CONSERVE PLUS TOTAL RESURFACING HIP SYSTEM

P030042 · Microport Orthopedics, Inc. · NXT · Nov 3, 2009 · Orthopedic

Device Facts

• Record ID: P030042
• Device Name: CONSERVE PLUS TOTAL RESURFACING HIP SYSTEM
• Applicant: Microport Orthopedics, Inc.
• Product Code: NXT · Orthopedic
• Decision Date: Nov 3, 2009
• Decision: APWD
• Device Class: Class 3
• Attributes: Therapeutic, Expedited Review

Intended Use

The CONSERVE® Plus Total Resurfacing Hip System is a single use device intended for hybrid fixation utilizing: cemented femoral head component and cementless acetabular component. The CONSERVE® Plus Total Resurfacing Hip System is intended for use in resurfacing hip arthroplasty for reduction or relief of pain and/or improved hip function in skeletally mature patients having the following conditions: - Non-inflammatory arthritis (degenerative joint disease) such as osteoarthritis, traumatic arthritis, avascular necrosis, or dysplasia/developmental dislocation of the hip (DDH), or - Inflammatory arthritis such as rheumatoid arthritis. The CONSERVE® Plus Total Resurfacing Hip System is intended for patients who, due to their relatively younger age or increased activity level, may not be suitable for traditional total hip arthroplasty due to an increased possibility of requiring future ipsilateral hip joint revision.

Device Story

Metal-on-metal hip resurfacing system; consists of cemented femoral head component and cementless, press-fit acetabular shell. Used in hip arthroplasty to reduce pain and improve function; preserves femoral bone stock compared to traditional total hip arthroplasty. Implanted by orthopedic surgeons in clinical settings. Femoral component features tapered stem geometry; acetabular shell features porous coating. Output is a restored hip joint articulation. Clinical benefit includes bone preservation and reduced risk of future revision in younger, active patients. Potential adverse effects include femoral neck fracture, loosening, dislocation, infection, and metal ion release.

Clinical Evidence

Prospective, multi-center, historically controlled IDE study (G990328) comparing CONSERVE® Plus to TRANSCEND® Ceramic and Metal THR systems. Primary endpoint: Composite Clinical Success (CCS) at 24+ months. Results demonstrated non-inferiority to controls. 2-year survival rates: 0.956 (CONSERVE® Plus), 0.980 (Ceramic), 0.970 (Metal). Complication rates were statistically higher for CONSERVE® Plus vs. Ceramic control (p=0.026) but not vs. Metal control (p=0.79). Risk factors for revision identified: female gender, small femoral component, surgeon learning curve, AVN/traumatic arthritis diagnosis, previous hip treatment, multiple femoral cysts, and acetabular malpositioning.

Technological Characteristics

Materials: Cast Cobalt Chrome Alloy (ASTM F75) for femoral and acetabular components; Cobalt Chrome sintered beads (ASTM F1377) for porous coating. Femoral component: 36-54mm diameter, tapered stem. Acetabular shell: 46-64mm OD, porous coated. Fixation: Cemented femoral, cementless acetabular. Sterilization: Gamma irradiation. No software/algorithm.

Indications for Use

Indicated for skeletally mature patients with non-inflammatory arthritis (osteoarthritis, traumatic arthritis, avascular necrosis, DDH) or inflammatory arthritis (rheumatoid arthritis) requiring hip resurfacing for pain relief or improved function, particularly younger or active patients unsuitable for traditional total hip arthroplasty. Contraindicated in patients with active/suspected infection, skeletal immaturity, inadequate bone stock (severe osteopenia, large femoral cysts >1cm, AVN >50% femoral head), vascular/neuromuscular disease, pregnancy, renal insufficiency, immunosuppression, obesity (BMI >35), or metal sensitivity.

Regulatory Classification

Identification

Prosthesis, hip, semi-constrained, metal/metal, resurfacing device relieves hip pain and improves hip function by replacing the parts of the hip that have been severely damaged by degenerative joint diseases. This device is indicated for patients with degenerative joint diseases including osteoarthritis, rheumatoid arthritis, traumatic arthritis, dysplasia, or avascular necrosis and for patients who, due to their relatively younger age or increased activity level, may not be suitable for traditional total hip replacement due to an increased possibility of requiring future hip joint revision.

Reference Devices

• TRANSCEND® Ceramic Total Hip Arthroplasty System
• TRANSCEND® Metal Total Hip Arthroplasty System

Submission Summary (Full Text)

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SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

I. GENERAL INFORMATION

Device Generic Name: Prosthesis, Hip, Semi-constrained, Resurfacing Metal/Metal hybrid fixation

Device Trade Name: CONSERVE® Plus Total Resurfacing Hip System

Applicant's Name and Address: Wright Medical Technology, Inc. 5677 Airline Road Arlington, TN 38002

Date of Panel Recommendation: None

Premarket Approval Application (PMA) Number: P030042

Date of FDA Notice of Approval: November 3, 2009

Expedited: Granted expedited review status on March 30, 2004 because total hip systems with a resurfacing femoral component and a metal-on-metal articulation may offer advantages in safety and effectiveness over existing alternatives; such as, the preservation of femoral bone stock during implantation as compared to metal-on-metal total hip systems and a decrease in adverse tissue reaction due to particulate wear debris as compared to metal-on-polyethylene resurfacing hip systems.

II. INDICATIONS FOR USE

The CONSERVE® Plus Total Resurfacing Hip System is a single use device intended for hybrid fixation utilizing: cemented femoral head component and cementless acetabular component. The CONSERVE® Plus Total Resurfacing Hip System is intended for use in resurfacing hip arthroplasty for reduction or relief of pain and/or improved hip function in skeletally mature patients having the following conditions:

- Non-inflammatory arthritis (degenerative joint disease) such as osteoarthritis, traumatic arthritis, avascular necrosis, or dysplasia/developmental dislocation of the hip (DDH), or
- Inflammatory arthritis such as rheumatoid arthritis.

The CONSERVE® Plus Total Resurfacing Hip System is intended for patients who, due to their relatively younger age or increased activity level, may not be suitable for traditional total hip arthroplasty due to an increased possibility of requiring future ipsilateral hip joint revision.

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# III. CONTRAINDICATIONS

The CONSERVE® Plus Total Resurfacing Hip System should not be implanted in patients with the following conditions:

- Patients with active or suspected infection in or around the hip joint.
- Patients who are skeletally immature.
- Patients with bone stock inadequate to support the device including:
- Patients with severe osteopenia should not receive the CONSERVE® Plus Total Resurfacing Hip procedure. Patients with a family history of severe osteoporosis or severe osteopenia;
- Patients with osteonecrosis or avascular necrosis (AVN) with >50% involvement of the femoral head (regardless of FICAT Grade) should not receive a CONSERVE® Plus Total Resurfacing Hip System device; or
- Patients with multiple cysts of the femoral head (>1cm) should not receive a CONSERVE® Plus Total Resurfacing Hip System device.

NOTE: In cases of questionable bone stock, a Dual-Energy X-ray Absorptiometry (DEXA) scan may be necessary to assess inadequate bone stock.

- Patients with any vascular insufficiency, muscular atrophy, or neuromuscular disease severe enough to compromise implant stability or postoperative recovery.
- Females of child-bearing age due to unknown effects of metal ion release on the fetus.
- Patients with known moderate to severe renal insufficiency.
- Patients who are immunosuppressed with diseases such as AIDS or persons receiving high doses of corticosteroids.
- Patients who are obese and/or with a BMI>35.
- Patients with known or suspected metal sensitivity (e.g., jewelry).

# IV. WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the CONSERVE® Plus Total Resurfacing Hip System labeling.

# V. DEVICE DESCRIPTION

The CONSERVE® Plus Total Resurfacing Hip System is a metal-on-metal hip resurfacing system. The system is composed of a stemmed resurfacing femoral component for cemented fixation; and a one-piece acetabular shell for cementless, press-fit fixation. The device is a “resurfacing” hip system because only the surface of the femoral head is removed to implant the femoral component.


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The design features of the CONSERVE® Plus Resurfacing Femoral Component are as follows:

- Manufactured from Cast Cobalt Chrome Alloy conforming to ASTM F75¹.
- Offered in a range of outer diameters from 36mm to 54mm in 2mm increments.
- The articulating surface of the implants is superfinished to insure form tolerance and a fine surface finish.
- The undersurface of the femoral component has a “glass-bead” blasted surface finish (125 Ra Max) and contains a shallow circumferential undercut band at the head’s equator.
- A tapered stem geometry.

The design features of the CONSERVE® Plus Acetabular Shells are summarized below:

- Manufactured from Cast Cobalt Chrome Alloy conforming to ASTM F75.
- Porous coated with Cobalt Chrome Alloy sintered beads conforming to ASTM F1377.
- The articulating surface of the implants is superfinished to insure form tolerance and a fine surface finish.
- Available Sizes: 36mm ID/46mm OD to 54mm ID/64mm OD in 2mm increments.

## Sizing and System Compatibility

The correct selection of the prosthesis is extremely important. The potential for success in total hip resurfacing arthroplasty is increased by selection of the proper size of the prosthesis. Total hip resurfacing prostheses require careful seating and adequate bone support.

The femoral heads are compatible with the following acetabular components:

| CONSERVE® Plus Total Resurfacing Hip System Sizing and System Compatibility | |
| --- | --- |
| Femoral Component (Nominal Outer Diameter) | Acetabular Component (Nominal Inner Diameter/ Nominal Outer Diameter of shell) |
| 36mm | 36mm ID/ 46mm OD |
| 38mm | 38mm ID/ 48mm OD |
| 40mm | 40mm ID/ 50mm OD |
| 42mm | 42mm ID/ 52mm OD |
| 44mm | 44mm ID/ 54mm OD |
| 46mm | 46mm ID/ 56mm OD |
| 48mm | 48mm ID/ 58mm OD |
| 50mm | 50mm ID/ 60mm OD |
| 52mm | 52mm ID/ 62mm OD |
| 54mm | 54mm ID/ 64mm OD |

## VI. ALTERNATIVE PRACTICES AND PROCEDURES

There are several other alternatives for the reduction or relief of pain and/or improved hip function including:

- Non-surgical treatment (e.g., reduced activity, medications, physical therapy) or no treatment at all;
- Other commercially available total hip replacement devices. Commonly used implant bearing materials for total hip arthroplasty include metal on ultra-high molecular weight polyethylene (UHMWPE), ceramic on UHMWPE, metal on metal, and ceramic on ceramic. Total hip replacement devices are implanted by either cemented or uncemented techniques;

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- Other commercially available total hip resurfacing devices, which consist of metal on metal bearings;
- Rotational osteotomy; and
- Hip fusion.

Each alternative has its own advantages and disadvantages. A patient should fully discuss these alternatives with his/her physician to select the method that best meets expectations and lifestyle.

## VII. MARKETING HISTORY

The CONSERVE® Plus Total Resurfacing Hip System has been marketed in the European Union since 2001. It has also been distributed in the countries listed below. The CONSERVE® Plus Total Resurfacing Hip System has not been withdrawn from marketing for any reason relating to the safety and effectiveness of the device.

| Worldwide Marketing History | |
| --- | --- |
| Argentina | Jamaica |
| Australia | Japan |
| Brazil | Russia |
| Canada | South Africa |
| Chile | South Korea |
| China | Taiwan |
| Colombia | Turkey |
| Egypt | United Arab Emirates |

## VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH

Below is a list of the potential adverse effects (e.g., complications) associated with the use of the device.

### Reported Device Related Adverse Effects

The most commonly reported adverse events related to the CONSERVE® Plus Total Resurfacing Hip System device are:

- Femoral neck fracture,
- Component migration/loosening,
- Femoral subsidence,
- Dislocation,
- Infection,
- Impingement, and
- Trochanteric fracture.

For the specific adverse events that occurred in the clinical studies, please see the Summary of Clinical Study section (Section X) below.

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# Potential Adverse Effects

The following adverse effects may occur in association with hip replacement surgery, including the CONSERVE® Plus Total Resurfacing Hip System:

- Device failure because the components cannot be expected to indefinitely withstand the activity level and loads of normal healthy bone.
- Surgical complications including, but not limited to: genitourinary disorders; gastrointestinal disorders; vascular disorders, including thrombus; bronchopulmonary disorders, including emboli; myocardial infarction or death.
- Sudden, pronounced, intraoperative blood pressure decrease due to the use of bone cement.
- Hematoma or damage to blood vessels resulting in large blood loss.
- Delayed wound healing.
- Superficial or deep infection. Infections may occur months to years after surgery. These infections are difficult to treat and may require reoperation with removal surgery and replacement at a later time.
- Temporary or permanent nerve damage resulting in pain or numbness of the affected limb.
- Metal sensitivity reactions, allergic reactions, or metallosis.
- Dislocation and subluxation leading to postoperative joint instability (which may be caused by malpositioning of the implants or muscle / fibrous tissue laxity).
- Loosening of hip resurfacing components can occur. Early mechanical loosening may result from inadequate initial fixation, malalignment, latent infection, premature loading of the prosthesis, or trauma. Late loosening may result from trauma, infection, biological complications (including osteolysis), or mechanical problems, with the subsequent possibility of bone erosion and/or pain.
- Limb length discrepancy.
- Device related noise such as, clicking, popping, squeaking or grinding.
- Increased hip pain and/or reduced hip function.
- Fatigue fracture of the implants as a result of excessive loading, malalignment, or trauma.
- Osteolysis and/or other peri-prosthetic bone loss.
- Bone perforation or fracture (occurring either intra-operatively or occurring post-operatively as a result of trauma, excessive loading, osteolysis or osteoporosis).
- Periarticular calcification or ossification.
- Wear and deformation of the articular surface (as a result of excessive loading or implant malalignment).
- Pseudotumor.
- Aseptic Lymphocyte Dominated Vasculitis Associated Lesion (ALVAL).

Any of these adverse effects may require medical or surgical intervention. In rare cases, these adverse effects may lead to death. The potential long-term biological effects of metal wear debris and metal ion production are not known.

# IX. SUMMARY OF PRECLINICAL STUDIES

## Laboratory Studies

Non clinical laboratory information was provided in support of the CONSERVE® Plus Total Resurfacing Hip System including the information regarding:

- Femoral Resurfacing Component: stem static and fatigue strength;

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- Acetabular Shell: impaction and fatigue strength, surface coating parameters;
- Bearing Couple: wear, frictional torque, and range of motion; and
- Sterilization and Shelf-Life Validation

## 1. Femoral Resurfacing Component

The static and fatigue strength of the CONSERVE® Plus Total Resurfacing Hip System Femoral Component stem were evaluated.

### Femoral Stem Static and Fatigue Strength

#### Worst case

The articulating surface of the test component was fixed and a cantilever load was applied to the distal tip of the femoral stem. Therefore, the component with the longest stem (56mm) was chosen as the worst case device.

#### Acceptance Criteria

The test components should survive 5 Million Cycles of fatigue loading at 267N (approximately 50% of the static failure load).

#### Methods

The articulating surface of the femoral component was fixed and a static load was applied to the distal tip of the stem until the material yielded and plastic deformation began. The maximum static load was recorded. Six samples were then dynamically tested at 267 N (approximately 50% of the static failure load) at 10Hz to five million cycles.

#### Results

The mean static failure load was 534 N. Six samples were then dynamically tested at 267 N at 10Hz to five million cycles without failure in the same test configuration. The results of these static and dynamic tests demonstrate that the femoral stem should withstand predicted in vivo loads.

## 2. Acetabular Shell

The impaction and fatigue strength and surface coating parameters of the CONSERVE® Plus Total Resurfacing Hip System Acetabular Shells were evaluated.

### Impaction Testing

#### Worst Case Design

Impaction testing was conducted on the CONSERVE® Plus Acetabular Shell to ensure that deformation upon impaction would not significantly impact articulation and clearance between the femoral and acetabular components. For this test configuration, worst case is determined by the thinnest wall thickness.

#### Acceptance Criteria

The deformation of the CONSERVE® Plus Acetabular Shell with a 5mm wall thickness should not significantly impact articulation and clearance between the femoral and acetabular components.

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# Methods

The ultimate compressive strength of the underlying structure (cortical bone) is most critical during impaction and torque testing. ULTEM™ 1000 was chosen to simulate cortical bone because its ultimate compressive strength most closely resemble cortical bone material properties (Cortical Bone= 155-163 MPa; ULTEM™ 1000= 150 MPa).

The impaction/torque studies are more severe than any typical in-vivo condition since they assume that the entire acetabulum consists of the cortical bone. However, they can have some merit as the "absolute worst case implantation" condition. The dimensional changes identified in the impaction/torque study could affect the clearances between the femoral component and the various acetabular shell designs. The Conserve® Plus Acetabular shells were impacted into ULTEM 1000 with a 1mm press-fit, per the recommended surgical technique.

# Results

The results of this study showed that the CONSERVE® Plus shell with a 5mm wall thickness had an average change in the inner diameter of 7 +/- 4μm after impaction with a 1mm press-fit. The result of the impaction testing demonstrates that the acetabular shell deformation should not significantly affect articulation or clearance between femoral and acetabular components.

# Fatigue Strength Testing

## Worst Case Design

The worst case design option chosen for testing was a shell with a constant 3mm wall thickness. Although this shell successfully passed fatigue testing, it was not chosen as the final CONSERVE® Plus Acetabular Shell to be marketed because of its performance in other testing. However, because it was thinner than the 5mm Conserve® Plus Acetabular Shell, the fatigue testing of this component was considered a worst-case design and was used as validation for the CONSERVE® Plus Acetabular Shell to be marketed.

## Acceptance Criteria

The shells should complete 5 million cycles at a peak load of 2500N without evidence of shell fracture.

## Methods

The acetabular shells were placed in support rings that provided a 3mm band of support around the rim of the shell. An MTS 858 Bionix biaxial servohydraulic test frame was used to apply a cyclic load of 250N-2500N through the femoral head to six components to represent typical compressive loading in the hip. The components were tested for 5 million cycles at 30 Hz.

## Results

All six components completed 5 million cycles of loading without any evidence of shell fractures. The result of the dynamic fatigue test demonstrates that the acetabular shell deformation should withstand predicted in vivo loads.

# Surface Coating Characterization

## Worst Case Design

The CONSERVE® Plus Acetabular Shells are coated with Cobalt Chrome sintered beads.

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## Acceptance Criteria

The criteria for porous-coated components are described in FDA’s Guidance Document for Testing Orthopedic Implants with Modified Metallic Surfaces Apposing Bone or Bone Cement², dated April 28, 1994.

## Methods

The porous coating was characterized with regard to coating thickness, bead morphology, pore size, porosity, and bond strength characteristics.

## Results

The results of the porous coating characterization are summarized in Table A below. The results demonstrate that the Conserve® Plus Acetabular Shell coating thickness, pore size, porosity, and structure (interconnecting porosity) meet the definition of a porous-coating.

### Table A: Porous Coating Characterization

| Mean Coating Thickness | 0.854 mm |
| --- | --- |
| Bead Shape | Spherical Powder |
| Average Bead Size | 0.278 mm |
| Mean Pore Size | 145 μm |
| Mean Volume Percent Porosity | 34.20% |
| Mean Shear Strength | 5819 psi |
| Mean Tensile Pull-off Strength | 7808 psi |

## 3. Bearing Couple

The wear rate, frictional torque, and range of motion of the CONSERVE® Plus Total Resurfacing Hip System were evaluated.

### Wear Testing

#### Worst Case Design

The 54mm bearing size is expected to be the worst case component tested. A mid-range size (44mm) was also tested.

#### Acceptance Criteria

The amount of wear was compared to results reported in the published literature for other total hip replacement bearings.

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# Methods

Twelve (12) 44mm bearings and four (4) 54mm bearings were tested for 5 million cycles in Shore Western Hip Simulators using bovine serum as the lubricant. The test was interrupted at regular intervals throughout the process for gravimetric assessment of the bearing wear. The gravimetric wear data was then converted into volumetric wear data that is shown in Table B.

# Results

Results of the wear tests referenced above are summarized in Table B below.

Table B: CONSERVE® Plus Wear Rates

| | Run-in wear rate @ 0.5 million cycles* (mm³/million cycles) | Run-in wear rate @ 2 million cycles* (mm³/million cycles) | Steady-state wear rate (mm³/million cycles) | Total wear, 5 million cycles (mm³)** |
| --- | --- | --- | --- | --- |
| 44mm Bearing Couple, 5mm wall | 2.462 | --- | 0.084 | 1.610 |
| 54mm Bearing Couple, 3 mm wall | --- | .956 | .145 | 2.345 |

Notes:
*The run-in wear period for the 44mm testing was 0.5 million cycles while the run-in period for the 54 mm testing was 2 million cycles.
**The total wear for 5 million cycles is calculated by the following equation: (run-in wear rate) x (run-in wear period) + (steady-state wear rate) x (steady-state wear period) = total wear.
For the 44mm couple, total wear was $(2.462 \times 0.5) + (0.084 \times 4.5) = 1.610$
For the 54 mm couple, total wear was $(0.956 \times 2.0) + (0.145 \times 3.0) = 2.345$

Both the 44mm and 54mm CONSERVE® Plus Total Resurfacing Hip System couples showed wear rates that are similar to results reported in published literature for other total hip replacement bearings.

# Frictional Torque Testing

## Worst Case Design

Since torque is proportional to head size, the 54mm bearing size is considered to be the worst case components tested.

## Acceptance Criteria

The torque generated by the bearing couple was compared to the results reported in the published literature for other total hip replacement bearings.

## Methods

Evaluated the frictional torque generated by 6 CONSERVE® Plus 54mm bearing size Couples. The frictional torque was recorded for each bearing couple in flexion-extension and internal-external rotation under a joint load of 2300N, using an MTS Bionix 858 test system.

## Results

Results of the frictional torque tests referenced above are summarized in Table C below.

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Table C: Average Frictional Torque After Simulated Impaction

| Bearing Description | Flexion-Extension Frictional Torque (N-m) | Internal-External Rotation Frictional Torque (N-m) |
| --- | --- | --- |
| CONSERVE® Plus Bearing Couple (5mm thick shell) | 6.21 | 1.79 |

All measured frictional torque values for the CONSERVE® Plus Total Resurfacing Hip System similar to results reported in the published literature for other total hip replacement bearings.

## Range of Motion

### Worst Case Design

A cylindrical “femoral neck” was utilized to detect impingement between the acetabular cup and femoral neck of a 56mm CONSERVE® Plus Femoral Resurfacing Component. Although the largest femoral resurfacing component available is 54mm, a 56mm component was used and results in a worst case range of motion as compared to the 54mm component. A cylindrical “femoral neck” was used as it results in the smallest angle of articulation.

### Acceptance Criteria

As outlined in ISO 21535 “Specific Requirements for Hip-joint Replacement Implants”³ the minimum allowable angle of flexion/extension is 80°, abduction/adduction is 60° and internal/external rotation is 90°.

### Method

Range of motion was evaluated using CAD models following a procedure that is based on that which is outlined in ISO 21535. The test protocol was modified to consider the bone conserving nature of hip resurfacing by adding a cylindrical femoral neck to simulate the worst case amount of bone possible. Range of Motion was determined by identifying the angle at which impingement occurs in the CAD models.

### Results

The worst case flexion/extension and abduction/adduction angle at which impingement occurred was 80°. The worst case internal/external degree of rotation at which impingement occurred was 128°. These values meet the minimum requirements specified in ISO 21535.

## 4. Sterilization and Shelf-Life Validation

Femoral head and acetabular components of the CONSERVE® Plus Total Resurfacing Hip System are sterilized by gamma irradiation. The sterilization process has been validated to achieve a sterility assurance level of 10⁻⁶ at a minimum dose of 25kGy in compliance with the requirements of ISO 11137 “Sterilization of health care products – Requirements for validation and routine control – Radiation sterilization.”⁴ The product is not labeled "pyrogen free". The components are packaged in

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Tyvek® and thermoformed trays to maintain sterility. Shelf life testing was performed to verify sterile packaging integrity equivalent to eight years.

## 5. Biocompatibility

Because the device is comprised of well-accepted materials for permanent implant (i.e., materials conforming to ASTM F75¹ and F1377⁵), additional biocompatibility testing was not required.

## Laboratory Studies Conclusion

CDRH determined that the preclinical mechanical bench testing provides a reasonable assurance of device safety.

## X. SUMMARY OF PRIMARY CLINICAL STUDY

The applicant performed a clinical study to establish a reasonable assurance of safety and effectiveness of total resurfacing arthroplasty with the CONSERVE® Plus Total Resurfacing Hip System for the above stated indications for use in the US under IDE # G990328. Data from this clinical study were the basis for the PMA approval decision. A summary of the clinical study is presented below.

### A. Purpose of the Investigation

The purpose of this investigation was to test the hypothesis that the CONSERVE® Plus Total Resurfacing Hip System is as safe and effective as conventional total hip arthroplasty. The CONSERVE® Plus Total Resurfacing Hip System (CONSERVE® Plus) was the investigational treatment and the TRANSCEND® Ceramic Total Hip Arthroplasty System (TRANSCEND® Ceramic) and the TRANSCEND® Metal Total Hip Arthroplasty System (TRANSCEND® Metal) served as the control groups. Safety was determined by collection of the incidence of peri-operative and post-operative complications, revisions, and device related adverse events. Effectiveness was measured via a Composite Clinical Success endpoint that included an evaluation of pain and function using the Harris Hip Score (HHS), patient self-evaluation of health related quality of life which included physical and metal-health components (SF-12), radiographic data, and survivorship as described below.

### B. Study Design

A prospective, multi-center, historically controlled Investigational Device Exemption (IDE) study was conducted using components of the CONSERVE® Plus Total Resurfacing Hip System in the United States. A priori objectives were used to demonstrate non-inferiority to historical control groups in terms of a composite clinical success (CCS) criterion, evaluated at Month 24 or later. The historical control groups were derived from the regulatory studies for the TRANSCEND® Ceramic IDE and the TRANSCEND® Metal IDE. The database for this PMA reflected third-party audited data collected through November 20, 2006.

The following table (Table 1) provides a comparison of the investigational and control group study parameters.

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Table 1: Comparisons of Investigational and Control Group Study Parameters

| Protocol Element | CONSERVE® Plus (I) | Ceramic TRANSCEND (C1) | Metal TRANSCEND (C2) |
| --- | --- | --- | --- |
| Type of Study | IDE Hip Resurfacing | IDE Total Hip Arthroplasty | IDE Total Hip Arthroplasty |
| Bearing Type | Metal on Metal | Ceramic on Ceramic | Metal on Metal |
| Study Design | Prospective, non-randomized, historical control | Prospective, non-randomized, historical control | Prospective, non-randomized, historical control |
| Number of Centers | 11 | 10 | 19 |
| Dates of First Enrollment | 29-Aug-2000 | 7-Apr-1997 | 15-Sep-1997 |
| Dates of Last Enrollment | 25-May-2006 | 12-Jun-2001 | 23-Jul-2001 |
| Number of Procedures | 1366 All Enrolled-Audited | 963 All Enrolled | 388 All Enrolled |
| | 292 Pivotal Unilateral Efficacy Cohort (Original Shell) | 341 Pivotal Unilateral Efficacy Cohort | 322 Pivotal Unilateral Efficacy Cohort |
| | 680 All Enrolled Unilateral (Original Shell) Cohort | 668 Complete Follow-up Safety Cohort | 345 Complete Follow-up Safety Cohort |
| | 203 Bilateral Cohort (Original Shell) | 255 Bilateral Cohort | 64 Bilateral Cohort |
| | | | |
| Follow-up Intervals | Preoperative | Preoperative | Preoperative |
| | Operative | Operative | Operative |
| | 6 month | 6 month | 6 month |
| | 12 month | 12 month | 12 month |
| | 24 month | 24 month | 24 month |
| | 24+ Month | 24+ Month | 24+ Month |
| Outcome Measures | Harris Hip Score | Harris Hip Score | Harris Hip Score |
| | SF-12 | SF-12 | SF-12 |
| | Radiographic Evaluation | Radiographic Evaluation | Radiographic Evaluation |
| | Adverse Event Reporting | Adverse Event Reporting | Adverse Event Reporting |

Note: For the purpose of including available data beyond the Month 24 window, a 24+ Month interval was created. The 24+ month evaluations include 24 month evaluations completed, as well as data from a later visit, if the 24 month evaluation was not available.

## 1. Study Inclusion and Exclusion Criteria

Enrollment in the study was limited to patients who met the inclusion/exclusion criteria. Table 2 lists the inclusion/exclusion criteria of the studies in which clinical data was collected for Groups I (CONSERVE® Plus), C1 (TRANSCEND® Ceramic) and C2 (TRANSCEND® Metal). If a criterion in Group I was identical to criteria in Groups C1 and/or C2, “identical criterion” is indicated. Where a criterion in a Group was not included in one or more of the other Groups “criterion not specified in protocol” is stated.

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Table 2: Inclusion / Exclusion Criteria for Studies on Groups I, C1 and C2

| Group I | Group C1 | Group C2 |
| --- | --- | --- |
| Primary hip surgery for Noninflammatory Degenerative Joint Disease (NIDJD) such as osteo/degenerative arthritis, traumatic arthritis, congenital hip dysplasia, and avascular necrosis. | Identical Criterion | Identical Criterion |
| Primary hip surgery for Inflammatory Degenerative Joint Disease (Rheumatoid arthritis) | Criterion not specified in protocol | Criterion not specified in protocol |
| Skeletally mature or at least 18 years of age. | Skeletally mature and 21 years of age or older. | Identical Criterion |
| Signs the Informed Consent form. | Identical Criterion | Identical Criterion |
| Already enrolled in the study and present with a need for revision of either or both resurfacing components. These patients may have the failed component(s) revised with an investigational(s) component. | Already enrolled into the study and present with a need for revision may have the failed component revised with an investigational component as long as all components including the shell and femoral stem are revised. Revision of ceramic components only is not allowed. | Already enrolled into the study and present with a need for revision of the metal liner/acetabular shell component or present with a need for revision of the metal head/femoral stem component may have the failed component revised with an investigational component. |
| Group I | Group C1 | Group C2 |
| --- | --- | --- |
| Previous fusion, acute femoral neck fracture and/or above knee amputation. | Criterion not specified in protocol | Criterion not specified in protocol |
| Active infection. | Identical Criterion | Identical Criterion |
| Pregnant. | Pregnant or whose pregnancy status is unknown. | Pregnant or whose pregnancy status is unknown. |
| Neurologic or musculoskeletal disease that may adversely affect gait or weight-bearing. | Identical Criterion | Identical Criterion |
| Previously undergone an ipsilateral hemi resurfacing, total resurfacing, total bipolar, unipolar or total hip replacement device. | Previously undergone a total bipolar or unipolar hip replacement device. | Previously undergone a total bipolar or unipolar hip replacement device. |
| Active hepatitis or HIV infection. | Identical Criterion | Identical Criterion |
| Prisoners. | Identical Criterion | Identical Criterion |
| Body Mass Index (BMI) of >35. | Three times normal body weight. | Three times normal body weight. |
| Neuropathic joints. | Identical Criterion | Identical Criterion |
| Severe documented psychiatric disease. | Criterion not specified in protocol | Severe documented psychiatric disease. |
| Require structural bone grafts. | Criterion not specified in protocol | Criterion not specified in protocol |
| Documented allergy to cobalt chromium molybdenum. | Criterion not specified in protocol | Criterion not specified in protocol |
| Ipsilateral girdlestone. | Criterion not specified in protocol | Criterion not specified in protocol |
| Sickle cell disease or trait | Criterion not specified in protocol | Criterion not specified in protocol |
| Significant femoral head or neck deformity or significant acetabular wall deficiency. | Criterion not specified in protocol | Criterion not specified in protocol |
| Criterion not specified in protocol | Criterion not specified in protocol | Diagnosed with osteoporosis. |
| Criterion not specified in protocol | Criterion not specified in protocol | History of malignancy. |

## 2. Follow-up Schedule

The follow-up time points and the intervals around these time points were analyzed in the same manner. Identified below are the follow-up time points and the corresponding intervals used

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within the study which are based on the number of days after the operative procedure (Table 3). For the purpose of including available data beyond the Month 24 window, when the Month 24 data was missing, a 24+ Month interval was created. The 24+ month evaluations include 24 month evaluations completed, as well as data from a later visit, if the 24 month evaluation was not available. As noted in Table 3, different intervals were used to analyze the data.

