Clinical trial NCT01799993
Conditions: Pneumonia, Bacterial
Keywords: Gram-negative pneumonia Intubation Mechanical ventilation Amikacin
Sponsor: Bayer
Start date: 2013-04-13; Completion date: 2017-04-07
Enrollment: 725 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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:

Arms: arm 1: 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. arm 2: Participants received 3.2 mL aerosolized placebo solution every 12 hours via PDDS Clinical from Day 1 to Day 10.
Interventions: intervention 1: Amikacin Inhalation Solution (BAY41-6551) intervention 2: Aerosolized Placebo
Intervention descriptions: intervention 1: 400 mg of aerosolized amikacin every 12 hours for 10 days to be administered using the Pulmonary Drug Delivery System (PDDS Clinical) intervention 2: Aerosolized placebo every 12 hours for 10 days to be administered using the Pulmonary Drug Delivery System (PDDS Clinical)

Protocol documents:
Prot_000.pdf: 
 
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 
NCT number: 
NCT01799993 
Document date: 
29 AUG 2017 
 


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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
This protocol version is an integration of the following documents:

Original Protocol, Version 1.0, Dated 10-JUL-2008

Amendment Number 1.0 
Forming integrated protocol Version 2.0, Dated 17 AUG 2009

Amendment Number 2.0
Forming integrated protocol Version 1.0, Dated 14 JUN 2010

Amendment Number 3.0
Forming integrated protocol Version 4.0, Dated 15 MAR 2011

Amendment Number 4.0
Forming integrated protocol Version 5.0, Dated 31 OCT 2012

Amendment Number 5.0
Forming integrated protocol Version 6.0, Dated 17 SEP 2014

Amendment Number 6.0
Forming integrated protocol Version 7.0, Dated 18 JUL 2016
Modifications are summarized in Section 16.6

Amendment Number 7.0
Forming integrated protocol Version 8.0, Dated 30 AUG 2016
Modifications are summarized in Section 16.7

Amendment Number 8.0
Forming integrated protocol Version 9.0, Dated 29 Aug 2017
Modifications are summarized in Section 16.8
This document integrates the original protocol and all global amendments.


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1.
Title Page - amended
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
Test Drug:
BAY 41-6551 (Amikacin Solution for Inhalation and the 
Pulmonary Drug Delivery System [PDDS Clinical])
Clinical study phase:
III
Date:
29 Aug 2017
EudraCT no.:1
2013-001048-73
Version no.:
9.0
Study Number:
13084
Sponsor:
Non-US territory:  Bayer AG, D-51368 Leverkusen, 
Germany
US territory:  Bayer HealthCare Pharmaceuticals Inc., 
100 Bayer Boulevard, P.O. Box 915 
Whippany NJ 07981-0915, USA
 
Bayer HealthCare Company Ltd
 
Phone no.: 
The study will be conducted in compliance with the protocol, ICH-GCP and any 
applicable regulatory requirements.
Confidential 
The information provided in this document is strictly confidential and is intended solely for the 
guidance of the clinical investigation. Reproduction or disclosure of this document - whether in 
part or in full - to parties not associated with the clinical investigation or its use for any other 
purpose without the prior written consent of the sponsor is not permitted. 
Throughout this document, symbols indicating proprietary names (®, TM) may not be displayed. Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.
                                                
1 Per Amendment 5
2 Per Amendment 5
PPD
PPD
PPD
PPD
PPD
PPD


29 Aug 2017 
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Signature of the sponsor's medically responsible persons 3 
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The signatories agree to the content of the final clinical study protocol as presented. 
Name: 
Role: 
Signature: 
Qci 
3 Changed per Amendments 5, 6 and 8 
PPD
PPD
PPD


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Signature of the principal investigator 
The signatory agrees to the content of the final clinical study protocol as presented.
Name:
Affiliation:
Date:
Signature:
Signed copies of this signature page are stored in the sponsor’s study file and in the respective 
center’s investigator site file.


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2.
Synopsis - amended
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
Study phase III
Investigational product, dosage, 
and route of administration
BAY 41-6551 (Amikacin Solution for Inhalation and the 
Pulmonary Drug Delivery System [PDDS Clinical])
Reference product
Standard of care antimicrobial treatment with consideration to 
include two antibiotics as per the 2005 American Thoracic Society 
(ATS) / Infectious Diseases Society of America (IDSA) Guidelines 
for the Management of Hospital-Acquired Pneumonia (HAP), 
Ventilator-Associated Pneumonia (VAP), or Healthcare-Associated 
Pneumonia (HCAP) 
Project code 214510
Indication Gram-negative pneumonia
Diagnosis and main criteria for 
inclusion/exclusion4
Patients of age 18 and older, who are hospitalized, have pneumonia 
suspected or confirmed to be caused by Gram-negative organisms, 
and who are intubated and mechanically-ventilated will be selected 
for this study.  In all patients where the pathogen is suspected of 
being Gram-negative, it should be confirmed as soon as culture 
results are available.  Patients with microbiologically-confirmed 
pneumonia are those who have a Gram-negative organism cultured 
from an appropriate respiratory tract specimen.  The main inclusion 
criteria are:

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) indicated by Gram-
stain, or culture of pre-therapy respiratory specimen, or 
suspected Gram-negative pathogen 

Impaired oxygenation 

Clinical Pulmonary Infection Score (CPIS) 6

The presence of a MDR organism in a pre-therapy respiratory 
specimen OR at least two risk factors for MDR organisms
The main exclusion criteria are:

A 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

Has primary lung cancer (including patients with small cell 
                                                
4 Per Amendment 5 and 8


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lung carcinoma/non-small cell lung carcinoma and patients 
with unknown histology) or another malignancy metastatic to 
the lungs or other known endobronchial obstructions.  
Exception: Please note that patients with complete resection 
of non-small cell lung carcinoma are eligible for the study. 

Known or suspected active tuberculosis, cystic fibrosis, 
human immunodeficiency virus (HIV) infection with 
CD 4 count 200 cell/mm3, or invasive fungal infection of 
the lung, lung abscess, or empyema 

Known or suspected bacteremia secondary to Staphylococcus 
aureus 

Known or suspected neuromuscular disorders such as 
myasthenia gravis or parkinsonism

Has had a stroke within five days

A positive urine and/or serum beta-human chorionic 
gonadotropin (-hCG) pregnancy test 

Burns greater than 40% of total body surface area

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 hemofiltration 
[CVVH] and continuous veno-venous hemofiltration with 
dialysis[CVVH-D]) or daily hemodialysis will receive the 
aerosol study drug treatment (Section 8.4.6.1) 

Neutropenia (screening absolute neutrophil count [ANC] 
103 neutrophils/mm3)

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 hours, or 
any concomitant conditions not related to VAP that, in the
opinion of the investigator, precludes completion of study 
evaluations and the course of therapy

Stem cell transplantation

Patients with documented Legionella infection (eg, Legionella 
pneumonia)

Has an Acute Physiology and Chronic Health Evaluation II 
(APACHE II) score < 10 

Patients receiving veno-venous extracorporeal circulation 
membrane oxygenation (V-V ECMO)


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Study objectives 5 The study objective is 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 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 primary efficacy variable is 
Survival as defined in Section 8.2.  The secondary 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 ICU.
Safety endpoints 6 The safety endpoints are to compare (BAY 41-6551 vs aerosolized 
placebo, as adjunctive therapy to IV antibiotics in both arms) as 
measured by:

The frequency of adverse events (AEs)

