| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| MRSA Infection - Nosocomical Pneumenia |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10052596 |
| E.1.2 | Term | Nosocomial pneumonia |
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| 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 compare the clinical efficacy of linezolid to vancomycin in the treatment of nosocomial pneumonia due to MRSA in hospitalized adults. |
|
| E.2.2 | Secondary objectives of the trial |
| To compare the bacteriological efficacy and the safety and tolerability of linezolid to vancomycin in the treatment of nosocomial pneumonia due to MRSA in hospitalized adults. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1 Hospitalized males and females ≥aged 18 years of age
2 Subject must have clinically documented
• Nosocomial pneumonia defined as pneumonia with clinical picture onset ≥48hrs after hospitalization in an acute in-patient healthcare facility. Subject may also be enroled upon transfer from another acute care facility if the clinical picture onset of pneumonia was after hospitalization at that facility for ≥48hrs
OR
Healthcare-associated pneumonia defined as pneumonia acquired in a long-term care or sub-acute/intermediate healthcare facility or in subject admitted with pneumonia following recent hospitalization or pneumonia in subject who has received chronic dialysis care within 30d prior to study enrolment WITH at least 2 of the following signs/symptoms present within 24 hrs of study enrolment in subjects who have not been treated pre-study with an antimicrobial active against subject’s MRSA isolate. In subjects who have been treated, symptoms and findings must be present within 24hrs prior to that treatment or within 72 hrs prior to enrolment:
new onset or worsening of cough
new onset of purulent sputum production or change in character of sputum or increased respiratory secretions or increased suctioning requirements
auscultatory findings on pulmonary exam of rales and/or pulmonary consolidation
dyspnea, tachypnea, or respiratory rate ≥30/min, particularly if any or all of these are progressive in nature
hypoxemia with PO2 <60 mm Hg while subject is breathing room air or respiratory failure requiring mechanical ventilation in a previously non-ventilated subject
worsening gas exchange
3 Subject must present with criteria described in 3a or 3b prior to enrolment. Signs/symptoms must have been present within 24hrs of study enrolment in subjects who have not been treated pre-study with an antimicrobial active against subject’s MRSA isolate. In subjects who have been treated, symptoms and findings must be present within either 24hrs prior to that treatment or 72hrs prior to enrolment.
a. At least two of the following:
Fever defined as body temperature ≥38°C orally; ≥38.4°C rectally, tympanically, via temporal artery or core; ≥ 37.5°C axillary or hypothermia defined as body temperature ≤35.5°C orally or ≤35.9°C rectally, tympanically, via temporal artery or core
Systolic hypotension (systolic blood pressure <90 mm Hg)
Temporarily altered mental status consistent with sepsis
Elevated total peripheral white blood cell count (WBC) >10,000/mm3 or >15% immature neutrophils regardless of total peripheral WBC or leukopenia with total WBC <4,500/mm3
Positive quantitative culture for MRSA from a baseline respiratory specimen obtained by an invasive procedure. Subject may be enrolled without either preliminary or final results of culture. In addition, subject may be enrolled based on planned procedure or prior to report of quantitative culture results.
OR
b. New onset of purulent sputum production or change in character of sputum or increased respiratory secretions or increased suctioning requirements AND at least one of the following:
Fever defined as body temperature ≥38°C orally; ≥38.4°C rectally, tympanically, via temporal artery or core; or ≥37.5°C taken axillary
Elevated total peripheral white blood cell count >10,000/mm3
4 Subject must have positive chest X-ray at baseline/screen consistent with diagnosis of pneumonia. Thorax CT scan may be used to confirm diagnosis of pneumonia. If chest X-ray findings consistent with pneumonia are not present prior to enrolment, these findings may be present within 48hrs following enrolment.
5 Subject must have a baseline respiratory specimen taken by either an invasive technique or have an endotracheal aspirate or suitable sputum. A suitable sputum specimen is defined as having 10 squamous epithelial cells and 25 leukocytes per low power field.
If an acceptable specimen is not available from within 24hr period prior to enrolment then baseline specimen may be one obtained up to 48hrs prior to study enrolment.
