Rifabutin Versus Rifampicin for Treatment of Staphylococcal PJI Treated With DAIR (RIFAMAB)

Rifabutin Versus Rifampicin for Treatment of Staphylococcal Prosthetic Joint Infection Treated With Debridement, Antibiotics and Implant Retention (DAIR Strategy): a Multicenter Randomized, Open-label, Non-inferiority Trial

Rifampicin, is key in the treatment of staphylococcal PJIs. Rifabutin has a better profile of tolerance than rifampicin regarding the risk of interaction with concomitant medications and liver disorders. The hypothesis is that rifabutin may be an alternative antibiotic option as efficient as rifampicin for the treatment of staphylococcal PJIs, with a better safety profile. The investigator aim to demonstrate the non-inferiority of rifabutin as compared with rifampicin prescribed in combination treatment for PJIs.

Study Overview

• Status: Recruiting
• Conditions: Prosthetic Infection
• Intervention / Treatment: Drug: Rifampicin; Drug: Rifabutin

• Study Type: Interventional
• Enrollment (Anticipated): 436
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Eric SENNEVILLE, MD PhD; Phone Number: 0320694949; Email: esenneville@ch-tourcoing.fr
• Study Contact Backup: Name: Solange TREHOUX; Phone Number: 0320694280; Email: strehoux@ch-tourcoing.fr

Study Locations

• France
  • Amiens, France
    • Not yet recruiting
    • CHU Amiens Picardie
    • Contact: Benoit BRUNSCHWEILER
  • Angers, France
    • Not yet recruiting
    • CHU Angers
  • Besançon, France
    • Recruiting
    • CHU Besançon
    • Contact: Kévin BOUILLER
  • Bordeaux, France
    • Not yet recruiting
    • CHU Bordeaux
    • Contact: Frédéric-Antoine DAUCHY
  • Boulogne-Billancourt, France
    • Not yet recruiting
    • APHP Hopital Ambroise Pare
    • Contact: Aurélien DINH
  • Brest, France
    • Recruiting
    • CHRU Brest
  • Béthune, France
    • Not yet recruiting
    • CH de Béthune
  • Caen, France
    • Recruiting
    • CHU caen
  • Contamine-sur-Arve, France
    • Not yet recruiting
    • CH Alpes Léman
  • Dijon, France
    • Not yet recruiting
    • CHU Dijon Bourgogne
    • Contact: Lionel PIROTH
  • Grenoble, France
    • Not yet recruiting
    • CHU Grenoble Alpes
  • Lille, France
    • Recruiting
    • CHRU Lille
    • Contact: Henry MIGAUD
  • Lille, France
    • Not yet recruiting
    • GHICL Hôpital Saint Vincent de Paul
  • Limoges, France
    • Recruiting
    • CHU de Limoges
  • Lomme, France
    • Not yet recruiting
    • GHICL Hôpital Saint Philibert
  • Lyon, France
    • Not yet recruiting
    • Hospices Civils de Lyon
    • Contact: Tristan FERRY
  • Lyon, France
    • Not yet recruiting
    • Clinique de la Sauvegarde
    • Contact: Anne-Laure BLANC
  • Marseille, France
    • Not yet recruiting
    • APHM Hôpital Nord
  • Nice, France
    • Not yet recruiting
    • CHU Nice
    • Contact: Johan COURJON
  • Pringy, France
    • Recruiting
    • CH Annecy Genevois
    • Contact: Violaine TOLSMA
  • Quimper, France
    • Not yet recruiting
    • Ch Cornouaille
    • Contact: Lydie KHATCHATOURIAN
  • Reims, France
    • Not yet recruiting
    • CHU Reims
  • Rennes, France
    • Recruiting
    • CHU de Rennes
  • Saint-Priest-en-Jarez, France
    • Not yet recruiting
    • CHU Saint Etienne
  • Strasbourg, France
    • Not yet recruiting
    • CHRU Strasbourg
    • Contact: Cécile RONDE-OUSTAU
  • Toulon, France
    • Recruiting
    • Hôpital d'Instruction des armées SAINTE ANNE
  • Toulouse, France
    • Not yet recruiting
    • Clinique Joseph Ducuing
  • Toulouse, France
    • Not yet recruiting
    • Clinique Médipole Garonne
  • Tourcoing, France
    • Recruiting
    • Ch Tourcoing
    • Contact: Eric SENNEVILLE
  • Tours, France
    • Recruiting
    • CHRU Tours

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Hip or knee Prosthetic joint infection treated by debridement, antibiotic therapy initiation and retention of prothesis (DAIR strategy)

2. Infected with at least one of the following microorganisms:

   1. Staphylococcus aureus
   2. Coagulase-negative staphylococci
3. Microorganisms susceptible to rifampicin and at least one other antibiotic suitable for the treatment of PJI (e.g., penicillin, fluoroquinolone, (doxy/mino)cycline, oxazolidinone, cotrimoxazole, daptomycin, glycopeptide, macrolide, fusidic acid), regardless of sensitivity to methicillin.
4. Age ≥ 18 years
5. At least 2 days of appropriate (i.e., covering pathogen(s) identified in the intraoperative samples) empirical agents are needed. Pre-randomization antimicrobial therapy could be: flucloxacillin, oxacillin, vancomycin, daptomycin. β-lactam plus β-lactamase-inhibitors (e.g. ampicillin+sulbactam, piperacillin+tazobactam), cephalosporins (except ceftazidime), carbapenems, teicoplanin, ceftaroline, ceftobiprole.
6. Signed Inform consent
7. Patient having the rights to French social insurance
8. For women of childbearing potential i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile and excluding oestroprogestative-based contraception, any effective contraceptive: vasectomy (for men), intrauterine device copper, feminine sterilization, condom, sexual abstinence is required. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause

Exclusion Criteria:

1. Suspicion of reduce absorption of oral treatment due to abdominal disorder Known or suspected malabsorption (imperfect absorption of food material by the small intestine)
2. Polymicrobial infection due to other than staphylococcus species susceptible to rifampicin
3. Known or suspected allergy to rifabutin and/or rifampicin
4. Diagnosis of endocarditis associated to PJI
5. Renal transplant or Chronic kidney disease with an eGFR of less than 30ml/min/1.73m²
6. Other Solid Organ Transplant
7. Liver cirrhosis, Child-Pugh score C
8. Any other concomitant infection which required a prolonged course of intravenous antibiotic therapy
9. Oestroprogestative-based contraception
10. Oral anticoagulant drugs
11. Other drug-drug interaction that contraindicated rifampicin or rifabutin
12. Porphyria
13. Unable to take oral treatment
14. Receive empirical postoperative antibiotic treatment by rifampicin or rifabutin prior to randomization
15. Pregnancy or lactating women
16. Curator or guardianship or patient placed under judicial protection
17. Participation in other interventional research during the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: RIFAMPICIN; Patient with staphylococcal PJI, treated with DAIR strategy, and randomized in the control group will receive rifampicin in association with another antibiotic except rifabutin, as-per recommendations for 12 weeks.	Drug: Rifampicin; 10 mg/kg per day (range 600 mg to 1,200 mg) rifampicin tablet in 1 daily dose for 12 weeks with a companion treatment
Experimental: RIFABUTIN; Patient with staphylococcal PJI treated with DAIR strategy, and randomized in the experimental group, will receive rifabutin in association with another antibiotic except rifampicin, as-per recommendations for 12 weeks.	Drug: Rifabutin; 2 tablets of 150 mg per day rifabutin tablet daily for 12 weeks in 1 administration with a companion treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment failure	Treatment failure defined as one of following events: The need for any further surgical procedure - i.e. implants removal, implants exchange or amputation;; And/or PJI related death;; And/or use of suppressive antibiotic therapy that was not planned before randomization	At one year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Occurrence of serious adverse events (SAEs), including death (i.e. all cause)	Proportion of patient which are free from SAEs occurrence, as defined by: -Patients who completed the entire 12 weeks duration of antibiotic treatment planned initially and; xWho did not experience grade 3-4 adverse events, including death, regardless of the link with antibiotic therapy; xWho did not experience adverse events which led to either to: Reduce the dosage or split the treatment to two take/day;; Or stop any component of the antibiotic treatment.	At the end of 12 weeks duration of antibiotic treatment planned
Occurrence of any adverse event that could be related to rifampicin or rifabutin	Number and rate of patients in each arm who experiences: Liver cytolysis (>=2N for ALT AND/OR AST); Acute Kidney failure as defined by serum creatinine increase in KDIGO; Digestive symptoms, including diarrhea; Who required a modification of antibiotic dosage during the 12 weeks' period of antibiotic treatment; Uveitis/ophthalmologic disorder; Neurological disorder	At the end of 12 weeks duration of antibiotic treatment planned
Proportion of patients from each arm who will complete the 12-week duration of rifampicin/rifabutin treatment, early termination of the planned 12 weeks' period of antibiotics	Early termination rate will be measured in each arm, as the number of patients having stopped rifampicin or rifabutin before the planned 12 weeks period over the total number of patients enrolled in the studied arm.	At the end of 12 weeks duration of antibiotic treatment planned
Adherence to antibiotics regimen	Adherence rate to medication will be measured as the number of days on which all doses were missed over the number of days of planned antibiotic therapy. Patients enrolled in the study will have to fill their pill count in a daily notebook.	At the end of 12 weeks duration of antibiotic treatment planned
Quality of life, as evaluated by EQ 5D 3L questionnaire	Quality of life, as evaluated by the use EQ 5D 3L auto-questionnaire as used in previous randomized clinical trial on bone and joint infection	At the end of the study follow up, an average of 24 months
Functional prognosis using Oxford questionnaire evolution according to location of PJI	Oxford Scores as used in previous randomized clinical trial on bone and joint infection	At the end of the study follow up, an average of 24 months
Long term efficacy of rifampicin and rifabutin treatment	Long term efficacy: treatment failure, as defined for primary outcome, at 24 months	At the end of the study follow up, an average of 24 months

Collaborators and Investigators

• Sponsor: Tourcoing Hospital
• Investigators: Principal Investigator: Eric SENNEVILLE, Md PhD, Ch Tourcoing

Study record dates

Study Major Dates

• Study Start (Actual): November 8, 2021
• Primary Completion (Anticipated): November 1, 2026
• Study Completion (Anticipated): June 1, 2027

Study Registration Dates

• First Submitted: October 11, 2020
• First Submitted That Met QC Criteria: December 16, 2020
• First Posted (Actual): December 17, 2020

Study Record Updates

• Last Update Posted (Actual): May 10, 2022
• Last Update Submitted That Met QC Criteria: May 9, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-Bacterial Agents; Leprostatic Agents; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Antitubercular Agents; Antibiotics, Antitubercular; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C8 Inducers; Cytochrome P-450 CYP2C19 Inducers; Cytochrome P-450 CYP2C9 Inducers; Rifampin; Rifabutin
• Other Study ID Numbers: RIPH_2019_01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No