The progression and incidence rates of organ failure

The all-cause mortality rate during therapy, at Day 15 and at 
Day 28 (also the primary efficacy endpoint)
Patient population  7 Randomized, adult patients (age 18 years) with a 
microbiologically-confirmed pneumonia caused by Gram-negative 
organisms who received at least one dose of study drug and have an 
APACHE II score ≥ 10 at the time of diagnosis of pneumonia 
(modified Intent-to-Treat [mITT] population) will be analyzed in 
the primary efficacy analysis. 
Study design 8 This is a prospective, randomized, double-blind, placebo-
controlled, multicenter study to evaluate the safety and efficacy of 
10 calendar day (20 doses) course of aerosolized BAY 41-6551 400 
mg (amikacin as free base) every 12 hours versus aerosolized 
placebo (normal saline), as adjunctive therapy to IV antibiotics in 
both arms, in intubated and mechanically-ventilated patients with 
known or suspected Gram-negative pneumonia.  All patients will 
receive parenteral antibiotics with consideration to include 2 
antibiotics as per the 2005 ATS/IDSA guidelines for 10 days. 
Patients who are extubated before completing the full course 
(10 calendar days if the first dose is administered in the AM or 
11 calendar days if the first dose is administered in the PM 
[20 doses]) of aerosol therapy will be continued on aerosolized 
therapy with the handheld adaptor. (Section 8.2)
Concurrent control 9 Aerosolized placebo
Duration of treatment 10 full days
                                                
5 Per Amendment 6 and 8
6 Per Amendment 6 and 8
7 Per Amendment 6
8 Per Amendment 6
9 Per Amendment 6


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Methodology 10 Eighteen to 22 days after completing 10 days of aerosolized 
treatment, patients will be evaluated for Survival. Patients who 
survive through the late follow up visit are considered a success, 
patients who suffer mortality for any reason on or before the Late 
Follow-up (LFU) visit are considered a failure.
Efficacy variables 11 The primary efficacy variable will be Survival in the mITT 
population (ie, the ITT population who prove to be culture positive 
for a Gram-negative pathogen and have an APACHE II score ≥ 
10).  Survival is achieved when the patient is documented as alive 
through the LFU visit.
The secondary objectives are to evaluate the efficacy of BAY 
41-6551 (versus aerosolized placebo), as adjunctive therapy to IV 
antibiotics in both arms, as measured by:

Pneumonia-related mortality to the LFU visit

Early Clinical Response based on CPIS scores, the presence 
of empyema or lung abscess, and all-cause mortality through 
Day 10

The number of days on mechanical ventilation through the 
LFU visit (Day 28-32)

The number of ICU days assessed at the LFU visit (Day 28-
32)
Three additional analysis of clinical success will be conducted.

Clinical success using the Foundation for the National 
Institute of Health (FNIH) recommendations is defined as 
mITT patients who survived through the LFU visit and did 
not have septic shock.

Investigator Assessment of Patient Outcome will be
determined at the TOC visit (Day17-19). The investigator 
will assess patient signs and symptoms at the TOC visit.

Clinical Success will be evaluated using 5 component 
criteria, which were the former primary end point for this 
study. 
Microbiology variables 12 Secondary microbiological objectives will include comparisons 
(aerosolized BAY 41-6551 versus aerosolized placebo), as 
adjunctive therapy to IV antibiotics in both arms, of the:

per pathogen microbiological response rates at the TOC visit

per patient microbiological response rate at the TOC visit

microbiological recurrence rates at the TOC and LFU visits

emergence of new respiratory pathogens during the aerosol 
treatment period, Days 1-10

emergence of resistance among baseline pathogens in those 
patients with persistent infection or colonization
                                                
10 Per Amendment 6 and 8
11 Per Amendment 6 and 8
12 Per Amendment 6


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Safety variables
All patients who have received at least one dose of the study 
drug(s) will be evaluated for safety in a descriptive manner.  The 
safety analysis will include tabulation of the type (using Medical 
Dictionary for Regulatory Activities [MedDRA] glossary) and 
frequency of all AEs.  Drug-related AEs, serious AEs (SAEs), and 
premature discontinuations due to AEs will also be summarized, as 
well as AEs by severity, outcome, and action taken.
Incidence tables will be presented for all AEs up to seven days after 
the end of treatment and for SAEs up to Day 28 visit.
All laboratory data will be analyzed using descriptive statistics 
including identification of laboratory data outside normal ranges.
Rates of organ failure will also be summarized by patient as well as 
by specific organ type. 
Mortality during the treatment period, and on Day 15 and Day 28 
visit will be summarized. 
Number of study centers 13 Approximately 130 study centers in North America, South 
America, Asia Pacific, and Europe.
Total number of patients 14 Approximately a combined total of 724 ITT patients will be 
recruited to this study and to study 13085 (being conducted in 
different countries; the protocols are identical with the exception 
that study 13085 has a pharmacokinetic substudy).  The 724 total 
patients will be recruited competitively between studies 13084 and 
13085; there are no minimum requirements for recruitment totals in 
either study.   The patients will be randomized 1:1 to receive either 
400 mg BAY 41-6551 (amikacin as free base) every 12 hours or 
aerosolized placebo every 12 hours in addition to ATS/IDSA 
guided IV antibiotic therapy to allow for completion of at least 
472 evaluable mITT patients in the primary efficacy analysis.
                                                
13 Per Amendment 5
14 Revised with Amendments 5 and 6


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3.
Table of Contents
1.
Title Page - amended .........................................................................................................2
Signature of the sponsor’s medically responsible persons....................................................3
Signature of the principal investigator ...................................................................................4
2.
Synopsis - amended............................................................................................................5
3.
Table of Contents.............................................................................................................10
Table of Tables........................................................................................................................13
Table of Figures.......................................................................................................................13
4.
Glossary and Abbreviations  - amended........................................................................14
5.
Introduction......................................................................................................................16
5.1
Background and Rationale - amended............................................................................16
5.2
Risk Factors....................................................................................................................18
5.3
Bacteriology ...................................................................................................................18
5.4
Aerosolized Antibiotic Therapy .....................................................................................18
5.4.1
Animal Studies............................................................................................................18
5.4.2
Human Studies - amended ..........................................................................................19
6.
Study Objectives - amended............................................................................................20
7.
Investigators and Other Study Participants - amended...............................................21
8.
Investigational Plan .........................................................................................................22
8.1
Study Design - amended.................................................................................................22
8.2
Study Plan - amended.....................................................................................................23
8.3
Selection of Study Population - amended ......................................................................25
8.3.1
Inclusion Criteria - amended.......................................................................................25
8.3.2
Exclusion Criteria - amended......................................................................................27
8.3.3
Discontinuation of Patients .........................................................................................29
8.3.3.1
Reasons for Premature Discontinuation of Study Drug - amended.........................29
8.3.3.2
Reasons for Premature Discontinuation from the Study..........................................30
8.3.3.3
Premature Termination of Study/Closure of Center................................................30
8.4
Treatments ......................................................................................................................30
8.4.1
Treatments to be Administered - amended .................................................................30
8.4.1.1
Antibiotic Selection .................................................................................................31
8.4.2
Identity of Investigational Products ............................................................................35
8.4.3
Method of Assigning Patients to Treatment Groups - amended.................................35
8.4.4
Selection of Doses in the Study ..................................................................................36
8.4.5
Administration and Dosing Regimen - amended........................................................36
8.4.6
Dose Modification.......................................................................................................37
8.4.6.1
Renal Impairment - amended...................................................................................37
8.4.6.2
Bronchospasm..........................................................................................................38


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8.5
Pulmonary Drug Delivery System (PDDS Clinical)......................................................38
8.5.1
Identity of Device - amended......................................................................................38
8.5.2
Ventilator Settings.......................................................................................................39
8.5.3
Device Supply – amended...........................................................................................40
8.5.4
Device Replacement....................................................................................................40
8.5.5
Device Malfunction or Failure....................................................................................40
8.6
Blinding/Unblinding - amended.....................................................................................40
8.7
Prior and Concomitant Medication ................................................................................41
8.8
Treatment Compliance ...................................................................................................41
9.
Study Procedures .............................................................................................................42
9.1
Schedule of Visits and Visit Specific Procedures and Assessments ..............................42
9.1.1
Screening Period (48 Hours Prior to Randomization) ................................................42
9.1.2
Treatment Period (Day 1 to Day 10) - amended.........................................................43
9.1.2.1
Assessments Performed Daily - amended................................................................43
9.1.2.2
Assessments Performed on Days 1, 3, 5, and 7 - amended .....................................44
9.1.3
Post-Treatment Period (Days 10-32) ..........................................................................45
9.1.3.1
End of Therapy Visit (Day 10) - amended...............................................................45
9.1.3.2
Test-of-Cure (TOC) Visit (Days 17 - 19) - amended ..............................................46
9.1.3.3
Late Follow-Up Visit (Days 28 - 32) - amended.....................................................47
9.2
Completion of Study.......................................................................................................48
9.3
Follow-Up Assessments .................................................................................................48
9.4
Unscheduled Assessments or Visits ...............................................................................48
9.5
Premature Discontinuation / Early Withdrawal from Study - amended.........................48
9.6
Study Measurements ......................................................................................................49
9.6.1
Efficacy Variables – amended.....................................................................................49
9.6.1.1
Primary Efficacy Variable:  Survival - amended.....................................................49
9.6.1.2
Additional Analysis of Clinical Success - amended................................................49
9.6.2
Safety Variables ..........................................................................................................55
9.6.2.1
Clinical Laboratory Tests.........................................................................................56
9.6.2.2
Bacteriological Response Assessments ...................................................................56
9.7
Data Quality....................................................................................................................58
9.8
Documentation ...............................................................................................................58
10. Ethical and Legal Aspects...............................................................................................58
10.1
Independent Ethics Committee (IEC) or Institutional Review Board (IRB) .................58
10.2
Ethical Conduct of the Study..........................................................................................58
10.3
Regulatory Authority Approvals/Authorizations ...........................................................59
10.4
Patient Information and Consent - amended ..................................................................59
10.5
Insurance.........................................................................................................................59
10.6
Confidentiality................................................................................................................59
11. Statistical Methods and Determination of Sample Size ...............................................60
11.1
Statistical and Analytical Plans ......................................................................................60
11.1.1
Analysis Populations - amended .................................................................................60
11.1.2
Analytical Plan - amended ..........................................................................................60
11.2
Determination of Sample Size - amended......................................................................60


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11.3
Methods for the Analysis of the Primary Efficacy Parameter (Survival) - amended.....61
11.4
Methods for the Analysis of Secondary Efficacy Parameters - amended ......................63
11.5
Additional Analyses of Clinical Success - amended......................................................64
11.5.1
Foundation for the National Institute of Health Criteria - amended ...........................64
11.5.2
Investigator Assessment of Patient Outcome - amended............................................65
11.5.3
Clinical Success (Former 5 Component Primary Endpoint) - amended.....................65
11.6
Analysis of Device Performance....................................................................................68
11.7
Analysis of Safety Data..................................................................................................68
11.8
Methods for the Analysis of the Microbiology Endpoints.............................................68
12. Adverse Events.................................................................................................................69
12.1
Definitions ......................................................................................................................69
12.1.1
Adverse Event .............................................................................................................69
12.1.2
Serious Adverse Event ................................................................................................69
12.1.3
Unexpected Adverse Event.........................................................................................70
12.1.4
Adverse Events of Special Safety Interest ..................................................................70
12.1.5
Relationship of Adverse Event to Investigational Product .........................................71
12.1.6
Severity of the Adverse Event.....................................................................................71
12.1.7
Adverse Event Documentation ...................................................................................72
12.2
Reporting of Serious Adverse Events/Pregnancy...........................................................72
12.2.1
Notification of the IECs/IRBs.....................................................................................72
12.2.2
Notification of the Authorities ....................................................................................72
12.2.3
Sponsor’s Notification of the Investigational Site ......................................................73
12.3
Definition of an Incident ................................................................................................73
12.3.1
Device Malfunction or Failure and Medical Device Reporting..................................73
13. Use of Data and Publication............................................................................................74
14. References - amended......................................................................................................76
15. Appendices........................................................................................................................80
15.1
Study Flow Chart and Schedule of Procedures - Amended ...........................................80
15.2
Pulmonary Drug Delivery System (PDDS Clinical)......................................................83
15.3
Clinical Pulmonary Infection Score (CPIS) - amended .................................................86
15.4
National Institute of Health Stroke Scale .......................................................................88
15.5
APACHE II Score / Glasgow Score - amended .............................................................89
15.6
Late Follow-Up Questionnaire.......................................................................................92
15.7
Guidance on Tracheal Aspirate Sampling Technique....................................................92
15.8
SpO2 – Estimated PaO2 Conversion Table.....................................................................93
15.9
Adjustment of Empiric IV Antibiotic Therapy (Treatment Algorithm).........................95
16. Protocol amendments ......................................................................................................97
16.1
Amendment 1 .................................................................................................................97
16.2
Amendment 2 .................................................................................................................97
16.3
Amendment 3 .................................................................................................................97
16.4
Amendment 4 .................................................................................................................97
16.5
Amendment 5 .................................................................................................................97
16.6
Amendment 6 .................................................................................................................97


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16.6.1
Overview of Changes..................................................................................................97
16.6.2
Changes to the Protocol Text ......................................................................................99
16.7
Amendment 7 ...............................................................................................................135
16.7.1
Overview of Change .................................................................................................135
16.7.2
Changes to the Protocol Text ....................................................................................135
16.8
Amendment 8 ...............................................................................................................135
16.8.1
Overview of Change .................................................................................................136
16.8.2
Changes to the Protocol Text ....................................................................................136
Table of Tables
Table 1:  Initial Empiric Antibiotic Therapy – For Patients With Late-Onset Disease or Risk 
Factors for MDR Pathogens...................................................................................32
Table 2:  Initial Intravenous, Adult Doses of Antibiotics for Empiric Therapy.......................33
Table 3:  Intravenous, Adult Doses of Antibiotics for Therapy of HAP, Including VAP, and 
HCAP in Patients With Acinetobacter species (adapted from ATS/IDSA 2005 
[5])..........................................................................................................................33
Table 4:  Study Drug Administration and Dosing Regimen.....................................................37
Table of Figures
Figure 1: PDDS Clinical for Ventilator Application ................................................................83
Figure 2: PDDS Clinical on Vent Configuration......................................................................84
Figure 3: PDDS Nebulizer/Reservoir Inserted Into the Handheld Adaptor .............................85


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4.
Glossary and Abbreviations 15 - amended
AARC
American Association for Respiratory Care
AC/DC adaptor
alternating current/direct current adaptor
AE
Adverse event
ALT
alanine aminotransferase
ANC
Absolute neutrophil count
AP
Aeroneb Pro
APACHE II
Acute Physiology and Chronic Health Evaluation II
ARDS
Acute respiratory distress syndrome
AST
aspartate aminotransferase
ATS
American Thoracic Society
BAL
Bronchoalveolar lavage
-hCG
beta-human chorionic gonadotropin 
BMI
Body mass index
BUN
Blood urea nitrogen
CD 4
Antigenic marker on helper/inducer T cells
CFR
Code of Federal Regulations
CPIS
Clinical Pulmonary Infection Score 
CRF
Case report form
CRO
Contract Research Organization
CT
Computed tomography
CVVH
Continuous veno-venous hemofiltration 
CVVH-D
Continuous veno-venous hemofiltration with dialysis
CXR
Chest X-ray
DMC 
Data Monitoring Committee 
ECMO
Extracorporeal circulation membrane oxygenation
eCRF
Electronic case report form
EOT
End of therapy
ESBL
Extended Spectrum Beta-Lactamase
FDA
Food and Drug Administration
FNIH
Foundation for the National Institute of Health
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
H
hour(s)
HAP
Hospital-acquired pneumonia
HCAP
Healthcare-associated pneumonia
HD
Hemodialysis
HIV
Human immunodeficiency virus
HME
Heat-moisture exchanger
IB
Investigators’ Brochure
ICF
Informed consent form
ICH
International Council for Harmonization
ICU
Intensive care unit
IDSA
Infectious Disease Society of America
IEC
Independent Ethics Committee
IM
Intramuscular
IME
Important medical event
IRB
Institutional Review Board
ITT
Intent-to-Treat
                                                
