Osteoarticular InfectionPhase 4EVRIOSNCT02599493
EVRIOS : Comparative Evaluation of Low Versus High Doses of Rifampicin
A Phase 4 study testing Rifampicin in people with Osteoarticular Infection, run by Rennes University Hospital at 16 sites in France.
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Osteoarticular Infection
- What is being tested?
- Rifampicin
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 544 participants
- Where
- 16 sitesFrance
- Study dates
- Jan 2016to Dec 2020
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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).
Trial locations and contacts
16 sites in 1 country.
16 sites in 1 country
France16 sites
Angers university hospital
Angers, 49933
Bordeaux university hospital
Bordeaux, 33076
Brest university hospital
Brest, 29609
Caen university hospital
Caen, 14033
La Roche sur Yon hospital
La Roche-sur-Yon, 85925
Lorient hospital
Lorient, 56322
Clinique du Parc et Hôpital Jean Mermoz
Lyon, 69100
Nantes university hospital
Nantes, 44093
Pau hospital
Pau, 64046
Poitiers university hospital
Poitiers, 86000
Rennes university hospital
Rennes, 35000
Saint-Brieuc hospital
Saint-Brieuc, 22027
Saint-Malo hospital
St-Malo, 35400
Toulouse university hospital
Toulouse, 35059
Tours university hospital
Tours, 37044
Vannes hospital
Vannes, 56017
About this study
Official title: EVRIOS : Comparative Evaluation of Low Versus High Doses of Rifampicin in the Treatment of Staphylococcal Bone and Joint Infections
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.
Read more
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.
Read the 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.
- Conditions
- Osteoarticular Infection
- Being tested
- Rifampicin
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
RifampicinDrug
Also called RIMACTAN
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.
| Study group | Role | What they receive |
|---|---|---|
| Low dose | Experimental | Patients will be randomly assigned to low dosage (10 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. Receives: Drug: Rifampicin |
| High dose | Active comparator | Patients will be randomly assigned to 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. Receives: Drug: Rifampicin |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 12 months
Secondary outcomes (8)
Possible failure
Possible failure rates: defined as the lack of documented bacteriology and presence of septic clinical manifestations according to French experts recommendations.
Measured: 12 months
Adverse events
Biological and clinical AEs.
Measured: 12 weeks
Dose modification
Rifampicin dose modification: each rifampicin dosages change or interruption.
Measured: 12 weeks
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.
Measured: 12 months
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.
Measured: 12 weeks
Real antibiotics treatment duration
Real antibiotics treatment duration
Measured: 12 weeks
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.
Measured: 12 hours
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.
Measured: 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Nov 2015 (estimated)
- Study startJan 2016
- Primary completionDec 2020
- Study completionDec 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Osteoarticular InfectionStudies of the same condition, open and under way.
- More trials run by Rennes University HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 544 participants (actual)
Sponsor and investigators
- Lead sponsor
- Rennes University Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Cédric ARVIEUX, MD, Principal investigator, Rennes University Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02599493
- Sponsor's protocol ID
- 35RC14_9741_EVRIOS
- Other IDs
- 2015-001519-11, 150790A-41, 15/18-980, 2015
- Acronym
- EVRIOS
- Status last verified
- Aug 2021
- First submitted
- 3 Nov 2015
- Last updated
- 23 Aug 2021
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 23 Aug 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- EVRIOS : Comparative Evaluation of Low Versus High Doses of Rifampicin in the Treatment of Staphylococcal Bone and Joint Infections
- ClinicalTrials.gov ID
- NCT02599493
- Acronym / sponsor ID
- EVRIOS / 35RC14_9741_EVRIOS
- Conditions
- Osteoarticular Infection
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 544 participants (actual)
- Lead sponsor
- Rennes University HospitalUniversity, hospital or other
- Study start
- Jan 2016
- Primary completion
- Dec 2020 (actual)
- Study completion
- Dec 2020 (actual)
- First posted
- 6 Nov 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Low dose | Experimental | Drug: RifampicinPatients will be randomly assigned to low dosage (10 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. |
| High dose | Active comparator | Drug: RifampicinPatients will be randomly assigned to 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- 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.
Key exclusion criteria (8 listed)
- 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®
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| RifampicinAlso: RIMACTANPatients 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. | Drug | High dose, Low dose |
Primary outcome
Proven failure
Time frame: 12 months
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.
8 secondary outcomes
Possible failure
Time frame: 12 months
Adverse events
Time frame: 12 weeks
Dose modification
Time frame: 12 weeks
Failure risk factors
Time frame: 12 months
Global health costs
Time frame: 12 weeks
Real antibiotics treatment duration
Time frame: 12 weeks
Plasma concentration
Time frame: 12 hours
Staphylococcus spp. resistance
Time frame: 12 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Aug 2021.
Related trials for Osteoarticular Infection
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All-Oral Fluoroquinolone-Based Triple Therapies for Adults With Imaging-Confirmed Osteoarticular Brucellosis
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RecruitingObservational study
Compliance and Tolerance to Oral AntiBiotherapy in Osteoarticular Infections (OTABIO)
Drug-Related Side Effects and Adverse Reactions, Treatment Adherence and Compliance
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Population Pharmacokinetic Model of Rifampicin in Staphylococcal Osteoarticular Infections
Prosthetic Joint Infection, Osteomyelitis
Not yet recruitingPhase 3
Enhancing Amoxicillin Pharmacokinetics and Pharmacodynamics Parameters With Probenecid in Bone and Joint Infections
Osteoarticular Infections (OAIs)
RecruitingPhase 4
Trimethoprim-sulfamethoxazole vs. Clindamycin for the Treatment of Children With Invasive MRSA Infections
Methicillin Resistant Staphylococcus Aureus, Osteomyelitis Acute
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Cédric ARVIEUX, MD principal investigator
Rennes University Hospital
16 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Rifampicin in people with Osteoarticular Infection, run by Rennes University Hospital at 16 sites in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 23 Aug 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 16 sites in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Proven failure (time frame: 12 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Aug 2021.