Total Joint Research Studies

• IRBPHS #4188 - Thromboprophylaxis with Low Molecular Weight Heparin (FRAGMIN®) vs. Warfarin in Patients Undergoing Primary Total Knee Replacement. A Multicenter, Prospective, Randomized, Open-Label Trial.
• IRBPHS #4457 - Zimmer LPS Flex Mobile Bearing Knee Study
• IRBPHS #4557 - DePuy Tri-Lock® Titanium vs. Cobalt Chrome Hip Study
• IRBPHS #4299 - Intraoperative Tibial Component Alignment in Total Knee Replacement
• Radiostereometric Analysis (RSA)
• Loosening of Total Joint Replacements

IRBPHS #4188 Thromboprophylaxis with Low Molecular Weight Heparin (FRAGMIN®) vs. Warfarin in Patients Undergoing Primary Total Knee Replacement. A Multicenter, Prospective, Randomized, Open-Label Trial.

Principal Investigator:
David C. Ayers, M.D.

Co-Investigators:
Timothy A. Damron, M.D.
Kenneth Mann, Ph.D.
David G. Murray, M.D.

FRAGMIN®(dalteparin sodium) is a low molecular weight heparin (LMWH) with antithrombotic properties. It was first marketed in Germany in 1985 and subsequently has been introduced for marketing in more than 50 additional countries. FRAGMIN® has been approved for marketing in the United States for thromboprophylaxis in patients undergoing abdominal surgery and at high risk for developing venous thromboembolism (VTE); for thromboprophylaxis of VTE following hip replacement surgery, and for the treatment of unstable angina and non-Q wave myocardial infarction.

Worldwide approved indications include thromboprophylaxis in patients undergoing major surgery, including total hip replacement (THR) and total knee replacement (TKR) surgery, treatment of acute deep venous thrombosis, thromboprophylaxis, and anticoagulant use in patients undergoing hemodialysis/hemofiltration, and treatment of unstable coronary artery disease, i.e., unstable angina pectoris, and non-Q wave myocardial infarction. Considering the use of different presentation forms for different indications, approximately 36 million patients have been treated with FRAGMIN®. Total knee replacement is an effective surgical procedure designed to restore functional recovery of the knee. In the United States 209,000 total knee arthroplasties were performed in 1994. In many areas, TKR is surpassing THR to become the most commonly performed orthopedic joint replacement. Deep venous thrombosis (DVT) is the most common postoperative complication of TKR, and the most common cause of hospital readmission. In the absence of thromboprophylaxis, TKR is associated with a 60 to 70 percent prevalence of lower extremity DVT. According to the ACCP Fifth Consensus Conference Guidelines, it is recommended that patients undergoing elective TKR surgery receive LMWH, warfarin or intermittent pneumatic compression (IPC) as thromboprophylaxis. Prophylaxis with a LMWH or warfarin 10 days is recommended.

The objective of this study is to demonstrate that FRAGMIN® is more efficacious than warfarin in preventing verified venous thromboembolism (VTE) in patients undergoing elective unilateral knee replacement by comparing the incidence of verified VTE (DVT and/or symptomatic PE) within 10 ±3 days postoperatively. Safety variables as well as incidence of proximal DVT will be evaluated as secondary objectives. Based on worldwide experience in other indications, FRAGMIN® should be efficacious as thromboprophylaxis in TKR. There is a definite medical need because patients undergoing TKR have the highest incidence of DVT when not treated prophylactically.

SPECIFIC AIMS

To compare FRAGMIN® to warfarin (test for superiority) in preventing VTE (DVT and/or symptomatic PE) within 10 +3 days following elective unilateral primary knee replacement surgery. The secondary objectives are to further evaluate efficacy and to study safety.

Inclusion Criteria

1. Scheduled to undergo elective unilateral primary knee replacement surgery within two weeks after initial screening.
2. Signed informed consent obtained from patient or patient's representative.

Exclusion Criteria

1. Serum creatinine > 200 umol/L or 1.7 mg/dL.
2. Known defective hemostasis, e.g., thrombocytopenia (platelet count <100 x 109/l).
3. ongoing use or previous use of anticoagulant drugs within 7 days of surgery.
4. severe hepatic failure.
5. documented gastrointestinal bleeding; injuries to and operation on the cns, eyes, ears or intracranial
6. contraindication or known hypersensitivity to heparin (including lmwh),contrast media or warfarin.
7. pregnancy or lactation.
8. untreated or unresponsive severe hypertension (i.e., diastolic bp>120 mmHg).
9. Scheduled use of IPC stockings or other mechanical compression devices.
10. Weight <90 lbs (40 kg).
11. previous participation in this study.
12. use of an investigational drug within 30 days of initiating treatment in this study or current participation in another investigation that would prevent completion of the venogram and follow-up.
13. inability of patient, family member or visiting nurse to perform daily subcutaneous injections as needed post-discharge from hospital until day of venography.
14. other medical condition that prevents the patient from completing study procedures.

irbphs #4457 zimmer lps flex mobile bearing knee study

Principal Investigator: David C. Ayers, M.D.

