A Randomized Feasibility Clinical Trial of Phage Therapy in Periprosthetic Joint Infections Treated With Debridement Antibiotic Implant Retention (DAIR) Procedure.
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 入组人数
- 10
- 试验地点
- 1
- 主要终点
- Incidence of treatment emergent adverse event
研究概览
简要总结
Total joint replacement (TJR) has revolutionized care provided for patients suffering from disabling joint pain. Unfortunately, periprosthetic joint infection (PJI) remains a devastating complication and the leading cause of failure after TJR. Current standard treatment for PJI requires multiple surgical revisions of the infected prosthesis in combination with a prolonged course of systemic antibiotic therapy. Debridement Antibiotic and Implant Retention (DAIR) procedure is one of the surgical options that is routinely used to manage PJI, due to its lower risk of morbidity and surgical cost. DAIR is often used for patients who present with an acute PJI or who cannot tolerate a complex implant revision. However, the overall success rate for DAIR is ranging between 60-70%. DAIR failures are often attributed to the residual infection and biofilm burden left behind on the retained implant surface, which cannot be targeted effectively with post-operative systemic antibiotics. Therefore, research has been ongoing to identify non-surgical multidrug resistance (MDR) treatment adjuncts that can synergize the therapeutic effects of antibiotics in PJI care.
Numerous preclinical bone and joint infection models have clearly demonstrated such therapeutic benefits using bacteriophages (phages). Phages target bacterial cells and breakdown biofilm that it forms on the implant surface. Each bacterial strain tends to have a particular phage that is susceptible to that bacterial strain. Due to this phage specificity and the fact that bacteria can still develop resistance against a single phage, the concept of using a phage cocktail (mixture of 2 or more phage candidates) has been the preferred treatment approach for applying phage therapy. Using a phage cocktail provides a broader spectrum of bacterial strain coverage and makes it harder for the bacteria to develop resistance. Published literature has considered phage therapy to be safe for direct administration at the infection site with minimal adverse events provided that the phage preparation administered meets Good Manufacturing Practice (GMP).
The DePHEAT PJI trail, is a prospective, single center, 1:1 non-blinded feasibility randomized controlled trial (RCT) that aims to assess the safety and the effectiveness of the experimental phage therapy cocktails for patients with hip or knee PJI caused by either Staphylococcus (S.) aureus or Pseudomonas (P.) aeruginosa and comparing it to standardized therapy.
The investigator hypothesizes that this pilot RCT will help evaluate the practicality and potential risks associated with adding phage therapy to the conventional standard of care treatment plan. This will initiate the development of a necessary infrastructure for future phage trials and programs that expand our understanding on the benefits of using phage therapy for acute PJI.
详细描述
Total joint replacement (TJR) has revolutionized care provided for patients suffering from disabling joint pain. Unfortunately, periprosthetic joint infection (PJI) remains a devastating complication and the leading cause of failure after TJR. While the current cost in Canada per hip or knee TJR averages $7k CAD, the cost to treat a PJI complication after a hip or knee TJR is five times that amount. In addition, data collected by national and international joint replacement registries demonstrate that the health and economic burden of PJI is a mounting crisis due to the exponential increase in demand for TJR. Current standard treatment for PJI requires multiple surgical revisions of the infected prosthesis in combination with a prolonged course of systemic antibiotic therapy. This standard treatment approach has a failure rate of 20-30%. Unfortunately, this treatment failure is often associated with high rates of psychological distress, limb amputations and death. Debridement Antibiotic and Implant Retention (DAIR) procedure is one of the surgical options that is routinely used to manage PJI, due to its lower risk of morbidity and surgical cost. DAIR is often used for patients who present with an acute PJI or who cannot tolerate a complex implant revision. However, the overall success rate for DAIR is at the lower end of the spectrum, ranging between 60-70%. DAIR failures are often attributed to the residual infection and biofilm burden left behind on the retained implant surface, which cannot be targeted effectively with post-operative systemic antibiotics. Therefore, research has been ongoing to identify non-surgical multidrug resistance (MDR) treatment adjuncts that can synergize the therapeutic effects of antibiotics in PJI care.
