| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Intubated and Mechanically-Ventilated, Adult Patients with severe Gram-Negative lower respiratory tract infection |
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| E.1.1.1 | Medical condition in easily understood language |
| Intubated and Mechanically-Ventilated, Adult Patients with severe Gram-Negative lower respiratory tract infection |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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. |
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| E.2.2 | Secondary objectives of the trial |
| 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. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 <35,0°C;
• leukocyte count >10,000/mm3 or <4,500/mm3, or an immature neutrophil (band) count >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)
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| E.4 | Principal 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 <100 cell/mm3 (HIV testing is not required as part of this protocol), or invasive fungal infection of the lung;
6. Neutropenia (screening absolute neutrophil count <103 neutrophils/mm3);
7. Bone marrow transplant;
8. Subjects who have primary lung cancer with known endobronchial obstruction (post-operative patients after lung cancer resection are eligible for the study);
9-. Subjects with another focus of infection requiring concurrent antibiotics that would interfere with evaluation of the response to study treatment;
10 Subjects for whom therapy will require aerosolized antibiotics;
11. Subjects for whom therapy will require intermittent hemodialysis (patients treated with continuous renal replacement techniques are eligible for the study);
12. Burns greater than 40% of total body surface area;
13. Subjects with intractable septic shock (subjects requiring ongoing treatment with vasopressors will be eligible for the study if their hypotension is controlled and acidosis has resolved);
14. Rapidly fatal illness with death likely within the next 72 hours;
15. Subjects who have been on mechanical ventilation for >28 days;
16. Subjects who were previously enrolled in this study;
17. Subjects under curatorship or tutorship.
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| E.5 End points |
| E.5.1 | 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 resistant to meropenem or those who died within the first two days after randomization or those who refused to be included into the study after recovery of consciousness (modified ITT).
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | 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 hospital length of stay in the modified ITT and Micro-ITT sets of patients.
• Number of mechanical ventilation-free days between days 1 and 28 after randomization, defined as the number of days of unassisted breathing in the modified ITT and Micro-ITT sets of patients.
• Number of antibiotic-free days between days 1 and 28, defined as the number of days without any antibiotics in the modified ITT and Micro-ITT sets of patients.
• CPIS and SOFA scores kinetics between day-1 and day-14 in the modified ITT and Micro-ITT sets of patients.
• Procalcitonin and/or C-reactive protein kinetics between day-1 and day-14 after randomization in the modified ITT and Micro-ITT sets of patients.
• Pharmacodynamic relationship existing between meropenem exposure in plasma and the probability of clinical and/or microbiological outcome in the modified ITT and Micro-ITT sets of patients.
• Pathogen-specific clinical and microbiological responses in the two treatment groups.
• Number of serious adverse effects [SAEs] observed in the two groups. A special attention will be brought to neurologic complications observed in the two groups.
• Rates of resistance of other Gram-negative bacteria (non-Pseudomonas or Acinetobacter spp) in the two treatment groups.
• Healthcare resource utilization in the two treatment groups, as assessed by numbers of ICU and hospital days, duration of mechanical ventilation and antimicrobial therapy in the modified ITT and Micro-ITT sets of patients.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
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| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 3 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The study is considered completed when the last patient recruited perform the last
scheduled visit |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 17 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 17 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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