E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Gram-negative Bacterial Pneumonia in Mechanically Ventilated Patients |
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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 | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10004051 |
E.1.2 | Term | Bacterial pneumonia, unspecified |
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 |
The primary purpose of this study is to demonstrate the safety and efficacy of the amikacin fosfomycin inhalation system (AFIS). |
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E.2.2 | Secondary objectives of the trial |
-To demonstrate that adjuvant therapy with AFIS, in conjunction with IV antibiotics, improves the clinical course of Gram-negative pneumonia in mechanically ventilated patients; and
-To demonstrate the safety of AFIS. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
OPTIONAL BACTERIAL DETECTION RESEARCH
The purpose of this research is to develop rapid identification methods for bacteria found in patients with pneumonia. No patient identifying information will be provided to the lab conducting this research. |
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E.3 | Principal inclusion criteria |
1. Males and non-pregnant, non-lactating females, ? 18 years and ? 80 years of age
2. Intubated and mechanically-ventilated
3. Diagnosis of pneumonia, defined as presence of a new or progressive infiltrate(s) on chest radiograph (within 24 hours prior to screening), as determined by the treating physician
4. Signs of infection (within 24 hours prior to screening):
-Fever (> 38ºC or > 100.4ºF); or
-Leukopenia (< 4,000 white blood cells [WBC]/mm3) or leukocytosis (? 12,000 WBC/mm3)
5. Impaired oxygenation (within 24 hours prior to screening):
-PaO2/FiO2 ? 300 mmHg
6. Acute Physiology and Chronic Health Evaluation (APACHE) II score > 10 on the day of intensive care unit (ICU) admission
7. Presence, or high suspicion, of Gram-negative organism(s) by either Gram stain or culture of respiratory secretions from a sample obtained within the previous 7 days (enrollment can occur before culture results are available) |
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E.4 | Principal exclusion criteria |
1. History of hypersensitivity to amikacin, other aminoglycosides, fosfomycin, imipenem, meropenem, or colistin
2. Received systemic antibiotic therapy for this episode of Gram-negative pneumonia for greater than 48 hours at the time of randomization
3. PaO2/FiO2 ? 100 mmHg plus diffuse infiltrates on Chest X-ray
4. Septic shock (defined as severe sepsis plus refractory [> 6 hours duration] hypotension)
5. Any of the following conditions that interfere with the assessment or interpretation of the diagnosis or response to therapy:
a. chest trauma with ongoing loss of stability of the thoracic cage following a fracture of the sternum, ribs, or both;
b. increased amounts of fluid in the lung cavities requiring chest tube drainage;
c. lung cancer within the last 2 years;
d. lung abscess(s);
e. anatomical bronchial obstruction;
f. suspected atypical pneumonia;
g. chemical pneumonitis (e.g., inhalation injury);
h. cystic fibrosis
6. Immunocompromised patients, including those with neutropenia NOT due to the current infection (absolute neutrophil count < 500/mm3), leukemia, lymphoma, human immunodeficiency virus (HIV) infection with CD4 count < 200 cells/mm3, or splenectomy; those who are early post-transplantation (< 3 months post-transplant, or > 3 months post-transplant with evidence of organ rejection by clinical criteria, pathologic confirmation, or modification of immunosuppression within the past 4 weeks), are on cytotoxic chemotherapy, or are on high-dose steroids (e.g., > 40 mg of prednisone or its equivalent [> 160 mg hydrocortisone, > 32 mg methylprednisolone, > 6 mg dexamethasone, > 200 mg cortisone] daily for > 2 weeks)
7. Evidence of significant renal impairment (serum creatinine > 2.0 mg/dL within 24 hours prior to screening)
8. Evidence of ototoxicity (history of hearing aid use prior to current hospitalization)
9. Evidence of hepatotoxicity (alanine aminotransferase [ALT] or aspartate aminotransferase [AST] >3X the upper limit of normal value within 24 hours prior to screening)
10. Positive urine and/or serum beta-hCG pregnancy test (only in women of reproductive age)
11. On mechanical ventilation for > 28 days
12. Head injury or stroke that will likely require continued mechanical ventilation after resolution of pneumonia, or Glasgow Coma Scale score ? 3 at Screening