In subjects treated pre-study with an antimicrobial initiated earlier than 24hrs prior to study enrolment, the specimen may be obtained within 24hrs prior to start of the pre-study antimicrobial or within 72hrs prior to enrolment. It is acceptable to obtain baseline respiratory specimen obtained by invasive technique within 24hrs post starting study drug.
6 Subject must have venous access available for IV dosing.
7 Subject or legally acceptable representative must give informed consent by signing and dating an informed consent form prior to study entry.
8 Subject must be willing to complete all study-related activities and follow-up visits.
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| E.4 | Principal exclusion criteria |
Subjects presenting with any of the following will not be included in the trial:
Subject with rapidly fatal underlying disease not expected to survive to complete the study.
Subject with high likelihood of death within 72 hours based on multiple organ dysfunction at the time of study enrollment.
Subject with known or suspected meningitis, endocarditis, or osteomyelitis.
Subject who has a CD4 cell count < 200 cells/mm3 secondary to HIV infection unless the subject has been on treatment with highly active anti-retroviral therapy (HAART) is on PCP prophylaxis, and clinically and immunologically stable (with CD4 counts from 100-199 and granulocytes≥ 1000). The subject may be enrolled at the discretion of the investigator after investigator discussion with the medical monitor.
Subject with sustained shock, defined as MAP < 55 mmHg (or if MAP not available, systolic BP < 85 mm Hg) for > 2 hours despite adequate fluid resuscitation and/or sympathomimetic agents to maintain blood pressure.
Subject who was treated with linezolid, vancomycin or teicoplanin for greater than 48 hours within the 72 hour period prior to the enrollment. Also excluded are subjects treated for greater than 48 hours with one of the above drugs, and drug began prior to the 72 hour preenrollment period but drug treatment continued into the 72 hour pre-study period. Subject who was treated for the infection under study prior to this timeframe may be enrolled unless the subject received 72 hours or more of treatment and did not respond.
Subject who was treated with a previous antibiotic with MRSA activity against the subject’s isolate (other than linezolid, vancomycin or teicoplanin) for greater than 48 hours within the 72 hour period prior to the enrollment. Also excluded are subjects treated for greater than 48 hours and drug began prior to the 72 hour pre- enrollment period but drug treatment continued into the 72 hour pre-study period. Subjects who received ≥ 72 hours of an antibiotic with activity against the subject’s MRSA isolate (other than linezolid, vancomycin or teicoplanin) for the infection under study and were documented to be a treatment failure may be enrolled. Certain drugs with variable MRSA activity (e.g. fluoroquinolones) may not be excluded if local susceptibility patterns will predict non-susceptibility and is subsequently documented.
Subject who has severe liver disease (Child-Pugh Class C hepatic insufficiency), or subject with SGPT and/or SGOT > 5 X ULN (upper limit of normal).
Subject who has severe neutropenia (neutrophils < 500 cells/mm3 including segmented cells and bands) unless neutropenia is reversible and count is expected to be >500 cells/ mm3 within 24 hours following first dose of study drug.
Subject who is currently on peritoneal dialysis or alternative treatment for renal failure (e.g., hemofiltration, CVVH). Subjects on hemodialysis may be enrolled.
Subject in whom his/her weight would require a vancomycin dosing frequency with intervals less than 12 hours if they were randomized to vancomycin, thereby not allowing the blind to be maintained.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Clinical response will be determined by the investigator and evaluated at EOT and EOS for subjects with a baseline MRSA pathogen. Clinical response will be based primarily on the global assessment of the clinical presentation of the subject made by the investigator at the evaluation timepoint. Bacteriological response will be determined by the Sponsor and evaluated at the EOT and at the EOS visits for subjects with a baseline MRSA pathogen. |
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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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 39 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| 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
|
| Subjects who do not confirm MRSA or an organism resistant to any of the study treatment should be discontinued from the study at any time if it is in their best interest. This study may be terminated or suspended at any time and the sponsor will inform the investigators, the IECs and the regulatory authorities and provide the reason(s) for the termination or suspension, as specified by the applicable regulatory requirement(s). |
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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 | 1 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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