| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| MRSA Infection - Nosocomial Pneumonia |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 7.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10052596 |
|
| 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. |
|
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the trial:
Male and female subjects with a diagnosis of nosocomial pneumonia meeting all criteria listed below will be included in the study.
Hospitalized (in acute, sub-acute or long-term care facility) males and females aged 18 years of age and over
Subject must have clinically documented
• Nosocomial pneumonia (NP) defined as pneumonia with clinical picture onset ≥ 48 hours after hospitalization in an acute in-patient healthcare facility. Subject may also be enrolled upon transfer from another acute care facility if the clinical picture onset of pneumonia was after they were hospitalized at that facility for ≥ 48 hours
OR
• Healthcare-associated pneumonia (HCAP) defined as pneumonia acquired in a long-term care or sub-acute/intermediate healthcare facility (eg., nursing home, rehabilitation center) or in subject who is admitted with pneumonia following a recent hospitalization (discharged within 90 days of current admission and previously hospitalized for ≥ 48 hours) or pneumonia in subject who has received chronic dialysis care within 30 days prior to study enrollment
WITH at least two of the following signs and symptoms present within 24 hours of study enrollment in subjects who have not been treated pre-study with an antimicrobial with activity against subject’s MRSA isolate. In subjects that have been treated pre-study with an antimicrobial with activity against subject’s MRSA isolate, symptoms and findings must be present within 24 hours prior to that treatment or within 72 hours prior to enrollment (whichever is closer to the time of enrollment):
• new onset or worsening of cough
• new onset of purulent sputum production or a change (worsening) in character of thesputum or increased respiratory secretions or increased suctioning requirements
• auscultatory findings on pulmonary exam of rales and/or pulmonary consolidation(dullness on percussion, bronchial breath sounds, or egophony)
• dyspnea, tachypnea, or respiratory rate 30/minute, particularly if any or all of theseare progressive in nature
• hypoxemia with a PO2 < 60 mmHg while subject is breathing room air or respiratoryfailure requiring mechanical ventilation in a previously non-ventilated subject
• worsening gas exchange (e.g., O2 desaturations [e.g., Pa O2/Fi O2 240], increasedoxygen requirements, or increased ventilation demand)
Subject must present with the criteria described in 3a or 3b prior to enrollment. Signs and symptoms must have been present within 24 hours of study enrollment in subjects who have not been treated pre-study with an antimicrobial with activity against subject’s MRSA isolate. In subjects that have been treated pre-study with an antimicrobial with activity against subject’s MRSA isolate, symptoms and findings must be present within 24 hours prior to that treatment or within 72 hours prior to enrollment (whichever is closer to the timeof enrollment).
a. At least two of the following:
• Fever defined as body temperature ≥ 38°C (100.4°F) taken orally, ≥ 37.5°C (99.5°F) axillary, or ≥ 38.4°C (101.1°F) taken rectally, typanically via temporal artery or core, or hypothermia defined as body temperature ≤ 35.5°C (96°F) taken orally or ≤ 35.9°C (96°F) taken 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% immatureneutrophils (bands) regardless of total peripheral WBC or leukopenia with total WBC < 4,500/mm3
• Positive, satisfactory quantitative culture for MRSA from a baseline respiratory specimen obtained by an invasive procedure (bronchoscopic or non-bronchoscopic). Subject may be enrolled prior to report of quantitative culture results.
OR
b. New onset of purulent sputum production or a change (worsening) in character of the sputum or increased respiratory secretions or increased suctioning requirements
AND at least one of the following:
• Fever defined as body temperature ≥ 38°C (100.4°F) taken orally; ≥ 38.4 °C (101.1°F) taken rectally, tympanically, via the temporal artery or core; or ≥ 37.5°C (99.5°F) taken axillary
• Elevated total peripheral white blood cell count (WBC) >10,000/mm3
Subject must have a positive chest X-ray (PA or AP with lateral if possible) at baseline/screen consistent with the diagnosis of pneumonia (new or progressive infiltrate(s) or consolidation). CT scan of the thorax may be used to confirm diagnosis of pneumonia. If Chest X-Ray findings consistent with pneumonia are not present prior to enrollment, it is acceptable for these findings to be present within 48 hours following enrollment.
... |
|
| 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 received 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 known 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.
... |
|
| 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 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. Ninety-five percent confidence intervals will be used to assess treatment effect. |
|
| 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 | Information not present in EudraCT |
| 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 | 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 | 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.8.5 | The trial involves multiple Member States | Yes |
| 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 | Information not present in EudraCT |
| 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 have confirmed MRSA or an organism resistant to any of the study treatments should be discontinued. Any subject may 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).
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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