E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10035701 |
E.1.2 | Term | Pneumonia gram-negative bacterial NOS |
E.1.2 | System Organ Class | 100000004862 |
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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 evaluate the efficacy (superiority) and safety of BAY 41-6551 as
measured by the comparison of the clinical cure rate of aerosolized BAY
41-6551, administered via the PDDS Clinical, versus placebo (normal
saline) at the TOC visit in patients with microbiologically confirmed Gram
negative pneumonia. |
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E.2.2 | Secondary objectives of the trial |
The secondary efficacy objectives include:
• The number of days on mechanical ventilation
• The number of ICU days at Day 28
• The total number of days of Gram-negative IV antibiotics per patient
• Clinical Pulmonary Infection Score (CPIS) changes to TOC
• The clinical relapse rates at Day 28
• The all cause mortality rate during therapy, at day 15 and 28
Other objectives:
• To determine that the PDDS Clinical device performs as intended
Safety Objectives:
• The frequency of AEs
• The progression and incidence rates of organ failure
• The all cause mortality rate during therapy, at Day 15 and 28
Secondary microbiological objectives include:
• per pathogen microbiological response rates at the TOC visit
• per patient microbiological response rate at the TOC visit
• microbiological recurrence rates at the TOC and Day 28 visit
• emergence of new respiratory pathogens during the treatment period
A full list is presented in the protocol. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Males and non-pregnant, non-lactating females, 18 years of age or older. For females of child-bearing potential, one of the following medically acceptable contraceptive methods must be used: or they agree to abstain from heterosexual intercourse while participating in the study. One or more of these methods should be used during the study and continue for 30 days after completion of the antibiotic therapy.
a) Double-barrier methods of contraception (eg, condoms plus spermicidal foam)
b) Intrauterine contraceptive device
c) Approved pharmaceutical contraceptive product (eg, birth control pills or patches, long-term injectable or implantable hormonal contraceptive)
2. Intubated and mechanically-ventilated (patients who have had a tracheotomy may be considered as possible study participants as long as they are being mechanically ventilated)
3. Diagnosis of pneumonia defined as presence of a new or progressive infiltrate(s) on chest radiograph
4. Presence of Gram-negative organism(s) indicated by:
a) Gram-stain OR
b) Culture of pre-therapy respiratory specimen (eg, acceptable TA, BAL, mini-BAL, PSB)
5. At least two of the following: signs of infection:
a) Fever, defined as an oral temperature of > 38.0°C (100.4°F) or a tympanic/ rectal/core temperature > 38.5°C (101.3°F), or hypothermia, defined as a tympanic/rectal/core body temperature of < 35.0°C (95.0°F)
b) Leukocyte count greater than or equal to 10,000/mm3 or less than or equal to 4,500/mm3, or an immature neutrophil (band) count > 15% regardless of the peripheral leukocyte count
c) New onset of purulent sputum or respiratory secretions, or a change in the character of sputum
6. Impaired oxygenation as demonstrated by the following:
a) A decrease in PaO2/FiO2 by at least 50 mm Hg compared to a PaO2/FiO2 value within the last 48 hours from enrollment OR
b) PaO2/FiO2 value of < 240 mm Hg (not including adult respiratory distress syndrome [ARDS] patients) (the PaO2/FiO2 value used should be the value used when the CPIS was calculated)
7. CPIS greater than or equal to 6, (Section 15.3)
8. At least two risk factors for MDR organisms (MDR organism: an organism resistant to representative agents in two or more of the following antibiotic classes - beta-lactams, including penicillins, cephalosporins, and monobactams; carbapenems; fluoroquinolones; and aminoglycosides):
a) Antimicrobial therapy in the preceding two weeks b) Current hospitalization greater than or equal to 5 days c) High frequency (> 10%) of antibiotic resistance in the community or in the specific hospital unit
d) Immunosuppressive disease and/or therapy e) Presence of the risk factors for HCAP
• Hospitalization for two days or more in the preceding 90 days
• Residence in a nursing home or extended care facility
• Home infusion therapy (including antibiotics)
• Chronic dialysis within 30 days
• Home wound care
• Family member with multidrug-resistant pathogen
9. Be willing and able to give written informed consent. If the patient is unable to give written informed consent, the patient's legally authorized representative (LAR) may provide written consent as approved by the Institutional Review Board (IRB)/Independent Ethics Committee (IEC). |
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E.4 | Principal exclusion criteria |
1. A history of hypersensitivity to amikacin or other aminoglyosides,
2. Has received antibiotic therapy for Gram-negative pneumonia for greater than 24 hours at the time of study drug administration. (There should be as minimal a time delay as possible between randomization and first dose of study drug but up to 24 hours will be acceptable. However, sites should still take into account that patients cannot receive more than 24 hours of prior antibiotic therapy for the current episode of Gram-negative pneumonia up to the time of study drug administration [not to the time of randomization]). Exceptions: Systemic antibiotic therapy for more than 24 hours in the 48 hours prior to enrollment is permitted in case the infection is caused by microbiologically-confirmed pathogens that are resistant to the antimicrobial agent used to treat the current episode of Gram-negative pneumonia.
