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Efficacy and Safety of Intravenous Fosfomycin in Prosthetic Joint Infection

Sponsor
Charite University, Berlin, Germany (Other)
Overall Status
Active, not recruiting
CT.gov ID
NCT05211011
Collaborator
Pro-Implant Foundation (Other)
226
Enrollment
16
Locations
1
Arm
63.2
Anticipated Duration (Months)
14.1
Patients Per Site
0.2
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The PROOF Study is an open prospective interventional non-randomized study which aim is to determine the outcome / effect and safety of fosfomycin in patients with hip, knee or shoulder PJI.

Condition or Disease Intervention/Treatment Phase
Phase 4

Detailed Description

To confirm a non-inferior effect and the safety of the investigated antimicrobial fosfomycin regimen in PJI of the hip, knee or shoulder against an assumed 80% effect (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).

Study Design

Study Type:
Interventional
Actual Enrollment :
226 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Intervention Model Description:
In this open prospective interventional clinical study patients with hip, knee or shoulder PJI (as defined below) caused by fosfomycin-susceptible staphylococci, streptococci, enterococci or gram-negative bacilli will be included. After inclusion and PJI-surgery, intravenous fosfomycin will be given 5 g every 8 hours for 1, 2, 3-or -4 weeks according to the pathogen and surgery procedure and generally as a part of the antibiotic combination therapy of the treatment algorithm. This Treatment is followed by oral antibiotics for a total of 3 months.In this open prospective interventional clinical study patients with hip, knee or shoulder PJI (as defined below) caused by fosfomycin-susceptible staphylococci, streptococci, enterococci or gram-negative bacilli will be included. After inclusion and PJI-surgery, intravenous fosfomycin will be given 5 g every 8 hours for 1, 2, 3-or -4 weeks according to the pathogen and surgery procedure and generally as a part of the antibiotic combination therapy of the treatment algorithm. This Treatment is followed by oral antibiotics for a total of 3 months.
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Efficacy and Safety of Intravenous Fosfomycin in Prosthetic Joint Infection (PJI) Caused by Staphylococci, Streptococci, Enterococci and Gram-negative Bacilli, Including Mixed Infections and Culture Negative PJI's ("PROOF-Study")
Actual Study Start Date :
Jan 23, 2018
Anticipated Primary Completion Date :
Apr 30, 2022
Anticipated Study Completion Date :
Apr 30, 2023

Arms and Interventions

Arm Intervention/Treatment
Experimental: Fosfomycin Arm

Include intravenous fosfomycin in the treatment of PJI according to predetermined algorithm

Drug: Fosfomycin
Infectofos 5 g
Other Names:
  • Infectofos

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Infection cure rate [1 year]

      Proportion of patients free of PJI relapse (i.e. infection cure rate) within 1 year after inclusion. Relapse is defined as new PJI diagnosis more than 4 weeks after the last surgical intervention of the initial 12 week treatment period.

    Secondary Outcome Measures

    1. Infection cure rate [2 years]

      Proportion of patients free of Prosthetic Joint-Infection relapse (infection cure rate) within 2 years after inclusion

    2. Proportion of patients with revision [1 year]

      Proportion of patients with revision (surgical intervention with or without prosthesis removal >4 weeks after last surgical intervention of the initial 12 week treatment period)

    3. Proportion of patients with revision due to hematogenous versus non-hematogenous infection [1 year]

      Proportion of patients with revision due to hematogenous (acute onset with duration of symptoms <3 weeks and onset of symptoms is >3 months after last surgery) versus non-hematogenous infection

    4. Proportion of patients with unscheduled early revisions [1 year]

      Proportion of patients with unscheduled early revisions (<4 weeks after last scheduled surgical intervention - deep (= bone/joint) revision versus superficial (= skin-soft tissue) revision)

    5. Proportion of patients with aseptic revision [1 year]

      Proportion of patients with aseptic revision

    6. Proportion of patients with implant failure [1 year]

      Proportion of patients with implant failure (any functionally affected or pain producing implant, clinically relevant abnormal laboratory test result indicating PJI, or presence of radiological signs of loosening, according to the investigator (Yes/No))

    7. Proportion of patients with treatment failure [1 year]

      Proportion of patients with treatment failure (insufficient primary therapy or PJI relapse)

    8. Proportion of patients with initially sufficient versus insufficient primary therapy [1 year]

      Proportion of patients with initially sufficient versus insufficient primary therapy (defined by the judgement of the investigator, based on combined clinical, laboratory, microbiological and radiological criteria, e.g. clear reduction of wound secretion)

    9. Specific functional joint scores [1 year]

      Development and changes vs baseline of specific functional joint scores

    10. EQ5D5L [1 year]

      EQ5D5L (in particular for 1 year follow up)

    11. Safety and tolerability of fosfomycin [1 year]

      Safety and tolerability of fosfomycin will be evaluated by measuring the frequency of adverse events, including potential side effects

    12. Peak Plasma Concentration (Cmax) [1 year]

      Pharmacokinetic profile of fosfomycin in plasma

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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);

    1. 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;

    2. Subject is willing to participate in the study, follow protocol study treatment regimen, and comply with all planned follow-up assessments.

    Exclusion Criteria:

    1. Allergy or intolerance (or other contraindication) to fosfomycin;

    2. Isolation of fungi (molds or yeasts) or mycobacteria;

    3. Isolation of one of the following pathogens: staphylococci fosfomycin MHK > 32 mg/ml, streptococci MHK > 128 mg/ml, enterococci MHK > 128 mg/ml , fosfomycin resistant gramnegative bacilli;

    4. Severely compromised bone/soft tissue pre or during surgery (if during surgery: exclusion/withdrawalbefore IMP application);

    5. Pregnancy, and/or woman wishing to become pregnant;

    6. Breast-feeding;

    7. Women of childbearing potential without at least one of the following contraception methods: correctly placed coopercontaining 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).

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 BG Universitätsklinikum Bergmannsheil Bochum Nordrhein-Westfalen Germany 44789
    2 Charité Berlin Germany 13353
    3 Universitätsklinikum Bonn Bonn Germany 53105
    4 Städtisches Klinikum Dresden Dresden Germany 01067
    5 Universitätsklinikum Dresden Dresden Germany 01307
    6 Universitätsklinikum Düsseldorf Düsseldorf Germany 40225
    7 Waldkrankenhaus Rudolf Elle GmbH Eisenberg Germany 07607
    8 St. Josef Krankenhaus Essen-Werden Essen Germany 45239
    9 Helios Klinikum Hildesheim Hildesheim Germany 31135
    10 Krankenhaus Köln-Merheim Köln Germany 51109
    11 Universitätsmedizin Mainz Mainz Germany 55131
    12 St. Franziskus Hospital Münster Münster Germany 48145
    13 Universitätsklinikum Regensburg Regensburg Germany 93053
    14 Sophien- und Hufelandklinikum GmbH Weimar Weimar Germany 99425
    15 Krankenhaus Johanneum Wildeshausen Germany 27793
    16 Krankenhaus St. Josef Wuppertal Germany 42105

    Sponsors and Collaborators

    • Charite University, Berlin, Germany
    • Pro-Implant Foundation

    Investigators

    • Principal Investigator: Andrej Trampuz, PD Dr, Charite University, Berlin, Germany

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Andrej Trampuz, Principle Investigator, Charite University, Berlin, Germany
    ClinicalTrials.gov Identifier:
    NCT05211011
    Other Study ID Numbers:
    • PROOF
    First Posted:
    Jan 27, 2022
    Last Update Posted:
    Jan 27, 2022
    Last Verified:
    Jan 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    No
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:
    Infections
    Communicable Diseases
    Arthritis, Infectious
    Fosfomycin

    Study Results

    No Results Posted as of Jan 27, 2022