<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03260010</url>
  </required_header>
  <id_info>
    <org_study_id>PROOF</org_study_id>
    <nct_id>NCT03260010</nct_id>
  </id_info>
  <brief_title>Efficacy and Safety of Intravenous Fosfomycin in Prosthetic Joint Infection</brief_title>
  <acronym>PROOF</acronym>
  <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 (&quot;PROOF-Study&quot;)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Pro-Implant Foundation</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Charite University, Berlin, Germany</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Pro-Implant Foundation</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The PROOF Study is an open prospective interventional non-randomized study which aim is to&#xD;
      determine the outcome / effect and safety of fosfomycin in patients with hip, knee or&#xD;
      shoulder PJI.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      To confirm a non-inferior effect and the safety of the investigated antimicrobial fosfomycin&#xD;
      regimen in PJI of the hip, knee or shoulder against an assumed 80% effect (PJI-free&#xD;
      proportion within one year for standard antibiotics aside fosfomycin), following a&#xD;
      standardized surgical therapy involving retention, one-stage exchange or two-stage exchange&#xD;
      (with short or long interval).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">January 15, 2018</start_date>
  <completion_date type="Anticipated">April 15, 2021</completion_date>
  <primary_completion_date type="Anticipated">April 15, 2020</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <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.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Infection cure rate</measure>
    <time_frame>1 year</time_frame>
    <description>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.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Infection cure rate</measure>
    <time_frame>2 years</time_frame>
    <description>Proportion of patients free of Prosthetic Joint-Infection relapse (infection cure rate) within 2 years after inclusion</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of patients with revision</measure>
    <time_frame>1 year</time_frame>
    <description>Proportion of patients with revision (surgical intervention with or without prosthesis removal &gt;4 weeks after last surgical intervention of the initial 12 week treatment period)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of patients with revision due to hematogenous versus non-hematogenous infection</measure>
    <time_frame>1 year</time_frame>
    <description>Proportion of patients with revision due to hematogenous (acute onset with duration of symptoms &lt;3 weeks and onset of symptoms is &gt;3 months after last surgery) versus non-hematogenous infection</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of patients with unscheduled early revisions</measure>
    <time_frame>1 year</time_frame>
    <description>Proportion of patients with unscheduled early revisions (&lt;4 weeks after last scheduled surgical intervention - deep (= bone/joint) revision versus superficial (= skin-soft tissue) revision)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of patients with aseptic revision</measure>
    <time_frame>1 year</time_frame>
    <description>Proportion of patients with aseptic revision</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of patients with implant failure</measure>
    <time_frame>1 year</time_frame>
    <description>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))</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of patients with treatment failure</measure>
    <time_frame>1 year</time_frame>
    <description>Proportion of patients with treatment failure (insufficient primary therapy or PJI relapse)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of patients with initially sufficient versus insufficient primary therapy</measure>
    <time_frame>1 year</time_frame>
    <description>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)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Specific functional joint scores</measure>
    <time_frame>1 year</time_frame>
    <description>Development and changes vs baseline of specific functional joint scores</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>EQ5D5L</measure>
    <time_frame>1 year</time_frame>
    <description>EQ5D5L (in particular for 1 year follow up)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety and tolerability of fosfomycin (frequency of adverse events)</measure>
    <time_frame>1 year</time_frame>
    <description>Safety and tolerability of fosfomycin will be evaluated by measuring the frequency of adverse events, including potential side effects</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic profile of fosfomycin in plasma</measure>
    <time_frame>1 year</time_frame>
    <description>Pharmacokinetic profile of fosfomycin in plasma (steady state after a single application per patient): Cmax</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic profile of fosfomycin in plasma</measure>
    <time_frame>1 year</time_frame>
    <description>Pharmacokinetic profile of fosfomycin in plasma (steady state after a single application per patient): Tmax</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic profile of fosfomycin in plasma</measure>
    <time_frame>1 year</time_frame>
    <description>Pharmacokinetic profile of fosfomycin in plasma (steady state after a single application per patient): Cmin 8 h</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic profile of fosfomycin in plasma</measure>
    <time_frame>1 year</time_frame>
    <description>Pharmacokinetic profile of fosfomycin in plasma (steady state after a single application per patient): t1/2</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic profile of fosfomycin in plasma</measure>
    <time_frame>1 year</time_frame>
    <description>Pharmacokinetic profile of fosfomycin in plasma (steady state after a single application per patient): AUC0-8</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic profile of fosfomycin in plasma</measure>
    <time_frame>1 year</time_frame>
    <description>Pharmacokinetic profile of fosfomycin in plasma (steady state after a single application per patient): extrapolated AUC0-24</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">224</enrollment>
  <condition>Prosthetic Joint Infection</condition>
  <arm_group>
