RIFAMAB : Rifabutin versus rifampicin, staphylococcal prosthetic joint infection, multicenter randomized, open-label, non-inferiority trial

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Hospitalier De Tourcoing

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Bacterial Infections and Mycoses [C01]

Decision date (initial)

2025-02-07

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-519894-20-01

EudraCT number

2020-000471-20

ClinicalTrials.gov

NCT04672525

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To demonstrate that in DAIR strategy for prosthetic joint infection due to staphylococci (S. aureus and CoNS) susceptible or resistant to methicillin, oral rifabutin is non-inferior to oral rifampicin.

Secondary objectives 7

1. Tolerance I: occurrence of serious adverse events (SAEs), including death (i.e. all cause);
2. Tolerance II: occurrence of any adverse event that could be related to rifampicin or rifabutin
3. Tolerance III: 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;
4. Adherence to antibiotics regimen
5. Quality of life, as evaluated by EQ 5D 3L questionnaire 24;
6. Functional prognosis using Oxford Hip and Knee Scores (Oxford questionnaire) evolution according to location of PJI 25;
7. Long term efficacy of rifampicin and rifabutin treatment (i.e., two year after the surgical intervention)

Conditions and MedDRA coding

Adult with an staphylococcal prosthetic joint infection treated with debridement, antibiotics and implant retention (DAIR strategy)

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Hip or knee Prosthetic joint infection treated by debridement, antibiotic therapy initiation and retention of prothesis (DAIR strategy)
2. Microbiologically documented infection corresponds to the isolation of staphylococcus aureus or coagulase-negative Staphylococcus aureus from reliable samples: intraoperatively (≥ 3 during synovectomywashing), joint puncture or blood culture; the microorganism(s) will be considered pathogenic if identified in ≥ 2 reliable samples.
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.
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 16

1. 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. Ongoing treatment that contraindicates the use of rifampicin or rifabutine
11. Porphyria
12. Unable to take oral treatment
13. Receive empirical postoperative antibiotic treatment by rifampicin or rifabutin prior to randomization
14. Pregnancy or lactating women
15. Curator or guardianship or patient placed under judicial protection
16. Participation in other interventional research during the study

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary outcome is treatment failure after one year of follow-up, 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

Secondary endpoints 7

1. Proportion of patient which are free from SAEs occurrence, as defined by: o Patients who completed the entire 12 weeks’ duration of antibiotic treatment planned initially and;  Who did not experience grade 3-4 adverse events, including death, regardless of the link with antibiotic therapy;  Who 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.
2. Number and rate of patients in each arm who experiences: o Liver cytolysis (>=2N for ALT AND/OR AST) o Acute Kidney failure as defined by serum creatinine increase in KDIGO o Digestive symptoms, including diarrhea o Who required a modification of antibiotic dosage during the 12 weeks’ period of antibiotic treatment o Uveitis/ophthalmologic disorder o Neurological disorder
3. 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.
4. 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.
5. Quality of life, as evaluated by the use EQ5D5L auto-questionnaire at week 6, month 6, month 12 and month 24 as used in previous randomized clinical trial on bone and joint infection.
6. Oxford Hip and Knee Scores evolution between week 6, month 6, month 12 and month 24 as used in previous randomized clinical trial on bone and joint infection.
7. Long term efficacy: treatment failure, as defined for primary outcome, occurring between 12 months and 24 months after initial surgery.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Hospitalier De Tourcoing

Sponsor organisation

Centre Hospitalier De Tourcoing

Address

155 Rue Du President Coty, Bp 40619 Bp 40619

City

Tourcoing Cedex

Postcode

59208

Country

France

Scientific contact point

Organisation

Centre Hospitalier De Tourcoing

Contact name

Jean-Jacques VITAGLIANO

Public contact point

Organisation

Centre Hospitalier De Tourcoing

Contact name

Jean-Jacques VITAGLIANO

Locations

1 EU/EEA country · 36 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 6 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications