E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Gram-negative Bacterial Pneumonia in Mechanically Ventilated Patients |
Neumonía bacteriana por gram-negativos en pacientes sometidos a ventilación mecánica |
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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). |
El objetivo principal de este estudio es demostrar la seguridad y la eficacia del sistema de inhalación de amikacina / fosfomicina (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. |
-Demostrar que el tratamiento adyuvante con AFIS, conjuntamente con los antibióticos i.v., mejora la evolución clínica de la neumonía por gram-negativos en pacientes sometidos a ventilación mecánica; y -Demostrar la seguridad de 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. |
INVESTIGACIÓN OPCIONAL DE DECTECCIÓN DE BACTERIAS El objetivo de dicha investigación será desarrollar métodos de identificación rápida de las bacterias aisladas en los pacientes con neumonía. No se proporcionará ninguna información que pueda identificar a los pacientes al laboratorio que lleve a cabo estas investigaciones. |
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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) |
1. Varones y mujeres no embarazadas y que no estén en la lactancia, >/=18 años y </= 80 años 2. Intubados y con ventilación mecánica 3. Diagnóstico de neumonía, definida como la presencia de un infiltrado nuevo o en progresivo en la radiografía de tórax (dentro de las 24 horas previas a la selección), determinada por el médico responsable 4. Signos de infección (dentro de las 24 horas previas a la selección): -Fiebre (> 38 ºC o > 100,4 ºF); o -Leucopenia (< 4.000 LEU/mm3) o leucocitosis (>/= 12.000 LEU/mm3) 5. Deterioro de la oxigenación (dentro de las 24 horas previas a la selección): -PaO2/FiO2 ? 300 mm Hg 6. Puntuación APACHE II (Acute Physiology and Chronic Health Evaluation II) > 10 el día del ingreso en la UCI 7. Presencia o elevada sospecha de microorganismos gram-negativos mediante tinción de Gram o cultivo de las secreciones respiratorias de una muestra obtenida dentro de los 7 días previos (la inclusión puede efectuarse antes de disponer de los resultados de los cultivos) |
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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 |
1. Antecedentes de hipersensibilidad a la amikacina, otros aminoglucósidos, fosfomicina, imipenem, meropenem o colistina 2. Haber recibido tratamiento antibiótico sistémico para este episodio de neumonía por gram-negativos durante más de 48 horas en el momento de la aleatorización 3. PaO2/FiO2 </= 100 mm Hg más infiltrados difusos en la radiografía de tórax 4. Shock séptico (definido como sepsis grave más hipotensión refractaria [> 6 horas de duración]) 5. Cualquiera de las siguientes alteraciones que interfiera en la evaluación o interpretación del diagnóstico o la respuesta al tratamiento: a. traumatismo torácico, actualmente con pérdida de estabilidad de la caja torácica después de una fractura de esternón, costillas o ambos; b. aumento de las cantidades de líquido en las cavidades pulmonares que precisa drenaje con tubo torácico; c. cáncer de pulmón dentro de los últimos 2 años; d. absceso(s) pulmonar(es); e. obstrucción bronquial anatómica; f. sospecha de neumonía atípica; g. neumonitis química (p. ej., lesión por inhalación); o bien h. fibrosis quística 6. Pacientes inmunodeprimidos, incluidos aquellos con neutropenia NO debida a la infección actual (recuento absoluto de neutrófilos < 500/mm3), leucemia, linfoma, infección por el virus de la inmunodeficiencia humana (VIH) con recuento de CD4 < 200 células/mm3 o esplenectomía; los que han recibido un trasplante recientemente (<3 meses post-trasplante o >3 meses post-trasplante con signos de rechazo del órgano según criterios clínicos, confirmación anatomopatológica o modificación de la inmunosupresión durante las 4 semanas previas), están recibiendo quimioterapia citotóxica o están recibiendo corticosteroides a dosis altas (p. ej., > 40 mg de prednisona o su equivalente [> 160 mg de hidrocortisona, > 32 mg de metilprednisolona, > 6 mg de dexametasona, > 200 mg de cortisona] diariamente durante > 2 semanas) 7. Signos de afectación renal significativa (creatinina sérica >2,0 mg/dl dentro de las 24 horas previas a la selección) 8. Indicios de ototoxicidad (empleo de audífonos con anterioridad a la hospitalización actual) 9. Signos de hepatotoxicidad (alanina aminotransferasa [ALT] o aspartato aminotransferasa [AST] > 3 veces el límite superior de normalidad dentro de las 24h previas a la selección) 10. Prueba de embarazo de beta-hCG positiva en orina y/o suero (solo en mujeres de edad reproductiva) 11. En ventilación mecánica durante > 28 días 12. Traumatismo craneal o ictus que probablemente precise ventilación mecánica continuada después de la resolución de la neumonía, o puntuación de la Escala de Coma de Glasgow </= 3 en el momento de la selección 13. Está participando o ha participado en otros estudios intervencionistas de investigación (con fármacos o dispositivos) dentro de los últimos 30 días (o 5 veces la semivida del compuesto en investigación administrado previamente, lo que sea más largo) antes del tratamiento del estudio |
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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 |
Cambio respecto al momento basal en la CPIS durante el periodo de tratamiento previsto de 10 días. |
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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. |
La CPIS diaria la determinará un revisor central, desconocedor del tratamiento, para reducir al mínimo la variabilidad entre observadores. |
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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. |
-El criterio de valoración jerárquico compuesto de mortalidad y días sin ventilador mediante el método del cociente de victoria de Pocock et al. - Nº días sin ventilación mecánica desde el día 1 al 28 - Nº días en la UCI desde el día 1 al 28 - Tasas de respuesta microbiológica el día 14 en pacientes cuyo LBA previo al tratamiento del estudio era positivo para bacterias gram-negativas MDR -Mortalidad desde el día 1 al 28 -Tasas de recaída clínica desde el día 11 al 28 -Análisis de las concentraciones sistémicas de amikacina y fosfomicina antes de las dosis matutinas los días 3 y 10 Ver info adicional en el protocolo-sección 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 |
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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LVLS |
última vista del último paciente |
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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 | 0 |
E.8.9.1 | In the Member State concerned months | 9 |
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 |