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IV
Intravenous
IVRS
Interactive voice response system
LAR
legally authorized representative
LDH
Lactate dehydrogenase
LFU
Late Follow-Up
MDR
Multidrug-resistant
MedDRA®
Medical Dictionary for Regulatory Activities
MIC
Minimum inhibitory concentration
mITT
Modified Intent-to-Treat
MN
AirLife TM   Misty Neb TM
MRSA
methicillin-resistant Staphylococcus aureus
NIH
National Institute of Health
NOAEL
no-observed-adverse-effect level
NP
Nosocomial pneumonia
PDDS 
Pulmonary Drug Delivery System
PEEP
Positive end-expiratory pressure
P/F
PaO2/FiO2
PI
Principal investigator
PO
Per os (Latin), By mouth
PSB
Protected specimen brush
Q
Quaque (Latin), Every
RBC
Red blood cell
SAE
Serious adverse event 
SGOT
serum glutamic oxalo-acetic transaminase 
SGPT
serum glutamate pyruvate transaminase 
SMQ
Standard medical queries
SUSAR
Suspected/Unexpected Serious Adverse Reaction
TA
Tracheal aspirate
TOBI®
Tobramycin
TOC
Test-of-Cure
V-A
Veno-arterial (as in ECMO)
V-V
Veno-venous (as in ECMO)
VAP
Ventilator-associated pneumonia
WBC
White blood cell 


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5.
Introduction
5.1
Background and Rationale - amended
Amikacin is a well-known aminoglycoside antibiotic used intravenously (IV) or 
intramuscularly (IM) for the treatment of infections caused by Gram-negative bacteria.  Its 
spectrum of activity makes it suitable for use in nosocomial pneumonia patients where 
Gram-negative organisms are major pathogens.  It has been administered and studied at 
several clinical centers as an aerosol treatment in patients with chronic, suppurative lung 
disease such as cystic fibrosis and bronchiectasis.1, 2  Several reports describe the use of 
aerosolized antibiotics, such as amikacin, as adjuncts to the therapy of ventilated patients with 
deep lung infections, specifically ventilator-associated pneumonia (VAP)3 and 
tracheobronchitis.4  Efforts to develop such therapies and to deliver high lung doses have 
been hampered by the low efficiency of pulmonary drug delivery when using conventional 
nebulizers connected to ventilator circuits.
16Inhalation delivery of BAY 41-6551 (amikacin solution for inhalation) offers an attractive 
addition to IV or IM delivery.  Inhalation administration minimizes systemic exposure while 
delivering drug directly to the site of infection.  Bayer is investigating the use of aerosolized 
BAY 41-6551 for the treatment of serious bacterial respiratory infections in intubated and 
mechanically-ventilated patients using a proprietary high efficiency Pulmonary Drug 
Delivery System (PDDS Clinical).
The 2005 American Thoracic Society (ATS) / Infectious Diseases Society of America (IDSA) 
guidelines combine hospital-acquired pneumonia (HAP), VAP, and healthcare-associated 
pneumonia (HCAP) in the same spectrum of disease, and recommend therapy for patients 
with these diseases who have risk factors for multidrug-resistant (MDR) pathogens.5  
Clinically, patients with the combination of Gram-negative pneumonia, mechanical 
ventilation, and risk factors for MDR pathogens present similarly, and are managed in a 
standard fashion regardless of whether mechanical ventilation preceded, or followed, the 
onset of pneumonia.
Hospital-acquired pneumonia, VAP, and HCAP are the most common nosocomial infections 
and represent the leading cause of death from infections that are acquired in the hospital.  The 
incidence of nosocomial pneumonia (NP) ranges from five to ten cases per 1,000 hospital 
admissions in patients without major risk factors, but increases six- to twenty-fold in 
intensive care unit (ICU) patients who are receiving mechanical ventilation.6  The duration of 
stay in the ICU and the duration of mechanical ventilation are the major predisposing factors 
for acquiring NP.  Ventilator-associated pneumonia is a severe respiratory infection with an 
associated mortality in the range of 25% to 50% 7, 8 despite broad-spectrum antibiotic therapy.  
Hospital-acquired pneumonia, VAP, and HCAP are major causes of morbidity and mortality 
despite progress in antimicrobial therapy, supportive care, and preventative measures.  
Ventilator-associated pneumonia complicates the hospital course of 8% to 28% of patients 
who require mechanical ventilation and the risk increases with increasing time on the 
                                                
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ventilator.7  Gram-negative pathogens are causative organisms in approximately 60% of 
cases.7  Hospital-acquired pneumonia accounts for up to 25% of all ICU infections (90% of 
episodes of HAP occur during mechanical ventilation), with an associated mortality estimated 
to be between 33% and 50%.9 Additionally, the rates of HAP due to MDR organisms have 
increased significantly in the ICU.10
Several investigators have shown that in VAP, patients who receive appropriate antibiotics 
have a good clinical response within the first 6 days of treatment.11, 45 Prolonged therapy (14 
to 21 days) leads to colonization of antibiotic-resistant bacteria, which may precede a 
recurrent episode of VAP.  Others have shown that treatment courses as short as 3 days 
(versus 10 to 21 days) resulted in better clinical outcomes; however, many of these patients 
may not have had pneumonia.12  Finally, a multicenter randomized controlled trial 
demonstrated that initial empiric therapy of VAP for 8 days had similar outcomes versus 
treatment for 14 days; however, a trend to greater rates of relapse for short-duration therapy 
was seen if the causative organism was P.aeruginosa or an Acinetobacter species.13  In 
summary, if patients receive an initially appropriate antibiotic regimen, efforts should be 
made to shorten the duration of therapy from the traditional 14 to 21 days to periods as short 
as 7 days, provided that the etiologic pathogen is not P.aeruginosa, and that the patient has a 
good clinical response with resolution of clinical features of infection.
While Gram-negative organisms can be treated with IV aminoglycoside antibiotics, 
parenteral delivery can cause significant adverse systemic side effects (eg, neurotoxicity, 
nephrotoxicity, and ototoxicity) and results in poor penetration of drug into respiratory 
secretions. 14  Local application to the lung has been shown to have rapid kinetics and a high 
therapeutic index. 3, 15, 16  Although aerosolized BAY 41-6551 has been demonstrated to offer 
benefit to non-intubated patients with bacterial infections, the impact in mechanically-
ventilated patients has been less clear.  Several investigators over the past 25 years have 
reported efforts to supplement IV therapy with aerosolized antibiotics, delivered via 
conventional nebulizers, with mixed results. 4  There is continued interest in aerosolized 
antibiotics in the critical care setting, which if delivered with higher efficiency than is 
possible with conventional nebulizers, may prove useful as adjunctive therapy.17,18
During normal conditions of mechanical ventilation, standard pneumatic (jet) nebulizers 
deliver less than 10% of the nominal dose to the patient’s lungs due to high residual drug 
volumes, loss of drug in the ventilator circuit and endotracheal tube, and loss to the 
atmosphere via the expiratory limb.17,19  By contrast, the PDDS Clinical is designed to deliver 
approximately 50% of the nominal dose to the lungs, based on in vitro data for both the on-
ventilator and handheld (off-ventilator) configurations (data on file, Novartis Report No. 
IDD061A_TESTR_699-ProdSpecStudy_01, May 2012).
17This clinical study will evaluate the Survival rate of patients treated with aerosolized 
amikacin, administered via PDDS Clinical, to that of aerosolized placebo (normal saline 
solution), as adjunctive therapy to IV antibiotics in both arms, in patients with 
microbiologically-confirmed Gram-negative pneumonia.  The PDDS Clinical is expected to 
                                                