3. Has primary lung cancer (including patients with small cell lung carcinoma/non-small cell lung carcinoma and patients with unknown histology) or another malignancy metastatic to the lungs or other known endobronchial obstructions. Exception: Note that patients with complete resection of non-small cell lung carcinoma are eligible for the study.
4. Known or suspected active tuberculosis, cystic fibrosis, human immunodeficiency virus (HIV) infection with CD 4 count < 200 cell/mm3 (HIV testing is not required as part of this protocol), or invasive fungal infection of the lung, lung abscess, or empyema.
5. Known or suspected bacteremia secondary to Staphylococcus aureus
6. Known or suspected neuromuscular disorders such as myasthenia gravis or parkinsonism
7. Has had a stroke within five days. Additionally, patients with stroke should not be enrolled if at least one or both of the following apply:
a) There is an increased risk of fatal brain edema as indicated by a history of hypertension or heart failure, major early computed tomography (CT) hypodensity exceeding 50% of the middle cerebral artery territory, and/or involvement of additional vascular territories.
b) There is indication for deterioration based on comparison of patient's neurological condition within six hours of planned study drug dosing and patient's neurological condition two days before, judged by applying the National Institute of Health (NIH) Stoke Scale (Section 15.4).
8. A positive urine and /or serum beta-human chorionic gonadotropin (B-hCG) pregnancy test
9. Burns greater than 40% of total body surface area
10. Patients with a serum creatinine > 2 mg/dL (177 μmol/L) Exception: Patients with a serum creatinine > 2 mg/dL (177 μmol/L) and being treated with continuous renal replacement therapy (continuous veno-venous hemofiltration [CVVH] and continuous venovenous hemofiltration with dialysis [CVVH-D]) or daily hemodialysis will receive the aerosol study drug treatment (Section 8.4.6.1).
11. Neutropenia (Screening absolute neutrophil count [ANC] < 103 neutrophils/mm3)
12. Has been on mechanical ventilation for > 28 days (ie, current event should not be more than 28 continuous days). A patient is not considered extubated if extubation lasts less than 24 hours.
13. Is participating in or has participated in other investigational interventional studies within the previous 28 days
14. The risk of rapidly fatal illness and death within 72 hours, or any concomitant conditions not related to VAP that, in the opinion of the investigator, precludes completion of study evaluations and the course of therapy.
15. Stem cell transplantation
16. Patients with documented Legionella infection (Legionella pneumonia)
17. Has an APACHE II score < 10
18. Previous assignment to treatment during this study
19. Close affiliation with the investigational site; e.g. a close relative of the investigator, dependent person (e.g. employee or student of the investigational site) |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy variable will be the clinical response at the Test-of-Cure (TOC) visit in the modified Intent-to-Treat (ie, ITT population plus
a pre-therapy culture positive for a respiratory tract pathogen) population. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints:
1. the number of days on mechanical ventilation through the day 28 visit
2. the number of ICU days at day 28 visit
3. the total number of days of Gram-negative IV antibiotics per patient
4. change in CPIS from the first day of study drug to TOC
5. Number of Hospital days at the day 28 visit
6. Clinical relapse rates at the day 28 visit
The safety endpoints are to compare (BAY 41-6551 vs placebo) as measured by:
1. The frequency of AEs
2. The progression and incidence rates of organ failure
3. The all cause mortality rate during therapy, at Day 15 and at Day 28 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary efficacy endpoints:
1-3, 5 and 6: days 1-28.
4: TOC visit
Safety endpoints: 1, 2: throughout the study 3: days 15 and at Day 28 |
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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 | 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) | No |
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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 80 |
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 |
China |
France |
Greece |
Italy |
Japan |
Netherlands |
Norway |
Portugal |
Czech Republic |
Germany |
Hungary |
Spain |
Thailand |
Israel |
Poland |
Russian Federation |
Ukraine |
United Kingdom |
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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
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The end of the study is defined as clean database |
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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 | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |