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

Phase 3

Completed

• Conditions: Pneumonia, Bacterial
• Interventions: Drug: Amikacin Inhalation Solution (BAY41-6551); Drug: Aerosolized Placebo

• Registration Number: NCT01799993
• Lead Sponsor: Bayer

Brief Summary

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).

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2013-02-25
• Study First Submitted QC: 2013-02-25
• Study First Posted: 2013-02-27
• Study Start: 2013-04-13
• Primary Completion: 2017-04-07
• Study Completion: 2017-04-07
• Results First Submitted: 2018-03-27
• Results First Submitted QC: 2018-05-14
• Results First Posted: 2018-06-26
• Status Verified: 2018-07
• Last Update Submitted: 2018-07-19
• Last Update Posted: 2018-07-23

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 725

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

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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)

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Amikacin inhale (BAY41-6551)	Amikacin Inhalation Solution (BAY41-6551)	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.
Placebo	Aerosolized Placebo	Participants received 3.2 mL aerosolized placebo solution every 12 hours via PDDS Clinical from Day 1 to Day 10.

Primary Outcome Measures

Name	Time	Method
Number of Participants Surviving Through LFU Visit	Up to 28-32 days after start of study treatment	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.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Early Clinical Response	Up to 10 days after start of study treatment	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.
Number of Participants With Adjudicated Pneumonia-Related Death Through LFU Visit	Up to 28-32 days after start of study treatment	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.
Number of Days on Mechanical Ventilation Through LFU Visit	Up to 28-32 days after start of study treatment	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.
Number of Days in the ICU Through LFU Visit	Up to 28-32 days after start of study treatment	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.