17 Sentence revised with Amendment 6 and 8.


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be a more efficient way of delivering aerosolized medication than a conventional pneumatic 
system.  The study will also provide information on the safety and tolerability of aerosolized 
amikacin.
5.2
Risk Factors
The incidence of NP is associated with many factors, with mechanical ventilation and the 
duration of ventilation being primary causes of HAP, VAP, or HCAP occurrence.  NP was 
associated with mechanical ventilation in 86% of cases in one study, and the risk for 
acquiring VAP increased from 5% in patients who received mechanical ventilation for 5 days 
to over 69% for patients who received mechanical ventilation for 30 days.10, 20  Other risk 
factors included witnessed aspiration, use of paralytic agents, and a primary admitting 
diagnosis of burns, trauma, or disease of the central nervous, respiratory, or cardiac systems.21
5.3
Bacteriology
The identification of microorganisms reported to be responsible for HAP, VAP, and HCAP 
varied substantially across different institutions, and was affected by factors such as 
underlying disease, previous antibiotic use, diagnostic methods, and local patterns of 
antibiotic-resistant organisms.  Hospital-associated pneumonia, VAP, and HCAP may be 
attributed to multiple organisms.  Gram-positive microorganisms isolated in patients with 
VAP included:  Staphylococcus aureus, Streptococcus pneumoniae, and enterococci.  Gram-
negative microorganisms isolated in VAP patients included:  Pseudomonas aeruginosa, 
Haemophilus influenzae, Escherichia coli, Klebsiella species, Enterobacter species, Proteus 
species, Serratia species, Citrobacter species, Hafnia alvei, Acinetobacter baumannii, 
Stenotrophomonas maltophilia, and Burkholderia cepacia.7, 22-24
Current therapeutic management strategies for adults with HAP, VAP and HCAP are based 
on the 2005 ATS/IDSA guidelines.5
5.4
Aerosolized Antibiotic Therapy
5.4.1
Animal Studies
Accumulation of amikacin was observed in the rat lung after 14 consecutive days of nose-
only inhalation exposure ranging from 20 to 109 mg/kg/day total inhaled nebulized amikacin 
(data on file, Bayer Report PH 36378, AT06142).  Amikacin (548 μg/g 1.13) was detected 
in lung tissue, but not plasma after a 2-week treatment-free period in high dose animals.  
Histological findings and bronchoalveolar lavage changes were suggestive of an affected 
surfactant homeostasis, possibly by amikacin bound to surfactant constituents with 
subsequent engulfment by alveolar macrophages serving as a depot for amikacin.  While no 
extrapulmonary toxicity was observed in this study, a no-observed-adverse-effect level 
(NOAEL) was not established in regard to local effects to the respiratory tract in the rat.
Recently, Goldstein 25 studied the administration of 45 mg/kg nebulized amikacin in piglets 
with experimentally induced E. coli pneumonia.  Amikacin concentrations in lung tissue 
homogenates were influenced by the severity of the lung lesions.  Amikacin concentration in 
“mild” areas of pneumonia averaged 188 175 µg/g, while in “severe” areas it averaged 40 
65 µg/g.  In all cases, lung tissue levels were lower than those previously seen by the same 
group in studies of healthy piglets.  Nonetheless, nebulized amikacin resulted in lung tissue 


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concentrations much higher (up to 30 times) than those resulting from the IV infusion of 
15 mg/kg amikacin.  In addition, lung tissue concentrations exceeded the minimum inhibitory 
concentrations (MICs) of common respiratory pathogens and 71% of the lung specimens 
cultured were negative for bacteria versus 16% in the IV group.  These investigators had also 
demonstrated a lack of lung tissue or systemic accumulation with four days of repeat aerosol 
dosing of amikacin in the same piglet model without experimentally induced E. coli
pneumonia.26  Noting that only half of the dose nominally administered to the lung was 
eliminated in the urine, the lack of lung tissue accumulation was attributed to removal by 
successive suctioning and/or physiologic mucociliary clearance. 
5.4.2
Human Studies - amended
Aerosolized antibiotics have been administered to critically ill patients to treat pulmonary 
infections in hospitalized patients and have been investigated in clinical studies for the 
prevention and treatment of pneumonia in hospitalized patients.3,24  The advantages of 
inhalation therapy include delivery of high doses directly to the site of infection and low 
systemic exposure with the potential for reducing systemic adverse events (AEs) such as 
neurotoxicity, nephrotoxicity, and ototoxicity.27-30  To date, only tobramycin for inhalation 
(TOBI®) is approved in the United States for inhalational administration and labeled 
specifically for the management of Pseudomonas aeruginosa infections in patients with 
cystic fibrosis.  TOBI® is not approved for the therapy of acute pulmonary exacerbations of 
cystic fibrosis.  TOBI® is also approved in Europe for the treatment of cystic fibrosis.
Though their use in aerosolized form has not been approved by the Food and Drug 
Administration (FDA), limited clinical and scientific testing of nebulized antibiotics has been 
conducted to determine and evaluate the pharmacokinetics and potential effectiveness of 
these agents in aerosolized form.  These agents, however, have not been evaluated for safety 
or effectiveness in randomized, controlled studies.3, 31-34  It is anticipated that aerosol delivery 
of these agents to treat pulmonary infections will offer potential advantages over parenteral 
routes of administration, as aerosol administration delivers medication directly to the site of 
infection.  Aerosol delivery of BAY 41-6551 may also minimize systemic exposures that, 
when administered by IV, are associated with AEs such as nephrotoxicity and irreversible 
ototoxicity. 
In clinical studies, amikacin has been aerosolized in nominal doses from 400 mg to 1200 
mg.1-2, 35-40 As with other aminoglycosides, systemic absorption is low and serum levels 
remain far below the standard trough levels that guide IV dosing. 2,3  Thus, the tolerance to 
inhalation and low systemic exposure appear to convey a high therapeutic index.  The fate of 
the inhaled drug may be assessed by measurement of sputum drug concentrations after 
tracheal aspiration3 and by 24-h urine collection.2,36
The longest duration of therapy reported for aerosolized amikacin was up to three weeks in 
ventilator-dependent patients with tracheobronchitis3 and up to two weeks in ambulatory 
patients with cystic fibrosis.1  In both studies, there was reported to be a favorable impact on 
sputum cultures.  Standridge et al.40 described a patient whose resolution of community-
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The BAY 41-6551 and PDDS Clinical safety experience is based on the five completed 
studies: AMIK-02-01, AMIK-04-02, 06-IN-AK003, 06-IN-AK004, and 06-IN-AK005 (data 
on file, Bayer Report Number RD00002318.00). 
The first study (a pilot study, AMIK-02-01) compared delivery of BAY 41-6551 via an early 
prototype of the PDDS Clinical versus Nektar’s marketed critical care nebulizer, the Aeroneb 
Pro® (AP), and the AirLife™ Misty Neb™ (MN), a pneumatic nebulizer, in mechanically-
ventilated patients.  Twelve patients on volume-cycled ventilation were enrolled to receive 
125 mg/mL sulfite-free BAY 41-6551 on separate study days (2 days washout) in 
randomized order: 800 mg via MN, 800 mg via AP, or 400 mg via PDDS.  BAY 41-6551 
levels were measured in urine and tracheal aspirates.  The PDDS Clinical demonstrated the 
greatest delivery efficiency (approximately 60%) to the lungs and was, therefore, selected for 
future clinical studies.
All treatments were considered by the investigator to be well tolerated.  Three patients 
experienced wheezing.  None of the episodes of wheezing were accompanied by significant 
changes in heart rate or widening of the peak-to-plateau difference in airway pressure, a 
measure of airways resistance, and none required treatment interruption.  There were no 
serious drug- or device-related AEs.
A Phase II study (AMIK-04-02) of aerosolized BAY 41-6551 in intubated and mechanically-
ventilated patients with VAP, HAP, or HCAP has also been completed.  Eligible patients 
were randomized in a 1:1:1 fashion to receive either aerosolized BAY 41-6551 (400 mg or 
800 mg) or placebo q 12 h for a period of 7 to 14 days.  Sixty-nine patients were enrolled in 
this multicenter, multinational study, with 67 patients receiving at least one dose of study 
medication.  Pharmacokinetic sampling for BAY 41-6551 levels in tracheal aspirates, serum, 
and urine were obtained on Day 1 and Day 3 during the treatment period.  Efficacy and safety 
variables were also measured.  A total of 25 serious AEs (SAEs) were reported.  One SAE 
was classified by the Principal Investigator (PI) as possibly related to study medication.  
Upon unblinding, this patient had been assigned to the placebo group.  No SAEs were 
reported as probably related to study medication or to the PDDS Clinical regardless of 
treatment group.  Based on the results of this trial the dose of 400 mg (amikacin as a free 
base) every 12 hours was chosen for further development in Phase III. 
Further details on the five clinical studies completed with BAY 41-6551 can be found in the 
Investigator’s Brochure18.41
6.
Study Objectives - amended
19The study objective is to demonstrate that as adjunctive therapy to IV antibiotics, BAY 41-
6551 400 mg (amikacin as free base) administered as an aerosol by the 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 primary efficacy variable is Survival as defined 
                                                