The LPS-Flex Mobile Bearing Knee is a meniscal bearing total knee replacement device designed to accommodate posterior cruciate ligament resection. It is a significant risk device as defined by the Investigational Device Exemption (IDE) regulation, Part 812, of the Code of Federal Regulations, Food and Drug Administration (FDA) and requires an IDE Clinical Study and PMA for marketing clearance.

Objectives of this study are to evaluate the safety and efficacy of the LPS-Flex Mobile Bearing Knee implanted with the full range of surgical techniques for which it has been designed. The safety of the LPS-Flex Mobile Bearing Knee will be evaluated by monitoring study patients for the occurrence of significant device-related reactions, complications and adverse events.

The trial is an open multicenter study with a randomized concurrent control group provided by using the NexGen LPS-Flex Fixed Bearing Knee. 204 osteoarthritis cases are planned to be enrolled per study arm (control and investigational device) from up to 15 centers into the LPS-Flex Mobile Bearing Knee test group for the primary analysis of safety and efficacy. Each site will enroll approximately 40 patients with a maximum of 60 patients per site. Enrollment period may be 12 months or longer to assure an adequate number of cases at each site.

Data on pain, function, deformity, radiographic parameters and complications will be tracked on all investigational devices. Follow-up examinations will be made at 6 weeks, 6 months, 12 months and 24 months after surgery to include both functional and radiographic evaluations. At two-year intervals thereafter, patients will be evaluated until the last patient enrolled has completed a two-year follow-up evaluation.

Inclusion Criteria:

1. Patients must be between 21 and 80 years of age.
2. Both males and females are included with no selection on gender.
3. Patients must weigh less than 250 pounds at the time of enrollment with a thigh/calf index of > 90.
4. Based on physical exam and history, candidates will include those suffering from severe knee pain and disability due to degenerative joint disease including: osteoarthritis, rheumatoid arthritis, primary and secondary traumatic arthritis, polyarthritis, collagen disorders, avascular necrosis of the femoral condyle or pseudogout, posttraumatic arthritis and varus/valgus/flexion deformities.
5. Knee Society and function scores of < 60.
6. Knee flexion > 90 degrees.
7. Patient exhibits preoperative radiographic evidence of joint degeneration consistent with TKA, including but not limited to decreased joint space, presence of osteophytes and/or other significant radiographic evidence of arthritic degeneration that cannot be treated in a non-operative fashion.
8. Patient is willing and able to cooperative in follow-up therapy.
9. Patient is in stable health based upon physical exam and medical history.

Exclusion Criteria:

1. Previous history of infection in the affected joint.
2. Previously failed knee endoprosthesis of any kind.
3. Contralateral knee implant in place.
4. Scheduled for bilateral knee replacement under the same anesthetic.
5. Charcot joint disease or other severe neurosensory deficits.
6. Previous patellectomy of the index knee.
7. Skeletal immaturity.
8. Grossly insufficient femoral or tibial bone stock (i.e. due to osteoporosis, metabolic bone disease, congenital anomaly or previous surgery to the index joint that could affect outcome, including but not limited to high tibial osteotomy or a patient requiring bone grafting).
9. Patients with loss of musculature or absence of musculoligamentous supporting structures required for appropriate soft tissue balance.
10. Pregnancy.
11. Varus or valgus deformity > 20 degrees.
12. Fixed flexion deformity > 15 degrees.
13. Knee flexion < 90 degrees.
14. Previous high tibial osteotomy.
15. Previous femoral osteotomy.
16. Poor compliance risk (i.e. history of ETOH or drug abuse or mental handicap that would compromise compliance with respect to rehabilitation or follow-up.

The statistical analysis has two major objectives: To evaluate both the efficacy and safety of the LPS-Flex Mobile Bearing Knee prosthesis in comparison to alternative treatment. For these purposes, we will evaluate failure and complication rates as well as several radiographic, symptom, functional and physical measurements.

IRBPHS #4557 DePuy Tri-Lock® Titanium vs. Cobalt Chrome Hip Study

Principal Investigator: David C. Ayers, M.D.

The cobalt chrome version of the Tri-Lock® femoral hip stem is a collarless hip implant proximally coated with Porocoat® Porous Coating. The titanium version of the Tri-Lock® hip stem is similar in design to the cobalt chrome version of this implant with only slight modifications made to compensate for the differences in strength in the materials. Both versions of the implant are cleared for general orthopedic use by the Food and Drug Administration (FDA). The use of the implant as required by the protocol is consistent with the labeling indications approved by the FDA.

Objectives of this study are to compare prospectively, in a randomized fashion, the clinical, functional and radiographic results of titanium and cobalt chrome Tri-Lock® cementless total hip arthroplasties. The study will focus particularly on assessment of thigh pain and radiographic observation of proximal fixation.

The trial a multi-center, prospective, randomized study in which 400 patients who meet all inclusion/exclusion criteria will be enrolled. There will be 10 investigational sites performing 40 surgeries each. Patients will be randomized into one of the two groups, resulting in 200 patients being allocated to each treatment group: Group A will represent the patients receiving titanium Tri-Lock® implants and Group B will receive the cobalt chrome version.

Inclusion Criteria:

1. Primary total hip replacement for non-inflammatory degenerative joint disease: osteoarthritis, post-traumatic arthritis without indwelling metal, core decompression shelf without indwelling metal, acute femoral neck fracture, Legg-Perthes disease or avascular necrosis of the femoral head.
2. Rheumatoid arthritis.
3. Radiographic evidence of sufficient sound bone stock to seat and support the prosthesis.
4. Signed Release of Medical Records form.

Exclusion Criteria:

1. Renal transplant.
2. History of active joint sepsis.
3. Recent systemic high dose of corticosteroids.
4. Primary or secondary carcinoma in last 5 years (prior to enrollment into study), excluding skin cancer.
5. Neurological disease (e.g. Parkinson's disease).
6. Psychosocial disorders that would limit rehabilitation.
7. Use of bone graft.
8. Disorders of other joints in either leg that could impair rehabilitation,
9. function or community ambulation.

With regard to randomization, the block size was chosen to facilitate equal enrollment in each group after 10 cases have been enrolled at each of the 10 sites; this is the point at which the sample size will be statistically calculated.

A 2-tailed Student's t-test will be utilized to detect a statistically significant difference between the 2 stem types using mean Dalhousie thigh pain score as the outcome. The same test will be utilized in measuring the other continuous outcomes of interest. Non-parametric test procedures may be used to verify the parametric test results. Categorical outcomes will be subjected to either Chi-Square analysis or Fisher's Exact Test.

IRBPHS #4299 Intraoperative Tibial Component Alignment in Total Knee Replacement

Principal Investigator: David C. Ayers, M.D.
Co-Investigators: Frederick W. Werner, MME and Kenneth A. Mann, PhD.

Over 150,000 patients undergo total knee replacement surgery annually in the United States. Successful function of the implant components is dependent upon accurate reconstruction of the mechanical axis of the lower extremity. Malposition of the prosthetic components may result in component loosening, severe wear of the articulating surfaces, and, ultimately, revision surgery. Intraoperative techniques are needed to assess the position of the implant prior to final implantation into the bony canals. One indicator of whether an implant is properly aligned could be how evenly the loading is balanced between the medial and lateral sides of the knee implant.

We propose to demonstrate that intraoperative contact pressure measurements between the articulating surfaces of a knee implant can detect implant malalignment. We are proposing a technique that will measure these pressures and will aid in correcting implant malalignment intraoperatively.

There are two specific aims for this project. First, a methodology will be developed to measure in real time total knee joint articulating contact pressures. The method has been validated in a series of cadaver knees, using a total knee implant correctly positioned in each knee and subsequently malaligned into valgus and varus positions. Second, this methodology will be applied to a series of subjects undergoing total knee replacement to determine its efficacy in detecting malalignment, to determine its usefulness, and to document the intraoperative pressure distribution on the tibial inserts for each patient.

The first phase of the project has been completed and we have determined the optimum geometry of the required sensor. Using a small sensor that only partly covered the knee joint, we demonstrated in a series of six cadaver knees that uneven loading of the tibial component of the knee implant can occur even when the implant has presumably been surgically implanted correctly. Changing the tibial component valgus or varus angulation in the cadaver knees by 3 degrees greatly increased the peak pressures and unbalanced the loading in the joint. We and others are concerned about poor positioning of the implants since many researchers have shown the adverse effects of uneven loading in the knee. It leads to implant loosening and causes increased wear of the articulating surfaces.

