Considering the paucity and the variability of data regarding the clinical control of infection in patients presenting a prosthesis Joint Infection (PJI) later than 1 month after the arthroplasty and treated with DAIR + suppressive antibiotics…
ID
Source
Brief title
Condition
- Bacterial infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Clinical control of infection at week 12±2 defined by:
- no clinical signs of evolutive infection:
o no fever (defined by a temperature less than 38°C) due to prosthesis infection
o no recurrence, no worsening pain assessed with an Visual Analog Scale (VAS)
and defined by an VAS at Week 12 below VAS prior to D0
- Peri articular Inflammatory and infectious Clinical signs will be collected :
o No local post surgical recurrence or worsening of local articular swelling
o No unusual aspect of scar as erythema or abnormal flow or a fistula or
inflammatory or local necrosis or no healing
- and no new surgical procedure requested before Week 12±2 and no
Staphylococcus aureus detected in joint fluid in case of aspiration for
suspicion of relapse before Week 12±2
Secondary outcome
1. Safety parameters: adverse events, physical examination, biological tests as
hematology and biochemistry during the whole study;
2. Initial activity of phages: active bacteriophages (PP1493 and/or PP1815)
according to phagogram results in regard of the clinical outcome (infection
control or relapse) of patients at Week 12±2
3. Clinical control of the infection (as described in primary endpoint) at Week
12±2 for superinfected patients (other species isolated during the surgical
procedure)
4. In case of failure before Week 12±2, aspiration of joint fluid at time of
failure for microbiological test and identification of Staphylococcus aureus
strain: antibiogram and phagogram
5. Microbiology:
- Joint fluid: Staphylococcus aureus quantification (CFU and qPCR) at D0 for
THA and TKA at D14±1 only for TKA
6. Immunology:
- Serum: anti Staphylococcus aureus phage antibodies, at D0, D2, D4, D14±1,
D28±2 and Week 12±2 and IL-6 at D0, D14±1 and W12±2
- Joint fluid: anti Staphylococcus aureus phage antibodies at D0 and at D14±1
only for patients with TKA
7. Pharmacokinetics:
- Serum: quantification of the phages by qPCR at D0, D0T4H, D2, D4, D14±1,
D28±2 and Week 12±2
- Blood: quantification of the phages by plaque assay at D0, D0T4H, D2, D4,
D14±1, D28±2 and Week 12±2 for patients in sites in Paris, Nantes and Lyon
- Joint Fluid: quantification of the phage by qPCR and plaque assay at D0 and
at D14±1 only for patients with TKA; the plaque assay will be performed only
for patients in sites in Paris, Nantes and Lyon;
8. Duration of hospitalization
9. Questionnaire EQ-5D-5L for quality of life at each visit (except D14±1 and
D28±2);
10. Evaluation of joint function during the pre-inclusion period or at D-1,
Week 12±2, Month 6 ±2 weeks, Month 12±1, Month 18±1 and Month 24±2 with:
- Knee: KOOS 12-Knee Survey
- Hip: HOOS 12-Hip Survey;
11. Clinical control of the infection (as described in primary endpoint) at
Month 6±2 weeks, Month 12±1, Month 18±1 and Month 24±2;
12. X Ray during the pre-inclusion period or at D-1, Week 12±2, Month6 ±2
weeks, Month 12±1, Month 18±1 and Month 24±2: to check potential appearance of
abnormal loosening (border with shifting of the prosthesis), or an abnormal
periprosthetic border;
13. In case of rescue treatment: clinical infection control at Week12-RT±2
after the first ultra-guided injection, safety parameters, pharmacokinetics,
bacteriological and immunological tests.
Background summary
The main causality of PJIs in THA and TKA are Gram-positive cocci, which are
largely driven by infection with Staphylococcus aureus and coagulase-negative
staphylococci. Together, these bacteria contribute to 50-60% of PJIs;
streptococci and enterococci only account for 10% of cases (8;11) and in 90% of
cases, infections are monomicrobial (5).
Beside the antibiotic resistance, the ability of a bacterium to form biofilm
largely contributes to treatment failure (14). Biofilms are formed when
microorganisms such as Staphylococcus spp. adhere to a substratum or interface
to form an aggregate. They have been reported to account for more than 80% of
microbial infections in the body, including prosthesis and internal fixation
devices (15). Bacteria, such as Staphylococcus aureus and Staphylococcus
epidermidis, can form biofilms on stainless steel and titanium orthopaedic
screws with ease (16). Therefore, when considering new anti-infectious
treatment, especially to fight PJI, the anti-biofilm activity is of major
concern.
Bacteriophage therapy, also referred to as phage therapy, could be an
improvement for treating PJIs. Phages are naturally occurring, highly specific
bacterial viruses that invade bacterial cells and disrupt metabolism, causing
lysis and destroying the microbe. There are limited nonclinical in vivo studies
published on phage therapy for bone-related infections. In a PJI model using
MRSA, in which the antibiotic and phages were incorporated in a biopolymer
coated on the implant before implantation. It was demonstrated that a
phage-antibiotic combination led to an effective control of the bacterial
burden and inflammatory response. The animals treated with phages showed a
faster restoration of locomotion as compared to the individual treatments.
Another preclinical model of implant related infection showed that the
phage-antibiotic combination decreased the biofilm thickness as compared to the
antibiotic alone (26).
In vitro anti-Staphylococcus aureus bacteriophages were shown to be effective
in reducing viable biofilm-associated cells and synergistic properties of
phages with certain antibiotics have been reported (27).
In a clinical setting, phage therapy is currently used as standard practice in
Georgia and Poland (28) and consequently, studies have been concentrated in
Eastern Europe. There is currently no phage therapy approved for use in Western
countries; however, some phage studies have been conducted in France, Belgium,
United States of America, United Kingdom and Switzerland (29,30, 31,32), for
chronic leg venous ulcer, chronic otitis media and burn wound infections.
Additional studies are in the pipeline (33).
Although some positive results have been published from in vivo studies using
implant-related infection models (25,26), an adequate model for PJIs is still
to be perfected. Indeed, Kaur et al. demonstrated phage efficacy when phages
were coated on the implant (25), and Yilmaz et al (26) demonstrated activity of
the phages on the biofilm thickness but not on the control of the bacterial
burden.
Lastly, as with all biological therapies, there are immunogenicity concerns.
Numerous studies have demonstrated in various animal species that repeated
phage injections trigger an antibody response with anti-phage IgM and IgG
production (34,35). Some studies have also shown in vitro that in some cases
they correspond to neutralizing antibodies, meaning that they decrease the
phage activity. However, it remains unclear whether the presence of
neutralizing antibodies has an impact on the therapeutic outcome of the phage
therapy. In samples from 20 patients having been administered a Staphylococcus
aureus phage cocktail orally and locally to treat a variety of infections, most
patients did not present with high levels of anti-phage antibodies in the
sampled serum. In patients with an increased immune response (induction of IgG
and IgM antibodies), in general, the clinical response was not greatly affected
(36,37).
Pherecydes Pharma is a French Biotechnology Company specializing in the
research and development of anti-infective therapies based on the use of
bacteriophages (phages). It currently owns collections of phages against
Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus.
Currently Pherecydes Pharma has two anti-Staphylococcus aureus phages in
development: PP1493 and PP1815. To date, these phages have undergone extensive
physiochemical tests, studies of anti-infective activity in vitro and in vivo,
pharmacokinetic (PK), and toxicity studies in laboratory animals. These phages
have shown promising in vitro efficacy as well as in vivo tolerance. The
anti-Staphylococcus aureus phages will be tested in vitro against the patient*s
specific Staphylococcus aureus strain: this will be referred to as a phagogram.
This allows the selection of phages active against a particular patient*s
infecting bacteria and only active phages will be administered to the patient.
Until now, no clinical trial has been carried out with the Pherecydes
anti-Staphylococcus aureus bacteriophages in prosthetic joint infection (PJI)
nor any other pathology.
PhagoDAIR I
Prosthesis exchange could be associated with a considerable loss of function,
especially if the patient needs a prosthesis revision with a complex
reconstruction, a resection arthroplasty of the hip (removal of the prosthesis
without possibility of a reimplantation), arthrodesis of the knee or
amputation. For these patients, using locally an antibiofilm agent facilitating
the rescue could be of importance, to limit the loss of function and the
considerable additional cost associated with complex surgeries. As anti-
Staphylococcus aureus bacteriophages demonstrated in vitro antibiofilm
activity, we hypothesized that they could facilitate the efficacy of DAIR with
antibiotics to control the infection, and to avoid prosthesis revision and
considerable loss of function.
PhagoDAIR I will be the first phagotherapy clinical trial in this indication.
Study objective
Considering the paucity and the variability of data regarding the clinical
control of infection in patients presenting a prosthesis Joint Infection (PJI)
later than 1 month after the arthroplasty and treated with DAIR + suppressive
antibiotics therapy and the absence of efficacy data in patients treated by
phagotherapy, a pilot study is necessary.