Numerous preclinical bone and joint infection models have clearly demonstrated such therapeutic benefits using bacteriophages (phages). Phages target bacterial cells and breakdown biofilm that it forms on the implant surface. Each bacterial strain tends to have a particular phage that is susceptible to that bacterial strain. Due to this phage specificity and the fact that bacteria can still develop resistance against a single phage, the concept of using a phage cocktail (mixture of 2 or more phage candidates) has been the preferred treatment approach for applying phage therapy. Using a phage cocktail provides a broader spectrum of bacterial strain coverage and makes it harder for the bacteria to develop resistance. Over the past decade, there has been a rise in international interest and effort to translate the antimicrobial therapeutic potential of phages towards this challenging group of patients suffering from bone and joint infections. Published literature has considered phage therapy to be safe for direct administration at the infection site with minimal adverse events provided that the phage preparation administered meets Good Manufacturing Practice (GMP).
The overarching purpose of this trial is to assess the feasibility, safety and effectiveness of phage therapy in patients with hip or knee PJI. The investigators hypothesize that this pilot RCT will help evaluate the practicality and potential risks associated with adding phage therapy to the conventional standard of care treatment plan. This will initiate the development of a necessary infrastructure for future phage trials and programs that expand our understanding on the benefits of using phage therapy for acute PJI.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients are 18 years or older
- •Patients have been diagnosed with bacterial PJI caused by a single organism (either S. aureus or P. aeruginosa) confirmed through synovial fluid cultures.
- •Patients are undergoing DAIR surgical procedure for hip or knee PJI
- •Patients are clinically stable and independently mobile
- •Patients are willing and able to consent
排除标准
- •Patients have cultured multiple bacteria, and it is difficult for physicians to determine which bacteria is causing the disease
- •Patients develop a life-threatening condition or a condition that leads to deterioration of the patient's medical condition and that is unrelated to the known PJI as cerebrovascular accident, angina, cancer.
- •Patient's clinical condition is no longer stable and deteriorating, for example, if the patient develops sepsis secondary to PJI prior to the commencement of the phage therapy.
- •Patients who have only been through a hemiarthroplasty or uni-compartmental arthroplasty with infected implant component
- •Patients receiving any immunomodulating or immunosuppressive therapy medications for malignancy or autoimmune disease (with exception to inflammatory arthritis), chronic glucocorticoid use (≥ 20mg of prednisolone daily for at least 1 month with another cause of immunosuppression), and history of solid organ and/or bone marrow transplantation.
- •Presence of concurrent active viral infection, or history of uncontrolled HIV (CD4 count <200 cells/uL).
- •Patient is pregnant or breast feeding
研究组 & 干预措施
Standard of care (DAIR + Antibiotics)
Patients will receive the standard of care for hip and knee periprosthetic joint infection which is DAIR ( Debridement Antibiotic and Implant Retention) and antibiotic according to the bacterial culture.
Bacteriophage treatment + DAIR + Antibiotics
In addition to the standard of care procedure (DAIR and antibiotics), patients in the experimental arm will receive 3 doses of intra-articular phage therapy. The first dose will be given intra-operatively after the DAIR and then will be done at day 14 and day 21 postoperatively. The second and third intra-articular injections will be done under image guidance.
干预措施: The investigational product specifically targeting P. aeruginosa (DP-QB-PSA-005) and that targeting S. aureus (DP-QB-STA-005), each formed of a mixture of 5 bacteriophages. (Biological)
结局指标
主要结局
Incidence of treatment emergent adverse event
时间窗: up to 12 months
focuses on documenting any adverse events (both transient and persistent) or reactions associated with phage therapy. * Monitoring for signs and symptoms of allergic reactions after each phage administration, which could be manifested as fever, rash, flushing, hypotension * Monitoring for any signs and symptoms of emerging new infections * Monitoring for emergence of resistance to phage therapy or to antibiotics
Evaluation of the feasibility of the trial design
时间窗: up to 3 months
To assess the practical aspect of administering phage therapy in a hospital setting. This trial will define the achievability of performing a future larger scale trial. This trial will be evaluating the following: * logistical challenges related to transportation, storage and handling of phage therapy * operational challenges including technical and time feasibility factors * patient recruitment and acceptance to participating in such a trial
次要结局
- Assessment of clinical response effectiveness to phage therapy(up to 12 months)
- Assessment of Microbiological effectiveness of phage therapy(up to 12 months)
- Assessment of biochemical effectiveness of the phage therapy(Up to 12 months)