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

Sponsor

University Hospital, Tours (Other)

Overall Status

Unknown status

CT.gov ID

NCT01757236

Collaborator

Pfizer (Industry), International Clinical Trials Association (Other)

100

Enrollment

Locations

Arms

Duration (Months)

11.1

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Hip Prosthetic Joint Infection	Drug: VANCOMYCIN Drug: CEFTRIAXONE Drug: CLINDAMYCIN Drug: SULFAMETHOXAZOLE AND TRIMETHOPRIM (CO-TRIMOXAZOLE) Drug: FLUOROQUINOLONE Drug: LINEZOLID Drug: RIFAMPIN	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

100 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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.

Study Start Date :

Oct 1, 2012

Anticipated Primary Completion Date :

Apr 1, 2016

Anticipated Study Completion Date :

Apr 1, 2016

Arms and Interventions

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: LINEZOLID Other Names: ZYVOXID Drug: RIFAMPIN Other Names: RIFADIN
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: LINEZOLID Other Names: ZYVOXID Drug: RIFAMPIN Other Names: RIFADIN

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: LINEZOLID

Other Names:

ZYVOXID

Drug: RIFAMPIN

Other Names:

RIFADIN

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: LINEZOLID

Other Names:

ZYVOXID

Drug: RIFAMPIN

Other Names:

RIFADIN

Outcome Measures

Primary Outcome Measures

Clinical cure rate [12 months after the end of treatment]
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.

Secondary Outcome Measures

Cure rate [12 months after the end of treatment]
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.
Cure rate [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.]
Patients will be declared cured if clinical, radiological, and laboratory signs of infection normalized.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

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:
Joint pain
Effusion
Erythema and sensation of heat at the implant site
Limited range of motion in the affected joint
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.
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.

All patients must undergo 1-stage revision surgery.
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.
Willing and able to comply with scheduled visits, up to 6 weeks of treatment with the study antibiotics, laboratory tests, and other study procedures.
Patient entitled to Health System benefits or other such benefits

Exclusion Criteria:

Concerning women of childbearing age:
intake of oral contraceptives (estroprogestins and progestins)
unability to use adequate mechanical contraceptive precautions
a positive pregnancy test result within 72 hours prior to randomization
pregnant, or are currently breastfeeding and unwilling to discontinue breastfeeding during therapy
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.
Platelet count less than 100 ×103/mm3 at the time of the examination performed during the screening period.
Hemoglobin < 9 g/dL at the time of the examination performed during the screening period.
Infection affecting several joints.
Rheumatological disease (e.g., rheumatoid arthritis, systemic lupus erythematosus, etc.)
Previously diagnosed immune function disease(s) (e.g., AIDS), neutropenia (neutrophils < 1000/mm3).
Alcoholism or substance abuse sufficient, in the investigator's judgment, to prevent treatment adherence to the study drug and/or follow-up.
Patients currently in peritoneal dialysis or receiving another treatment for renal failure (e.g., hemofiltration, CVVH).
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.
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.
Previous randomization in this protocol.
Not expected or not likely to survive for the entire duration of the treatment period and TOC (12 months after the end of treatment).
Hypersensitivity to the study drugs or their excipients.
Identification of a pathogen resistant to the investigational drugs.
Patients treated with a protease inhibitor(e.g. indinavir, ritonavir), or with delavirdine, or with nevirapine.
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,
Patients with a degenerative neurological disease (Parkinson's disease, multiple sclerosis, Alzheimer's disease, etc.).
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.
Patient who is participating or has participated in a clinical trial in the month prior to the study screening visit.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	CHRU de Tours	Tours	Indre et Loire	France	37044
2	CHU de Nantes	Nantes		France
3	CHU de Poitiers	Poitiers		France
4	Centre de Chirurgie Orthopédique et de la Main	Strasbourg		France	67400
5	CH de Tourcoing	Tourcoing		France	59208
6	Azienda Opedaliera Universitaria San Maria della Misericordia	Udine		Italy	33100
7	Hospital Clinic of Barcelona	Barcelona		Spain	08036
8	Hospital General Universitario Gregorio Maranon	Madrid		Spain	28007
9	Hospital Son Llatzer	Palma de Mallorca		Spain	07198

Sponsors and Collaborators

University Hospital, Tours
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