Intubated and Mechanically-Ventilated, Adult Patients with severe Gram-Negative lower respiratory tract infection
Conditions
Interventions
Pharmaceutical Form: Powder for injection
INN or Proposed INN: MEROPENEM TRIHYDRATE
CAS Number: 119478-56-7
Concentration unit: mg/ml milligram(s)/milli
Sponsors
FUNDACIÓN PARA INVESTIGACIÓN BIOMÉDICA DEL HOSPITAL UNIVERSITARIO RAMÓN Y CAJAL
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Males and non-pregnant, non-lactating females, 18 years of age or older; 2. Currently intubated and mechanically-ventilated subjects in the ICU; 3. a. Suspicion of Lower Respiratory Tract infection defined as at least two of the following: • fever, defined as a tympanic/ rectal/core temperature >38,3°C , or hypothermia, defined as a rectal/core body temperature of 10,000/mm3 or 15% regardless of the peripheral leukocyte count; • new onset of purulent sputum or respiratory secretions, or a change in the character of sputum; • a new or progressive pulmonary infiltrate on chest X-rays.(criterion only applicable for Spain and Belgium) b. A new or progressive pulmonary infiltrate on chest X-rays. (only for France). As indicated in section 2.4, in France, only patients fullfilling all the criteria for nosocomial pneumonia will be included. 4. Presence of Gram-negative organism(s) by Gram stain OR by culture of pre-therapy respiratory specimen (eg, endotracheal aspirate [ETA], bronchoalveolar lavage [BAL], or mini-BAL) OR previous colonization 48 hours before screening; 5. Initial empiric antimicrobial regimen combining meropenem with an aminoglycoside or a fluoroquinolone active on Pseudomonas, plus MRSA coverage when indicated, in accordance with the 2016 ATS/IDSA guidelines for HAP/VAP/HCAP; 6. At least two of the risk factors described as associated with HAP/VAP caused by multidrug-resistant organisms in the guidelines of the ATS/IDSA for HAP/VAP (Clin Infect Dis. 2016 Sep 1;63(5):e61-e111) and those of the ESICM/ECCMID societies (Eur Respir J. 2017 Sep 10;50(3): • Antimicrobial therapy in the preceding two weeks; • Current hospitalization =5 days; • High frequency (>10%) of antibiotic resistance in the community or in the specific hospital unit, depending in particular on data issued from local official committees in line with the national epidemiological surveillance program; ; • Immunosuppressive disease and/or therapy; • Residence in a nursing home or extended care facility. 7. Clinical pulmonary infection score (CPIS) =6; 8. Expected to remain intubated and mechanically ventilated for =72 hours based on investigator estimate; 9. Expected to participate in the study through 28 days post first dose of meropenem; 10. Provision of written informed consent by the subject or subject’s, family member or a closerelative. [A waiver of consent will be asked to each Ethical Committee allowing for randomizing patients when he/she is unable to give consent and no, family member or a close relative can be contacted, in accordance with law specifications of emergency consent. In that case, family member or close relative or patients will be asked to give his/her consent for continuation of the trial when his/her condition permits]; 11. Affiliation to a social security system (recipient or assign) Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age
Exclusion criteria
Exclusion criteria: Subjects who have received antibiotic therapy for Gram-negative LRT infection for = 36 hours at the time of randomization; 2. Hypersensitivity to meropenem, Hypersensitivity to any other carbapenem antibacterial agent, Severe hypersentivity (eg anaphylactic reaction, severe skin reaction) to any other type of beta-lactam antibacterial agent (e.g.penicillins or cephalosporins) 3. Subjects taking valproic/acid sodium valproat/valpromide for a seizure disorder (other anticonvulsivants are allowed) 4. Subjects who have had a left hemisphere stroke (right hemisphere affected is allowed) within five days and there is an increased risk of fatal brain oedema as indicated by a major early computerized tomography hypodensity exceeding 50% of the middle cerebral artery territory, and/or involvement of additional vascular territories; 5. Subjects who have cystic fibrosis, human immunodeficiency virus (HIV) infection with CD4 count 28 days; 16. Subjects who were previously enrolled in this study; 17. Subjects under curatorship or tutorship.