A Second Trial of the Abbreviated Protocol Two-Stage Exchange

Study Overview
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Brief Summary
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Apex-2 is a multi-site, parallel group, randomized trial. Patients will be randomly assigned in a 1:1 ratio to the Experimental Arm or the Control Arm. The objective of the study is to evaluate safety and determine efficacy of the VT-X7 system. Efficacy is evaluated as superiority of the Experimental Arm in a composite endpoint of Overall Success at 180 days, consisting of a revision prosthesis implanted at Stage 2, absence of periprosthetic joint infection (PJI), absence of continued antibiotic therapy for treatment or prophylaxis of PJI, absence of revision surgery and absence of mortality. Secondary objectives are to evaluate overall success at 365 days, overall safety of the VT-X7 procedure, quality of life (QoL), and patient survival. The exploratory objective is to compare Experimental and Control Arms in exploratory endpoints. Follow-up: Patients will be evaluated at 90-, 180-, and 365-day follow-up visits.

Official Title
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A Second Randomized Controlled Trial of Alternating Irrigation of Vancomycin Hydrochloride and Tobramycin Sulfate in Patients Undergoing Two-Stage Exchange Arthroplasty for Periprosthetic Joint Infection of the Hip or Knee

Conditions
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Prosthetic-joint Infection

Intervention / Treatment
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* Combination Product: VT-X7 Treatment System
* Procedure: Two-stage exchange arthroplasty
* Drug: Standard of Care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Scheduled for two-stage exchange arthroplasty due to hip or knee periprosthetic joint infection (PJI) Signed informed consent 22 to 84 years of age (inclusive) Medical clearance for surgery Preoperative diagnosis of PJI of the hip or knee per the International Consensus Meeting of Musculoskeletal Infection (ICMMI) 2018 definition of Periprosthetic Hip and Knee Infection Exclusion Criteria: Patients with 2 or more prior exchange arthroplasties (septic or aseptic) of the infected joint. Exchange of modular components only is not considered an exchange arthroplasty; Patients with 2 or more prior failed spacers for PJI; Patients for whom a Stage 2 procedure within one year is contraindicated; Patients with bacteremia or positive bacterial blood culture in the last 30 days; Patients with concurrent PJI of more than one joint; Patients with ongoing active infection of an intravenous (IV) site; Patients who require long-term anticoagulation or antiplatelet therapy, and for whom bridging or withholding therapy is not recommended based on the individual's clinical condition; Patients with advanced renal insufficiency (i.e., chronic kidney disease Stage 4 or 5 or patients with an estimated glomerular filtration rate <30 mL/min); Patients on chemotherapy for malignant disease; Patients on systemic glucocorticoid therapy (prednisone >10 mg/day or equivalent); Patients who are immunodeficient (e.g., splenectomy, sickle cell anemia, Stage 3 human immunodeficiency virus infection, primary immunodeficiency disease), except patients who are immunodeficient due to immunosuppressive therapy; Patients who have an allergy to vancomycin hydrochloride or tobramycin sulfate (Note: prior history of red man syndrome is not considered an allergy); Patients who have an allergy to titanium, titanium alloys, polymethylmethacrylate or polyurethane; Patients who are pregnant or planning to become pregnant in the next 12 months; Patients with a fungal PJI as determined by one or more positive fluid and/or tissue cultures; Patients who have a skeletal defect greater than 150 mm in length in the tibia or femur of the infected joint; Patients who have a planned surgical procedure within 6 months of enrollment that can impact the conduct of the study; Patients who are breastfeeding; Patients who are incarcerated or are facing impending incarceration; Patients who have been in treatment or referred to treatment for substance abuse within the past year; Patients with any medical condition, including schizophrenia or another psychiatric disorder with hallucinations and/or delusions, that would interfere with the interpretation of the study results, the conduct of the study, or patient participation would not be in the best interest of the patient in the opinion of the Study Site Principal Investigator; Patients who will participate in another clinical study of an investigational drug or investigational device or have participated in another clinical study of an investigational drug or investigational device within the past 30 days that would interfere with the interpretation of the study results or the conduct of the study; Patients who are judged by the Study Site PI to be unsuitable for the study; Patients receiving immunosuppressive drug therapy for bone marrow or another transplant; Patients currently or previously enrolled in this study or the APEX study (JPS-0301); Patients who receive therapy including any of the following biologic agents, which will not be withheld for a period beginning at least one dosing cycle (minimum 7 days) prior to planned surgery and ending at least 14 days following planned surgery: Adalimumab (Humira); Tocilizumab (Actemra); Etanercept (Enbrel); Anakinra (Kineret); Golimumab (Simponi); Secukinumab (Cosentyx); Infliximab (Remicade); Ustekinumab (Stelara); Abatacept (Orencia); Rituximab (Rituxan); Certolizumab (Cimzia); Tofacitinib (Xeljanz); Belimumab (Benlysta)

Ages Eligible for Study
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Minimum Age: 22 Years
Maximum Age: 84 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental<br>Local antibiotic irrigation via the VT-X7 Treatment System adjuvant to two-stage exchange arthroplasty per SOC. | Combination Product: VT-X7 Treatment System<br>* Seven-day local antibiotic irrigation (alternating vancomycin hydrochloride and tobramycin sulfate) via the temporary VT-X7 Knee or Hip Spacer.<br>Procedure: Two-stage exchange arthroplasty<br>* Stage 1 consists of surgical removal of the infected prosthesis, debridement, and implantation of a temporary spacer. Stage 2 surgery consists of explantation of the temporary spacer, debridement, and implantation of a permanent prosthesis, followed by systemic administration of postoperative antibiotics for 42 days (inclusive) to 90 days (inclusive).<br>|
| Active Comparator: Control<br>SOC for treatment of chronic PJI - two-stage exchange arthroplasty: surgical removal of the infected implant, aggressive debridement, and exchange arthroplasty with administration of adjuvant systemic antibiotics and temporary antibiotic-impregnated cement spacer. | Procedure: Two-stage exchange arthroplasty<br>* Stage 1 consists of surgical removal of the infected prosthesis, debridement, and implantation of a temporary spacer. Stage 2 surgery consists of explantation of the temporary spacer, debridement, and implantation of a permanent prosthesis, followed by systemic administration of postoperative antibiotics for 42 days (inclusive) to 90 days (inclusive).<br>Drug: Standard of Care<br>* Forty-two days (minimum) systemic antibiotic administration adjuvant to two-stage exchange arthroplasty with temporary antibiotic-impregnated cement spacer per standard of care (SOC). Antibiotics will be selected by treatment provider and administered in accordance with national and local treatment guidelines.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Treatment Success | Stage 2 revision prosthesis implanted and Absence of PJI post-Stage 2 and Absence of continued antibiotic therapy for treatment or prophylaxis of PJI and Absence of revision surgery of the affected joint pre- and post-Stage 2 and Absence of mortality. | 180 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Treatment Success | Stage 2 revision prosthesis implanted and Absence of PJI post-Stage 2 and Absence of continued antibiotic therapy for treatment or prophylaxis of PJI and Absence of revision surgery of the affected joint pre- and post-Stage 2 and Absence of mortality. | 365 days | 
| Adverse Event Rate | Comparison of the cumulative proportion of subjects with reported adverse events between the study arms. | 365 days | 
| Quality Adjusted Life Years | Comparison of Quality Adjusted Life Years between the study arms as estimated by EQ-5D-3L. | 365 days | 
| Survival | Comparison of the survival between the study arms. | 365 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hip, Knee, Biofilm, Minimum-biofilm-eradication-concentration