Clinical trial NCT02599493: EVRIOS : Comparative Evaluation of Low Versus High Doses of Rifampicin
Official title: EVRIOS : Comparative Evaluation of Low Versus High Doses of Rifampicin in the Treatment of Staphylococcal Bone and Joint Infections
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Osteoarticular Infection
Lead sponsor: Rennes University Hospital
Sponsor class: OTHER
First posted: 2015-11-06
Enrollment: 544
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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).

Primary outcomes:
measure: Proven failure
timeFrame: 12 months
Secondary outcomes:
measure: Possible failure
timeFrame: 12 months
measure: Adverse events
timeFrame: 12 weeks
measure: Dose modification
timeFrame: 12 weeks
measure: Failure risk factors
timeFrame: 12 months
measure: Global health costs
timeFrame: 12 weeks
measure: Real antibiotics treatment duration
timeFrame: 12 weeks
measure: Plasma concentration
timeFrame: 12 hours
measure: Staphylococcus spp. resistance
timeFrame: 12 months
Other outcomes:
Locations:
city: Angers
country: France
facility: Angers university hospital
city: Bordeaux
country: France
facility: Bordeaux university hospital
city: Brest
country: France
facility: Brest university hospital
city: Caen
country: France
facility: Caen university hospital
city: La Roche sur Yon
country: France
facility: La Roche sur Yon hospital
city: Lorient
country: France
facility: Lorient hospital
city: Lyon
country: France
facility: Clinique du Parc et Hôpital Jean Mermoz
city: Nantes
country: France
facility: Nantes university hospital
city: Pau
country: France
facility: Pau hospital
city: Poitiers
country: France
facility: Poitiers university hospital
city: Rennes
country: France
facility: Rennes university hospital
city: Saint-Brieuc
country: France
facility: Saint-Brieuc hospital
city: Saint-Malo
country: France
facility: Saint-Malo hospital
city: Toulouse
country: France
facility: Toulouse university hospital
city: Tours
country: France
facility: Tours university hospital
city: Vannes
country: France
facility: Vannes hospital
Study officials:
affiliation: Rennes University Hospital
name: Cédric ARVIEUX, MD
role: PRINCIPAL_INVESTIGATOR
References: