Efficacy and Safety Study of Antibiotic Treatment to Treat Hip Prosthetic Joint Infection (LIZ-BONE)

Prospective,Randomized,Open Label,European Multicenter Study of the Efficacy of the Linezolid-rifampin Combination Versus Standard of Care in the Treatment of Gram-positive.

The purpose of this study is to evaluate the efficacy of oral linezolid-rifampin combination therapy (over 4 or 6 weeks) versus the standard of care in the treatment of Gram-positive prosthetic hip joint infection with a one-stage surgical treatment.

Study Overview

• Status: Unknown
• Conditions: Hip Prosthetic Joint Infection
• Intervention / Treatment: Drug: VANCOMYCIN; Drug: CEFTRIAXONE; Drug: CLINDAMYCIN; Drug: SULFAMETHOXAZOLE AND TRIMETHOPRIM (CO-TRIMOXAZOLE); Drug: FLUOROQUINOLONE; Drug: RIFAMPIN; Drug: LINEZOLID

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Nantes, France
    • Recruiting
    • CHU de Nantes
    • Contact: David BOUTOILLE
  • Poitiers, France
    • Not yet recruiting
    • CHU de Poitiers
    • Contact: Gwenaël LE MOAL
    • Principal Investigator: Gwenaël LE MOAL
  • Strasbourg, France, 67400
    • Recruiting
    • Centre de Chirurgie Orthopédique et de la Main
    • Contact: Jeannot GAUDIAS; Email: Jeannot.GAUDIAS@chru-strasbourg.fr
    • Principal Investigator: Jeannot GAUDIAS
  • Tourcoing, France, 59208
    • Not yet recruiting
    • CH de Tourcoing
    • Contact: Eric SENNEVILLE; Email: esenneville@ch-tourcoing.fr
  • Indre et Loire
    • Tours, Indre et Loire, France, 37044
      • Recruiting
      • CHRU de Tours
      • Contact: Louis BERNARD; Phone Number: +33 (0) 2 47 47 97 74; Email: l.bernard@chu-tours.fr
• Italy
  • Udine, Italy, 33100
    • Recruiting
    • Azienda Opedaliera Universitaria San Maria della Misericordia
    • Contact: Matteo BASSETTI; Email: mattba@tin.it
    • Principal Investigator: Matteo BASSETTI
• Spain
  • Barcelona, Spain, 08036
    • Recruiting
    • Hospital Clinic of Barcelona
    • Contact: Alex SORIANO; Email: ASORIANO@clinic.ub.es
    • Principal Investigator: Alex SORIANO
  • Madrid, Spain, 28007
    • Not yet recruiting
    • Hospital General Universitario Gregorio Marañón
    • Contact: Mar SANCHEZ SOMOLINOS
    • Principal Investigator: Mar SANCHEZ SOMOLINOS
  • Palma de Mallorca, Spain, 07198
    • Not yet recruiting
    • Hospital Son Llatzer
    • Contact: Bartolome LLADO FERRER
    • Principal Investigator: Bartolome LLADO FERRER

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Men or women ≥ 18 to ≤ 80 years of age, weight ≥ 40 kg, BMI < 35, who have received a diagnosis of chronic PJI (lasting more than 4 weeks but less than 24 months) requiring a one-stage surgical procedure and presenting at least ONE of the following clinical signs and symptoms:

   1. Joint pain
   2. Effusion
   3. Erythema and sensation of heat at the implant site
   4. Limited range of motion in the affected joint
2. Intraoperative microbiological specimens: during the surgical resection, 5 separate surgical specimens (at least 3) must be sent for culture and susceptibility testing. These specimens must be taken from different locations such as: Hip capsule, femoral membrane, acetabular membrane, synovium, and synovial fluid with separate instruments. A minimum of 2 surgical specimens must be positive. If a preoperative puncture revealed the presence of an acceptable (Gram+) pathogen, it is acceptable if only one pathogen similar to the previously revealed one is identified during the surgical procedure.

3. Documented presence of Gram-positive bacteria as sole pathogen responsible for the infection.

   Note: This criterion must be verified after obtaining the results of the susceptibility test performed on the specimens taken during the surgical procedure. The verification will occur between Day 2 and Day 7 of the study.

