E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Hospital-acquired Bacterial Pneumonia, Ventilator-associated Bacterial Pneumonia, or Healthcare-associated Bacterial Pneumonia Caused by Gram-negative Pathogens. |
|
E.1.1.1 | Medical condition in easily understood language |
Bacterial Pneumonia Caused by Gram-negative Pathogens acquired during hospitalization or during a stay in a healthcare institution or after a patient is intubated and received mechanical ventilation. |
|
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 | 20.0 |
E.1.2 | Level | SOC |
E.1.2 | Classification code | 10021881 |
E.1.2 | Term | Infections and infestations |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10076918 |
E.1.2 | Term | Hospital acquired pneumonia |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10065153 |
E.1.2 | Term | Ventilator associated pneumonia |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
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 all-cause mortality at Day 14 of subjects who receive S-
649266 with that of subjects who receive the comparator, meropenem,
in adults with hospital-acquired bacterial pneumonia (HABP),ventilatorassociated
bacterial pneumonia (VABP), or healthcare-associated
bacterial pneumonia (HCABP) caused by Gram-negative pathogens |
|
E.2.2 | Secondary objectives of the trial |
Key Secondary Objectives:
• To compare the clinical outcome of treatment with S-649266 with that
of
meropenem in subjects at test of cure (TOC)
• To compare the microbiologic outcome of treatment with S-649266
with that of meropenem at TOC
Other Secondary Objectives:
Efficacy:
• To compare the clinical outcome of treatment with S-649266 with that
of meropenem in subjects at early assessment (EA)2, end of treatment
(EOT), and follow-up (FU)
• To compare the microbiologic outcome of treatment with S-649266
with that of meropenem at EA, EOT, and FU
• To compare the all-cause mortality at Day 28 of subjects treated with
S-649266 with that of subjects treated with meropenem
• To compare the all-cause mortality during treatment and the FU period
of subjects treated with S-649266 with that of meropenem
• To compare the resource utilization required for the 2 study
treatments for the study-qualifying infection
Safety:
• To assess the safety of S-649266 |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Subjects 18 years or older at the time of signing informed consent
2. Subjects who have provided written informed consent or their informed consent has been provided by Legally Authorized Representative (LAR) (Note: Country-specific rules and local Ethics Committee approval for LAR informed consent will determine whether or not and how a subject unable to comprehend or sign the informed consent is allowed to be enrolled in the study)
3. Subjects who meet the clinical diagnosis criteria for HABP/VABP/HCABP
4. All subjects must fulfill at least 1 of the following clinical criteria at
screening:
a. New onset or worsening of pulmonary symptoms or signs, such as
cough, dyspnea, tachypnea (eg, respiratory rate greater than 25
breaths/minute), expectorated sputum production, or requirement for
mechanical ventilation
b. Hypoxemia (eg, a partial pressure of oxygen [PaO2] less than 60 mm
Hg while the subject is breathing room air, as determined by arterial
blood gas [ABG], or worsening of the ratio of the PaO2 to the fraction of
inspired oxygen [PaO2/FiO2])
c. Need for acute changes in the ventilator support system to enhance
oxygenation, as determined by worsening oxygenation (ABG or
PaO2/FiO2) or needed changes in the amount of positive end-expiratory
pressure
d. New onset of or increase in (quantity or characteristics) suctioned
respiratory secretions, demonstrating evidence of inflammation and
absence of contamination
5. All subjects must have at least 1 of the following signs:
a. Documented fever (ie, core body temperature [tympanic, rectal,
esophageal] not less than [NLT] 38°C [100.4°F], oral temperature NLT
37.5°C, or axillary temperature NLT 37°C)
b. Hypothermia (ie, core body temperature [tympanic, rectal,
esophageal] not more than [NMT] 35°C [95.0°F], oral temperature NMT
35.5°C and axillary temperature NMT 36°C)
c. Leukocytosis with a total peripheral white blood cell (WBC) count NLT
10,000 cells/mm3
d. Leukopenia with total peripheral WBC count NMT 4500 cells/mm3
e. Greater than 15% immature neutrophils (bands) noted on peripheral
blood smear
6. All subjects must have a chest radiograph during screening or have a
previous chest radiograph within 48 hours prior to randomization
showing the presence of new or progressive infiltrate(s) suggestive of
bacterial pneumonia. A computed tomography (CT) scan in the same
time window showing the same findings could also be acceptable.
7. All subjects must have evidence of a Gram-negative infection
involving the lower respiratory tract as documented by 1 or more of the
following:
a. Gram stain of lower respiratory secretions showing Gram-negative
bacteria either alone or mixed with Gram-positive bacteria at or within
72 hours prior to randomization
b. Microbiologic culture of respiratory tract secretions within 72 hours
prior to randomization identifying Gram-negative aerobic bacteria
c. Other diagnostic tests, including molecular tests, which provide
evidence of Gram-negative bacterial infection of the lower respiratory
tract
d. Pneumonia highly suspected to be due to a Gram-negative bacteria
based on prior antibiotic use or local epidemiologic evidence of Gramnegative
infection outbreak.
