Multicenter Trial of Antibiotic Eluting Graft for Promoting New Bone Growth in/Near Infected Bone Cavities

Study Overview
=================
Brief Summary
-----------------
This is a pivotal, prospective, multi-center, randomized, concurrent control, patient and assessor-blinded study with two arms: a treatment arm (where subjects will be treated with the EP Granules with Tobramycin investigational device in the 1st stage of a 2-stage surgical treatment for periprosthetic joint infection (PJIs), and a control arm (where subjects are treated with the standard-of-care 2-stage surgical treatment for infected PJIs).

Detailed Description
-----------------
This is a pivotal, prospective, multi-center, randomized, concurrent control, patient and assessor-blinded study to demonstrate superiority of new bone growth and a reduction in recurring infections, and thereby improve outcomes for patients undergoing a 2-stage surgical revision treatment for periprosthetic joint infections (PJIs). The standard of care for treatment of PJIs typically involves a 2-stage revision which entails loss of bone stock resulting from debridement of infected bone in Stage 1. In the Stage 2 procedure, surgeons use metal cones to make up for this bone loss and better support the revision implant. Inadequate bone growth could result in gaps at the the voids below the level of the cortical bone, resulting in regions with no contact with the revision implant or cement mantle. Such gaps could result in dead-space regions, and zones without new bone growth required to support the revision implant. Both deficiencies affect long-term survival of the revision implant. The study has two arms: a treatment arm (where subjects will be treated with the EP Granules with Tobramycin investigational device in the 1st stage of the 2-stage surgical treatment, and a control arm where subjects are treated with the standard-of-care 2-stage surgical treatment for infected PJIs. Outcomes are demonstration of new bone growth and reduction of recurrent infections.

Official Title
-----------------
Multicenter Trial of Antibiotic Eluting Graft for Promoting New Bone Growth in/Near Infected Bone Cavities

Conditions
-----------------
Periprosthetic Joint Infections

Intervention / Treatment
-----------------
* Device: EP Granules with Tobramycin
* Device: empty voids


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Ages and sexes eligible: at least 22 years, male and female Candidates with known infected TKA, according to MSIS standard: getting an erythrocyte sedimentation rate and C-reactive protein followed by selective aspiration of the joint if these values are elevated or if the clinical suspicion is high. Synovial fluid obtained should be sent for a synovial fluid white blood cell count, differential, and cultures. Radiographs demonstrating bone voids on the preoperative X-ray in patients with known Prosthetic Joint Infection (PJI) Life expectancy of at least 1 year Patient is willing to provide informed consent, is geographically stable and able to comply with the required follow up visits, testing schedule and medication regimen Adequate soft tissue coverage Signed institutional review board approved informed consent Exclusion Criteria: Renal failure or documented chronic kidney disease with creatinine ≥3.5 mg/L or being treated with dialysis Known hypersensitivity to aminoglycoside antibiotics, calcium sulfa calcium hydroxyapatite Pre-existing calcium metabolism disorder Uncontrolled diabetes mellitus (hemoglobin A1c levels > 8) A current endocrine or metabolic disorder known to affect osteogenesis (e.g., Paget's disease, renal osteodystrophy, hyperthyroid parathyroid hormone disorder, Ehler- Danlos syndrome, osteogenesis imperfecta) Neuromuscular disorders such as myasthenia gravis Untreated malignant neoplasm(s), or currently undergoing radiation chemotherapy Inadequate neurovascular status in the involved limb that may jeopardize healing Previous history of osteomyelitis in the index limb HIV Pregnancy Adult patients requiring a legal guardian to sign informed consent form

Ages Eligible for Study
-----------------
Minimum Age: 22 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Arm<br>The device will be placed in voids at Stage 1. This will be followed by IV therapy for a minimum of six weeks, followed by a pathology assessment of infection by needle aspiration, after week 8, with a stage 2 surgery scheduled after week 9. During the stage 2 surgery, the surgeon makes a qualitative assessment of new bone, and completes the procedure with affixing the revision implants. If the surgeon observes a depression in the surface layer resulting from subsidence due to partial resorption of the device, the surgeon may fill such gaps with additional granules of the device. An intraoperative set of radiographic images are taken during the stage 2 surgery. | Device: EP Granules with Tobramycin<br>* EP Granules with Tobramycin is a Ca-salt resorbable intended for orthopedic applications as a bone void filler for bone gaps or voids and in cases where risk of post-operative infection is high, such as the first stage of a two-stage revision of an infected total joint.<br>|
| Active Comparator: Control Arm<br>In the standard of care arm, voids are left empty and a bone cement spacer placed during stage 1 surgery. This is followed by IV therapy for a minimum of six weeks, followed by a pathology assessment of infection by needle aspiration, after week 8, with a stage 2 surgery scheduled after week 9. During the stage 2 surgery, the spacer is removed and procedure completed by affixing the revision implants. | Device: empty voids<br>* Voids are left empty<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| New bone growth | This endpoint is assessed radiographically: A] New bone growth observed at 12 months after 2nd stage surgery compared to 1st stage surgery Success = new bone growth present Failure = no new bone growth present | 12 months after stage 2 surgery | 
| Absence of serious device related adverse events requiring re- operation | B] A serious device related adverse event requiring re-operation Success = no adverse event occurs Failure = adverse event occurs | 12 months after stage 2 surgery | 
| Reduction in recurring infection rate. | This outcome is an endpoint of reduction in recurrent infections 3. Reduction in recurring infection rate. | 12 months after stage 2 surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Secondary outcome: patient reported quality of life. | SF-12 or PROMIS -10 score | 12 months after stage 2 surgery | 
| Secondary outcome: number of metal augments | number of metal augments used | stage 2 surgery | 
| Secondary outcome: AKSS Score | 1. AKSS Pain and Function Scores | 12 months after stage 2 surgery |