| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Inflammation of lung tissue |
| Inflamación del tejido pulmonar |
|
| 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 | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10060946 |
| E.1.2 | Term | Pneumonia bacterial |
| 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 |
| The primary objective of this study is to demonstrate a low rate of emergence of antibiotic resistance in P. aeruginosa and Acinetobacter spp during the treatment of hospitalized patients with pneumonia requiring mechanical ventilation treated with PD optimized meropenem administered as a prolonged infusion in combination with a parenteral aminoglycoside plus tobramycin by inhalation (Group 1) compared to therapy with meropenem alone (Group 2 - control arm). |
| El objetivo principal de este estudio es demostrar una baja tasa de aparición de resistencia antimicrobiana en P. aeruginosa y Acinetobacter spp durante el tratamiento de pacientes hospitalizados con neumonía que requiere ventilación mecánica tratados con meropenem farmacodinámicamente (PD) optimizado, administrado como infusión prolongada en combinación con un aminoglucósido parenteral y tobramicina inhalada (Grupo 1) comparado con tratamiento con meropenem en monoterapia (Grupo 2, control). |
|
| E.2.2 | Secondary objectives of the trial |
-Efficacy and safety of PD optimized/combination therapy when compared to monotherapy meropenem
-Pharmacodynamic relationship between meropenem exposure in plasma and ELF and the probability of clinical and/or microbiological outcome
-14 and 28 day all-cause mortality between the groups
-Microbiological response at EOT, TOC and LFU between groups
-Observed rates of pathogen response to those seen in the control arm
-Rates of resistance of other Gram-neg. bacteria between the groups
-Proportion of subjects whose repeat cultures are negative at Day 5 between the groups and among fermentor and non-fermentor pathogens
-Outcome in the proportion of subjects who received prior antibiotics vs. those with no prior antibiotics across treatment arms and the impact on rates of resistance per type of prior antibiotic received together with the appropriateness of the antibiotic therapy based upon susceptibility
-Health care resource utilization between the groups |
-Eficacia y seguridad del tratamiento.
-Relación farmacodinámica entre la exposición a meropenem en plasma y en líquido pulmonar y la probabilidad de presentar los diversos resultados clínicos y/o microbiológicos
-Mortalidad por cualquier causa a los 14 y 28 días.
-Respuesta microbiológica al final del tratamiento (EOT), en la evaluación del test de curación (TOC) y en el seguimiento tardío (LFU).
-Tasa observada de respuesta patógena.
-Tasa de aparición de resistencias en otras bacterias Gram negativas.
-Proporción de sujetos cuyos cultivos repetidos son negativos en el Día 5 y entre patógenos fermentadores y no fermentadores.
-Resultados en el subgrupo de pacientes que habían recibido antibióticos previamente frente al subgrupo que no habían recibido e impacto sobre las tasas de resistencia según el tipo de antibiótico previo recibido, junto con la adecuación del tratamiento antibiótico en base a la susceptibilidad.
-Utilización de recursos sanitarios. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Provision of written informed consent by the subject or subject's legal representative.
2. Hospitalized males or females, 18 years or older, with respiratory failure requiring mechanical ventilation and clinical suspicion of HABP, HCAP or VABP.
3. Onset or exacerbation of pneumonia at least 72 hours after admission to an acute care facility or onset of pneumonia in a nursing home or rehabilitation facility with subsequent transfer to an acute care facility (HCAP definition: and as defined in Inclusion criteria 6, 7, and 8).
4. Women of childbearing potential may be entered if their pregnancy test (urine or serum) is negative, and they are instructed to abstain from sexual intercourse for the duration of the study, or contraceptive measures are used until all follow-up procedures are complete. Medically acceptable contraceptives include: (1) surgical sterilization, (2) approved hormonal contraceptives as advised by your study doctor (such as birth control pills, Depo-Provera, or Lupron Depot), (3) two barrier methods (such as a condom or diaphragm) used with a spermicide, or (4) an intrauterine device (IUD).
5. Subjects who have received previous antibacterial therapy within 14 days of pre-treatment bronchoscopy entry may be entered only if the subject has not responded clinically (as defined in Inclusion Criteria 6, 7, and 8).
6. Patients should have the following clinical findings that support a diagnosis of HABP/VABP/HCAP:
-Documented fever, defined as an oral or tympanic temperature greater than or equal to 38.0 degrees Celsius (100.4 degrees Fahrenheit), or a core temperature greater than or equal to 38.3 degrees Celsius (101 degrees Fahrenheit) or hypothermia, defined as a core body temperature of less than 35 degrees Celsius (95.2 degrees Fahrenheit); axillary temperatures are not recommended.