Then, the overall objective of this pilot study is to generate data which will
allow to optimize the design of future comparative studies on the efficacy of
phage therapy in patients presenting a prosthesis Joint Infection (PJI) later
than 1 month after the arthroplasty.
To estimate the rate of clinical control of infection due to Staphylococcus
aureus at Week 12±2 of two different therapeutic regimens: DAIR + curative
antibiotics therapy combined with bacteriophages or solution of NaCl 0.9%; in
patients presenting a Prosthesis Joint Infection (PJI) later than 1 month after
the arthroplasty, with the indication of DAIR + Suppressive Antibiotics Therapy
(SAT) which will allow to calculate the sample size for future comparative
studies.
Study design
This is a pilot, randomized, non-comparative, double-blind study in patients
with knee or hip prosthetic joint infection (PJI) due to Staphylococcus aureus,
with the indication of DAIR and suppressive antibiotic therapy. A
stratification will be based on the affected area of arthroplasty: knee, hip
and on study site.
Intervention
anti- Staphylococcus aureus bacteriophages
Study burden and risks
- Chance of measurements during examination (blood sampling, puncture)
- Extra visits to the hospital (9)
- Keep to agreements that are part of the research
- There are no known risks for the use of bacteriophages
Avenue Rockefeller 60
Lyon 69008
FR
Avenue Rockefeller 60
Lyon 69008
FR
Listed location countries
Age
Inclusion criteria
1. Male or female >= 18 years
2. Staphylococcus aureus monomicrobial knee or hip PJI *1 month after
prosthesis implantation with clinical signs of infection and with indication of
DAIR with direct closure (if associated flap, arthrotomy must be sealed), and
Suppressive Antibiotics Therapy (SAT)
3. Staphylococcus aureus only in joint fluid within 6 months before
randomization or in case of relapse of infection under antibiotics therapy
after a DAIR performed within 6 months before pre-inclusion visit
4. Without preoperative diagnosis of superinfection due to another pathogen if
treatment is administered at the end of the DAIR
5. Without diagnosis of superinfection due to another pathogen identified
within 72h after a bacteriological sample performed during a DAIR if treatment
is administered 14±2 days after a DAIR.
6. Phagogram displaying the susceptibility of the strain to at least one of the
phages.
7. Patient with a life expectancy of 2 years and more as determined by the
principal investigator
8. Females of childbearing potential/Sexually active males with partner of
childbearing potential: commitment to consistently and correctly use an
acceptable effective method of birth control (oral, transdermal, systemic or
implant contraception birth control, intrauterine devices, condom) for 1 month
after the last study drug administration
9. Females of non-childbearing potential: either surgically sterilized or at
least 1 year postmenopausal (amenorrhea duration at least 12 months)
10. Negative pregnancy test
11. Signing a written informed consent before any study related procedures
including phagogram
12. Affiliated to a national social security system and / or private health
insurance in compliance with the
Exclusion criteria
1. Early Staphylococcus aureus Prosthesis Joint infection (*1month after the
prosthesis implantation)
2. Other germ found in culture of joint fluid sample
3. Phagogram displaying no susceptibility of the strain to anti-Staphylococcus
aureus bacteriophages
4. Patients with ASA score >= 4
5. Severe sepsis or Septic shock or hemodynamic instability
6. Patients with an indication to prosthesis replacement or amputation
7. Immunosuppressed patients
8. Known allergic reactions to components of phages products
9. Relapse between DAIR and treatment administration planned 14±2 days after a
DAIR
10. Medical history which in the opinion of the investigator would mean that
the patient is unsuitable for participation in the study
11. Patient who, in the judgment of the Investigator, is likely to be
non-compliant or uncooperative during the study, or unable to cooperate because
of a language problem, poor mental development
12. Currently in exclusion period from a previous study
13. Concomitant participation to another interventional clinical trial or
previous participation with active drug levels still present, i.e. the last
medication intake is less than 4 half-lives ago
14. Patients who are pregnant or breastfeeding. Patients should not be enrolled
if they plan to become pregnant during the treatment period and up to 1 month
after the last administration of study drug
15. Women/Men refusing to use an acceptable effective contraception during 1
month after the last administration of study drug
16. No possibility of contact in case of emergency
17. Minors, persons deprived of liberty by judicial or administrative decision,
persons receiving psychiatric care and persons admitted to a health or social
institution, to adult patient under legal protection or unable to express
consent.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2021-004469-11-NL |
| ClinicalTrials.gov | NCT05369104 |
| CCMO | NL83287.000.23 |