13. Participating in or has participated in other investigational interventional studies (drug or device) within the last 30 days (or 5 times the half-life of the previously administered investigational compound, whichever is longer) prior to study treatment |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change from baseline in Clinical Pulmonary Infection Score (CPIS) during the planned 10-day treatment period |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Daily CPIS will be determined by one blinded, central reviewer in order to minimize inter-observer variability. |
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E.5.2 | Secondary end point(s) |
Secondary Outcome Measures:
-The hierarchical composite endpoint of mortality, and ventilator-free days using the win ratio method of Pocock et al1
- Number of days free of mechanical ventilation from Day 1 through Day 28
- Number of ICU days from Day 1 through Day 28
- Microbiological response rates at Day 14 in patients whose pre-study treatment bronchoalveolar lavage (BAL) was positive for MDR Gram-negative bacteria
- Mortality from Day 1 through Day 28
- Clinical relapse rates (defined as a new episode of pneumonia requiring reinstitution of IV antibiotics)
from Day 11 through Day 28
Pharmacokinetic Endpoints:
- Analysis of amikacin and fosfomycin systemic concentrations prior to the AM doses on Days 3 and 10
- Analysis of amikacin and fosfomycin tracheal aspirate concentrations 15 minutes after the AM doses on Days 3 and 10 (only if the patient continues to be intubated)
Safety Endpoints:
- Adverse events (AEs)
- Serial hematology, biochemistry, and urinalysis
- Changes in airway peak and plateau pressures before and after Investigational Product administration
-Oximetry during Investigational Product administration
Exploratory Endpoints:
-Clinical response at Day 14
Clinical response would require the following: improvement in CPIS from pre-study treatment score, and no rescue IV antibiotics needed from Day 1 through Day 14
-Total number of days of Gram-negative IV antibiotics per patient from Day 1 through Day 14, and from Day 15 through Day 28
- Number of hospital days from Day 1 through Day 28
- % Failed, as measured by a PaO2/FiO2 ratio worsened by > 30% compared to baseline value, measured over the 10 days of study drug treatment
- % Failed, as measured by change in CPIS from baseline, during the planned 10-day treatment period
- % Successful, as measured by a PaO2/FiO2 ratio improved by >30% compared to baseline value, measured over the 10 days of study drug treatment
- Microbiological response rates at Day 14 in patients whose pre-study treatment BAL was positive for MRSA
- Microbiological response rates at Day 14 in all patients
- Microbiological response rates at Day 14 in patients whose pre-study treatment BAL was positive for extremely drug resistant (XDR) Gram-negative bacteria
- Change from baseline in Procalcitonin levels collected at Screening and on Days 3, 7, 10, and 14 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
-The hierarchical composite endpoint of mortality, and ventilator-free days using the win ratio method of Pocock et all
-No. of days free of mechanical ventilation from Day 1-28
-No. of ICU days from Day 1-28
-Microbiological response rates at Day 14 in patients whose pre-study treatment BAL was positive for MDR Gram-negative bacteria
-Mortality from Day 1-28
-Clinical relapse rates from Day 11-28
-Analysis of amikacin and fosfomycin systemic concentrations prior to the AM doses on Days 3 and 10
-Analysis of amikacin and fosfomycin tracheal aspirate concentrations 15 minutes after the AM doses on Days 3 and 10 (only if the patient continues to be intubated)
-AEs- Day 1-28
-Serial hematology, biochemistry, and urinalysis
Please see the further info in the protocol-section 3.3. |
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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 | 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 | 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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 23 |
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 |
Argentina |
France |
Greece |
Hungary |
Puerto Rico |
Spain |
Turkey |
United States |
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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
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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 | 1 |
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 | 3 |