Safety and efficacy of a novel knee prosthesis for knee arthroplasty: study protocol for a randomized, positive parallel controlled, non-inferiority, clinical trial

Zhi-feng Li, Jing-dong Sun, Jiang Zhang, Tai-fang Gong＊

First Ward, Department of Orthopedics, Taihe Hospital (Affiliated Hospital of Hubei University of Medicine), Shiyan, Hubei Province,China

INTRODUCTION

Background

Total knee arthroplasty is one of the major methods used to treat end-stage knee disease.1-4Therefore, there is an urgent need to develop a safe, effective, high-quality and inexpensive knee prosthesis to meet the huge demand for knee replacement in patients with knee disease in China.5-8Combined with international advanced design concepts,Wuhan Yijiabao Biomaterial Co., Ltd. in China has developed a novel knee prosthesis system using cobalt-chromiummolybdenum alloy and high cross-linked polyethylene as the main materials. This novel knee prosthesis system contains a femoral condyle, meniscus, tibial tray, and patella. It uses cobalt-chrome-molybdenum and high cross-linked polyethylene as the active friction interface, which has excellent wear resistance, and provides an ideal treatment for patients with knee disease. The efficacy and safety of this newlydeveloped knee prosthesis need to be compared with current knee prostheses widely used in total knee arthroplasty in a randomized, controlled, clinical trial.9-12

Trial significance

This trial will assess the safety and efficacy of the newlydeveloped knee prosthesis (Wuhan Yijiabao Biomaterial Co., Ltd.) in total knee arthroplasty. A widely used knee prosthesis (Beijing AKEC Medical Co., Ltd., Beijing,China) will be used as a control.

METHODS/DESIGN

Study design

A prospective, single-center, randomized, positive parallel controlled, non-inferiority, clinical trial.

Study setting

First Ward, Department of Orthopedics, Taihe Hospital,Shiyan, Hubei Province, China.

Study procedures

Seventy-two patients with knee disease who are scheduled to undergo knee arthroplasty will be equally randomized into the trial group or the control group using a randomized block design.

Patients in the trial and control groups will undergo knee arthroplasty with knee prostheses purchased from Wuhan Yijiabao Biomaterial Co., Ltd., Wuhan, China (newlydeveloped) and Beijing AKEC Medical Co., Ltd., Beijing,China (approved by the China Food and Drug Administration; approval number: 20153461366), respectively. Indicators in both groups will be analyzed preoperatively, and at postoperative 2 weeks (± 5 days), 6 weeks (± 15 days), 3 months (± 15 days), 6 months (± 15 days), and 12 months(± 15 days).

The follow-up period will be 12 months. All clinical trials will be completed within approximately 8 months. Thus,the expected duration of participation for each patient will be 12 months. The overall duration of the trial will be approximately 20 months.

Patient recruitment began in February 2017 and will be finished in September 2017. Data analysis will be completed in November 2018.

A flow chart of the trial protocol is exhibited inFigure 1.

Strengths and limitations

? This system uses cobalt-chrome-molybdenum and high cross-linked polyethylene as the active friction interface, which has excellent wear resistance.

? This prospective, single-center, randomized, positive parallel controlled, non-inferiority, clinical trial is designed to assess the eきcacy and safety of a knee prosthesis newly developed by Wuhan Yijiabao Biomaterial Co., Ltd. to determine its suitability for clinical use.

? The result indicators of the study are relatively simple.

? Some stratification factors, such as disease type, age,sex, and duration of disease, can affect the reliability of the outcome.

Figure 1: Flow chart of the trial protocol.

Ethical requirements

The study protocol has been approved by the Ethics Committee of Taihe Hospital of China (approval number: 2016(34)). The ethics committee will supervise the clinical trial at the institution. If the rights and interests of the patients are compromised, the ethics committee may suspend or terminate the clinical trial at any time. The suspended or terminated clinical trial cannot be resumed without the consent of the ethics committee. All protocols will be performed in accordance with the Ethical Principles for Medical Research Involving Human Subjects in theDeclaration of Helsinki.The writing and editing of the article will be performed in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) (Additional file 1). Written informed consent will be provided by each patient and their family members after they indicate that they fully understand the treatment plan.

Study participants

Inclusion criteria

Patients presenting with all of the following criteria will be considered for study inclusion.

? At least one of the following knee diseases: primary or secondary knee osteoarthritis, traumatic arthritis,rheumatoid arthritis or ankylosing spondylitis and other systemic diseases involving the knee, degenerative arthritis, tumor resection of the knee, varus or valgus correction of the knee, and fracture of the knee joint

? Aged at least 35 years, irrespective of sex

? Mature bone, that is, epiphyseal closure evident on knee radiography

? No prior history of total knee arthroplasty

? Willing and able to sign informed consent

Exclusion criteria

Patients with one or more of the following conditions will be excluded from this study.

? Neuromuscular dysfunction (such as paralysis,rhabdomyolysis, or abductor weakness) that may lead to instability or gait abnormalities in the knee postoperatively

? Mentally incapable or unable to understand the requirements for participation in research

? Expected to be unsuitable (such as alcoholics, drug addicts, drug abusers; those unwilling to accept a 12-month study plan; those whose expected outcome is unrealistic or those with a clear emotional problem)

? Allergy to one or more implant

? Active infection in the knee joint or other parts of the body

? Severe osteoporosis, bone defect, metabolic bone disease,and/or radioactive bone disease around the knee joint

? Frail or unable to tolerate surgery because of other systemic disease, or with a life expectancy of less than 2 years

? Pregnancy, lactation, or planning for pregnancy

? A combination of other diseases that restricts participation in the study; failure to follow-up or conditions that may influence the scientific nature and integrity of the study (for example, other lower limb joint (ankle) disorders that cause severe functional impairment and influence assessment, and the presence of joint prostheses in other primary joints (knee and hip))

? Participation in other clinical trials investigating drugs,biological agents, or instruments

Withdrawal criteria

Patients who meet one or more of the following criteria during the trial will be withdrawn from this study.

? Withdrawal of informed consent for any reason

? Serious breach of the verification program

? The occurrence of adverse events, especially serious adverse events, which causes the ethics committee to suspend the study

? An adverse event occurs during the trial that necessitates removal of the implant or other treatment

? Incomplete informed consent process or lack of informed consent

? The researchers believe that the patient is no longer suitable for continuing clinical validation

? Lost to follow-up, without any medical data

? Non-trial-induced major illness or death that occurs during follow-up and affects data assessment

? The trial is discontinued for other reasons

Treatment of withdrawal cases

All source data and source files related to all withdrawn participants will be retained for retention and intent-to-treat analysis. After withdrawal, the researchers will attempt to contact the patient by telephone or mail to ask the reasons for withdrawal. The time and cause of withdrawal will be recorded on the case report form in detail. If there is judged to be a causal relationship with the prosthesis, withdrawal due to adverse events will be recorded in the case report form and the applicant will be notified. For such patients, follow-up will be conducted until adverse events are resolved or stabilized.

Baseline analysis

Baseline information is presented inTable 1.

Sample size

In accordance with our experience, we hypothesize that the Hospital for Special Surgery (HSS) knee scores will be 80–90 points at 1 year postoperatively in the trial group.When compared with the mean score of 86 points, the actual difference is set at –1.5 points. The maximum total HSS score is 100. In clinical practice, a difference of less than 10 points does not affect the therapeutic outcome. A HSS score of 70 points or more is considered to indicate a good therapeutic effect. HSS scores in the control group are expected to be above 85 points from postoperative 6 months, mainly indicating an excellent therapeutic effect.Therefore, the evidence of efficacy is sufficient to use the prosthesis manufactured by Beijing AKEC Medical Co.,Ltd. as a positive control in this clinical trial. After discussion with orthopedic experts, the excellent and good rate πCof the control group (positive control) was set at 98%; noninferiority marginδ= 10.0%. Takingβ= 0.2 and Power = 0.8 withα= 0.05 on one side, and an allocation ratio of the trial and control groups of 1:1, the final effective sample size was calculated asn= 36 per group (72 patients in total), using PASS 11.0 software (PASS, Keysville, UT, USA). If we assume a patient loss rate of 10%, we will require a total of 80 patients. However, because of the limited inclusion criteria,72 subjects will be included in this trial (n= 36 per group),and all subjects will be followed up as much as possible.