18 Removed IB version and date per Amendment  6
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in Section 8.2.  The secondary objectives are to evaluate the superiority of aerosolized BAY 
41-6551 versus aerosolized placebo in pneumonia-related mortality to the Late Follow-up
(LFU) visit, the Early Clinical Response at Day 10, the days on ventilation through the LFU 
visit, and the days in the ICU assessed at the LFU visit.
7.
Investigators and Other Study Participants - amended
20The 
  The role of the coordinating investigator 
has been assigned to Michael S. Niederman, MD, New York-Presbyterian University 
Hospital of Columbia and Cornell, 
Bayer will utilize an independent Data Monitoring Committee (DMC) to oversee this Phase 
III trial to ensure the ongoing safety of patients participating in the studies.  The DMC will 
regularly review the safety data of enrolled patients, including all-cause mortality and safety 
signals, as well as the continuing scientific merit of the trials.  The DMC can only 
recommend stopping the trial early due to negative safety findings.  Bayer and the CRO study 
staff will remain blinded throughout all DMC activities.  The DMC will be comprised of a 
minimum of two clinicians experienced in the field of clinical research, a clinician with 
expertise in pulmonology and at least one statistician knowledgeable in statistical methods for 
clinical trials.  Each committee member will be screened for evidence of an absence of 
serious conflicts of interest. The operation of the DMC will be governed by a charter that will 
describe the group’s frequency of meetings, procedures (including, but not limited to, 
periodic safety monitoring), and requirements for reporting its observations to the sponsor. 
                                                
20 SponsorPer Amendment 5
21 Updated affiliation with Amendment 6
PPD
PPD


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Bayer will utilize an independent Adjudication Committee for the evaluation of the secondary 
variable, pneumonia-related mortality. The Adjudication Committee will be comprised of 3 
clinicians experienced in the field of clinical research and anti-infective drug products.  Each 
committee member will be screened for evidence of an absence of serious conflicts of 
interest. The operation of the Adjudication Committee will be governed by a charter.22
In brief, the adjudication committee will review all deaths to determine the subset of deaths 
that are pneumonia-related. These pneumonia-related deaths should more likely be influenced 
by superior antibacterial treatment than pneumonia-unrelated deaths. The pneumonia-related 
death evaluation will be based on the death being plausibly related to:
(1) pulmonary infection (example, pneumonia)
(2) spread (metastasis) of infection (example, septicemia, septic shock)
(3) complications related to respiratory function (example, respiratory distress)
The Adjudication Committee will have a single binary decision: pneumonia-related death: 
yes/no
All other study personnel, including the contract research organization (CRO) and central 
laboratories, not included in this section are identified in a separate personnel list (not part of 
this clinical study protocol) as appropriate.  This list will be updated as needed; an 
abbreviated version with personnel relevant for the centers will be available in each center’s 
investigator site file.
Whenever the term ‘the investigator’ is noted in the protocol text, it may refer to either the 
principal investigator at the site, or an appropriately qualified, trained and delegated 
individual of the investigational site.
The principal investigator of each center must sign the protocol signature sheet before patient 
recruitment may start at the respective center. Likewise, all protocol amendments/integrated 
protocols must be signed and dated by the principal investigator before coming into effect at 
the respective center.
A complete list of all participating centers and their investigators, as well as all required 
signature documents, will be maintained in the sponsor study file.
The global sponsor of this study is identified on the title page of this protocol. If required by 
local law, local co-sponsors will be nominated; they will be identified on the respective 
country-specific signature pages.
8.
Investigational Plan
8.1
Study Design - amended
This is a Phase III, prospective, randomized, double-blind, placebo-controlled, multicenter, 
multinational study designed to show that aerosolized BAY 41-6551 400 mg (amikacin as 
free base) every 12 hours is more effective than placebo (aerosolized normal saline), as 
                                                
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adjunctive therapy to IV antibiotics, in intubated and mechanically-ventilated patients with 
Gram-negative pneumonia.  The safety and tolerability of aerosolized BAY 41-6551 and the 
microbiological endpoints will also be evaluated. Patients who are extubated before 
completing the full course (10 calendar days if the first dose is administered in the AM or 11 
calendar days if the first dose is administered in the PM [20 doses, Section 8.2]) of aerosol 
therapy will be continued on aerosolized BAY 41-6551 with the handheld adaptor.  All 
patients will receive standard of care IV antibiotic therapy with consideration to include 2 
antibiotics as per the ATS/IDSA Guidelines5.  The doses in the guidelines are the minimum 
doses to be used in patients with normal renal and hepatic function.  Intravenous antibiotic 
treatment will be administered during the entire period of aerosol treatment.23
The study will be conducted at approximately 130 study centers in North America, South 
America, Asia Pacific, and Europe.24
8.2
Study Plan - amended
Patients who have met all of the inclusion criteria and none of the exclusion criteria will be 
stratified by geographic region (or country) and disease severity using the Acute Physiology 
and Chronic Health Evaluation (APACHE II) score (Stratum I: APACHE II score < 20; 
Stratum II: APACHE II score ≥20) and  randomized in a 1:1 ratio to one of two treatment 
groups:  standard of care IV antibiotics with aerosolized BAY 41-6551 400 mg (amikacin as 
a free base) every 12 hours or standard of care IV antibiotics without aerosolized BAY 41-
6551 (aerosolized placebo every 12 hours).  The APACHE II score (Section 15.5) that will be 
used to stratify the patient is the score calculated at the time the patient is evaluated for entry 
into the study and a diagnosis of Gram-negative pneumonia is considered.  Values used to 
calculate the APACHE II score (e.g. temperature, WBC counts, etc.) may be obtained at any 
time during the 48-hour screening period 25.  Regardless of the treatment group, the duration 
of all therapy will be 10-12 full days, as described.  
Patients will receive 20 doses of aerosol treatment at 12-hour intervals.  Twenty doses of 
aerosol treatment correspond to 10 calendar days.  When aerosol treatment begins with a 
“morning dose (AM)” the last dose (“evening dose” [PM]) will be given on the tenth day.  
Alternatively, if the first dose of aerosol treatment is an “evening dose” (and thus only one 
dose can be given on the first calendar day) the last aerosol treatment will be given as a 
“morning dose” on the eleventh calendar day. 
Aerosolized study drug treatment and IV antibiotic treatment will both be administered for 10 
full days.  Both treatments will be administered in parallel.  However, the protocol allows 
beginning empiric IV antibiotic treatment for Gram-negative pneumonia 0-48 hours before 
start of aerosolized study drug (Section 8.3.2).  As a result, IV antibiotic therapy may extend 
                                                
