| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Ventilated Gram-positive nosocomial pneumonia |
|
| E.1.1.1 | Medical condition in easily understood language |
| Ventilated patients with hospital-acquired bacterial pneumonia or ventilator-associated bacterial pneumonia. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10052596 |
| E.1.2 | Term | Nosocomial pneumonia |
| E.1.2 | System Organ Class | 100000004862 |
|
| 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 |
| The primary objective is to determine the noninferiority (NI) in all-cause mortality (ACM) within 28 days after randomization of intravenous (IV) TR-701 FA compared with IV linezolid in the Intent to Treat (ITT) Analysis Set in ventilated patients with presumed gram-positive hospital-acquired bacterial pneumonia (HABP) or gram-positive ventilator-associated bacterial pneumonia (VABP), collectively defined as ventilated nosocomial pneumonia (VNP). |
|
| E.2.2 | Secondary objectives of the trial |
* To compare the ACM observed with TR-701 FA and linezolid within 28 days after randomization in the microbiological ITT (Micro-ITT) Analysis Set
* To compare clinical response for TR-701 FA and linezolid treatment at Test of Cure (TOC) in the ITT and Clinically Evaluable (CE) Analysis Sets. Clinical response at TOC is derived from the Investigator’s assessment at the End of Therapy (EOT) and TOC Visits as detailed in the Statistical Analysis Plan (SAP)
* To compare the per-patient favorable microbiological response rate at EOT in the Micro-ITT and Microbiologically Evaluable (ME)-1 Analysis Sets and at TOC in the Micro-ITT and ME-2 Analysis Sets
* To evaluate the safety profile of TR-701 FA and compare with that of linezolid
* To assess the population pharmacokinetic (PK) and PK/pharmacodynamic (PD) profile of TR-700 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients who meet all the following diagnostic and inclusion criteria are eligible for the study.
1. Males or females ≥ 18 years old
2. Adequate venous access for IV study drug administration
3. Intubated (via endotracheal tube, including tracheostomy patients) and mechanically ventilated, AND
• For HABP, at least 1 of the following signs or symptoms presenting within 24 hours prior to intubation of a patient hospitalized, including patients institutionalized in long-term care facilities, for ≥48 hours. If the patient has been discharged, discharge must have been within 7 days:
o A new onset of cough (or worsening of baseline cough)
o Dyspnea, tachypnea, or respiratory rate >30/minute, particularly if any or all of these signs or symptoms are progressive in nature
o Hypoxemia (eg, a partial pressure of oxygen <60 mm Hg while the patient is breathing on room air as determined by arterial blood gas (ABG) or oxygen saturation <90% while the patient is breathing on room air as determined by pulse oximetry, or worsening (decline from any earlier finding) of the ratio of the partial pressure of oxygen to the fraction of inspired oxygen (PaO2/FiO2), or respiratory failure requiring mechanical ventilation
• For VABP, receiving mechanical ventilation ≥48 hours:
Acute changes made in the ventilator support system to enhance oxygenation, as determined by ABG, or worsening PaO2/FiO2
4. Chest radiograph shows the presence of new or progressive infiltrate(s) suggestive of bacterial pneumonia (based on Investigator evaluation; report from qualified medical professional who is not the Investigator to be provided)
5. Clinical findings to support diagnosis of HABP/VABP
• New onset of suctioned respiratory secretions characterized by purulent appearance indicative of bacterial pneumonia
• And at least 1 of the following:
o Documented fever (oral ≥38°C [100.4°F] or a tympanic, temporal, rectal, or core temperature ≥38.3°C [101°F]) OR
o Hypothermia (core body temperature ≤35°C [95.2°F]) OR
o Total peripheral white blood cell (WBC) count ≥10,000 cells/mm3 OR
o Leukopenia with total WBC ≤4500 cells/mm3 OR
o ≥15% immature neutrophils (bands; if local laboratory has capabilities to measure)
6. High probability of pneumonia caused by gram-positive cocci only or in a mixed infection defined as follows:
Respiratory Sample
o Sample acquired and Gram stain performed within 24 hours prior to first infusion of study drug using an acceptable purulent respiratory specimen such as sputum or endotracheal aspirate sample with <10 squamous epithelial cells (SEC) per low-power field and more than 25 polymorphonuclear cells per low-power field showing gram-positive bacteria (with or without gram-negative bacteria) OR
o Sample acquired and Gram stain performed within 24 hours prior to first infusion of study drug using an acceptable respiratory specimen such as protected specimen brush, bronchoalveolar lavage (BAL), mini-BAL, or sample from an exudative pleural effusion showing gram-positive bacteria (with or without gram-negative bacteria) OR
o Culture from sample obtained within 72 hours prior to first infusion of study drug positive for methicillin-resistant Staphylococcus aureus (MRSA) |
|
| E.4 | Principal exclusion criteria |
Patients who meet any of the following criteria are not eligible to participate in this study:
1. Known or suspected community-acquired bacterial pneumonia or viral, fungal, or parasitic pneumonia
2. Any of the following health conditions:
• Legionella infection (Legionella pneumophila pneumonia)
• Cystic fibrosis
• Bronchiectasis
• Human immunodeficiency virus (HIV) infection with last known CD4 count <200 cell/mm³ (HIV testing is not required)
• Known or suspected Pneumocystitis jiroveci pneumonia
• Known or suspected active tuberculosis
• Lung abscess
• Evidence of endocarditis
• Tracheobronchitis (if no evidence of pneumonia)
3. Received systemic or inhaled antibiotic therapy effective for gram-positive pathogens that cause VNP for >24 hours (for example, >1 dose of a once-daily antibiotic, >2 doses of a twice daily antibiotic) in the last 72 hours
EXCEPTIONS
• Progression of disease on the prior antibacterial regimen for this episode of VNP after >48 hours of treatment; requires microbiological confirmation of a gram-positive pathogen,
OR
• Patient developed symptoms of pneumonia and a new infiltrate while receiving the prior antibacterial regimen for reasons other than the current VNP,
OR
• Patient received systemic antibacterial therapy that does not cover the gram positive pathogen isolated on respiratory culture,
OR
• Antibiotic therapy for gut decontamination or gut motility (example, low-dose erythromycin) or C. difficile infection
4. Receipt of monoamine oxidase A and B inhibitors (see Appendix 1) from 2 weeks prior to randomization or planned use through the End of Therapy (EOT) Visit
5. Planned use of agents with serotonergic activity (see Appendix 1 and Section 1.4) through the EOT Visit
6. Administration of linezolid or tedizolid phosphate ≤30 days before the first infusion of study drug, except for receipt of a single administration of linezolid, within 24 hours prior to the first administration of study drug to treat the current VNP.