Table 3: Study Intervals

| | Actual (B)
Extended Interval
(Days) | Actual (A)
FDA Guidance Interval^{6}
(Days) |
| --- | --- | --- |
| Immediate | 1-45 | 1-56 |
| Month 6 | 46-210 | 168-196 |
| Month 12 | 211-425 | 305-425 |
| Month 24 | 426-790 | 670-790 |
| Month 24 + | Any evaluation 22+ months = 24+ | Any evaluation 22+ months = 24+ |

## 3. Clinical Endpoints

The safety of the CONSERVE® Plus Total Resurfacing Hip System was evaluated in terms of the following analyses:

- Device Revision,
- Risk Factors,
- Survivorship,
- Adverse Events, and
- Metal Ions.

Effectiveness was evaluated primarily by the Composite Clinical Success definition (immediately below). Harris Hip Score, radiographic outcome, and Health Related Quality of Life (SF-12) Scores were also evaluated as a measure of effectiveness.

With regards to success/failure criteria, a patient was defined as a success at the Month 24+ follow-up timepoint if all of the following Composite Clinical Success (CCS) Endpoints were met:

- No worse than ‘mild’ pain (Harris Hip Score item ≥ 30 points).
- Ability to walk at least ‘2 to 3 blocks’ (Harris Hip Score item ≥ 5 points).
- Ability to climb stairs ‘in any manner’ (Harris Hip Score item ≥ 1 point).
- Ability to ‘enter public transportation’ (Harris Hip Score item = yes).
- Comfortable in a high chair for at least one-half hour (Harris Hip Score item ≥ 3 points).
- Putting on shoes and socks ‘with ease’ (Harris Hip Score item = 4 points).
- An overall Harris Hip Score ≥ 80 points.
- An increase in the Harris Hip Score of at least 15 points relative to baseline.
- A value for the total SF-12 score (sum of physical component score and mental-health component score) at least as large as the pre operative value.
- Absence of complete radiolucency, which was determined by independent radiographic evaluation of four views: acetabular AP view (3 regions), acetabular lateral view (3 regions), femoral stem

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AP view (3 regions), and femoral stem lateral view (3 regions). Complete radiolucency in a view was defined to be present if there was any radiolucency of any size present in all zones comprising that view.

- Did not undergo revision, removal, or replacement of any component of the device up to that point in time.
- Did not experience a serious, device-related adverse event up to that point in time.

## C. Study Population

Clinical study data was collected on 1851 hips implanted with the CONSERVE® Plus. A subset of the data was audited and these audited 1366 procedures (1206 patients) constitute the All Enrolled Audited cohort. Of these 1366 procedures, 680 were unilateral procedures implanted with the CONSERVE® Plus resurfacing femoral component and the original acetabular shell (described in the Device Description above) and were eligible, based on date of surgery, for the 24+ Month follow-up. There were 458 procedures within the 1366 procedure cohort that also received the CONSERVE® Plus resurfacing femoral component but a different version of the acetabular shell which is not included in this Summary. These procedures are included in the 1366 procedure cohort to provide a complete description of device safety.

Table 4 describes the various cohorts assessed in this clinical study. The core data collected from these cohorts was the same.

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Table 4: Study Populations

| COHORT | SAMPLE SIZES | DEFINITION |
| --- | --- | --- |
| All Enrolled Audited | 1366 procedures
1206 patients | This cohort has dates of surgery from 8/29/00 to 11/20/06. Data includes procedures implanted with resurfacing femoral component and either the original version of the acetabular shell (described in the Device Description above) or a different version of the acetabular shell which is not included in this Summary. Cohort used to provide supporting evidence of safety. All 1366 procedures were audited by a 3^{rd} party. |
| Pivotal Unilateral Efficacy Cohort (Original Shell) | 292 procedures
292 patients | This cohort has dates of surgery from 10/17/00 to 04/08/02. Includes unilateral non-inflammatory degenerative joint disease (NIDJD) procedures. Staged bilateral patients whose 24 month evaluation occurred prior to having the contralateral hip replacement are also included. Patients enrolled in separate training arm during this time period are not included. All patients in this cohort received the original version of the acetabular shell. Used to evaluate safety and efficacy and the Composite Clinical Success (CCS) definition to determine study success. |
| All Enrolled Unilateral (Original Shell) | 680 procedures
680 patients | This cohort has dates of surgery from 8/28/00 to 01/19/06. This cohort includes all unilateral NIDJD procedures implanted after enrollment was completed for the Pivotal Unilateral Efficacy cohort; all unilateral rheumatoid arthritis procedures; all unilateral training arm procedures; and, were due, based on date of surgery, for Month 24 follow-up or later. All patients in this cohort received the original version of the acetabular shell. This cohort is used to provide supporting evidence of safety. |
| Bilateral Arm (Original Shell) | 203 procedures
118 patients | This cohort has dates of surgery from 11/20/00 to 05/11/06. This cohort includes all patients implanted bilaterally (simultaneously or staged) prior to their Month 24 assessment. All patients in this cohort received the original version of the acetabular shell. This cohort is used to provide supporting evidence of safety. |

Note: Due primarily to the fact that the All Enrolled Audited cohort contains 458 procedures implanted with a different version of the acetabular shell which is not included in this Summary, the Pivotal Unilateral Efficacy (Original Shell), All Enrolled Unilateral (Original Shell) and Bilateral Arm (Original Shell) cohorts, described in the above table, do not completely comprise the total 1366 procedures. The composition of the 1366 procedures in the All Enrolled Audited cohort is as follows: 292 Pivotal Unilateral Efficacy procedures, 656 Continued Access procedures, 318 Bilateral procedures, 35 Inflammatory Arm procedures, 8 Training Arm procedures and 57 procedures performed by a site whose data was excluded from the Pivotal Unilateral Efficacy cohort (Original Shell) due to audit findings.

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# D. Patient Accounting

The accounting of follow-up evaluations for the CONSERVE® Plus Pivotal Unilateral Efficacy cohort (Original Shell) (Group I) and the control groups (C1 and C2) are provided in Table 5.

Table 5: Procedure Accounting and Follow-up Compliance Table
Pivotal Unilateral Efficacy Cohort (Original Shell) (I), Ceramic THR Unilateral Controls (C1), Metal THR Unilateral Controls (C2)

| As of Date of Database Closure | Pre-Op | | | Post-Op | | | Month 6 | | | Month 12 | | | Month 24 | | | Month 24+ | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | I | C1 | C2 | I | C1 | C2 | I | C1 | C2 | I | C1 | C2 | I | C1 | C2 | I | C1 | C2 |
| (1) Theoretical follow-up | 292 | 341 | 322 | 292 | 341 | 322 | 292 | 341 | 322 | 292 | 341 | 322 | 292 | 341 | 322 | 292 | 341 | 322 |
| (2) Cumulative deaths including non-theoretically due | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 3 | 1 | 0 | 3 | 1 |
| (3) Cumulative revisions including non-theoretically due | 0 | 0 | 0 | 7 | 5 | 3 | 7 | 5 | 4 | 7 | 6 | 7 | 13 | 7 | 9 | 19 | 10 | 15 |
| (4) Expected due for clinic visit | 292 | 341 | 322 | 285 | 336 | 319 | 285 | 336 | 318 | 285 | 334 | 314 | 279 | 331 | 312 | 279 | 331 | 312 |
| (5) Expected due + revisions among theoretically due | 292 | 341 | 322 | 292 | 341 | 322 | 292 | 341 | 322 | 292 | 340 | 321 | 292 | 338 | 321 | 292 | 338 | 321 |
| All Evaluated Accounting (Actual^{®}) Among Expected Due Procedures | | | | | | | | | | | | | | | | | | |
| | I | C1 | C2 | I | C1 | C2 | I | C1 | C2 | I | C1 | C2 | I | C1 | C2 | I | C1 | C2 |
| (6) Numbers of procedures with any clinical data in interval | 291 | 341 | 322 | 232 | 220 | 237 | 238 | 261 | 294 | 248 | 258 | 229 | 235 | 208 | 208 | 268 | 280 | 276 |
| (7) All Evaluated Visit Compliance (%) | 99.7% | 100.0% | 100.0% | 81.4% | 65.5% | 74.3% | 83.5% | 77.7% | 92.5% | 87.0% | 77.2% | 72.9% | 84.2% | 62.8% | 66.7% | 96.1% | 84.6% | 88.5% |
| (8) CCS at Mos. 24, 24+ or HHS+SF12+radio. | | | | | | | 202 | 247 | 227 | 239 | 229 | 212 | 228 | 192 | 189 | 270 | 260 | 249 |
| (9) Actual^{®} % Follow up for CCS or HHS+SF12+radio. | | | | | | | 70.9% | 73.5% | 71.4% | 83.9% | 68.6% | 67.5% | 78.1% | 56.8% | 58.9% | 92.5% | 76.9% | 77.6% |
| Within Window Accounting (Actual^{®}) Among Expected Due | | | | | | | | | | | | | | | | | | |
| | I | C1 | C2 | I | C1 | C2 | I | C1 | C2 | I | C1 | C2 | I | C1 | C2 | I | C1 | C2 |
| (10) CCS at Mos. 24, 24+ or HHS+SF12+radio | | | | | | | 116 | 87 | 100 | 212 | 201 | 187 | 177 | 157 | 148 | 252 | 202 | 202 |
| (11) Actual^{®} % Follow-up for CCS or HHS+SF12+radio | | | | | | | 40.7% | 25.9% | 31.4% | 74.4% | 60.2% | 59.6% | 60.6% | 46.4% | 46.1% | 86.3% | 59.8% | 62.9% |

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| Notes for Procedure Accounting and Follow-up Accounting Tables |
| --- |
| ROM/Deformity Imputations - If post baseline Harris Hip Score evaluations were complete with the exception of ROM and Deformity, then ROM and/or Deformity were defined to be zero. This is a conservative imputation for both the primary CCS and secondary HHS efficacy criteria, since both require HHS to be equal to 80 points or greater and the maximum HHS score for this imputation can be 91, 95 or 96 points instead of 100 points (depending on whether ROM, Deformity or both were missing). |
| Actual^{B} intervals: Immediate Post 1-45 days; 6 Mo. 46-210; 1 Yr. 211-425; 2 Yr. 426-790. For the purpose of including available data beyond the Month 24 window, a 24+ Month interval was created. The 24+ month evaluations include 24 month evaluations completed, as well as data from a later visit, if the 24 month evaluation was not available. |
| Actual^{A} intervals: Immediate Post 1-56 days; 6 Mo. 168-196; 1 Yr. 305-425; 2 Yr. 670-790. For the purpose of including available data beyond the Month 24 window, a 24+ Month interval was created. The 24+ month evaluations include 24 month evaluations completed, as well as data from a later visit, if the 24 month evaluation was not available. |
| 1 The theoretical follow-up is the number of implants that would have been examined if all patients returned on the exact anniversary of their respective initial surgery dates. |
| 2 Cumulative deaths up to and including the current interval. Although the cumulative numbers of deaths are recorded on this row, only deaths among implants that are theoretically due for that interval are subtracted from theoretically due to determine the number expected due. |
| 3 This row records the cumulative number of failures that have taken place according by the exact anniversary of scheduled follow-up visit. Although the cumulative numbers of failures are recorded on this row, only failures among implants that are theoretically due for that interval are subtracted from theoretically due to determine the number expected due. |
| 4 Expected due for clinic visit is equal to theoretically due minus deaths and revisions among theoretically due. This row serves as denominator for clinical evaluation % followup. |
| 5 Expected due plus theoretically due revisions is computed by adding expected due to the number of cumulative revisions among theoretical procedures. This row serves as the denominator for composite clinical success (CCS) outcomes since revisions are known to be CCS failures. |
| 6 All Evaluated Accounting (Actual^{B}) is based on the evaluations on-file among those expected due without regard to whether assessment was within the assessment window. |
| 7 All Evaluated Visit Compliance (%) is computed as the number on-file among those expected due divided by the expected number due expressed as a percentage. All evaluated compliance is based on the presence of any clinical data, even if incomplete, and demonstrates that the procedure is actively followed at least up to the specific interval. |
| 8 CCS at Mos. 24, 24+ or HHS+ change in SF12+radiographic, otherwise (Actual^{B}). For Months 24 and 24+, this row indicates the numbers of procedures with all components on-file that are necessary to evaluate composite clinical success with revisions included as CCS failures. For other time points, this row only indicates that Harris Hip Total scores, change from baseline in SF12, and radiographic evaluations are on-file. |
| 9 Actual^{B} % Follow-up for CCS or HHS+SF12+radio. This is the count of CCS procedures divided by the count of the expected due + revisions among theoretically due. |
| 10 CCS at Mos. 24, 24+ or HHS+change in SF12+radiographic, otherwise (Actual^{A}). For Months 24 and 24+, this row indicates the numbers of procedures with all components on-file that are necessary to evaluate composite clinical success with revisions included as CCS failures. For other time points, this row only indicates that Harris Hip Total scores, change from baseline in SF12, and radiographic evaluations are on-file. |
| 11 Actual^{A} % Follow-up for CCS or HHS+SF12+radio. This is the count of CCS procedures divided by the count of the expected due + revisions among theoretically due. |

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The following cohort follow-up rates are also noted:

All Enrolled Audited Cohort

The follow-up rate at Month 24+ for patients with complete information to determine safety was 76.4% (821/1074) for Group I, 60.4% (568/963) for Group C1, and 79.0% (305/386) for Group C2.

All Enrolled Unilateral (Original Shell) Cohort

The follow-up rate at Month 24+ for patients with complete information to determine safety was 81.2% (540/665).

Bilateral arm (Original Shell) Cohort

The follow-up rate at Month 24+ for patients with complete information to determine safety was 83.8% (160/191).

## E. Baseline Characteristics of Investigational and Control Groups

The summary statistics / comparisons for patient demographics and baseline variables for the Pivotal Unilateral Efficacy (Original Shell), All Enrolled Audited, All Enrolled Unilateral (Original Shell), and Bilateral Arm (Original Shell) cohorts and the two historical controls are displayed in Tables 6 and 7 below.

Significantly different (p<0.05) preoperative demographic variables between the CONSERVE® Plus Pivotal Unilateral Efficacy cohort (Original Shell) and the TRANSCEND® Metal (Group C2) were gender, age, BMI, height in females, and preoperative mean Harris Hip total score. Harris Hip pain score was borderline significant (p=0.052). Significantly different (p<0.05) preoperative demographic variables between the CONSERVE® Plus Pivotal Unilateral Efficacy cohort (Original Shell) and the TRANSCEND® Metal (Group C2) were gender, age, BMI, weight in males, and preoperative Harris Hip total and pain scores.

To assess any potential selection bias resulting from a non-randomized study design, a Propensity Score analysis and adjustment was performed. This analysis was performed separately for the CONSERVE® Plus cohort versus the TRANSCEND® Ceramic control and CONSERVE® Plus cohort versus the TRANSCEND® Metal control. The covariates entered into the propensity score adjustment were gender, age at surgery, BMI, diagnosis, baseline HHS, presence of marked pain at baseline, previous treatment, other joint involvement, and any bone graft used during the procedure, as these were the covariates believed to most affect outcome. The propensity score model estimated each subject's likelihood of receiving one device versus the other as a function of the covariates put in the model, thus determining whether the subjects were "exchangeable." The propensity scores were then put into quintiles and used to determine an adjusted odds ratio of being a Composite Clinical Success (CCS) in the CONSERVE® Plus cohort relative to each control group. This analysis showed that the likelihood of being a Month 24+ CCS was not significantly lower for patients in the CONSERVE® Plus cohort relative to each control group. This implies that any between group differences in patient populations for the covariates included in the model did not affect the conclusion of the non-inferiority analysis for CCS.

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Table 6: Demographic Characteristics and Baseline Function in Pivotal Unilateral Efficacy Cohort (Original Shell) Patients and Unilateral Control Patients

| | Pivotal Unilateral Efficacy Cohort (Original Shell) (I) | | Ceramic THR Controls (C1) | | Metal THR Controls (C2) | | I vs. C1^{1}
p-values | I vs. C2^{2}
p-values |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Number of procedures | 292 | . | 341 | . | 322 | . | . | . |
| Number of patients | 292 | . | 341 | . | 322 | . | . | . |
| Gender | n | % | n | % | n | % | 0.046 | 0.046 |
| Males | 202 | 69.2% | 210 | 61.6% | 198 | 61.5% | . | . |
| Females | 90 | 30.8% | 131 | 38.4% | 124 | 38.5% | . | . |
| Age | Mean | SD | Mean | SD | Mean | SD | <0.001 | <0.001 |
| ≥65 | 13 | 4.5% | 65 | 19.1% | 66 | 20.5% | . | . |
| <65 | 279 | 95.5% | 276 | 80.9% | 256 | 79.5% | . | . |
| Males | Mean | SD | Mean | SD | Mean | SD | | |
| Age at surgery (yrs) | 48.8 | 9.6 | 52.5 | 11.5 | 53.3 | 11.9 | <0.001 | <0.001 |
| Body Mass Index (kg/m²) | 28.1 | 4.3 | 29.6 | 5.8 | 30.1 | 6.0 | 0.020 | 0.001 |
| Height (inches) | 70.3 | 3.0 | 69.7 | 3.3 | 70.2 | 3.3 | 0.433 | 0.776 |
| Weight (lbs) | 197.8 | 32.9 | 204.2 | 40.2 | 210.8 | 42.9 | 0.171 | 0.002 |
| Females | Mean | SD | Mean | SD | Mean | SD | | |
| Age at surgery (yrs) | 48.9 | 8.9 | 53.3 | 13.0 | 53.7 | 11.7 | 0.006 | 0.001 |
| Body Mass Index (kg/m²) | 27.1 | 6.1 | 29.3 | 8.1 | 29.0 | 7.3 | 0.038 | 0.050 |
| Height (inches) | 65.1 | 2.9 | 64.2 | 3.5 | 64.4 | 3.1 | 0.035 | 0.125 |
| Weight (lbs) | 163.1 | 37.2 | 171.1 | 43.2 | 171.0 | 43.2 | 0.251 | 0.281 |
| Diagnosis | n | % | n | % | n | % | 0.157^{4} | 0.363^{4} |
| Osteo/degenerative arthritis | 230 | 78.8% | 243 | 71.3% | 243 | 75.5% | . | . |
| Avascular necrosis | 34 | 11.6% | 58 | 17.0% | 53 | 16.5% | . | . |
| Traumatic arthritis | 13 | 4.5% | 21 | 6.2% | 13 | 4.0% | . | . |
| Congenital hip dysplasia | 15 | 5.1% | 19 | 5.6% | 13 | 4.0% | . | . |
| Rheumatoid Arthritis | 0 | 0.0% | 0 | 0.0% | 0 | 0.0% | . | . |
| Health Related Quality of Life (SF-12) | Mean | SD | Mean | SD | Mean | SD | | |
| SF-12 PCS Z-score^{5} | -1.82 | 1.19 | -1.88 | 1.09 | -1.85 | 1.18 | 0.991 | 0.924 |
| SF-12 MCS Z-score^{5} | 0.00 | 1.16 | 0.05 | 1.18 | -0.01 | 1.10 | 0.877 | 0.365 |
| Harris Hip Score | Mean | SD | Mean | SD | Mean | SD | | |
| Harris Hip Total Score | 49.4 | 11.7 | 45.3 | 12.8 | 47.6 | 14.2 | <0.0001 | 0.026 |
| Harris Pain Category^{6} | n | % | n | % | n | % | 0.052^{5} | <0.0001^{5} |
| None/Ignores | 0 | 0.0% | 1 | 0.3% | 5 | 1.6% | . | . |
| Slight | 0 | 0.0% | 2 | 0.6% | 10 | 3.1% | . | . |
| Mild | 5 | 1.7% | 9 | 2.6% | 11 | 3.4% | . | . |
| Moderate | 105 | 36.1% | 88 | 25.8% | 90 | 28.0% | . | . |
| Marked | 175 | 60.1% | 229 | 67.2% | 185 | 57.6% | . | . |
| Totally disabled | 6 | 2.1% | 12 | 3.5% | 20 | 6.2% | . | . |
| | n | % | n | % | n | % | | |
| Any Previous Treatment | 45 | 15.4% | 58 | 17.0% | 46 | 14.3% | 0.587 | 0.695 |
| Other Joint Involvement | 75 | 25.7% | 70 | 20.5% | 86 | 26.7% | 0.124 | 0.773 |
| Any bone graft | 63 | 21.6% | 85 | 24.9% | 77 | 23.9% | 0.321 | 0.491 |

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# Notes:

1. I vs. C1 is Pivotal Unilateral Efficacy Cohort (Original Shell) vs. Ceramic THR controls: For interval variables, p-values are from ANOVA pairwise contrasts; for nominal variables, p-values are from pairwise chi-square statistics; for Harris Hip Total, p-values are from pairwise Wilcoxon rank sum tests.
2. I vs. C2 is Pivotal Unilateral Efficacy Cohort (Original Shell) vs. Metal THR controls: For interval variables, p-values are from ANOVA pairwise contrasts; for nominal variables, p-values are from pairwise chi-square statistics; for Harris Hip Total, p-values are from pairwise Wilcoxon rank sum tests.
3. SF-12 PCS and MCS Z-scores are age-adjusted and based on US national reference values.
4. A 2 X 5 Chi square test was performed for Diagnosis versus controls
5. A 2 X 6 Chi square test was performed for the Harris Hip Score Pain Category versus controls.
6. One patient was missing pain assessment in baseline Harris Hip Score.

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Table 7: Baseline and Demographic Characteristics for All Enrolled Unilateral (Original Shell), Bilateral (Original Shell), and All Enrolled Audited Cohorts

| | All Enrolled Unilateral (Original Shell) n = 680 | | Bilateral (Original Shell) n = 203 | | All Enrolled Audited n = 1366 | |
| --- | --- | --- | --- | --- | --- | --- |
| | N | % | N | % | N | % |
| Number of procedures | 680 | | 203 | | 1366 | |
| Number of patients | 680 | | 118 | | 1206 | |
| Gender | N | % | N | % | N | % |
| Males | 484 | 71.2% | 153 | 75.4% | 981 | 71.8% |
| Females | 196 | 28.8% | 50 | 24.6% | 385 | 28.2% |
| Age | n | % | n | % | n | % |
| ≥65 | 42 | 6.2% | 11 | 5.4% | 104 | 7.6% |
| <65 | 638 | 93.8% | 192 | 94.6% | 1262 | 92.4% |
| Males | Mean | SD | Mean | SD | Mean | SD |
| Age at surgery (yrs) | 50.1 | 9.9 | 49.1 | 10.0 | 50.3 | 9.9 |
| Body Mass Index (kg/m²) | 28.1 | 4.2 | 27.4 | 3.7 | 28.0 | 3.9 |
| Height (inches) | 70.4 | 2.7 | 70.7 | 3.0 | 70.6 | 2.8 |
| Weight (lbs) | 198.6 | 32.9 | 195.7 | 32.4 | 198.3 | 32.0 |
| Females | Mean | SD | Mean | SD | Mean | SD |
| Age at surgery (yrs) | 48.7 | 10.1 | 45.3 | 8.5 | 49.6 | 10.7 |
| Body Mass Index (kg/m²) | 26.2 | 5.3 | 27.3 | 6.5 | 26.4 | 5.4 |
| Height (inches) | 64.9 | 2.8 | 65.6 | 3.6 | 65.2 | 3.0 |
| Weight (lbs) | 157.2 | 33.6 | 166 | 37.2 | 159.8 | 34.1 |
| Diagnosis | n | % | n | % | n | % |
| Osteo/degenerative arthritis | 519 | 76.3% | 159 | 78.3% | 1054 | 77.2% |
| Avascular necrosis | 70 | 10.3% | 28 | 13.8% | 138 | 10.1% |
| Traumatic arthritis | 31 | 4.6% | 0 | 0.0% | 39 | 2.9% |
| Congenital hip dysplasia | 41 | 6.0% | 16 | 7.9% | 100 | 7.3% |
| Rheumatoid Arthritis | 19 | 2.8% | 0 | 0.0% | 35 | 2.6% |
| Health Related Quality of Life (SF-12) | Mean | SD | Mean | SD | Mean | SD |
| SF-12 PCS Z-score | -1.88 | 1.16 | -2.21 | 1.22 | -1.92 | 1.16 |
| SF-12 MCS Z-score | 0.15 | 1.10 | 0.22 | 1.13 | 0.20 | 1.10 |
| Harris Hip Score | Mean | SD | Mean | SD | Mean | SD |
| Total Score | 50.6 | 12.0 | 49.6 | 12.9 | 50.7 | 11.9 |
| Harris Pain Category¹ | n | % | n | % | n | % |
| None/Ignores | 1 | 0.1% | 1 | 0.5% | 2 | 0.1% |
| Slight | 5 | 0.7% | 1 | 0.5% | 7 | 0.5% |
| Mild | 12 | 1.8% | 8 | 4.0% | 36 | 2.6% |
| Moderate | 267 | 39.4% | 70 | 34.7% | 507 | 37.2% |
| Marked | 377 | 55.6% | 112 | 55.4% | 781 | 57.3% |
| Totally disabled | 16 | 2.4% | 10 | 5.0% | 29 | 2.1% |
| Any Previous Treatment | 96 | 14.1% | 10 | 4.9% | 167 | 12.2% |
| Other Joint Involvement | 172 | 25.3% | 170 | 83.7% | 550 | 40.3% |
| Any bone graft | 164 | 24.1% | 35 | 17.2% | 281 | 20.6% |
| Note:¹ Two patients were missing pain assessment in baseline Harris Hip Score. | | | | | | |

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# F. Safety and Effectiveness Results

## 1. Safety Results

The safety of the CONSERVE® Plus Total Resurfacing Hip System was evaluated in terms of the following analyses:

- Device Revision,
- Risk Factors,
- Survivorship
- Adverse Events, and
- Metal Ions.

The risk analysis section identifies the factors which were shown to contribute to revision. Survivorship analyses were conducted according to the Kaplan-Meier approach.

### Device Revision

There were a total of 66 (8.0%) revisions reported out of 821 procedures in the CONSERVE® Plus Total Resurfacing Hip System. All Enrolled Audited cohort, 36 (6.7%) revisions reported out of 540 procedures in the All Enrolled Unilateral (Original Shell) cohort, 19 (7.0%) revisions reported out of 270 in the Primary Unilateral Efficacy cohort (Original Shell), and 11 (6.9%) revisions out of 160 in the Bilateral (Original Shell) cohort at the 24+ Month interval. A summary of the reason for revision, stratified by study cohort, is provided in Table 8 below.

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Table 8: All Revisions/Removals Reported By Cohort for the 24+ Month Interval

| | All Enrolled Audited (N=1366) (24+ Month N = 821) | | | All Enrolled Unilateral (Original Shell) (N=680) (24+ Month N = 540) | | | Pivotal Unilateral Efficacy Cohort (Original Shell) (N=292) (24+ Month N = 270) | | | Bilateral Cohort (Original Shell) (N=203) (24+ Month N = 160) | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | n/N | % | Mean # Months | n/N | % | Mean # Months | n/N | % | Mean # Months | n/N | % | Mean # Months |
| Revision | 66/821 | 8.0% | 18 | 36/540 | 6.7% | 19 | 19/270 | 7.0% | 22 | 11/160 | 6.9% | 29 |
| Acetabular Loosening | 10 | 1.2% | 16 | 3 | 0.6% | 31 | 3 | 1.1% | 31 | 1 | 0.6% | 10 |
| Acetabular Migration | 4 | 0.5% | 9 | 1 | 0.2% | 16 | 0 | 0.0% | N/A | 0 | 0.0% | N/A |
| Acetabular Protrusion | 1 | 0.1% | 31 | 1 | 0.2% | 31 | 0 | 0.0% | N/A | 0 | 0.0% | N/A |
| Acetabular Loosening & Femoral Neck Fracture | 1 | 0.1% | 52 | 0 | 0.0% | N/A | 0 | 0.0% | N/A | 1 | 0.6% | 52 |
| Femoral Loosening | 7 | 0.9% | 36 | 3 | 0.6% | 23 | 1 | 0.4% | 19 | 4 | 2.5% | 46 |
| Femoral Neck Fracture | 28 | 3.4% | 11 | 19 | 3.5% | 12 | 11 | 4.1% | 16 | 4 | 2.5% | 13 |
| Impingement | 2 | 0.2% | 54 | 2 | 0.4% | 54 | 1 | 0.4% | 69 | 0 | 0.0% | N/A |
| Infection | 8 | 1.0% | 14 | 4 | 0.7% | 15 | 2 | 0.7% | 21 | 1 | 0.6% | 18 |
| Other Increase resistance to bearing motion | 1 | 0.1% | 0.23 | 1 | 0.2% | 0.23 | 0 | 0.0% | N/A | 0 | 0.0% | N/A |
| Abductor Rupture | 1 | 0.1% | 16 | 0 | 0.0% | N/A | 1 | 0.4% | 16 | 0 | 0.0% | N/A |
| *Unknown | 1 | 0.1% | 31 | 1 | 0.2% | 31 | 0 | 0.0% | N/A | 0 | 0.0% | N/A |
| Pain | 2 | 0.2% | 17 | 1 | 0.2% | 11 | 0 | 0.0% | N/A | 0 | 0.0% | N/A |
| Total | 66 | 8.0% | 18 | 36 | 6.7% | 19 | 19 | 7.0% | 22 | 11 | 6.9% | 29 |
| Note: * bilateral after 2 years | | | | | | | | | | | | |

It should be noted that not all of the 66 revisions in the CONSERVE® Plus Total Resurfacing Hip System All Enrolled Audited cohort were deemed to be device-related. Of the 66 revisions, 57 were deemed device-related and 9 were deemed non-device-related. Two patients were revised for impingement, 1 for abductor rupture, 1 due to acetabular protrusion, and 4 for infection. All 8 of these revisions were deemed to be non-device related. One patient was revised for unknown reasons and was not evaluable by the Data Safety Monitoring Board (DSMB).

Revision rates for the All Enrolled TRANSCEND® Ceramic and All Enrolled TRANSCEND® Metal controls were 29 (5.11%) out of 568 procedures and 20 (6.56%) out of 305 procedures, respectively, at the 24+ Month interval. Revision rates for the Pivotal Efficacy TRANSCEND® Ceramic and Pivotal Efficacy TRANSCEND® Metal controls were 10 (3.85%) out of 260 procedures and 15 (6.02%) out of 249 procedures, respectively, at the 24+ Month interval.

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# Device Failure Risk Analysis

## Methods

Risk Factor Analyses were performed to identify factors associated with increased risk of device failure. These analyses were performed for the All Enrolled Unilateral (Original Shell) cohort (N=680), the Pivotal Unilateral Efficacy cohort (Original Shell) (N=292) and the Bilateral (Original Shell) (N=203) cohort. Data to evaluate potential risk factors were collected as part of a retrieval analysis or during the clinical study.

## Retrieval Analysis

At revision, the femoral components were resected with a portion of the femoral neck where possible, and immediately fixed in buffered formalin. If the acetabular components were also removed, these were fixed in formalin as well. The components were inspected, photographed, and then in selected cases (long term, or when unusual wear was expected) measured for wear depth and clearance using a coordinate measuring machine with 2 micron resolution at an independent laboratory. In the early period of the study, femoral components were sectioned into a variable number of sections to allow inspection of the cement/ bone interfaces and access to samples of the bone from various locations for decalcified histological analysis. Later, a more systematic sectioning protocol was followed to facilitate comparison between specimens (i.e., a slice was taken from the anterior and posterior segments equidistant from the middle). After decalcification, paraffin embedding and H &amp; E staining, the sections were inspected. Finally, the general appearance of the tissues was used to determine if the failure was related to avascular necrosis, cement interface loosening or infection using standard histopathological criteria.

## Variables Assessed in Risk Factor Analysis

Data for the following variables were collected either as part of a retrieval analysis study or clinical study:

| Variables assessed via retrieval analysis: |
| --- |
| • Non-osteoarthritis diagnosis |
| • Avascular Necrosis |
| • Large (>1cm) and/or multiple femoral cysts |
| • Poor bone quality such as loss of femoral head bone |
| • DEXA scan showing severe osteopenia |
| • Absence of collagen disease |
| • Femoral neck notching during implantation |
| • Impacting femoral component beyond surgical technique recommendations |
| • Failing to suction excess blood or bone debris before femoral component implantation |
| • Increased number of drilled holes in top of femoral head along with chamfer holes |
| • Incomplete removal of cystic debris in femoral head |
| • Removal of anterior osteophyte |
| • Too much bone removal either on the acetabular or femoral side |
| • Loss of acetabular press-fit either during initial operation or post-operatively |
| • Improper distribution of cement |
| • Leaving the femoral component proud on the femoral head |
| • Malpositioning of the acetabular component (<30° or >60°) |

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| Variables assessed via clinical data: |
| --- |
| • Female vs. male gender |
| • A non-osteoarthritis diagnosis (AVN, Traumatic Arthritis, Congenital Hip Dysplasia, Rheumatoid Arthritis) |
| • Pre-surgical Harris Hip Score in the lowest quartile (defined as less than 43.6 points) |
| • Pre-surgical Harris Hip pain category rated as 'marked pain' or worse |
| • Any previous treatment on involved hip (i.e., osteotomy, core decompression, hemi-resurfacing, or internal fixation) |
| • Other joint involvement |
| • Any bone graft used during procedure |
| • Presence of femoral cysts (single vs. none and multiple v. none) |
| • Procedures done within first 60 at a specific site {learning curve effect} |
| • Small femoral component (≤ 44mm) |
| • Femoral neck angle (<135) in relation to the femoral shaft |
| • Femoral component stem angle (<135) in relation to the femoral shaft |
| • Horizontal acetabular component (< 30 degrees) |
| • Vertical acetabular component (>60 degrees) |

## Key Findings

Analysis of the above variables led to the determination of risk factors. For the retrieval analysis, a variable was deemed a risk factor if findings of at least one specimen suggested failure due to that variable. Of the 66 revised implants from the All Enrolled Audited cohort, 37 were available for retrieval analysis.

Variables meeting the definition of risk factor from those analyses included:

- diagnosis of traumatic arthritis, congenital hip dysplasia, or avascular necrosis,
- large (&gt;1cm) and/or multiple femoral cysts,
- poor bone quality such as loss of femoral head bone,
- DEXA scan showing severe osteopenia,
- femoral neck notching during implantation,
- impacting femoral component beyond surgical technique recommendations,
- failing to suction excess blood or bone debris before femoral component implantation,
- too few or too many drilled holes in top of femoral head along with chamfer holes,
- incomplete removal of cystic debris in femoral head,
- removal of anterior osteophyte,
- too much bone removal either on the acetabular or femoral side,
- loss of acetabular press-fit either during initial operation or post-operatively,
- improper distribution of cement,
- leaving the femoral component proud on the femoral head, and
- malpositioning of the acetabular component (&lt;30° or &gt;60°).

Risk factors were also determined based on clinical data collected within the study. Table 9 provides a summary of the risk of revision in the All Enrolled Unilateral (Original Shell) cohort, Pivotal Unilateral Efficacy cohort (Original Shell), and Bilateral (Original Shell) cohort.

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Table 9: Risk of Revision in All Enrolled Unilateral (Original Shell), Pivotal Unilateral Efficacy Cohort (Original Shell), and Bilateral (Original Shell)
Stratified by All Procedures in Cohort and Only Procedures with At Least 24 Months Follow-up

| | | All Enrolled Unilateral (Original Shell) | All Enrolled Unilateral (Original Shell) 24+ month follow-up | Pivotal Unilateral Efficacy Cohort¹ (Original Shell) | Pivotal Unilateral Efficacy Cohort (Original Shell) 24+ month follow-up | Bilateral (Original Shell) | Bilateral (Original Shell) 24+ month follow-up |
| --- | --- | --- | --- | --- | --- | --- | --- |
| | Revisions N % | 36 680 5.3 | 36 540 6.7 | 19 292 6.5 | 19 270 7.0 | 11 203 5.4 | 11 160 6.9 |
| Female gender | Female Male | 7.7% (15/196) 4.3% (21/484) | 9.0% (15/167) 5.6% (21/373) | 11.1% (10/90) 4.5% (9/202) | 11.5% (10/87) 4.9% (9/183) | 16.0% (8/50) 2.0% (3/153) | 18.2% (8/44) 2.6% (3/116) |
| Non osteoarthritis DX | AVN/RA+ Osteoarthritis | 8.7% (14/161) 4.2% (22/519) | 11.1% (14/126) 5.3% (22/414) | 6.5% (4/62) 6.5% (15/230) | 7.0% (4/57) 7.0% (15/213) | 9.1% (4/44) 4.4% (7/159) | 12.5% (4/32) 5.5% (7/128) |
| Baseline HHS < 43.6 (1st quartile)² | HHS<43.6 HHS>=43.6 | 4.7% (8/169) 5.4% (27/496) | 6.1% (8/132) 6.8% (27/400) | 5.1% (4/78) 7.1% (15/212) | 5.8% (4/69) 7.5% (15/199) | 3.3% (2/61) 6.7% (9/135) | 4.3% (2/47) 8.1% (9/111) |
| Baseline Pain >=Marked² | Marked/Disabled Other | 5.3% (21/393) 5.3% (15/285) | 6.6% (21/319) 6.8% (15/220) | 6.1% (11/181) 7.3% (8/110) | 6.6% (11/167) 7.8% (8/102) | 3.3% (4/122) 8.8% (7/80) | 4.3% (4/93) 10.4% (7/67) |
| Any Previous Treatment | Prev Treatment none | 6.3% (6/96) 5.1% (30/584) | 7.5% (6/80) 6.5% (30/460) | 8.9% (4/45) 6.1% (15/247) | 9.3% (4/43) 6.6% (15/227) | 20.0% (2/10) 4.7% (9/193) | 28.6% (2/7) 5.9% (9/153) |
| Other Joint Involvement | Joint Involved none | 9.3% (16/172) 3.9% (20/508) | 12.4% (16/129) 4.9% (20/411) | 9.3% (7/75) 5.5% (12/217) | 10.1% (7/69) 6.0% (12/201) | 5.9% (10/170) 3.0% (1/33) | 7.6% (10/132) 3.6% (1/28) |
| Any Bone Graft | Bone Graft none | 4.3% (7/164) 5.6% (29/516) | 5.4% (7/130) 7.1% (29/410) | 7.9% (5/63) 6.1% (14/229) | 8.6% (5/58) 6.6% (14/212) | 2.9% (1/35) 6.0% (10/168) | 3.3% (1/30) 7.7% (10/130) |
| Femoral Cysts (Multiple vs not multiple) | >1 0,1 | 4.0% (8/199) 5.8% (28/481) | 4.7% (8/171) 7.6% (28/369) | 3.4% (3/89) 7.9% (16/203) | 3.5% (3/85) 8.6% (16/185) | 12.0% (6/50) 3.3% (5/153) | 14.3% (6/42) 4.2% (5/118) |
| Femoral Cysts (Any vs none) | Any None | 6.5% (10/153) 4.9% (26/527) | 8.3% (10/120) 6.2% (26/420) | 12.2% (9/74) 4.6% (10/218) | 12.9% (9/70) 5.0% (10/200) | 1.8% (1/55) 6.8% (10/148) | 2.2% (1/45) 8.7% (10/115) |
| 1st 60 procedures at a specific site | Within 1st 60 After 1st 60 | 8.0% (28/350) 2.4% (8/330) | 9.1% (28/308) 3.4% (8/232) | 7.7% (18/234) 1.7% (1/58) | 8.2% (18/220) 2.0% (1/50) | 11.0% (10/91) 0.9% (1/112) | 12.0% (10/83) 1.3% (1/77) |
| Small Femoral Component | < 44 >=44 | 9.0% (18/199) 3.7% (18/481) | 10.5% (18/171) 4.9% (18/369) | 12.5% (12/96) 3.6% (7/196) | 13.2% (12/91) 3.9% (7/179) | 19.5% (8/41) 1.9% (3/162) | 22.2% (8/36) 2.4% (3/124) |
| Femoral Comp. Neck angle<135°4,5 | <135° >=135° | 4.8% (17/354) 5.0% (16/318) | 5.4% (17/313) 7.2% (16/223) | 6.3% (12/192) 4.2% (4/96) | 6.6% (12/181) 4.7% (4/86) | 5.1% (5/99) 5.0% (5/100) | 5.7% (5/87) 6.9% (5/72) |
| Stem Neck angle<135°4,5 | <135° >=135° | 4.1% (10/246) 5.4% (23/426) | 4.6% (10/216) 7.2% (23/320) | 6.1% (7/114) 5.2% (9/174) | 6.5% (7/108) 5.7% (9/159) | 4.4% (3/68) 5.3% (7/131) | 5.1% (3/59) 7.0% (7/100) |
| Too Horizontal Acetabular Component (<30° vs not <30°)4,4 | <30° not <30° | 12.5% (5/40) 4.4% (28/632) | 14.7% (5/34) 5.6% (28/502) | 13.8% (4/29) 4.6% (12/259) | 14.3% (4/28) 5.0% (12/239) | 18.8% (3/16) 3.8% (7/184) | 21.4% (3/14) 4.8% (7/145) |
| Too Vertical Acetabular Component4,4 | >60° not <60° | 4.9% (33/672) | 6.2% (33/536) | 5.6% (16/288) | 6.0% (16/267) | 5.0% (10/200) | 6.3% (10/159) |

Note:
1. There were no Rheumatoid Arthritis patients included in the Pivotal Unilateral Efficacy Cohort (Original Shell).
2. Regarding Baseline HHS &lt; 43.6 (1st Quartile): 15 evaluations in the All Enrolled Unilateral Cohort (Original Shell), 8 evaluations in the All Enrolled Unilateral Cohort (Original Shell) 24+ Month follow-up, 2 evaluations in the Pivotal Unilateral Efficacy Cohort (Original Shell), 2 evaluations in the Pivotal Unilateral Efficacy Cohort 24+ Month follow-up, 8 evaluations in the Bilateral Cohort (Original Shell) and 2 evaluations in the Bilateral Cohort (Original Shell) 24+ Month follow-up had an incomplete HHS evaluation at Baseline.
3. Regarding Baseline Pain &gt;= Marked: 2 evaluations in the All Enrolled Unilateral Cohort (Original Shell), 1 evaluation in the All Enrolled Unilateral Cohort (Original Shell) 24+ Month follow-up, 1 evaluation in the Pivotal Unilateral Efficacy Cohort (Original Shell), 1 evaluation in the Pivotal Unilateral Efficacy Cohort 24+ Month follow-up, and 1 evaluation in the Bilateral Cohort (Original Shell) had an incomplete Harris Hip Score Pain assessment at Baseline.
4. Regarding Femoral Component Neck Angle, Stem Neck Angle, Too Horizontal Acetabular Component, and Too Vertical Acetabular Component: 8 evaluations in the All Enrolled Unilateral Cohort (Original Shell), 4 evaluations in the All Enrolled Unilateral Cohort (Original Shell) 24+ Month

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follow-up, 4 evaluations in the Pivotal Unilateral Efficacy Cohort (Original Shell), 3 evaluations in the Pivotal Unilateral Efficacy Cohort 24+ Month follow-up did not have baseline post-operative radiographic evaluation performed.

5. 4 evaluations in the Bilateral Cohort (Original Shell) did not have Femoral neck or stem angle assessed at the baseline.
6. 3 evaluations in the Bilateral Cohort (Original Shell) did not have Acetabular cup inclination assessed at the baseline.

Table 10 summarizes the Cox proportional hazards regression analyses for each variable assessed for the Pivotal Unilateral Efficacy (Original Shell), All Enrolled Unilateral (Original Shell) and Bilateral (Original Shell) cohorts. Variables were analyzed and deemed risk factors if the lower bound of the 95% confidence interval for the hazards ratio was ≥ 1. On the basis of that statistical definition of risk factor, eight variables were deemed risk factors:

- female gender,
- small femoral component (≤ 44mm),
- procedures within the surgeon’s first 60 cases,
- diagnosis of avascular necrosis, traumatic arthritis, congenital hip dysplasia, or rheumatoid arthritis,
- any previous treatment to the hip,
- multiple femoral cysts,
- acetabular component position of &lt; 30°, and
- any other joint involvement.

Table 10: Cox Regression Hazard Ratios and 95% Confidence Intervals for Each Potential Revision Risk Factor Evaluated One-at-a-Time

| | | Pivotal Unilateral Efficacy Cohort (Original Shell) | All Enrolled Unilateral (Original Shell) | Bilateral (Original Shell) |
| --- | --- | --- | --- | --- |
| | Revisions
N = Overall
N = Month 24+
% | 19
292
270
7.0% | 36
680
540
6.7% | 11
203
160
6.9% |
| Female gender | Hazard
LB
UB | 2.24
0.91
5.55 | 1.63
0.84
3.17 | 6.87
1.82
25.96 |
| Non osteoarthritis Diagnoses | Hazard
LB
UB | 0.77
0.24
2.42 | 1.98
1.00
3.89 | 2.17
0.63
7.45 |
| Any Previous Treatment | Hazard
LB
UB | 1.33
0.44
4.04 | 1.11
0.46
2.68 | 5.57
1.19
26.00 |
| Other Joint Involvement | Hazard
LB
UB | 1.79
0.70
4.55 | 2.61
1.35
5.05 | 2.19
0.28
17.15 |
| Femoral Cysts Multiple vs none | Hazard
LB
UB | 0.61
0.16
2.37 | 0.65
0.30
1.43 | 3.43
1.05
11.26 |
| Procedures done | Hazard | 3.68 | 2.60 | 7.39 |

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| within first 60
at a specific site | LB
UB | 0.49
27.80 | 1.17
5.77 | 0.92
59.13 |
| --- | --- | --- | --- | --- |
| Small Femoral
Component | Hazard
LB
UB | 3.34
1.31
8.50 | 2.26
1.17
4.34 | 9.73
2.58
36.70 |
| Acetabular
Comp.
<30° vs not <30° | Hazard
LB
UB | 3.04
0.98
9.47 | 2.54
0.98
6.61 | 6.37
1.59
25.56 |

In summary, all risk factors pertain to surgical training and technique and/or patient selection. Therefore, obtaining adequate surgeon training, and consideration of these surgical technique and patient selection risks factors may help decrease the risk of device failure.

## Survival Analyses – All Enrolled Audited Cohort

Device survival analyses were performed for the following cohorts:

- CONSERVE® Plus All Enrolled Audited cohort (1366 procedures in 1206 patients) as compared to the Ceramic THR (C1) and Metal THR (C2) Controls [Table 11].
- CONSERVE® Plus Pivotal Unilateral Efficacy cohort (Original Shell) (N=292 patients) as compared to the Ceramic THR (C1) and Metal THR (C2) Controls [Table 12].

For each cohort listed above, life-tables were tabulated indicating the number of failures and the number of at-risk procedures over time. Since the number of patients at risk (i.e., being followed) diminishes over time, Peto’s method⁷ was used to determine standard errors for estimates of cumulative survival. Kaplan-Meier survival curves⁸ were plotted on the same graph for the three All Enrolled cohorts in order to facilitate graphical comparisons of survivorship over time.

There was a total of 66 procedures requiring revision, replacement, or removal prior to November 20, 2006 among the 1366 All Enrolled Audited CONSERVE® Plus procedures. Of these, 49 procedures required revision on or before the 2-year anniversary date (i.e., within 730 days of the date of surgery). At the same 2-year timepoint, there were 16 of 963 and 11 of 388 procedures requiring revision, replacement, or removal, in the TRANSCEND® Ceramic (C1) and Metal (C2) control patients, respectively. Cumulative 2-year survival rates (Standard Error (SE)) for CONSERVE® Plus, TRANSCEND® Ceramic (C1), and TRANSCEND® Metal (C2) control patients were 0.956 (SE = 0.0071), 0.980 (SE = 0.0034), and 0.970 (SE = 0.0093), respectively (Table 11). The survival distributions did not significantly differ between CONSERVE® Plus and TRANSCEND® Metal (C2) control at two years (log-rank p=0.30) or based on all available follow-up (log-rank p=0.42). In contrast, survival distributions were significantly lower for the CONSERVE® Plus device as compared to the TRANSCEND® Ceramic (C1) control at two years (log-rank p=0.004) as well as based on all available follow-up (p=0.02).

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# Survival analyses – Pivotal Unilateral Efficacy Cohort (Original Shell)

There was a total of 19 procedures requiring revision, replacement, or removal prior to November 20, 2006 among the 292 Pivotal Unilateral Efficacy cohort (Original Shell) CONSERVE® Plus procedures. Of these, 13 procedures required revision on or before the 2-year anniversary date (i.e., within 730 days of the date of surgery). At the same 2-year timepoint, there were 7 of 341 and 9 of 322 procedures requiring revision, replacement, or removal, in the TRANSCEND® Ceramic (C1) and TRANSCEND® Metal (C2) control patients, respectively. Cumulative 2-year survival rates (SE) for CONSERVE® Plus, TRANSCEND® Ceramic (C1), and TRANSCEND® Metal (C2) control patients were 0.955 (0.0127), 0.979 (0.0085), and 0.970 (0.0102), respectively (Table 12). There were no statistically significant differences in survival rates between Groups.

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## Summary of Adverse Events

CONSERVE® Plus (Group I) device-related and other specific adverse events (complications) were compared to the TRANSCEND® Ceramic (Group C1) and TRANSCEND® Metal (Group C2) control groups for the All Enrolled Audited cohorts.

An independent Data Safety Monitoring Board (DSMB) was convened to assess complications for all three device Groups. The DSMB consisted of independent orthopedic surgeons who were not investigators in the CONSERVE® Plus IDE. The approach taken by the DSMB for evaluation of control group complications was to assess severity and relatedness for only those complications deemed to be hip-related by the study investigators. The approach taken by the DSMB for evaluation of investigational group complications was to assess relatedness for all complications and severity for all device/procedure-related complications. The total pool of complications submitted to the DSMB for review included many unrelated to the device or to the surgery. Among this inclusive pool, the primary safety endpoint was defined to be the occurrence of any complication which the DSMB deemed both severe and at least possibly device-related.

Among the All Enrolled Audited procedures, 67 of 1366 (4.9%) CONSERVE® Plus procedures, 29 of 963 (3.0%) TRANSCEND® Ceramic (C1) controls, and 20 of 388 (5.2%) TRANSCEND® Metal (C2) controls experienced at least one complication assessed by the DSMB as severe and as possibly, probably, or definitely device-related (Table 13). There was a statistically significantly higher complication rate for the CONSERVE® Plus device as compared to the TRANSCEND® Ceramic (C1) control (Fisher’s exact test p=0.026). In contrast, there was no statistically significant difference between CONSERVE® Plus and

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TRANSCEND® Metal (C2) control (Fisher's exact test p=0.79). For specific hip-related complications that led to these observed differences, please see Table 14.

Table 13: Comparisons of Summary…