Rifabutin Versus Rifampicin for Treatment of Staphylococcal PJI Treated With DAIR

Prosthetic Infection Clinical Trial

— RIFAMAB  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04672525
• Other study ID #: RIPH_2019_01
• Status: Recruiting
• Phase: Phase 3
• Start date: November 8, 2021
• Est. completion date: June 2027

Study information

• Verified date: May 2022
• Source: Tourcoing Hospital
• Contact: Eric SENNEVILLE, MD PhD
• Phone: 0320694949
• Email: esenneville[@]ch-tourcoing.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 436
• Est. completion date: June 2027
• Est. primary completion date: November 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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. ß-lactam plus ß-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

Related Conditions & MeSH terms

• Infections
• Prosthetic Infection

Intervention

Drug:
• Rifabutin
2 tablets of 150 mg per day rifabutin tablet daily for 12 weeks in 1 administration with a companion treatment
• 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

Locations

Country	Name	City	State
France	CHU Amiens Picardie	Amiens
France	CHU Angers	Angers
France	CHU Besançon	Besançon
France	CH de Béthune	Béthune
France	CHU Bordeaux	Bordeaux
France	APHP Hôpital Ambroise Paré	Boulogne-Billancourt
France	CHRU Brest	Brest
France	CHU Caen	Caen
France	CH Alpes Leman	Contamine-sur-Arve
France	CHU Dijon Bourgogne	Dijon
France	CHU Grenoble Alpes	Grenoble
France	CHRU Lille	Lille
France	GHICL Hôpital Saint Vincent de Paul	Lille
France	CHU de Limoges	Limoges
France	GHICL Hôpital Saint Philibert	Lomme
France	Clinique de la Sauvegarde	Lyon
France	Hospices Civils de Lyon	Lyon
France	APHM Hôpital Nord	Marseille
France	CHU Nice	Nice
France	CH Annecy Genevois	Pringy
France	CH Cornouaille	Quimper
France	CHU Reims	Reims
France	CHU de Rennes	Rennes
France	CHU Saint Etienne	Saint-Priest-en-Jarez
France	CHRU Strasbourg	Strasbourg
France	Hôpital d'instruction des armées Sainte Anne	Toulon
France	Clinique Joseph Ducuing	Toulouse
France	Clinique Médipole Garonne	Toulouse
France	CH Tourcoing	Tourcoing
France	CHRU Tours	Tours

Sponsors (1)

Lead Sponsor	Collaborator
Tourcoing Hospital

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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