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 | 16.1 |
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 | No |
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 | 7 |
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 |
France |
Greece |
Argentina |
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 | 3 |
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 |