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

Pneumonia, Bacterial Clinical Trial

— INHALE 1  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01799993
• Other study ID #: 13084
• Secondary ID: 2013-001048-73
• Status: Completed
• Phase: Phase 3
• Start date: April 13, 2013
• Est. completion date: April 7, 2017

Study information

• Verified date: July 2018
• Source: Bayer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Other known NCT identifiers

• NCT00805168

Recruitment information / eligibility

• Status: Completed
• Enrollment: 725
• Est. completion date: April 7, 2017
• Est. primary completion date: April 7, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Pneumonia
• Pneumonia, Bacterial

Intervention

Drug:
• Amikacin Inhalation Solution (BAY41-6551)
400 mg of aerosolized amikacin every 12 hours for 10 days to be administered using the Pulmonary Drug Delivery System (PDDS Clinical)
• Aerosolized Placebo
Aerosolized placebo every 12 hours for 10 days to be administered using the Pulmonary Drug Delivery System (PDDS Clinical)

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
Bayer	Nektar Therapeutics

Countries where clinical trial is conducted

United States,  Australia,  Brazil,  Canada,  Colombia,  Czechia,  Korea, Republic of,  Mexico,  Philippines,  Taiwan,  Thailand,  Turkey, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Number of Participants With Microbiological Response Per Pathogen at TOC Visit	The number of participants with microbiological response for each pathogen among the total number of participants with baseline pathogen isolates for each pathogen was determined. If a participant had 3 pathogens, all 3 were tabulated. Eradication ( defined as the absence of the original pathogen(s) at the post-treatment test-of-cure [TOC] visit culture of specimens from the original site of infection) and presumed eradication (defined as absence of appropriate culture material in a participant judged to be a clinical cure; he or she was unable to produce sputum and invasive procedures were not warranted) rates were reported to reveal the microbiological responses. The data were displayed for each bacterial genus/species. Baseline pathogen was defined as pathogens tested at Screening and Day 1 visit by central laboratory.	Up to 17-19 days after start of study treatment
Other	Number of Participants With Microbiological Response at TOC Visit	The responses of eradication (defined as the absence of the original pathogen(s) at the post-treatment TOC culture of specimens from the original site of infection) and presumed eradication (defined as absence of appropriate culture material in a participant judged to be a clinical cure; he or she was unable to produce sputum and invasive procedures were not warranted) were tabulated for each participant to reveal the microbiological responses. All pathogen isolates from a participant must be eradicated (or presumed eradicated) to tabulate an eradicated (or presumed eradicated) response. Baseline pathogen was defined as pathogens tested at Screening and Day 1 visit by central laboratory.	Up to 17-19 days after start of study treatment
Other	Number of Participants With Microbiological Recurrence at LFU Visit	The responses of recurrence were tabulated for each participant. Recurrence was defined as the reappearance of the original pathogen(s) from a specimen taken after the TOC visit. If one or more pathogen reappeared, all isolates from a participant were tabulated as "recurrence". Baseline pathogen was defined as pathogens tested at Screening and Day 1 visit by central laboratory.	Up to 28-32 days after start of study treatment
Other	Number of Participants With Emergence of New Respiratory Pathogens During the Aerosol Treatment Period	New pathogens also denoted as superinfection was defined as the isolation of a new pathogen (not the original baseline pathogen) from a specimen taken while the participant was on antibiotic therapy (Day 1 to EOT) and having a need for alternative antimicrobial therapy. Rates of emergence of any new pathogen by participant after start of study drug were summarized for each treatment group.	Up to 10 days after start of study treatment
Other	Number of Participants With Emergence of Resistance Among Pathogens	Resistance to amikacin was determined for the bacterial isolates by using a standardized microbiology laboratory test that generates a minimum inhibitory concentration (MIC) for amikacin and bacterial isolate. The same microbiology resistance standard was used for all bacteria tested against amikacin. Resistant bacteria have a MIC value of 64 µg/mL or greater. Percentages of resistance were calculated based on the percentage of participants infected with any treatment-emergent pathogens resistant to amikacin. If a participant had a more than one occurrence of a specific pathogen during pre-treatment period, the worst case of testing was used.	Up to 28-32 days after start of study treatment
Other	Number of Participants Who Received at Least One Dose of Study Drug and Reported an Adverse Event	AE was untoward medical occurrence in participant who received study drug without regard to possibility of causal relationship. AEs, occurred any time after the first dose of therapy and through 7 days after the EOT were recorded as treat-emergent AEs (TEAEs).	Up to 7 days after the end of study treatment
Other	Number of Participants Who Received at Least One Dose of Study Drug and Reported a Serious Adverse Event	AE was untoward medical occurrence in participant who received study drug without regard to possibility of causal relationship. Serious AE: AE resulting in following outcomes or deemed significant for any reason: death; life-threatening; inpatient hospitalization or prolongation of existing hospitalization; persistent; significant disability/incapacity; congenital anomaly/birth defect; medical important serious event judged by investigator. SAEs, occurred any time after the first dose of therapy and through 7 days after the EOT were recorded as treat-emergent SAEs (TESAEs).	Up to 7 days after the end of study treatment
Other	Number of Participants With Organ Failure	The overall number of participants with any organ failure was summarized for each treatment group. Organ failure was defined by a specific organ type and by a collection of MedDRA version 20.0 preferred terms that were determined by the sponsor's clinical team. A participant with multiple AEs within a system organ class or preferred term is counted a single time for that system organ class (SOC) or preferred term.	Up to 7 days after the end of study treatment
Other	Number of Death Due to Any Reason Through Day 10 and Day 15	Number of deaths due to any reason through Day 10 and Day 15 were summarized for each treatment group.	Up to 10 days and 15 days after start of study treatment, respectively
Primary	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	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
Secondary	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
Secondary	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
Secondary	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

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