4. All patients must undergo 1-stage revision surgery.
5. IRB or IEC approved informed consent form signed and dated. Informed consent will be obtained from each patient before participation in this research study. If any patient is unable to give consent, it may be obtained from the patient's next of kin or legal representative in accordance with current laws and regulations.
6. Willing and able to comply with scheduled visits, up to 6 weeks of treatment with the study antibiotics, laboratory tests, and other study procedures.
7. Patient entitled to Health System benefits or other such benefits

Exclusion Criteria:

1. Concerning women of childbearing age:

   1. intake of oral contraceptives (estroprogestins and progestins)
   2. unability to use adequate mechanical contraceptive precautions
   3. a positive pregnancy test result within 72 hours prior to randomization
   4. pregnant, or are currently breastfeeding and unwilling to discontinue breastfeeding during therapy
2. Patients with a prosthetic joint infection caused by: Gram-negative, mixed Gram-negative and Gram-positive, fungal, or mycobacterial microorganisms. If a previous radiologically guided puncture has revealed the presence of a Gram-negative microorganism, the patient must not be enrolled in this study.
3. Platelet count less than 100 ×103/mm3 at the time of the examination performed during the screening period.
4. Hemoglobin < 9 g/dL at the time of the examination performed during the screening period.
5. Infection affecting several joints.
6. Rheumatological disease (e.g., rheumatoid arthritis, systemic lupus erythematosus, etc.)
7. Previously diagnosed immune function disease(s) (e.g., AIDS), neutropenia (neutrophils < 1000/mm3).
8. Alcoholism or substance abuse sufficient, in the investigator's judgment, to prevent treatment adherence to the study drug and/or follow-up.
9. Patients currently in peritoneal dialysis or receiving another treatment for renal failure (e.g., hemofiltration, CVVH).
10. Liver failure with alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) and/or total bilirubin levels upper or egal to 5 times the upper limit of normal.
11. Patients with other concurrent serious infections such as: endocarditis, meningitis, or central nervous system (CNS) infections, decubitus and ischemic ulcers with underlying osteomyelitis, necrotizing fasciitis, gas gangrene. If suspected, these diagnoses must be ruled out prior to enrollment in the study.
12. Previous randomization in this protocol.
13. Not expected or not likely to survive for the entire duration of the treatment period and TOC (12 months after the end of treatment).
14. Hypersensitivity to the study drugs or their excipients.
15. Identification of a pathogen resistant to the investigational drugs.
16. Patients treated with a protease inhibitor(e.g. indinavir, ritonavir), or with delavirdine, or with nevirapine.
17. Patients treated or having been treated within two weeks prior surgery with an MAOI (A or B), an antiserotonergic drug, a tricyclic antidepressant, an agonist of 5HT1-receptor(triptan), a direct or indirect sympathomimetic drug (including adrenergic bronchodilator, pseudoephedrin, phenylpropanolamin), a vasopressor (adrenalin, noradrenalin), dopaminergic drug, pethidin or buspirone,
18. Patients with a degenerative neurological disease (Parkinson's disease, multiple sclerosis, Alzheimer's disease, etc.).
19. Patient presenting an uncontrolled hypertension, a pheochromocytoma, a carcinoid syndrome, a hyperthyroidism, a bipolar depression, a dysthymic schizophrenia, an acute confusional state, pophyria or a history of retrobulbar optic neuritis.
20. Patient who is participating or has participated in a clinical trial in the month prior to the study screening visit.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Treatment A; IV vancomycin (15mg/kg every 12 hours or in a continuous infusion) and IV ceftriaxone (2g daily) until Day 2 to 7 (until the susceptibility test results are obtained). Patients with only a confirmed Gram-positive infection will continue the study and will receive standard of care antibiotic therapy including oral rifampin (10-15mg/kg every 12 hours) combined with either oral clindamycin (600 mg every 8 hours) or oral sulfamethoxazole and trimethoprim (800/160 mg every 8 hours) or oral fluoroquinolone (Ofloxacin 200 mg every 12 hours). The total duration of antibiotic therapy from the day of the surgical procedure until the end of treatment (EOT) will be 6 weeks.	Drug: VANCOMYCIN; Other Names: VANCOCIN; Drug: CEFTRIAXONE; Other Names: ROCEPHIN; Drug: CLINDAMYCIN; Other Names: DALACIN; Drug: SULFAMETHOXAZOLE AND TRIMETHOPRIM (CO-TRIMOXAZOLE); Other Names: BACTRIM; Drug: FLUOROQUINOLONE; Other Names: OFLOCIN; Drug: RIFAMPIN; Other Names: RIFADIN
EXPERIMENTAL: Treatment B; IV vancomycin (15mg/kg every 12 hours or in a continuous infusion) and IV ceftriaxone (2g daily) until Day 2 to 7 (until the susceptibility test results are obtained). Patients with only a confirmed Gram-positive infection will continue the study and will receive oral linezolid (600mg every 12 hours) combined with oral rifampin (10-15mg/kg every 12 hours). The total duration of antibiotic therapy from the day of the surgical procedure until the end of treatment (EOT) will be 6 weeks.	Drug: VANCOMYCIN; Other Names: VANCOCIN; Drug: CEFTRIAXONE; Other Names: ROCEPHIN; Drug: RIFAMPIN; Other Names: RIFADIN; Drug: LINEZOLID; Other Names: ZYVOXID
EXPERIMENTAL: Treatment C; IV linezolid (600 mg every 12 hours)and IV ceftriaxone (2g daily) until Day 2. Oral or IV rifampin (10-15 mg/kg every 12 hours) will be added 48 hours after initiating the study treatment. Treatment with the study drug will continue until Day 2 to 7 (until the susceptibility test results are obtained). Patients with only a confirmed Gram-positive infection will continue the study. Treatment with ceftriaxone will be discontinued and the patient will switch to oral linezolid and oral rifampin. The total duration of antibiotic therapy from the day of the surgical procedure until the end of treatment (EOT) will be 4 weeks.	Drug: VANCOMYCIN; Other Names: VANCOCIN; Drug: CEFTRIAXONE; Other Names: ROCEPHIN; Drug: RIFAMPIN; Other Names: RIFADIN; Drug: LINEZOLID; Other Names: ZYVOXID