-An elevated total peripheral white blood cell (WBC) count (WBC greater than 10000/mm3); or greater than 15 percent immature neutrophils (bands), regardless of total peripheral WBC count; or leukopenia with total WBC less than 4500/mm3.
-New onset of expectorated or suctioned respiratory secretions characterized by purulent appearance indicative of bacterial pneumonia.
In addition, patients with HABP should have at least one of the following present at enrollment:
-A new onset of cough (or worsening of baseline cough) during 48 or more hours of hospitalization or within 7 days after discharge from a hospital.
-Auscultatory findings on pulmonary examination of rales and/or evidence of pulmonary consolidation (e.g., dullness on percussion, bronchial breath sounds, or egophony).
-Dyspnea, tachypnea, or respiratory rate greater than 30/minute, particularly if any or all of these signs or symptoms are progressive in nature:
-Hypoxemia (e.g., a partial pressure of oxygen less than 60 mm Hg while the patient is breathing on room air as determined by arterial blood gas or oxygen saturation less than 90 percent while the patient is breathing on room air as determined by pulse oximetry, or worsening of the ratio of the partial pressure of oxygen to the fraction of inspired oxygen (PaO2/FiO2), respiratory failure requiring mechanical ventilation).
7. Radiographic Findings: Within 48 hours before starting empiric therapy a subject's chest radiograph should show the presence of a NEW or progressive infiltrate, cavitation, or effusion suggestive of pneumonia.
8. Microbiologic Findings: Within 24 hours before the start of empiric study therapy, a quantitative culture of Bronchoscopic BAL fluid must be obtained.
9. In addition, patients with VABP should have a Clinical Pulmonary Infection Score of greater than 6, and at least one of the following present at enrollment:
-Auscultatory findings on pulmonary examination of rales and/or evidence of pulmonary consolidation (e.g., dullness on percussion, bronchial breath sounds, or egophony).
-Acute changes made in the ventilator support system to enhance oxygenation, as determined by arterial blood gas, or worsening PaO2/FiO2.
10. DEFINITIONS for ventilator-associated bacterial pneumonia (VABP):
a. Definite VABP: Microbiological diagnosis based on quantitative culture of Bronchoscopic BAL (? 104 CFU/ml).
b. Probable VABP: Clinical diagnosis based on a new and persistent radiographic infiltrate plus qualifying clinical signs as noted above in number 6 for HABP.
c. Suspected VABP: Clinical suspicion of VABP triggering quantitative culture. Based on new radiographic infiltrate plus qualifying clinical signs, or any physician suspicion of VABP. |
| Sujetos hospitalizados, varones y mujeres ? 18 años, con neumonía bacteriana adquirida en el hospital (HABP) confirmada por cultivo o neumonía asociada a cuidados sanitarios (HCAP) que requieren ventilación mecánica, o neumonía bacteriana asociada a ventilación (VABP). Por lo tanto, los sujetos participantes comprenden sujetos atendidos en centros de agudos que desarrollan neumonía 72 o más horas después del ingreso y sujetos residentes en residencias de ancianos o centros de rehabilitación que desarrollan una neumonía y son trasladados a un centro de agudos |
|
| E.4 | Principal exclusion criteria |
1. Subjects with pneumonia caused by pathogens resistant to meropenem (MIC >16?g/ml) or a prior meropenem therapy failure.
2. Subjects with contra-indications to ANY study medication, in particular with known or suspected allergy or hypersensitivity. This is inclusive of type I hypersensitivity (e.g., anaphylaxis) to cephalosporins, penicillins, monobactams, or carbapenems, and to vancomycin or linezolid.
3. Women who are pregnant or lactating.
4. Subjects taking anticonvulsant medications for a known seizure disorder.
5. Subjects with known or suspected community acquired bacterial pneumonia (CABP) or viral pneumonia; or Subjects with acute exacerbation of chronic bronchitis without evidence of pneumonia.
6. Subjects with primary lung cancer or another malignancy metastatic to the lungs.
7. Subjects who were previously enrolled in this study.
8. Subjects who have had an investigational drug or have used an investigational device within 30 days prior to entering the study.
9. Subjects with another focus of infection requiring concurrent antibiotics (e.g. other broad spectrum agents or those agents providing gram negative coverage) that would interfere with evaluation of the response to study drug.
10. Subjects with cystic fibrosis, acquired immune deficiency syndrome (AIDS) with a CD4 lymphocyte count <200 cells/µl, neutropenia (absolute neutrophil count <500 cells/ml), known or suspected active tuberculosis.