7. Bronchial obstruction or a history of postobstructive pneumonia (this does not exclude patients with pneumonia who have underlying chronic obstructive pulmonary disease)
8. Primary lung cancer or another malignancy metastatic to the lungs
9. Recent opportunistic infections where the underlying cause of the infection is still active (eg, leukemia, transplant, acquired immunodeficiency syndrome)
10. Expected survival <72 hours or any 1 of the following:
• Comfort care measures only
• Acute respiratory distress syndrome/acute lung injury secondary to septic shock, or due to third degree burns or inhalation injury
• Nonresolving pulmonary edema secondary to congestive heart failure
11. Severe confounding respiratory condition due to penetrating chest trauma or chest trauma with paradoxical respiration
12. Burns >40% of total body surface area
13. Current or anticipated neutropenia with absolute neutrophil count <500 cells/mm3
14. Severe renal disease requiring peritoneal dialysis. Patients with severe renal disease on hemodialysis, venovenous dialysis, or other forms of renal filtration may be enrolled
15. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥10× upper limit of normal OR severe hepatic disease with Child Pugh score >9
16. Investigator’s opinion of clinically significant electrocardiogram (ECG) finding such as ischemia, infarct, or ventricular arrhythmia with immediate potential for a fatal outcome, or, prior to the current infection, a history of New York Heart Association Class IV cardiac failure defined as severe limitations - experiences symptoms even while at rest, mostly bedbound patients, within 1 year
17. Patients with uncontrolled hypertension (defined as high blood pressure that is clinically an issue and uncontrolled on multiple medications), pheochromocytoma, carcinoid syndrome, or thyrotoxicosis
18. Treatment with investigational medicinal product ≤30 days before the first infusion of study drug or prior randomization in this protocol
19. Investigational device present, or removed <30 days before the first infusion of study drug or presence of device-related infection
20. Hypersensitivity to oxazolidinones (eg, linezolid) or any component in the formulation
21. Women who are pregnant or nursing, or who are of childbearing potential and unwilling to use an acceptable method of birth control (eg, intrauterine device, double-barrier method [eg, condoms, diaphragm, or cervical cap with spermicidal foam, cream or gel], or male partner sterilization);excluding women ≥2 years postmenopausal or surgically sterile |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary outcome is ACM within 28 days after randomization in the ITT Analysis Set. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Secondary outcomes include the following:
• ACM within 28 days after randomization (Micro-ITT Analysis Set)
• Clinical response at TOC (ITT and CE Analysis Sets). Clinical response at TOC is derived from the Investigator’s assessment at the EOT and TOC Visits
• Microbiological response at EOT and TOC (Micro-ITT, ME-1 and ME-2 Analysis Sets)
• ACM in patients with or methicillin-susceptible Staphylococcus aureus (MSSA) or MRSA (Micro-ITT Analysis Set)
• Clinical response by Investigator in patients with MSSA or MRSA (Micro-ITT and ME-2 Analysis Sets) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | 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) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| 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 | No |
| 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 | Yes |
| E.8.2.3 | Other | No |
| 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
| 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 | 70 |
| 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 | No |
| 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 |
| Austria |
| Belarus |
| Belgium |
| Bosnia and Herzegovina |
| Croatia |
| Czech Republic |
| Estonia |
| France |
| Georgia |
| Germany |
| Greece |
| Hungary |
| India |
| Israel |
| Kazakhstan |
| Latvia |
| Lebanon |
| Russian Federation |
| Serbia |
| Slovakia |
| South Africa |
| Spain |
| Sri Lanka |
| Switzerland |
| Turkey |
| Ukraine |
| United Arab Emirates |
| United Kingdom |
| Jordan |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 4 |
| 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 | 4 |
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