Recruitment

Patients will be recruited from the out-patient clinic of Taihe Hospital of China. The researchers will be responsible for recruiting patients, talking to the patients or their guardians(relatives), informing them of the details of the medical devices and the clinical trial, and describing possible benefits and known and foreseeable risks. Written informed consent will be provided by each patient and their family members after they have indicated that they fully understand the treatment plan. The researcher or other participant in the test cannot force or coerce the patients to participate in the trial.

Randomization

A statistician will design a randomized electronic form.SAS 9.3 software (SAS Institute Inc., Cary, NC, USA)will be used to fix the seed number. A computer will use a randomized block design and central randomization system to automatically assign random numbers and groupings. The researchers will treat each patient with the corresponding randomly assigned knee prosthesis, and a list of the randomized assignments will be printed and retained.

Table 1: Baseline data and general disease history of included patients

Blinding

Evaluation will be done using the single-blind method. HSS scores will be assessed by an independent third party who will be blinded to the group assignments.

Interventions

The newly-developed knee prosthesis system consists of the femoral condyle, meniscus, tibial tray, and patella. Each component has many different specifications, so the physician will choose these according to each patient’s individual condition.The femoral condyle made from cobalt-chrome-molybdenum alloy and the meniscus made from high cross-linked polyethylene will be considered as the active friction interface. The surface of femoral condyle will be processed by a precision grinding machine. Compared with common polyethylene,the chemical properties of this novel prosthesis are stable, the wear resistance is greatly improved, and the biocompatibility is excellent. Moreover, this prosthesis has been widely used in developed countries, and the clinical outcome is reportedly excellent. The knee joint is an implantable joint prosthesis designed and manufactured according to the structure of the human knee, with good biocompatibility and good mechanical properties. It is used to replace a knee joint damaged by disease or trauma.

In the control group, the knee prostheses will be composed of an A3 femoral condyle, tibial pad, A3 tibial plateau, and patella. Each component has many different specifications,so the physician will choose these according to each patient’s individual condition. The femoral condyle and tibial plateau are made from cobalt-chrome-molybdenum alloy,which can perfectly simulate the human knee. The tibial pad is made from ultra-high molecular weight polyethylene. The meniscal surface is smooth, and wear resistance is high.

Specification for new prosthesis use

Test products and surgical instruments will be provided by the sponsor. Test products will be locked in areas accessible only by authorized persons. The conditions for the preservation of the test products will comply with the requirements of the product specifications provided by the sponsor. The researcher or his/her designated person or equipment keeper will be responsible for and understand the inventory and ship-ment of the test items. Other instruments needed during the operation will be provided by the hospital in accordance with routine procedures. Each clinical research unit will assign a relevant person to be in charge of the management of the test products. The researchers will ensure that the test products are used in strict accordance with the prescribed methods. The person in charge of the test products will accurately record the transportation, acceptance, distribution, and destruction of test products, and all records will be saved.

Knee arthroplasty

The same knee arthroplasty method will be used in the trial and control groups. A median longitudinal incision will be made in the knee, and the pulp will be opened in the intercondylar fossa of the femur. The precise site will be between the highest point of the intercondylar fossa of the femur and the lowest point of the femoral patellar trochlea, in a slightly medial position. The site will be adjusted according to the longitudinal axis of the femur and the junction of the intercondylar fossa as revealed on preoperative radiography. The femoral intramedullary positioning rod will be inserted into the femoral medullary cavity. The rotational axis of the femoral prosthesis will be consistent with the line of the medial and lateral femoral epicondyles of the knee. After removal of the soft tissue posterior to the joint, any hyperplastic osteophyte and/or loose body behind the joint will be removed. The balance of the flexion and extension clearance will be determined at a genuflection of 90° and in knee extension. Under varus or valgus stress, the medial or lateral opening will not exceed 2 mm at 90° flexion or extension. Afterwards, the femoral and tibial prostheses will be tested and reset. Postoperatively, the operation condition and product usage will be recorded, and the operative image will be preserved.