During the clinical phase of this project, the new sensor will be used in a series of 50 patients undergoing total knee joint replacement. This is the same pressure sensor utilized in this study over the past 5 years, although protype inserts available now allow us to use a variety of thicknesses with having the sensor the same depth beneath the condylar surface. During the patient's surgery, after the initial components are put in place, the pressure sensor will be inserted between two halves of the trial tibial insert. Forces that are typically used in surgery to determine the implant laxity and allowed motion will be applied. They include valgus, varus, and compressive forces. A passive range of motion will be made. Real time pressure mapping will be performed to determine how evenly the force is transmitted from the femoral component to the tibial component during the motion and during each applied force. The real time display will allow the surgeon to visually monitor the pressure distribution between the components.

The pressure sensor is being used for research purposes only and all data collected is considered basic science information. No changes will be made to the actual surgical procedure (bone cuts). The tool will not be used for surgical correction in this study.

A database correlating clinical results with pressure patterns will be developed. The pressure pattern parameters to be studied include the peak pressure, the centroid of pressure, and the resultant force in each condyle. The clinical parameters to be recorded include the functional range of motion and those measured by the Knee Society Scoring System including an objective evaluation of the patient, a numerical rating of the radiographic findings, and a numerical score for the patient's functional assessment.

There are several questions that can be answered during the clinical phase. First, will this technology prove to be an aid to the surgeon in detecting malalignment in the operating room? Second, will those patients having a more balanced loading of their knee implant have fewer complications (loosening, wear, etc.)? Statistical analysis of each patient's pressure patterns and preliminary clinical correlations with pressure patterns will be performed using a multi-variate linear regression analysis method.

Subjects who are undergoing total knee joint replacement will be recruited to participate in this study. These will be patients who are already scheduled for surgery with Dr. Ayers. A total of 50 patients will be recruited. No subjects under the age of 18 will be included. No restrictions on sex or type of subject will be made. Both women and minorities are eligible for inclusion in this study.

Inclusion Criteria:

1. Patients scheduled for elective, primary, unilateral total joint arthroplasty of the knee.
   
2. Age 18 years or older.
3. Male or female.
4. Patients must read and sign the informed consent document after the nature of the study has been fully explained.

Subjects will be enrolled in this study for a period of five (5) years. All subjects will be required to return for follow-up appointments annually for five (5) years. At these annual appointments, x-rays and assessment of the knee implant will be performed. Although these x-rays and assessments are part of the study, an annual x-ray and assessment of the knee implant are standard of care on all patients.

Loosening of Total Joint Replacements

(Inv. Mann, Ayers): Aseptic loosening continues to be the leading cause of total joint replacement failure. We are using a combination of experimental and computational techniques to investigate how loosening occurs and develop designs and surgical procedures to minimize the risk of loosening. (Funded by the National Institutes of Health.)

Radiostereometric Analysis (RSA)

(Inv: Ayers, Werner, Mann): RSA provides an accurate method to study the in vivo motion between implants and bones (or between bones). RSA resolution (30 mm) is much greater than plain x-ray film and can be used to predict long-term outcome of total joint replacements, fusion rates, etc. This is a new clinical and basic science research tool-one of few in the country. The method of RSA has earlier been called Roentgen Stereophotogrammetric Analysis. Other names are radiostereometry or stereoradiography. Radiostereometry is the science of obtaining accurate three-dimensional measurements from radiographs. Radiostereometric analysis includes several steps:

1. Insertion of radio-opaque markers.
2. Radiographic examination.
3. Scanning of radiographs.
4. Marking of radiographs.
5. Measurements on radiographs.
6. Computation of the three-dimensional position of each marker.
7. Computation of movements occurring between one or several examinations.

Each step is dependent on correct handling of equipment especially designed for the RSA procedure, indicating that errors in any of the steps presented above may contribute to poor accuracy or useless data. In many instances, the error can be corrected during the evaluation if it does not originate in steps 1 or 2. Marking and measurement errors are the most common ones when manual marking and measurement are used. The introduction of the digitized technique has substantially reduced this problem.

The method of RSA was originally designed for research. It is applicable when you are interested in accurate measurements of skeletal or implant movements, and especially when it is considered to be of interest to measure these movements in three dimensions. RSA can and has been used to measure soft tissue motions and it can be used for anatomical measurements.