). Prolonged hospitalisation (>14 days) will be reported as an SAE or as an SADE. Rehospitalisation (for any reason) will also be reported and handled as an SAE or as an SADE. All AEs will be followed until the event has resolved, or until a stable situation has been achieved.