Postoperative care

Anticoagulant therapy will be used to prevent deep vein thrombosis of the lower extremity. Infection prevention protocols will be followed. The patients will be guided to perform knee functional exercises.

Outcome measures

Primary outcome measure

The rate of excellent and good HSS knee scores at postoperative 12 months (± 15 days). That is, the percentage of patients with excellent and good HSS scores after surgery in each group. The maximum HSS scores is 100, excellent is 85–100, good is 70–84, average is 60–69, and poor is less than 59.13

Secondary outcome measures

? The morphology of the knee as revealed by anteroposterior and lateral radiographic views taken preoperatively,and at postoperative 2 weeks (± 5 days), 6 weeks (± 15 days), 3 months (± 15 days), 6 months (± 15 days), and 12 months (± 15 days) will be used to assess the recovery of the knee after surgery.

? Incidence of adverse reactions at postoperative 2 weeks(± 5 days), 6 weeks (± 15 days), 3 months (± 15 days),6 months (± 15 days), and 12 months (± 15 days) will be used to assess the safety of the knee prostheses. Incidence of adverse reactions = number of patients with adverse reactions/total number of patients × 100%.

? Correlation between various types of adverse reactions and knee prostheses at postoperative 2 weeks (± 5 days),6 weeks (± 15 days), 3 months (± 15 days), 6 months(± 15 days), and 12 months (± 15 days) will be used to analyze the correlation between the complications and the prosthesis type (loosening and subsidence). Type, quantity, and percentage of complications will be recorded in each group.

The schedule of outcome measurement assessments is shown inTable 2.

Table 2: Timing of outcome assessment

Adverse events

Definition

Any adverse medical event that occurs from the time that the patient signs informed consent and is selected for the trial is defined as an incident, regardless of whether there is a causal relationship with the instrument. Adverse events will be recorded accurately during the trial, including the name,time of occurrence and termination, severity, relationship with the known event, measures taken, and outcome. The severity of adverse events will be graded as mild (does not affect daily activities), moderate (affects daily activities),or severe (prevents performance of daily activities).

Severe adverse events

A severe adverse event is defined as any event that occurs during the clinical trial and results in death, prolonged hospitalization or readmission, fatal illness or injury, permanent defect in the body structure or function, or requires medical or surgical intervention to avoid permanent defects in the structure or function of the body.

Reporting procedures for severe adverse events

When adverse events are detected during the trial, the patients will be actively managed until their conditions are under control. The adverse event will be recorded in the case report form and analyzed statistically. If a severe adverse event occurs, researchers will report the details (including the date of occurrence and measures taken to treat the adverse event) to the principle researcher, the institutional review board, and the clinical examiner within 24 hours,regardless of the relationship with the test product.

Prediction and management of adverse events

Adverse events associated with prostheses include prosthesis fracture, loosening and dislocation, unsatisfactory functional recovery, excessive wear, and stress fracture at the site of implantation. The patient’s postoperative condition and the stability of the prosthesis will be closely observed and evaluated. If the patient is injured, the trial will be terminated and the patient will be treated in a timely manner.

Adverse events associated with knee replacement include pulmonary embolism and deep venous thrombosis of the lower extremity. Treatment measures include routine preoperative venous thrombosis screening; anticoagulant drugs will be used postoperatively and mechanical assistance measures will be undertaken simultaneously. Patients with suspected embolic or thrombotic issues will undergo color Doppler ultrasound on the veins of the lower extremity. Patients with deep venous thrombosis will undergo conventional treatment.