8. Subject is male (no contraception required) or female (if woman of
child-bearing potential, must use highly effective birth control method,
see protocol for details in line with CTFG recommendations)
9. Subjects who failed empiric therapy will be allowed in this study.
However, confirmation of both clinical and microbiological failure is
necessary: see protocol for details |
|
E.4 | Principal exclusion criteria |
1. Subjects who have a known or suspected community-acquired bacterial pneumonia (CABP), atypical pneumonia, viral pneumonia, or chemical pneumonia (including aspiration of gastric contents, inhalation injury)
2. Subjects who have a history of any hypersensitivity to cephalosporins
or to carbapenems, or severe hypersensitivity to any other type of β-
lactams other than cephalosporins and carbapenems (eg, penicillins,
monobactams), or hypersensitivity to linezolid (Note: For β lactams, a
history of a mild rash followed by uneventful re-exposure is not a
contraindication to enrollment)
3. Subjects with a Gram-negative infection caused by a carbapenem resistant
pathogen, if known at the time of randomization (Note:
Subjects who have a carbapenem-resistant pathogen identified after
randomization should be evaluated clinically before discontinuation of
study treatment.)
4. Subjects with coinfection caused by invasive aspergillosis,
mucormycosis or other highly lethal mold
5. Subjects who have central nervous system infection (eg, meningitis,
brain abscess, shunt infection)
6. Subjects with cystic fibrosis
7. Subjects in refractory septic shock, defined as persistent hypotension
despite adequate fluid resuscitation or despite vasopressive therapy at
the time of randomization
8. Subjects with neutropenia (ie, polymorphonuclear neutrophils < 500
cells/μL)
9. Female subjects who have a positive pregnancy test at screening, who
are lactating, or who refuse to use 1 of the previously specified methods
of contraception
10. Subjects with an Acute Physiology and Chronic Health Evaluation II
(APACHE) II score of > 35
11. Subjects who have received potentially effective antibiotic therapy
for a continuous duration of more than 24 hours during the previous 72
hours prior to randomization (Note: Subjects failing empiric therapy as
defined in inclusion criterion 9 may be eligible for inclusion.)
12. Subjects with any condition or circumstance that, in the opinion of
the investigator, would compromise the safety of the subject or the
quality of the study data
13. Subjects receiving peritoneal dialysis (hemofiltration and
hemodialysis are permitted)
14. Subjects requiring continued treatment with methotrexate,
procainamide, probenecid, monoamine oxidase inhibitors, or valproic
acid (see Section 5.2)
15. Subjects who have received another investigational drug or device
within 30 days prior to study entry
16. Subjects who have previously been randomized in this study or have
previously received S-649266
17. Subjects with 1 or more of the following laboratory abnormalities in
baseline specimens: aspartate aminotransferase (AST), alanine
aminotransferase (ALT), alkaline phosphatase, or total bilirubin level > 3
times the upper limit of normal (ULN), absolute neutrophil count <
100/μL, platelet count < 40,000/μL
18. Subjects with bronchiectasis with symptoms of persistent or
recurrent bronchial infection related to irreversibly damaged and dilated
bronchi; namely, subjects with clinical bronchiectasis
19. Subjects with lung abscesses |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Primary Endpoint:
All-cause mortality at Day 14 for S-649266 or the active-comparator, meropenem.
|
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
Key secondary endpoints:
- The clinical outcome of treatment with S-649266 or meropenem per subject at TOC
- The microbiologic outcome of treatment with S-649266 or meropenem per subject at TOC
Other secondary efficacy:
The clinical outcome of treatment with S-649266 or meropenem per subject at EA, EOT, and FU.
The microbiologic outcome of treatment with S-649266 or meropenem per subject at EA, EOT, and FU.
The all-cause mortality at Day 28.
The all-cause mortality during the full duration of the study.
The resource utilization required for the treatment of the study qualifying infection |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Clinical and Microbiological outcome will be evaluated at TOC, EA, EOT, and FU.
The all-cause mortality will be also evaluated at Day 28 and until end of study.
Facility utilization will be assessed by determination of the time in 24-hour days associated with the treatment of the infection. |
|
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 | 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 | Yes |
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 | 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.8.2.4 | 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 | 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 | 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 |
Belgium |
Brazil |
Canada |
Colombia |
Czech Republic |
Estonia |
France |
Georgia |
Germany |
Hungary |
Israel |
Japan |
Latvia |
Philippines |
Russian Federation |
Serbia |
Spain |
Taiwan |
Ukraine |
United Kingdom |
United States |
|
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
|
End of study treatment + 28 days. |
|
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 | 10 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 10 |