Efficacy and safety of intravenous fosfomycin in prosthetic joint infection (PJI)

Phase 1

• Conditions: Prosthetic joint infection of knee, hip or shoulder; Therapeutic area: Diseases [C] - Musculoskeletal Diseases [C05]

• Registration Number: EUCTR2016-002673-35-DE
• Lead Sponsor: PRO-IMPLANT Foundation

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2016-12-07
• Last Update Posted: 30 April 2019

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: Not specified
• Target Recruitment: 226

Inclusion Criteria

1. Informed consent has been obtained (prior to planned surgical PJI treatment);
2. Subject is =18 years of age;
3. Subject has either a culture negative or a culture positive PJI of the hip, knee or shoulder prosthesis:
(i) visible purulence of a preoperative aspirate or intraoperative periprosthetic tissue (as determined by the surgeon),or
(ii) presence of a sinus tract communicating with the prosthesis, or
(iii) acute inflammation in intraoperative permanent tissue sections by histopathology (as determined by the pathologist), or
(iv) microbial growth in preoperative joint aspirate, intraoperative periprosthetic tissue or sonication fluid of the removed implant (>50 CFU/ml sonication fluid), or
(v) synovial fluid with >2000 leukocytes/µl or >70% granulocytes;
or reasonable evidence for a suspected PJI (based on clinical, laboratory, and radiological criteria) to undergo joint surgery to proof the PJI diagnosis (according to standard of care, Zimmerli W et al. NEJM 2004);
4. For culture positive PJI’s at least one of the following isolates: staphylococci (fosfomycin MHK = 32 mg/ml), streptococci (MHK = 128 mg/ml), enterococci (MHK = 128 mg/ml), fosfomycin susceptible gram-negative bacilli, including also mixed infections with other pathogens (fosfomycin susceptible or not);
5. Subject is planned to/will undergo appropriate surgical procedure following the state of the art PJI treatment algorithm, which includes either debridement & retention of the prosthesis or exchange of the prosthesis. The exchange includes a one-stage exchange, two-stage prosthesis exchange with a short interval (2-3 weeks) or long interval (6-8 weeks), according to the treatment algorithm;
6. Subject is willing to participate in the study, follow protocol study treatment regimen, and comply with all planned follow-up assessments.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 46
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 180

Exclusion Criteria

1. Allergy or intolerance (or other contraindication) to fosfomycin;
2. Isolation of fungi (molds or yeasts) or mycobacteria ;
3. Isolation of at least one of the following pathogens: staphylococci MHK > 32 mg/ml, streptococci MHK > 128 mg/ml, enterococci MHK > 128 mg/ml, fosfomycin resistant gram-negative bacilli;
4. Severely compromised bone/soft tissue pre or during surgery (if during surgery: exclusion/withdrawal before IMP application);
5. Pregnancy, and/or women wishing to become pregnant;
6. Breast-feeding;
7. Women of childbearing potential* without at least one of the following contraception methods: correctly placed cooper-containing or progestin-containing intrauterine device (IUD); female condom used WITH a spermicide (i.e. foam gel, film, cream, or suppository); bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive procedure (at least till the end of the ambulatory treatment phase)**;
8. Subject has been previously enrolled in this study or was enrolled in another interventional medicinal product or medical device study in the last 30 days;
9. Subject had prior exposure to fosfomycin within the past 4 weeks;
10. Inability to read and understand the participant’s information;
11. Subjects institutionalized by warrant or court order;
12. Employees of the sponsor or an involved CRO;
13. In pre surgery culture negative patients: All isolates unsusceptible to fosfomycin after surgery (exclusion / early withdrawal after surgery);
14. Suspected PJI not proven after surgery (exclusion / early withdrawal after surgery).

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To confirm the non-inferior effect and safety of the investigated antimicrobial fosfomycin regimen in prosthetic joint infection (PJI) of the hip, knee or shoulder against an assumed 80% efficacy (PJI-free proportion within one year for standard antibiotics aside fosfomycin), following a standardized surgical therapy involving retention, one-stage exchange or two-stage exchange (with short or long interval). ;Secondary Objective: An additional objective is to characterize the population pharmacokinetic profile of fosfomycin in plasma to quantify inter- and intra-patient variability and to identify sources of variability in drug concentrations. ;Primary end point(s): Proportion of patients free of PJI-relapse within 1 year after inclusion (according to PJI definition, s. inclusion - only PJIs of the initially affected joint). ;Timepoint(s) of evaluation of this end point: Primary analysis after completion of the 1 year follow up data set.