11. Subjects with little chance of survival for the duration of study therapy (7-14 days) because of antecedent illness or underlying comorbidities.
12. Subjects with an APACHE II score >35.
13. Subjects with underlying condition(s) which would make it difficult to interpret response to the study drugs.
14. Subjects with hypotension (systolic BP of < 85mmHg) or acidosis (arterial pH <7.25 or serum bicarbonate <15 mg/dl) despite attempts at fluid resuscitation. Subjects requiring ongoing treatment with vasopressors will be eligible for the study if their hypotension is controlled and acidosis has resolved. Subjects with intractable septic shock are not eligible for enrollment.
15. Subjects who have undergone bone marrow transplantation.
16. Subjects with profound hypoxia as defined by a PaO2/FiO2 ratio <100. |
1. Los sujetos con neumonía causada por patógenos resistentes a meropenem o un fracaso de la terapia meropenem anterior.
2. Los sujetos con contraindicación para cualquiera de los medicamentos en investigación, especialmente aquellos con historia conocida o sospecha de alergia o hipersensibilidad. Esto incluye reacciones de hipersensibilidad tipo I (p. e., anafilaxia) a las cefalosporinas, penicilinas, monobactamas o carbapenems, y a vancomicina o linezolid.
3. Mujeres embarazadas o en periodo de lactancia.
4. Los pacientes tratados con antiepilépticos.
5. Los sujetos con neumonía bacteriana adquirida en la comunidad o neumonía viral, o sujetos con exacerbación aguda de la bronquitis crónica sin evidencia de neumonía.
6. Los sujetos con cáncer de pulmón primario o de otro tumor maligno metastásico en los pulmones.
7. Los sujetos con otro foco de infección que requiere antibióticos concurrentes que pudieran interferir con la evaluación de la respuesta al fármaco del estudio.
8. Los pacientes con fibrosis quística, síndrome de inmunodeficiencia adquirida (SIDA) con un recuento de linfocitos CD4 <, neutropenia, e infección o sospecha de infección tuberculosa activa.
9. Los sujetos con pocas posibilidades de sobrevivir durante la duración del tratamiento de estudio (7-14 días) debido a una enfermedad antecedente o comorbilidades subyacentes.
10. Los sujetos con una puntuación APACHE II> 35.
11. Los sujetos con enfermedad subyacente (s) que haría difícil interpretar la respuesta a los fármacos del estudio.
12. Los pacientes con hipotensión o acidosis a pesar de los intentos de reanimación con líquidos. Los sujetos que requieren tratamiento continuo con vasopresores serán elegibles para el estudio si la hipotensión se controla y la acidosis se ha resuelto. Los pacientes con shock séptico intratable no son elegibles.
13. Los sujetos que se han sometido a un trasplante de médula ósea.
14. Los sujetos con profunda hipoxia definidos por una relación de <100 PaO2/FiO2. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the suppression of the emergence of resistance in the Microbiologically Evaluable (ME) statistical population. |
| La variable principal es la supresión de la aparición de resistencia en (EM) de la población microbiológicamente evaluable |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| - Day 5 / Early Extubation Evaluation |
| Día 5 / Evaluación extubación precoz |
|
| E.5.2 | Secondary end point(s) |
| All subjects will be evaluated for a clinical response to the treatments. Clinical response will be based on the assessment reflecting the course of the primary infectious disease (i.e., pneumonia [HABP, VABP or HCAP] requiring mechanical ventilation). |
| Todos los sujetos serán evaluados para una respuesta clínica a los tratamientos. La respuesta clínica se basa en la evaluación que reflejada por el curso de la enfermedad infecciosa primaria (es decir, la neumonía [HABP, VABP o HCAP] que requieren ventilación mecánica). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Day 5 / Early Extubation Evaluation
- End of Study Treatment (EOT)
- Test of Cure (TOC) Evaluation 7 to 14 days after completion of all antibiotic treatment |
- Día 5 / Evaluación extubación precoz
- Fin del tratamiento del estudio (EOT)
- La prueba de curación (TOC) Evaluación 7 a 14 días después de la finalización de todos los tratamientos antibióticos |
|
| 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 | 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| All of the microbiologic isolates (BAL fluid, blood, etc...) will be reanalyzed by a central lab for determination of susceptibilities and the presence of any resistance determinants. |
| Todas las muestras recogidas para realizar análisis microbiológicos(BAL, sangre, etc...) serán reanalizadas en un laboratorio central para determinar susceptibilidad y presencia de determinantes de resistencia. |
|
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 3 |
| 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 |
| Germany |
| Spain |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| 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 |
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