    <arm_group_label>Fosfomycin Arm</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Include intravenous fosfomycin in the treatment of PJI according to predetermined algorithm</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Fosfomycin</intervention_name>
    <description>Infectofos 5 g</description>
    <arm_group_label>Fosfomycin Arm</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Informed consent has been obtained (prior to planned surgical PJI treatment);&#xD;
&#xD;
          2. Subject is ≥18 years of age;&#xD;
&#xD;
          3. Subject has either a culture negative or a culture positive PJI of the hip, knee or&#xD;
             shoulder prosthesis: (i) visible purulence of a preoperative aspirate or&#xD;
             intraoperative periprosthetic tissue (as determined by the surgeon),or (ii) presence&#xD;
             of a sinus tract communicating with the prosthesis, or (iii) acute inflammation in&#xD;
             intraoperative permanent tissue sections by histopathology (as determined by the&#xD;
             pathologist), or (iv) microbial growth in preoperative joint aspirate, intraoperative&#xD;
             periprosthetic tissue or sonication fluid of the removed implant (&gt;50 CFU/ml&#xD;
             sonication fluid), or (v) synovial fluid with &gt;2000 leukocytes/μl or &gt;70%&#xD;
             granulocytes; or reasonable evidence for a suspected PJI (based on clinical,&#xD;
             laboratory, and radiological criteria) to undergo joint surgery to proof the PJI&#xD;
             diagnosis (according to standard of care, Zimmerli W et al. NEJM 2004);&#xD;
&#xD;
          4. For culture positive PJI's at least one of the following isolates:&#xD;
&#xD;
             staphylococci (fosfomycin MHK ≤ 32 mg/ml), streptococci (MHK ≤ 128 mg/ml), enterococci&#xD;
             (MHK ≤ 128 mg/ml), fosfomycin susceptible gram-negative bacilli, including also mixed&#xD;
             infections with other pathogens (fosfomycin susceptible or not);&#xD;
&#xD;
          5. Subject is planned to/will undergo appropriate surgical procedure following the state&#xD;
             of the art PJI treatment algorithm, which includes either debridement &amp; retention of&#xD;
             the prosthesis or exchange of the prosthesis. The exchange includes a one-stage&#xD;
             exchange, two-stage prosthesis exchange with a short interval (2- 3 weeks) or long&#xD;
             interval (6-8 weeks), according to the treatment algorithm;&#xD;
&#xD;
          6. Subject is willing to participate in the study, follow protocol study treatment&#xD;
             regimen, and comply with all planned follow-up assessments.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Allergy or intolerance (or other contraindication) to fosfomycin;&#xD;
&#xD;
          2. Isolation of fungi (molds or yeasts) or mycobacteria;&#xD;
&#xD;
          3. Isolation of one of the following pathogens: staphylococci fosfomycin MHK &gt; 32 mg/ml,&#xD;
             streptococci MHK &gt; 128 mg/ml, enterococci MHK &gt; 128 mg/ml , fosfomycin resistant&#xD;
             gramnegative bacilli;&#xD;
&#xD;
          4. Severely compromised bone/soft tissue pre or during surgery (if during surgery:&#xD;
             exclusion/withdrawal before IMP application);&#xD;
&#xD;
          5. Pregnancy, and/or woman wishing to become pregnant;&#xD;
&#xD;
          6. Breast-feeding;&#xD;
&#xD;
          7. Women of childbearing potential without at least one of the following contraception&#xD;
             methods: correctly placed cooper containing or progestin-containing intrauterine&#xD;
             device (IUD); female condom used WITH a spermicide (i.e. foam gel, film, cream, or&#xD;
             suppository); bilateral tubal ligation/bilateral salpingectomy or bilateral tubal&#xD;
             occlusive procedure (at least till the end of the ambulatory treatment phase);&#xD;
&#xD;
          8. Subject has been previously enrolled in this study or was enrolled in another&#xD;
             interventional medicinal product or medical device study in the last 30 days;&#xD;
&#xD;
          9. Subject had prior exposure to fosfomycin within the past 4 weeks;&#xD;
&#xD;
         10. Inability to read and understand the participant's information;&#xD;
&#xD;
         11. Subjects institutionalized by warrant or court order;&#xD;
&#xD;
         12. Employees of the sponsor or an involved CRO;&#xD;
&#xD;
         13. In pre surgery culture negative patients: All isolates unsusceptible to fosfomycin&#xD;
             after surgery (exclusion / early withdrawal after surgery);&#xD;
&#xD;
         14. Suspected PJI not proven after surgery (exclusion / early withdrawal after surgery).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Andrej Trampuz, PD Dr.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Charité - Univeristätsmedizin</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Alessandra Bardelli, MSCPH, MScAC</last_name>
    <phone>(+49) 030 450 652416</phone>
    <email>alessandra-catalina.bardelli@charite.de</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Andrej Trampuz, PD Dr</last_name>
    <phone>(+49) 030 450 615073</phone>
    <email>andrej.trampuz@charite.de</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Charité - Univeristätsmedizin</name>
      <address>
        <city>Berlin</city>
        <zip>13353</zip>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Svetlana Karbysheva</last_name>
      <phone>+49 30 450 615 048</phone>
      <email>svetlana.karbysheva@charite.de</email>
    </contact>
  </location>
  <location_countries>
    <country>Germany</country>
  </location_countries>
  <verification_date>August 2017</verification_date>
  <study_first_submitted>August 15, 2017</study_first_submitted>
  <study_first_submitted_qc>August 21, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 24, 2017</study_first_posted>
  <last_update_submitted>April 17, 2018</last_update_submitted>
  <last_update_submitted_qc>April 17, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">April 19, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Infections</mesh_term>
    <mesh_term>Communicable Diseases</mesh_term>
    <mesh_term>Arthritis, Infectious</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Fosfomycin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03260010
org study id: PROOF
nct id: NCT03260010
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
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.