To minimize the risk of periprosthetic infection, the supplied prostheses will be cleaned, packed, and sterilized by radiation in accordance with national standards. The same batch of sterilized products will be microbiologically tested to ensure sterility. Clinical medical staff will follow protocols to prevent infection. Infection will be treated actively in various parts of the body preoperatively. The principles of asepsis and fine operation will be strictly followed, and prophylactic antibiotics will be administered intraoperatively.If periprosthetic infection occurs, appropriate antibiotics will be administered and the wound will be thoroughly cleaned. One- or two-stage prosthetic replacement will be considered during debridement. If the patient’s condition does not allow prosthetic replacement, we will consider simply removing the prosthesis and keeping the joint open.

Countermeasures to prevent the poor recovery of limb function caused by improper selection of prosthesis model or poor position and angle will be performed as follows.The operation will be performed by an experienced doctor.The appropriate type and size of prosthesis will be selected preoperatively through radiographic data measurement and template matching. Intraoperatively, the implant model will be finally confirmed after adjustment. If an error is detected, the prosthesis will be removed and installed again if necessary. The location and size of the prosthesis will be confirmed again on imaging.

Data collection, management, analysis, and open access

Data collection: The researchers will fill out a paper case report form for each case. The case report form will be truthfully and carefully recorded in detail to ensure that the case report form is complete, authentic and reliable.

Data management: The entire experiment will be performed under strictly enforced quality management specifications for clinical trials. All paper case report form records will be complete, true, clear, and objective. All data will be entered into a computer, which will be locked and stored. The completed case report forms will be reviewed by the inspector. The first page of the case report forms will be handed over to the data manager for data entry and management. From then on, the contents of the case report forms will not be altered.

Data analysis: After the test plan has been determined, the statisticians will consult with the major researchers and formulate a statistical analysis plan. All data will be analyzed using SAS 9.3 software. Statistical analysis will include the actual number of participants in the two groups, the conditions of drop-out and eliminated cases, demographic and other baseline characteristics, efficacy analysis, and safety analysis. Besides the statistical methods listed below, detailed and additional exploratory analyses may be necessary,and may be identified in the study report and analysis plan.

Data open access: If the researchers want to publish or disclose the results obtained from the products of this clinical trial, they must have prior written consent from the sponsor. The sponsor will review and respond to the contents of the proposed disclosure within 30 working days.The sponsor will not use the names of the researchers in the advertising of the test equipment without the researchers’ consent. However, in the case of a clinical trial of the test instrument and the submission of a production license to the China Food and Drug Administration, the sponsor can directly use all results obtained from the clinical trial without the consent of the researchers.

Quality control

The researchers will strictly comply with the state regulations regarding the clinical trials of medical devices and the relevant operating procedures. The research center must obtain the qualification of a national clinical drug testing institution in orthopedics. Before the trial, all related personnel will be trained regarding clinical protocols, informed consent procedures, equipment use, and record completing. During the trial,the researchers and test-related personnel will receive targeted training according to the clinical situation.

Statistical analysis

Data will be analyzed using SAS 9.3 software. Measurement data will be expressed as the mean ± standard deviation,and minimums and maximums. Measurement data and registration data will be described by frequency.

The difference in the rate of excellent and good HSS scores between the trial and control groups and its 95%CIwill be calculated. A lower limit greater than –10.0% can be considered as non-inferiority. Measurement data will be compared between the two groups using the two-samplet-test or Mann-WhitneyUrank sum test. Intergroup comparison will be conducted using Pearson’s chi-squared test or Fisher’s exact test. Ranked data in both groups will be analyzed using the Wilcoxon rank-sum test or Cochran-Mantel-Haenszel test.

Efficacy evaluation: The rate of excellent and good HSS scores between the trial and control groups will comprise a non-inferiority trial. Non-inferiority marginδ= 10.0%.The test is assumed to be:

H0: Difference in the rate of excellent and good HSS scores between the trial and control groups (πT–πC) ≤ –δ;

H1: Difference in the rate of excellent and good HSS scores between the trial and control groups (πT–πC) ＞ –δ.

The Cochran-Mantel-Haenszel test will be used to compare the difference in the rate of excellent and good HSS scores between the trial and control groups, and to calculate the lower limit of the 95%CIon one side. A lower limit greater than –10.0% will be considered as non-inferiority.

Safety evaluation: The incidence of adverse events in the two groups will be compared using the chi-square test.

Data processing for patients undergoing arthroplasty on both knees: If the indicators are evaluated separately on both sides,the data on one side are included in the statistical analysis set under two conditions. When both knees are operated on simultaneously, data of the knee with poor postoperative efficacy will be entered into the analysis set. When both knees are operated in different stages, data of the knee undergoing the second operation will be entered into the analysis set.

Report deviated from the original statistical plan: In case of“incomplete implementation of the statistical analysis plan”,the change procedure will be applied in advance. For example,changes in the statistical plan will be faithfully recorded in the statistical analysis plan, including the place, reason, and time.

Patients’ selection criteria and set analysis:

Full analysis set: According to the intention-to-treat principle, this will be the data set consisting of patients who participated in the treatment and underwent baseline efficacy evaluation. For patients who do not undergo the overall efficacy evaluation, the last observation carry forward principle will be used for data conversion.

Per protocol set: Data set consisting of patients who have finished the trial, but for whom a breach of the inclusion or exclusion criteria is discovered.

TRIAL STATUS

Patient recruitment is ongoing, and will be finished in September 2017. Data analysis will be completed in November 2018.

DISCUSSION

Significance of this study

Wuhan Yijiabao Biomaterial Co., Ltd. is a national high-tech enterprise for professional research, development, production, and sale of implants for orthopedics. This company can provide the best solution for the design and treatment of joint prostheses, and has accumulated a wealth of practical experience for this clinical trial. This prospective,single-center, randomized, positive parallel controlled, noninferiority, clinical trial is designed to assess the efficacy and safety of a knee prosthesis newly developed by Wuhan Yijiabao Biomaterial Co., Ltd. to determine its suitability for clinical use.

Analysis of the possibility of failure

The following conditions may cause test failure and will be avoided to the greatest extent possible: (1) Patients are not screened strictly according to inclusion and exclusion criteria. (2) Improper selection of replacement indications.(3) The type and size of the product do not meet the patient’s actual needs. (4) The number of cases lost to follow-up is large. (5) After non-inferiority comparison, if the clinical efficacy is not significant, and there is no statistical signif icance, the clinical application of the knee prosthesis system needs further study and is not suitable for clinical practice.(6) Product quality problems lead to a high incidence of adverse reactions or severe adverse events, indicating that the knee prosthesis system is not safe and is not suitable for clinical use.

Limitations of this study

The result indicators of the study are relatively simple. Inclusion criteria are broad. Some stratification factors, such as disease type, age, sex, and duration of disease, can affect the reliability of the outcome. These defects will be improved in future studies.14,15

Evidence for contribution to future studies

The researchers have devised a complete test plan. The hospital has complete equipment and technical resources.The clinical trial manager has extensive clinical experience.Therefore, we hope to verify the good safety and efficacy of the knee prosthesis newly developed by Wuhan Yijiabao Biomaterial Co., Ltd. for knee arthroplasty, and to show that it is not inferior to the control knee prosthesis approved by the China Food and Drug Administration.

Author contributions

Study concept and design: TFG. Manuscript writing, reading review and final approval of publication: ZFL. Experiment assistant: ZFL, JDS, and JZ.

Conflicts of interest

None declared.

Research ethics

The study protocol has been approved by the Ethics Committee of Taihe Hospital of China (approval number: 2016 (34)). The study protocol will be conducted in accordance with the principles of theDeclaration of Helsinkiand Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidance for protocol reporting.

Declaration of patient consent

The authors certify that they will obtain all appropriate patient consent forms. In the form the patients will give their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Contributor agreement

A statement of “Publishing Agreement” has been signed by an authorized author on behalf of all authors prior to publication.

Plagiarism check

Checked twice by iThenticate.

Peer review

Externally peer reviewed.

Open access statement

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

Additional file

Additional file 1: SPIRIT checklist (48.0 kb).

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