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical cure rate	Clinical cure rate in the modified intent-to-treat (mITT)population during the hospital visit. Patients will be declared cured if clinical signs of infection are normalized.	12 months after the end of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cure rate	Cure rate ine the modified intent-to-treat population during the hospital visit. Patients will be cdeclared cured if radiological and laboratory signs of infection are normalized.	12 months after the end of treatment
Cure rate	Patients will be declared cured if clinical, radiological, and laboratory signs of infection normalized.	6 and 24 months after the end of treatment for the modified intent-to-treat population and at 12 months for the per protocol population.

Collaborators and Investigators

• Sponsor: University Hospital, Tours
• Collaborators: Pfizer; International Clinical Trials Association
• Investigators: Principal Investigator: Louis BERNARD, CHRU de Tours FRANCE; Principal Investigator: David BOUTOILLE, CHU de Nantes FRANCE; Principal Investigator: Gwenael LE MOAL, CHU de Poitiers FRANCE; Principal Investigator: Matteo BASSETTI, Azienda Opedaliera Universitaria San Maria della Misericordia ITALY; Principal Investigator: Silvano ESPOSITO, Facolta di Medicina e Chirugia ITALY; Principal Investigator: Jeannot GAUDIAS, Centre de Chirurgie Orthopédique et de la Main FRANCE; Principal Investigator: Alex SORIANO, Hospital Clinic of Barcelona SPAIN; Principal Investigator: Bartolome LLADO FERRER, Hospital Son Llatzer Palma Balears SPAIN; Principal Investigator: Mar SANCHEZ SOMOLINOS, HGU Gregorio Maranon Madrid SPAIN; Principal Investigator: Eric SENNEVILLE, CH de Tourcoing FRANCE

Study record dates

Study Major Dates

• Study Start: October 1, 2012
• Primary Completion (ANTICIPATED): April 1, 2016
• Study Completion (ANTICIPATED): April 1, 2016

Study Registration Dates

• First Submitted: December 20, 2012
• First Submitted That Met QC Criteria: December 27, 2012
• First Posted (ESTIMATE): December 28, 2012

Study Record Updates

• Last Update Posted (ESTIMATE): May 28, 2014
• Last Update Submitted That Met QC Criteria: May 27, 2014
• Last Verified: May 1, 2014

More Information

Terms related to this study

• Keywords: Antibiotic; linezolid; linezolid/rifampin
• Additional Relevant MeSH Terms: Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-Bacterial Agents; Cytochrome P-450 Enzyme Inhibitors; Leprostatic Agents; Protein Synthesis Inhibitors; Cytochrome P-450 Enzyme Inducers; Antiprotozoal Agents; Antiparasitic Agents; Cytochrome P-450 CYP3A Inducers; Antitubercular Agents; Antimalarials; Folic Acid Antagonists; Antibiotics, Antitubercular; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C8 Inducers; Cytochrome P-450 CYP2C19 Inducers; Cytochrome P-450 CYP2C9 Inducers; Anti-Dyskinesia Agents; Anti-Infective Agents, Urinary; Renal Agents; Cytochrome P-450 CYP2C8 Inhibitors; Vancomycin; Linezolid; Ceftriaxone; Rifampin; Clindamycin; Fluoroquinolones; Trimethoprim; Sulfamethoxazole; Trimethoprim, Sulfamethoxazole Drug Combination
• Other Study ID Numbers: PHAO2011/LB/LIZ-BONE; 2012-000781-38 (EUDRACT_NUMBER)