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).
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.
primary purpose: Treatment
masking: None (Open Label)
measure: Infection cure rate
time frame: 1 year
description: 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.
measure: Infection cure rate
time frame: 2 years
description: Proportion of patients free of Prosthetic Joint-Infection relapse (infection cure rate) within 2 years after inclusion
measure: Proportion of patients with revision
time frame: 1 year
description: 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)
measure: Proportion of patients with revision due to hematogenous versus non-hematogenous infection
time frame: 1 year
description: 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
measure: Proportion of patients with unscheduled early revisions
time frame: 1 year
description: Proportion of patients with unscheduled early revisions (<4 weeks after last scheduled surgical intervention - deep (= bone/joint) revision versus superficial (= skin-soft tissue) revision)
measure: Proportion of patients with aseptic revision
time frame: 1 year
description: Proportion of patients with aseptic revision
measure: Proportion of patients with implant failure
time frame: 1 year
description: 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))
measure: Proportion of patients with treatment failure
time frame: 1 year
description: Proportion of patients with treatment failure (insufficient primary therapy or PJI relapse)
measure: Proportion of patients with initially sufficient versus insufficient primary therapy
time frame: 1 year
description: 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)
measure: Specific functional joint scores
time frame: 1 year
description: Development and changes vs baseline of specific functional joint scores
measure: EQ5D5L
time frame: 1 year
description: EQ5D5L (in particular for 1 year follow up)
measure: Safety and tolerability of fosfomycin (frequency of adverse events)
time frame: 1 year
description: Safety and tolerability of fosfomycin will be evaluated by measuring the frequency of adverse events, including potential side effects
measure: Pharmacokinetic profile of fosfomycin in plasma
time frame: 1 year
description: Pharmacokinetic profile of fosfomycin in plasma (steady state after a single application per patient): Cmax
measure: Pharmacokinetic profile of fosfomycin in plasma
time frame: 1 year
description: Pharmacokinetic profile of fosfomycin in plasma (steady state after a single application per patient): Tmax
measure: Pharmacokinetic profile of fosfomycin in plasma
time frame: 1 year
description: Pharmacokinetic profile of fosfomycin in plasma (steady state after a single application per patient): Cmin 8 h
measure: Pharmacokinetic profile of fosfomycin in plasma
time frame: 1 year
description: Pharmacokinetic profile of fosfomycin in plasma (steady state after a single application per patient): t1/2
measure: Pharmacokinetic profile of fosfomycin in plasma
time frame: 1 year
description: Pharmacokinetic profile of fosfomycin in plasma (steady state after a single application per patient): AUC0-8
measure: Pharmacokinetic profile of fosfomycin in plasma
time frame: 1 year
description: Pharmacokinetic profile of fosfomycin in plasma (steady state after a single application per patient): extrapolated AUC0-24
arm group label: Fosfomycin Arm
arm group type: Experimental
description: Include intravenous fosfomycin in the treatment of PJI according to predetermined algorithm
intervention type: Drug
intervention name: Fosfomycin
description: Infectofos 5 g
arm group label: Fosfomycin Arm
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Andrej Trampuz, PD Dr.
role: Principal Investigator
affiliation: Charité - Univeristätsmedizin
last name: Alessandra Bardelli, MSCPH, MScAC
phone: (+49) 030 450 652416
email: alessandra-catalina.bardelli@charite.de
last name: Andrej Trampuz, PD Dr
phone: (+49) 030 450 615073
email: andrej.trampuz@charite.de
facility: 
status: Recruiting
contact: 
country: Germany
responsible party type: Sponsor
mesh term: Infections
mesh term: Communicable Diseases
mesh term: Arthritis, Infectious
mesh term: Fosfomycin
sharing ipd: No