Inhaled Amikacin Solution BAY41-6551 as Adjunctive Therapy in the Treatment of Gram-Negative Pneumonia (INHALE 1)

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

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).

Study Overview

• Status: Completed
• Conditions: Pneumonia, Bacterial
• Intervention / Treatment: Drug: Amikacin Inhalation Solution (BAY41-6551); Drug: Aerosolized Placebo

• Study Type: Interventional
• Enrollment (Actual): 725
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Wollongong, Australia, 2500
  • New South Wales
    • Blacktown, New South Wales, Australia, 2148
  • Victoria
    • Clayton, Victoria, Australia, 3168
• Brazil
  • Minas Gerais
    • Belo Horizonte, Minas Gerais, Brazil, 30150 221
  • Sao Paulo
    • Campinas, Sao Paulo, Brazil, 13060904
    • São José do Rio Preto, Sao Paulo, Brazil
• Canada
  • Quebec, Canada, G1V 4G5
  • Ontario
    • Kingston, Ontario, Canada
    • Ottawa, Ontario, Canada, K1H 8L6
    • Toronto, Ontario, Canada, M5T 2S8
  • Quebec
    • Montreal, Quebec, Canada, H1T 2M4
• Colombia
  • Atlántico
    • Barranquilla, Atlántico, Colombia
  • Valle Del Cauca
    • Cali, Valle Del Cauca, Colombia
• Czechia
  • Praha 10, Czechia, 100 34
  • Zlin, Czechia, 762 75
• Korea, Republic of
  • Seoul, Korea, Republic of, 137-701
  • Seoul, Korea, Republic of, 138-736
  • Seoul, Korea, Republic of, 136-705
• Mexico
  • Aguascalientes, Mexico, 20000
  • San Luis Potosí, Mexico, 78240
  • Distrito Federal
    • México, D.F., Distrito Federal, Mexico, 07760
  • Jalisco
    • Guadalajara, Jalisco, Mexico, 44340
  • Nuevo Leon
    • Monterrey, Nuevo Leon, Mexico, 64460
• Philippines
  • Quezon City, Philippines, 1105
  • Quezon City, Philippines, NCR 1100
• Taiwan
  • Kaohsiung, Taiwan, 82445
  • Tainan, Taiwan, 710
  • Taipei, Taiwan
  • Taipei, Taiwan, 11217
• Thailand
  • Chiang Mai, Thailand, 50200
  • Khon Kaen, Thailand, 40002
• Turkey
  • Ankara, Turkey, 06100
  • Trabzon, Turkey, 61080
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
    • Mobile, Alabama, United States, 36617
  • Arizona
    • Phoenix, Arizona, United States, 85008-4956
  • Connecticut
    • Danbury, Connecticut, United States, 06810
    • Hartford, Connecticut, United States, 06102
  • Delaware
    • Newark, Delaware, United States, 19713
  • Florida
    • Hollywood, Florida, United States, 33021-5421
    • Miami, Florida, United States, 33125
    • Tampa, Florida, United States, 33606-3508
  • Georgia
    • Atlanta, Georgia, United States, 30342
  • Illinois
    • Springfield, Illinois, United States, 62702
  • Indiana
    • Muncie, Indiana, United States, 47303
  • Iowa
    • Iowa City, Iowa, United States, 52242
  • Kentucky
    • Hazard, Kentucky, United States, 41701
  • Michigan
    • Kalamazoo, Michigan, United States, 49007
  • Missouri
    • Saint Louis, Missouri, United States, 63110-1093
    • Springfield, Missouri, United States, 65803
  • Montana
    • Butte, Montana, United States, 59701
  • Nevada
    • Las Vegas, Nevada, United States, 89109
  • New York
    • Brooklyn, New York, United States, 11215
    • Mineola, New York, United States, 10065
    • New York, New York, United States, 10065
    • New York, New York, United States, 10019
  • North Carolina
    • Asheville, North Carolina, United States, 28801
    • Greensboro, North Carolina, United States, 27401
  • Ohio
    • Cincinnati, Ohio, United States, 45267-0769
    • Cleveland, Ohio, United States, 44195
    • Cleveland, Ohio, United States, 44109-1998
    • Columbus, Ohio, United States, 43215
    • Youngstown, Ohio, United States, 44501
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73117
  • South Carolina
    • Charleston, South Carolina, United States, 29425

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Amikacin inhale (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.	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)
Placebo Comparator: Placebo; Participants received 3.2 mL aerosolized placebo solution every 12 hours via PDDS Clinical from Day 1 to Day 10.	Drug: Aerosolized Placebo; Aerosolized placebo every 12 hours for 10 days to be administered using the Pulmonary Drug Delivery System (PDDS Clinical)

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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
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
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
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
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
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

Collaborators and Investigators

• Sponsor: Bayer
• Collaborators: Nektar Therapeutics

Publications and helpful links

General Publications

• Niederman MS, Alder J, Bassetti M, Boateng F, Cao B, Corkery K, Dhand R, Kaye KS, Lawatscheck R, McLeroth P, Nicolau DP, Wang C, Wood GC, Wunderink RG, Chastre J. Inhaled amikacin adjunctive to intravenous standard-of-care antibiotics in mechanically ventilated patients with Gram-negative pneumonia (INHALE): a double-blind, randomised, placebo-controlled, phase 3, superiority trial. Lancet Infect Dis. 2020 Mar;20(3):330-340. doi: 10.1016/S1473-3099(19)30574-2. Epub 2019 Dec 19.

Helpful Links

• Click here to find information about studies related to Bayer Healthcare products conducted in Europe.

Study record dates

Study Major Dates

• Study Start (Actual): April 13, 2013
• Primary Completion (Actual): April 7, 2017
• Study Completion (Actual): April 7, 2017

Study Registration Dates

• First Submitted: February 25, 2013
• First Submitted That Met QC Criteria: February 25, 2013
• First Posted (Estimate): February 27, 2013

Study Record Updates

• Last Update Posted (Actual): July 23, 2018
• Last Update Submitted That Met QC Criteria: July 19, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Keywords: Intubation; Amikacin; Mechanical ventilation; Gram-negative pneumonia
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Pneumonia; Pneumonia, Bacterial; Anti-Infective Agents; Anti-Bacterial Agents; Amikacin
• Other Study ID Numbers: 13084; 2013-001048-73 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No