Inhaled Amikacin Solution BAY41-6551 as Adjunctive Therapy in the Treatment of Gram-Negative Pneumonia (INHALE 1)
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| ClinicalTrials.gov Identifier: NCT01799993 |
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Recruitment Status :
Completed
First Posted : February 27, 2013
Results First Posted : June 26, 2018
Last Update Posted : July 23, 2018
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Sponsor:
Bayer
Collaborator:
Nektar Therapeutics
Information provided by (Responsible Party):
Bayer
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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).
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Pneumonia, Bacterial | Drug: Amikacin Inhalation Solution (BAY41-6551) Drug: Aerosolized Placebo | Phase 3 |
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 725 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) |
| Primary Purpose: | Treatment |
| 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 |
| Actual Study Start Date : | April 13, 2013 |
| Actual Primary Completion Date : | April 7, 2017 |
| Actual Study Completion Date : | April 7, 2017 |
| Arm | Intervention/treatment |
|---|---|
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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.
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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) |
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Placebo Comparator: Placebo
Participants received 3.2 mL aerosolized placebo solution every 12 hours via PDDS Clinical from Day 1 to Day 10.
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Drug: Aerosolized Placebo
Aerosolized placebo every 12 hours for 10 days to be administered using the Pulmonary Drug Delivery System (PDDS Clinical) |
Primary Outcome Measures :
- Number of Participants Surviving Through LFU Visit [ Time Frame: 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 :
- Number of Participants With Adjudicated Pneumonia-Related Death Through LFU Visit [ Time Frame: 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 Participants With Early Clinical Response [ Time Frame: 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 Days on Mechanical Ventilation Through LFU Visit [ Time Frame: 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 [ Time Frame: 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.
Other Outcome Measures:
- Number of Participants With Microbiological Response Per Pathogen at TOC Visit [ Time Frame: Up to 17-19 days after start of study treatment ]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.
- Number of Participants With Microbiological Response at TOC Visit [ Time Frame: Up to 17-19 days after start of study treatment ]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.
- Number of Participants With Microbiological Recurrence at LFU Visit [ Time Frame: Up to 28-32 days after start of study treatment ]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.
- Number of Participants With Emergence of New Respiratory Pathogens During the Aerosol Treatment Period [ Time Frame: Up to 10 days after start of study treatment ]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.
- Number of Participants With Emergence of Resistance Among Pathogens [ Time Frame: Up to 28-32 days after start of study treatment ]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.
- Number of Participants Who Received at Least One Dose of Study Drug and Reported an Adverse Event [ Time Frame: Up to 7 days after the end of study treatment ]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).
- Number of Participants Who Received at Least One Dose of Study Drug and Reported a Serious Adverse Event [ Time Frame: Up to 7 days after the end of study treatment ]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).
- Number of Participants With Organ Failure [ Time Frame: Up to 7 days after the end of study treatment ]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.
- Number of Death Due to Any Reason Through Day 10 and Day 15 [ Time Frame: Up to 10 days and 15 days after start of study treatment, respectively ]Number of deaths due to any reason through Day 10 and Day 15 were summarized for each treatment group.
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
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)
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01799993
Locations
Show 65 study locations
Sponsors and Collaborators
Bayer
Nektar Therapeutics
Investigators
| Study Director: | Bayer Study Director | Bayer |
Study Documents (Full-Text)
Documents provided by Bayer:
Documents provided by Bayer:
Study Protocol [PDF] August 29, 2017
Statistical Analysis Plan [PDF] November 3, 2017
Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | Bayer |
| ClinicalTrials.gov Identifier: | NCT01799993 |
| Obsolete Identifiers: | NCT00805168 |
| Other Study ID Numbers: |
13084 2013-001048-73 ( EudraCT Number ) |
| First Posted: | February 27, 2013 Key Record Dates |
| Results First Posted: | June 26, 2018 |
| Last Update Posted: | July 23, 2018 |
| Last Verified: | July 2018 |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
Keywords provided by Bayer:
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Gram-negative pneumonia Intubation Mechanical ventilation Amikacin |
Additional relevant MeSH terms:
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Pneumonia Pneumonia, Bacterial Respiratory Tract Infections Infections Lung Diseases Respiratory Tract Diseases |
Bacterial Infections Bacterial Infections and Mycoses Amikacin Anti-Bacterial Agents Anti-Infective Agents |