The purpose of this study is to learn if an experimental antibiotic called TR-701 FA can safely and effectively treat ventilated patients with hospital-acquired bacterial pneumonia (HABP) or ventilator-associated bacterial pneumonia. The experimental antibiotic will be tested against the already approved antibiotic Linezolid. The sponsor of the study wants to prove, that the new medication isn't inferior regarding efficacy and safety as compared to the already approved medication Linezolid.

• Register: EUCTR
• Last refreshed on: 10 December 2019
• Main ID: EUCTR2013-004154-22-DE
• Date of registration: 25/02/2014
• Prospective Registration: Yes
• Primary sponsor: Cubist Pharmaceuticals, LLC., an indirect wholly-owned subsidiary of Merck Sharp & Dohme Corp.
• Public title: The purpose of this study is to learn if an experimental antibiotic called TR-701 FA can safely and effectively treat ventilated patients with hospital-acquired bacterial pneumonia (HABP) or ventilator-associated bacterial pneumonia. The experimental antibiotic will be tested against the already approved antibiotic Linezolid. The sponsor of the study wants to prove, that the new medication isn't inferior regarding efficacy and safety as compared to the already approved medication Linezolid.
• Scientific title: A Phase 3 Randomized Double-blind Study Comparing TR-701 FA and Linezolid in Ventilated Gram-positive Nosocomial Pneumonia
• Target sample size: 726
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2013-004154-22
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: yes; Placebo: yes; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Austria, Belarus, Belgium, Bosnia and Herzegovina, Croatia, Czech Republic, Estonia, France, Georgia, Germany, Greece, Hungary, India, Israel, Italy, Jordan, Kazakhstan, Latvia, Lebanon, Portugal, Russian Federation, Serbia, Slovakia, South Africa, Spain, Sri Lanka, Switzerland, Turkey, Ukraine, United Arab Emirates, United Kingdom

Contacts

• Name: Carisa DeAnda, PharmD
• Affiliation: Cubist Pharmaceuticals, LLC, an indirect wholly-owned subsidiary of Merck Sharp & Dohme Corp.

• Name: Carisa DeAnda, PharmD
• Affiliation: Cubist Pharmaceuticals, LLC, an indirect wholly-owned subsidiary of Merck Sharp & Dohme Corp.

Key inclusion & exclusion criteria

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:
o Acute changes made in the ventilator support system to enhance oxygenation, as determined by ABG, or worsening PaO2/FiO2
o Hypoxemia (eg, a partial pressure of oxygen less than 60 millimeters of
mercury while receiving FiO2 of 25-30%, as determined by ABG or
worsening of the ratio of the partial pressure of oxygen to the fraction of
inspired oxygen (PaO2/FiO2)
o New onset or worsening pulmonary symptoms or signs, such as cough,
asymmetric breath sounds, tachypnea (eg, respiratory rate greater than 25
breaths per minute), need for increased oxygenation or ventilation support

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 bacteria only or in a mixed infection defined as follows:

Respiratory Sample

o Sample acquired and Gram stain performed within 36 hours prior to first infusion of study drug using an accepta
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 (presence of Candida in lower respiratory tract is not exclusionary), or parasitic pneumonia
2. Any of the following health conditions:
• Legionella infection (Legionella pneumophila pneumonia)
• Cystic fibrosis
• 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;
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. Burns >40% of total body surface area
12. Current or anticipated neutropenia with absolute neutrophil count <500 cells/mm3
13. Severe renal disease requiring peritoneal dialysis. Patients with seve

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Ventilated Gram-positive nosocomial pneumonia
MedDRA version: 20.1 Level: LLT Classification code 10052596 Term: Nosocomial pneumonia System Organ Class: 100000004862

Therapeutic area: Diseases [C] - Bacterial Infections and Mycoses [C01]

Intervention(s)

Product Name: TR-701 FA Powder for Concentrate for Solution for Infusion
Product Code: TR-701 FA
Pharmaceutical Form: Powder for concentrate for solution for infusion
INN or Proposed INN: Tedizolid Phosphate
CAS Number: 856867-55-5
Current Sponsor code: TR-701 FA
Other descriptive name: TR-701 FA
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 200-
Pharmaceutical form of the placebo: Solution for injection/infusion
Route of administration of the placebo: Intravenous use

Trade Name: Linezolid
Product Name: Linezolid
Product Code: Linezolid
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: Linezolid
CAS Number: 165800-03-3
Current Sponsor code: Linezolid
Other descriptive name: LINEZOLID
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 600-
Pharmaceutical form of the placebo: Solution for injection/infusion
Route of administration of the placebo: Intravenous use

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: Day 28

Main Objective: 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).

Secondary Objective: * To compare the ACM observed with TR-701 FA and linezolid within 28 days after randomization in the microbiological ITT (Micro-ITT) Analysis Set
* Clinical response at TOC in the ITT (EMA and Japan Ministry of Health, Labour, and Welfare primary endpoint) and Clinically Evaluable CE Analysis Sets. Clinical response at TOC is derived from the Investigator’s assessment at the 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

Primary end point(s): The primary outcome is ACM within 28 days after randomization in the ITT Analysis Set.

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Day 28

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)

Secondary ID(s)

2013-004154-22-LV

TR701-132

Source(s) of Monetary Support

Cubist Pharmaceuticals, LLC, an indirect wholly-owned subsidiary of Merck Sharp & Dohme Corp.

Ethics review

Status: Approved
Approval date:
Contact:

Results

• Results available: Yes
• Date Posted: 26/06/2019
• Date Completed: 22/06/2018
• URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-004154-22/results