Inhaled Amikacin Solution BAY41-6551 as Adjunctive Therapy in the Treatment of Gram-Negative Pneumonia

Study Overview
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Brief Summary
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To demonstrate that as adjunctive therapy to intravenous (IV) antibiotics, BAY 41-6551 400 mg (amikacin as free base) administered as an aerosol by the Pulmonary Drug Delivery System (PDDS) Clinical every 12 hours is safe and more effective than placebo (aerosolized normal saline) administered as an aerosol by the PDDS Clinical every 12 hours, in intubated and mechanically-ventilated patients with Gram-negative Pneumonia. The secondary endpoint objectives are to evaluate the superiority of aerosolized BAY 41-6551 versus aerosolized placebo in pneumonia-related mortality, the Early Clinical Response at Day 10, the days on ventilation, and the days in the intensive care unit (ICU).

Official Title
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A Prospective, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Safety and Efficacy of BAY 41-6551 as Adjunctive Therapy in Intubated and Mechanically-Ventilated Patients With Gram-Negative Pneumonia

Conditions
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Pneumonia, Bacterial

Intervention / Treatment
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* Drug: Amikacin Inhalation Solution (BAY41-6551)
* Drug: Aerosolized Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and non-pregnant, non-lactating females, 18 years of age or older Intubated and mechanically-ventilated Diagnosis of pneumonia defined as presence of a new or progressive infiltrate(s) on chest radiograph Presence of Gram-negative organism(s) by either Gram stain or culture of respiratory secretions, or suspected Gram-negative pathogen Impaired oxygenation Clinical Pulmonary Infection Score (CPIS) of at least 6 Presence of a multi-drug resistant (MDR) organism in a pre-therapy respiratory specimen OR at least two risk factors for MDR organisms Exclusion Criteria: History of hypersensitivity to amikacin or other aminoglycosides Has received antibiotic therapy for Gram-negative pneumonia for greater than 48 hours at the time of randomization Known or suspected bacteremia secondary to Staphylococcus aureus A positive urine and/or serum beta-human Chorionic Gonadotropin pregnancy test 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 Hemodialysis and CVVHemoDiafiltration) or daily hemodialysis will receive the aerosol study drug treatment] Has been on mechanical ventilation for > 28 days Is participating in or has participated in other investigational interventional studies within the last 28 days prior to study treatment The risk of rapidly fatal illness and death within 72 hrs, or any concomitant condition not related to ventilator-associated pneumonia that, in the opinion of the investigator, precludes completion of study evaluations and the course of therapy Has an Acute Physiology and Chronic Health Evaluation (APACHE) II score < 10 Patients receiving veno-venous extracorporeal circulation membrane oxygenation (V-V ECMO)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Amikacin inhale (BAY41-6551)<br>Participants received 400 mg (3.2 mL) aerosolized Amikacin (BAY41-6551) solution every 12 hours via Pulmonary Drug Delivery System (PDDS) Clinical from Day 1 to Day 10. | Drug: Amikacin Inhalation Solution (BAY41-6551)<br>* 400 mg of aerosolized amikacin every 12 hours for 10 days to be administered using the Pulmonary Drug Delivery System (PDDS Clinical)<br>|
| Placebo Comparator: Placebo<br>Participants received 3.2 mL aerosolized placebo solution every 12 hours via PDDS Clinical from Day 1 to Day 10. | Drug: Aerosolized Placebo<br>* Aerosolized placebo every 12 hours for 10 days to be administered using the Pulmonary Drug Delivery System (PDDS Clinical)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Surviving Through LFU Visit | The primary efficacy variable is Survival through the late follow-up (LFU) visit. Survival is achieved when the participant is alive through the LFU visit. No other factors are considered in the evaluation of survival. | Up to 28-32 days after start of study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adjudicated Pneumonia-Related Death Through LFU Visit | Death through LFU visit was adjudicated as pneumonia-related or pneumonia-unrelated for participants in the amikacin inhale group and participants in the placebo group. | Up to 28-32 days after start of study treatment | 
| Number of Participants With Early Clinical Response | Early Clinical Response was determined by the following: 1. CPIS scoring at Days 3, 5, and 10 compared to baseline (a. On Day 3, CPIS increase from baseline by at least 2 points was considered a failure. b. On Day 5, CPIS decrease from baseline of at least 1 point was not a failure. CPIS of no change from baseline was considered a failure. Any CPIS increase from baseline was a failure. c. On Day 10, CPIS decrease from baseline of at least 2 points was not a failure. CPIS decrease of only 1 point is a failure. Clinical Pulmonary Infection Score of no change was considered a failure. Any CPIS increase from baseline was a failure). 2. All-cause mortality through EOT visit was a failure. 3. The development of empyema or lung abscess through the EOT visit was a failure. | Up to 10 days after start of study treatment | 
| Number of Days on Mechanical Ventilation Through LFU Visit | Number of days on mechanical ventilator was summarized by descriptive statistics. Duration was defined as the number of days from the date of first study drug through the LFU visit. For participants who lived through the LFU visit, the ventilation days were actual days on ventilation with a maximum value of 28 days. For participants who died after Day 28 but on or before their LFU visit, the days on ventilator was censored at 28 days. For participants who died or discontinued off ventilation, the number of days on ventilation was actual days on ventilation with a maximum value of 28 days. For participants who died or discontinued on ventilation, the number of days on ventilation was 28 days. Further analysis of the number of days on mechanical ventilator was to be performed with censoring at Day 28 for subset of participants on ventilation without censoring. | Up to 28-32 days after start of study treatment | 
| Number of Days in the ICU Through LFU Visit | Number of days in ICU was summarized by descriptive statistics. Duration was defined as the number of days from the date of first study drug through the LFU visit. For participants who lived in ICU through the LFU visit, the ICU days were actual days in ICU with a maximum value of 28 days. For participants who died after Day 28 but on or before their LFU visit, the days in ICU was censored at 28 days. For participants who died or discontinued in ICU, the number of days in ICU was 28 days. Further analysis of the number of days in ICU was to be performed with censoring at Day 28 for subset of participants on ventilation and without censoring. | Up to 28-32 days after start of study treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gram-negative pneumonia, Intubation, Mechanical ventilation, Amikacin