EVRIOS : Comparative Evaluation of Low Versus High Doses of Rifampicin

Osteoarticular Infection Clinical Trial

— EVRIOS  

Official title:

EVRIOS : Comparative Evaluation of Low Versus High Doses of Rifampicin in the Treatment of Staphylococcal Bone and Joint Infections

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02599493
• Other study ID #: 35RC14_9741_EVRIOS
• Secondary ID: 2015-001519-1115
• Status: Completed
• Phase: Phase 4
• Start date: January 2016
• Est. completion date: December 2020

Study information

• Verified date: August 2021
• Source: Rennes University Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Rifampicin is an antibiotic usually required to treat susceptible Staphylococcus spp. osteo-articular infections, most frequently in association with a fluoroquinolone when the strain is susceptible to both agents. It is the reference treatment for orthopedic infections with implanted material.

For tuberculosis treatment the dosage of 10 mg/kg/j is usually prescribed, while in the treatment of Staphylococcus spp. infections the highest dosage of 20 mg/kg/j is proposed by French experts' recommendations from 2009.

However, there is little evidence in the literature, which could set out arguments to choose the best dosage of rifampicin, which may vary from 5 to 20 mg/kg.

The issue with rifampicin is side effects, in particular with long-term treatment. Many side effects may occur in 10 to 20% of patients and sometimes leads to dosage reduction or treatment interruption.

In the literature, there is little evidence that higher rifampicin dosage is associated with higher frequency of adverse effects. Depending on the nature of the toxicity, one could say that hypersensitivity could be independent from dosage, when digestive disorders may be related. Plasmatic concentrations studies have not given strong arguments to link higher rifampicin dosages with side effects occurrence rates. After oral absorption, plasmatic peak occurs after two to five hours and varies among individuals but also in the same patient overtime. This particular pharmacokinetic profile could explain discrepancy in adverse events (AEs) frequencies.

Description:

Primary objective :

To demonstrate that a daily weight-based low dose of rifampicin is non-inferior to a high dose in the treatment of susceptible Staphylococcus spp. osteo-articular infections.

Secondary objectives :

To compare, in the two treatment groups (weight-based low dose rifampicin versus weight-based high dose):

• Possible failure rates (when no bacteriological samples are available or when clinical manifestations are not straightforward),

• AEs distribution:

• Those self-patient reported,

• Those medical or biological reported,

• - Rifampicin dose modifications:

• Dosage decrease,

• Treatment interruption (temporary or definitive),

• Failure risk factors analysis,

• Health costs related to the osteo-articular infection care: number and length of hospitalizations, number of follow-up visits, nature and number of all biological samples prescribed in both groups.

• Comparison of the planned rifampicin exposure in each randomization group

• Differences in rifampicin duration (planned versus effective duration) according to allocated group,

• Rifampicin pharmacokinetics sub-study in a small sample of 60 patients,

• Rifampicin resistance bacteriological study in patients with proven failure.

Methodology :

Non-inferiority prospective, multicentre, randomized, open-label, controlled phase IV trial evaluating two different rifampicin dosages (high versus low dose) in the treatment of staphylococcal bone and joint infections.

Treatment :

Patients will be randomly assigned to low dosage (10 mg/kg/j) rifampicin group or high dosage (20 mg/kg/j) rifampicin group. Rifampicin treatment will be prescribed in association with another antibiotic chosen by investigator according to the antibiogram results. Association with fluoroquinolones is the first choice combination, if it is possible. The global antibiotic treatment duration depends on the investigator's choice.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 544
• Est. completion date: December 2020
• Est. primary completion date: December 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Adult patients (over 18 years old) who gave their signed inform consent,

• Who present an osteo-articular infection with susceptible Staphylococcus spp.,

• To whom a rifampicin based regimen is prescribed, in association with another antibiotic, for at least 14 days,

• Patients covered by Health Insurance.

Exclusion Criteria:

• Patients weighing less than 45 kg or more than 150 kg,

• Patients with active TB (whatever its localization),

• Patients needing the imperative use of a treatment presenting a contraindication for concomitant use in the SPC of Rimactan®

• Patients with a known and documented rifampicin allergy or severe rifampicin intolerance,

• Patients with galactose intolerance, total lactase deficiency or glucose or galactose malabsorption syndrome, or any other contraindication to the administration of Rimactan® listed in the SPC for Rimactan®

• Pregnant or breastfeeding woman,

• Adults legally protected (under judicial protection, guardianship or supervision), persons deprived of their liberty,

• Patients participating in another interventional clinical trial (biomedical trial or standard care clinical trial).

Related Conditions & MeSH terms

• Infection
• Osteoarticular Infection

Intervention

Drug:
• Rifampicin
Patients will be randomly assigned to low dosage (10 mg/kg/j) rifampicin group or high dosage (20 mg/kg/j) rifampicin group. Rifampicin treatment will be prescribed in association with another antibiotic chosen by investigator according to the antibiogram results. Association with fluoroquinolones is the first choice combination, if it is possible. The global antibiotic treatment duration depends on the investigator's choice.

Locations

Country	Name	City	State
France	Angers university hospital	Angers
France	Bordeaux university hospital	Bordeaux
France	Brest university hospital	Brest
France	Caen university hospital	Caen
France	La Roche sur Yon hospital	La Roche sur Yon
France	Lorient hospital	Lorient
France	Clinique du Parc et Hôpital Jean Mermoz	Lyon
France	Nantes university hospital	Nantes
France	Pau hospital	Pau
France	Poitiers university hospital	Poitiers
France	Rennes university hospital	Rennes
France	Saint-Brieuc hospital	Saint-Brieuc
France	Saint-Malo hospital	Saint-Malo
France	Toulouse university hospital	Toulouse
France	Tours university hospital	Tours
France	Vannes hospital	Vannes

Sponsors (1)

Lead Sponsor	Collaborator
Rennes University Hospital

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Proven failure	The rate of proven failure between the two groups, 12 months after the end of antibiotics.; The proven failure is defined as a documented bacteriological failure, with the same Staphylococcus spp. strain isolated before the onset of antibiotics and at diagnosis of failure.	12 months
Secondary	Possible failure	Possible failure rates: defined as the lack of documented bacteriology and presence of septic clinical manifestations according to French experts recommendations.	12 months
Secondary	Adverse events	Biological and clinical AEs.	12 weeks
Secondary	Dose modification	Rifampicin dose modification: each rifampicin dosages change or interruption.	12 weeks
Secondary	Failure risk factors	Failure risk factors: collected for each patient and include those already known in the literature: bacterial strains type, anatomic site of infection, presence of prosthetic material, duration of infectious signs, waiting period between first infectious signs and medical care, type of surgical intervention (with or without prosthetic material removal), type, duration and administration road of antibiotics treatment, patient's age, concomitant pathologies.	12 months
Secondary	Global health costs	Global health costs: rhythm of visits defined by investigator site until the end of antibiotic treatment, all additional visit and/or exams or concomitant treatment prescriptions will be collected at each schedule visit, analysed and compared in two groups of rifampicin treatment.	12 weeks
Secondary	Real antibiotics treatment duration	Real antibiotics treatment duration	12 weeks
Secondary	Plasma concentration	Rifampicin Pharmacokinetic: it will be studied in a sub-sample of 60 patients (30 in each group) at the onset of rifampicin-based regimen and will estimate rifampicin plasmatic concentration, self-induction mechanism and possible links with ARs or adverse occurrences.	12 hours
Secondary	Staphylococcus spp. resistance	Analysis of Staphylococcus spp. resistance: in case of proven failure, will compare strains in the same patient and resistant strains incidence into the two groups.	12 months