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To document the superiority of the MON4STRAT approach for reaching and maintaining a meropenem pre-determined PK-PD target (optimized for efficacy, mitigation of drug resistance and control of adverse effects) during the whole duration of treatment of hospitalized subjects with severe lower respiratory tract infection requiring mechanical ventilation caused by Gram-negative pathogens when compared to conventional therapies.;Secondary Objective: To determine whether the MON4STRAT approach is associated with a relevant clinical benefit in terms of clinical cure rate, mortality, duration of mechanical ventilation, pathogen eradication, emergence of drug resistance, safety, and healthcare utilization.; Primary end point(s): The primary endpoint of the study is the proportion of time from day 1 after randomization to end of therapy (EOT) in which the free meropenem trough concentration in plasma was maintained above 8 mg/L or above 4 x MIC if antibiotic MIC >2 and =8 µg/mL, without exceeding 140 mg/L at peak level, as determined by a method of reference (HPLC). The main PK/PD efficacy assessment will be determined every day during antibiotic treatment course in the modified intention-to-treat (ITT) study population from the meropenem peak and trough concentrations results: target attainment will be considered as achieved when the meropenem trough concentration in serum was maintained above 8 mg/L or above 4 x MIC if antibiotic MIC >2 and =8 µg/mL, without exceeding 140 mg/L at peak level, as determined by a method of reference (HPLC) )(Pr. Wallemacq (Université Catholique de Louvain, Laboratory of Therapeutic Drug Monitoring, Louvain La Neuve, Belgique). We will also determine and compare the proportion of time spent in the PK/PD target during Day 2 in the 2 groups of patients. The modified ITT population includes all patients randomized in the trial after exclusion of patients documented as being infected by a strain resi | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): •? Proportion of time from day 1 after randomization to end of therapy (EOT) in which the free meropenem trough concentration in serum was maintained above 8 mg/L or above 4 x MIC if antibiotic MIC >2 and =8 µg/mL, without exceeding 140 mg/L at peak level, as determined by a method of reference (HPLC) in the modified Micro-ITT (patients with microbiologically confirmed severe lower respiratory tract infection) sets of patients. In order to be included in the primary microbiologically evaluable population (Micro-ITT Analysis Set), subjects must demonstrate presence of Gram-negative organism(s) by semi-quantitative or quantitative cultures of pre-therapy respiratory secretions in concentrations above prespecified values (ETA cultures =105 CFU/mL; BAL cultures =104 CFU/mL) •? Clinical response rates observed at test of cure (TOC) visit (7 to 10 days after last study drug infusion) in the modified ITT and Micro-ITT (patients with microbiologically confirmed severe lower respiratory tract infection) sets of patients. •? Rate of emergence of antibiotic resistance in P. aeruginosa and Acinetobacter •? spp.: defined as a change of antibiotic MIC by two tube dilutions (four fold) from baseline in the modified ITT and Micro-ITT sets of patients. •? Microbiological response rates at EOT and TOC (7 to 10 days after last meropenem infusion): will be judged as satisfactory (documented eradication, presumed eradication,) or unsatisfactory (documented persistence, presumed persistence, or recurrence), based on the results of the respiratory specimen cultures obtained at EOT and TOC. •? Time to LRT bacterial eradication, as assessed by follow-up cultures of ETA obtained on days 3, 5, 7 and EOT in the modified ITT and Micro-ITT sets of patients. •? Day-14 and day-28 all-cause mortality in the modified ITT and Micro-ITT sets of patients. •? ICU and ho | — |
Countries
Belgium, France, Spain
Contacts
Public ContactItziar de Pablo
Fundación Investigación Biomédica Hospital Ramón y Cajal
Outcome results
None listed