23 Paragraph revised with Amendments 5, 6 and 8
24 Per Amendment 5
25 Per Amendment 5


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up to 12 days total dosing.  Every effort should be made to start study drug as close as 
possible to initiation of systemic antibiotic therapy.26
Missing doses of inhaled study drug will not extend the treatment period of 10 calendar days.
Aerosolized therapy will be administered via the PDDS Clinical placed in a ventilator circuit 
(when the patient is intubated and mechanically-ventilated) or when the patient has been 
extubated and removed from mechanical ventilation via the handheld adaptor.
Patients will be started empirically on study drug therapy based on clinical signs of 
pneumonia and known or suspected 27 presence of Gram-negative organisms by either Gram 
stain or culture of pre-therapy respiratory secretions (eg, acceptable tracheal aspirate [TA], 
bronchoalveolar lavage [BAL], mini-BAL, and /or protected specimen brush [PSB]).  The 
Gram stain results may be disregarded if Gram-negative pneumonia is clinically suspected or 
confirmed by culture.28  Aerobic blood cultures will also be obtained.  
During the course of therapy for Gram-negative pneumonia, respiratory secretions, when 
available, will be collected via tracheal aspirate suctioning and semi-quantitatively or
quantitatively cultured on Days 3, 5, 7, 10, 17, and 28.  Patients who are not producing 
sputum should not have sputum induced.29
All assessments at Day 10/11 (20 doses) should be done after the last dose of aerosolized 
treatment.
30The Test-of-Cure (TOC) visit will be conducted on Day 17-19 of the study. The late follow-
up (LFU) visit will be conducted on Day 28-32 of the study.  Survival will be evaluated 
through the LFU visit. 31  If available, respiratory secretions will be obtained, cultured, and 
evaluated for the emergence of resistance to study drug therapy among baseline organisms.  
32The primary efficacy variable of the study is Survival in the mITT population through the 
LFU visit.
Local microbiology laboratories will perform Gram stains, identify organisms to genus and 
species (this information will be recorded in the case report form [CRF]) and when 
performing susceptibility testing will include amikacin in the sensitivity panel.  The local 
microbiology laboratories will send a slide (air dried and not stained) of the clinical specimen 
(examples tracheal aspirate, sputum) to the Central Microbiology Laboratory. Instructions for 
preparing and shipping the slide will be provided in the investigator Manual for 
Microbiology.  Subculture(s) of all identified pathogens that are considered clinically relevant 
                                                
26 Per Amendment 5
27 Per Amendment 5
28 Per Amendment 5
29 Per Amendment 5
30 Per Amendment 8
31 Per Amendment 6
32 Revised with Amendments 5, 6 and 8


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will be sent to the Central Microbiology Laboratory. Instructions for shipping the subcultures 
will be provided in the investigator Manual for Microbiology. 
The Central Microbiology Laboratory will execute the Gram stain and record the findings. 
The sub-cultures of the pathogens will be identified to genus and species, and susceptibility 
testing will be performed. Specific instructions will be provided in the Central Microbiology 
Laboratory Manual.  The results of all Gram stain readings, cultures and susceptibility testing 
will be recorded by the Central Microbiology Laboratory and used by the sponsor for 
reporting purposes in the final Clinical Study Report.  The local microbiology laboratory 
results will be used by the investigators for clinical decision making. Local microbiology 
results will not be used by the sponsor for reporting purposes. 
8.3
Selection of Study Population - amended
33Patients of age 18 and older, who are hospitalized, have pneumonia suspected or confirmed 
to be caused by Gram-negative organisms, and who are intubated and mechanically-
ventilated will be selected for this study.  In all patients where the pathogen is suspected of 
being Gram-negative, it should be confirmed as soon as culture results are available.  Patients 
with microbiologically-confirmed pneumonia are those who have a Gram-negative organism 
cultured from an appropriate respiratory tract specimen.  
The patient must meet all of the inclusion criteria and none of the exclusion criteria to 
participate in this study.  Approximately 724 patients will be randomized 1:1 in the 2 Phase 
III studies (13084 and 13085; study 13085 is being conducted in different countries; the 
protocols are identical with the exception that study 13085 has a pharmacokinetic sub-study) 
to receive either BAY 41-6551 400 mg (amikacin as free base) aerosolized every 12 hours or 
aerosolized placebo every 12 hours in addition to ATS/IDSA-guided IV therapy to allow for 
completion of at least 472 evaluable patients (mITT) in the primary efficacy analysis.
8.3.1
Inclusion Criteria - amended
A patient must meet all of the following inclusion criteria to be eligible to participate in the 
study:
1) Males and non-pregnant, non-lactating females, 18 years of age or older. For 
females of child-bearing potential, one of the following medically acceptable 
contraceptive methods must be used or they agree to abstain from heterosexual 
intercourse while participating in the study.  One or more of these methods should 
be used during the study and continue for 30 days after completion of the 
antibiotic therapy.
a.
Double-barrier methods of contraception (eg, condoms plus spermicidal foam)
b. Intrauterine contraceptive device
c.
Approved pharmaceutical contraceptive product (eg, birth control pills or 
patches, long-term injectable or implantable hormonal contraceptive)
                                                
33 Section revised with Amendments 5 and 6


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2) Intubated and mechanically-ventilated (patients who have had a tracheostomy may 
be considered as possible study participants as long as they are being mechanically 
ventilated)
3) Diagnosis of pneumonia defined as presence of a new or progressive infiltrate(s) 
on chest radiograph 
4) Presence of Gram-negative organism(s) indicated by:
a) Gram-stain OR
b) Culture of pre-therapy respiratory specimen (eg, acceptable TA, BAL, 
mini-BAL, PSB) OR
c) Suspected Gram-negative pathogen based on local surveillance data and 
medical history.  Local surveillance data reflects the local patterns of 
bacterial prevalence and antibiotic resistance.  Consideration should be 
given to the recent incidence of infections with Gram-negative organisms 
in the hospital 34
5) Criterion deleted per Amendment 5
6) Impaired oxygenation (within 48 hours35 prior to screening):  a PaO2/FiO2
≤ 300 mmHg 36
7) CPIS 6 (Section 15.3)
8) The presence of a MDR organism in a pre-therapy respiratory specimen OR 37 at 
least two risk factors for MDR organisms (MDR organism: an organism resistant 
to representative agents in two or more of the following antibiotic classes - beta-
lactams, including penicillins, cephalosporins, and monobactams; carbapenems; 
fluoroquinolones; and aminoglycosides): 
a) Antimicrobial therapy in the preceding two weeks
b) Current hospitalization 5 days 
c) High frequency (> 10%) of antibiotic resistance in the community or in the 
specific hospital unit
d) Immunosuppressive disease and/or therapy
e) Presence of the risk factors for HCAP

Hospitalization for two days or more in the preceding 90 days

Residence in a nursing home or extended care facility
                                                
34 Per Amendment 5
35 Corrected with Amendment 6 (erroneously said 24 hours)
36 Per Amendment 5
37 Per Amendment 5


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
Home infusion therapy (including antibiotics)

Chronic dialysis within 30 days

Home wound care

Family member with multidrug-resistant pathogen
9) Be willing and able to give written informed consent.  If the patient is unable to 
give written informed consent, the patient’s authorized38 representative may 
provide written consent as approved by the Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC).
8.3.2
Exclusion Criteria - amended
A patient who meets any of the following exclusion criteria will be excluded from study 
participation:
1) A history of hypersensitivity to amikacin or other aminoglycosides 
2) Has received antibiotic therapy for Gram-negative pneumonia for greater than 
48 hours39 at the time of study drug administration.  There should be as minimal 
a time delay as possible between randomization and first dose of study drug but 
up to 48 hours will be acceptable  
Exceptions: Systemic antibiotic therapy for more than 48 hours for Gram-negative 
pneumonia prior to randomization is permitted if the infection is caused by pathogens that are 
resistant to the antimicrobial agent(s) used, or the patient’s pneumonia is worsening.  The 
evidence for “worsening of pneumonia” should be recorded40.
3) Has primary lung cancer (including patients with small cell lung carcinoma/non-
small cell lung carcinoma and patients with unknown histology) or another 
malignancy metastatic to the lungs or other known endobronchial obstructions.  
Exception: Note that patients with complete resection of non-small cell lung 
carcinoma are eligible for the study.
4) Known or suspected active tuberculosis, cystic fibrosis, human 
immunodeficiency virus (HIV) infection with CD 4 count 200 cell/mm3  (HIV 
testing is not required as part of this protocol), or invasive fungal infection of the 
lung, lung abscess, or empyema 
5) Known or suspected bacteremia secondary to Staphylococcus aureus 
6) Known or suspected neuromuscular disorders such as myasthenia gravis or 
parkinsonism
                                                
38 Per Amendment 5
39 Per Amendment 5
40 Per Amendment 5


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7) Has had a stroke within five days.  Additionally, patients with stroke in the acute 
or sub-acute phase 41 should not be enrolled if at least one or both of the 
following apply: 
a) There is an increased risk of fatal brain edema as indicated by a history of
hypertension or heart failure, major early computed tomography (CT) 
hypodensity exceeding 50% of the middle cerebral artery territory, and/or 
involvement of additional vascular territories.
b) There is indication for deterioration based on comparison of patient’s 
neurological condition within six hours of planned study drug dosing and 
patient’s neurological condition two days before, judged by applying the 
National Institute of Health (NIH) Stoke Scale (Section 15.4).
8) A positive urine and/or serum beta-human chorionic gonadotropin (-hCG) 
pregnancy test
9) Burns greater than 40% of total body surface area
10) 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 hemofiltration [CVVH] and 
continuous veno-venous hemofiltration with dialysis [CVVH-D]) or daily hemodialysis will 
receive the aerosol study drug treatment (Section 8.4.6.1).  
11) Neutropenia (Screening absolute neutrophil count [ANC] 
103 neutrophils/mm3)
12) Has been on mechanical ventilation for 28 days (ie, current event should not 
be more than 28 continuous days).  A patient is not considered extubated if 
cessation of mechanical ventilation 42 lasts less than 24 hours.
13) Is participating in or has participated in other investigational interventional 
studies within the previous 28 days 
14) The risk of rapidly fatal illness and death within 72 hours, or any concomitant 
conditions not related to VAP that, in the opinion of the investigator, precludes 
completion of study evaluations and the course of therapy. 
15) Stem cell transplantation 
16) Patients with documented Legionella infection (Legionella pneumonia)
17) Has an APACHE II score < 10 
18) Previous assignment to treatment during this study
                                                
41 Per Amendment 5
42 Per Amendment 5


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19) Close affiliation with the investigational site; e.g. a close relative of the 
investigator, dependent person (e.g. employee or student of the investigational 
site)
20) Patients receiving veno-venous extracorporeal circulation membrane 
oxygenation (V-V ECMO) 43
8.3.3
Discontinuation of Patients
Patients may prematurely discontinue study drug and/or prematurely discontinue or terminate 
from the study for a number of reasons.  The reason(s) for premature discontinuation or 
termination should be clearly stated in the CRF.
A follow-up contact will be arranged as appropriate.
At the time of discontinuation, every effort should be made to ensure all procedures and 
evaluations scheduled for the final study visit are performed.  
8.3.3.1
Reasons for Premature Discontinuation of Study Drug - amended
Since study drug is provided only as an adjunctive therapy and not the primary treatment for 
the patient’s Gram-negative pneumonia, every effort should be made to allow patients to 
complete a full course of inhaled study drug to determine the impact of adjunctive therapy on 
the course of Gram-negative pneumonia.  However, several reasons may exist to discontinue 
study drug.

AE(s)

Absence of a Gram-negative organism in a pre-therapy respiratory culture 44

Clinical failure (ie, lack of therapeutic effect)

Non-adherence to study regimen

Death

Lost to follow-up

Withdrawal of consent
Patients who prematurely discontinue study drug should have a Premature Withdrawal Visit 
at the time of discontinuation and continue to be followed for safety through the Late Follow-
Up Visit.45  The disposition of patients who are prematurely discontinued is listed in Section 
11.3.46
                                                
43 Per Amendment 5
44 Per Amendment 5
45 Per Amendment 5
46 Per Amendment 6.


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8.3.3.2
Reasons for Premature Discontinuation from the Study

Lost to follow-up

Withdrawal of consent

At the specific request of the sponsor
8.3.3.3
Premature Termination of Study/Closure of Center
The sponsor has the right to close this study, and the investigator/sponsor has the right to 
close a study center, at any time, although this should occur only after consultation between 
involved parties.  The IEC/IRB must be informed.  Should the study/center be closed 
prematurely, all study materials (except documentation that has to remain stored at the site) 
must be returned to the sponsor.  The investigator will retain all other documents until 
notification is given by the sponsor for destruction.
8.4
Treatments
8.4.1
Treatments to be Administered - amended
47Treatment will consist of standard of care IV antibiotics for intubated patients with Gram-
negative pneumonia with consideration to include 2 antibiotics as per the 2005 ATS/ IDSA 
Guidelines, plus aerosolized BAY 41-6551 or aerosolized placebo (Section 8.2).  If the 
patient develops a new infection, other than pneumonia, while on the aerosol treatment the 
patient will continue in the study.
Each inhalation or aerosol dose will be administered via the PDDS Clinical (instruction 
manual provided).  If a patient is subsequently extubated, the aerosol treatment will be 
continued via the handheld adaptor for the remainder of the 10 full days of treatment course.  
Extending the IV antibiotic therapy beyond the aerosolized therapy might be necessary if in 
the opinion of the investigator, the patient continues to have clinical signs and symptoms of 
pneumonia.  The clinical signs and symptoms of pneumonia will be documented on the CRF 
as will the reason(s) for continuation of IV treatment past the treatment period.  Aerosol 
treatment will not extend beyond 10 full days corresponding to 20 doses (Section 8.2).
The administration of aerosolized antibiotics other than the aerosol study medication is 
prohibited.
The use of an IV aminoglycoside during the treatment period will be permitted; however, the 
only aminoglycoside allowed will be amikacin.  This will simplify aminoglycoside trough 
serum level monitoring, if an IV aminoglycoside is used with the aerosol study drug.  The 
monitoring of a single aminoglycoside (amikacin) will allow for safer use of IV therapy, if IV 
aminoglycoside therapy is required.  
Tobramycin, gentamicin, and netelmicin will not be permitted as part of IV antibiotic therapy.  
This is a slight deviation from the 2005 ATS/IDSA guidelines and has been instituted in this 
protocol as a safeguard for patients.
                                                
47 Section revised per Amendments 5 and 6


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8.4.1.1
Antibiotic Selection
8.4.1.1.1 Initial Empiric Antibiotic Therapy - amended
In cases where specific bacterial pathogens from the respiratory tract have not yet been 
positively identified48, the selection of the initial IV antibiotic regimen will be empiric and 
based on several factors including the patient’s allergy history, previous antibiotic therapy 
(within the past 2 weeks), risk factors for MDR pathogens, anticipated AEs, and hospital 
antibiogram data. The decision on specific antibiotics to use for initial empiric combination 
therapy will be that of the investigator; however consideration should be given to include two 
(2) antibiotics, as per the 2005 ATS/IDSA Guidelines, for treating patients at risk for MDR 
Gram-negative pathogens (Table 1, Table 2, and Table 3 below for further guidance).  
Bearing in mind these Guidelines, empiric antibiotic therapy should be chosen to have 
activity against common circulating pathogens in the setting where the patient is being treated 
based on local resistance patterns.  If the susceptibilities of the infecting Gram-negative 
pathogens are known at the time that the patient is randomized, then IV antibiotics may be 
targeted accordingly. 
8.4.1.1.2 HAP, VAP, or HCAP in Patients with Late Onset Disease or Risk 
Factors for MDR Pathogens and All Disease Severity 
Patients at risk for infection with Pseudomonas aeruginosa, Acinetobacter species, Klebsiella 
pneumoniae, Enterobacter species, and methicillin-resistant Staphylococcus aureus (MRSA) 
should initially receive combination therapy that can provide a broad spectrum of coverage to 
minimize the potential for initial inadequate antibiotic treatment.  In the therapy of suspected 
pseudomonal infection, therapy should include a selected -lactam plus either an 
antipseudomonal quinolone or an aminoglycoside. (Note: The only IV aminoglycoside 
permitted in this protocol is amikacin.)  The choice of agents should be based on factors 
mentioned above in Section 8.4.1.1.1 and not repeat the same antimicrobial class, if possible.  
                                                
48 Per Amendment 5


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Table 1:  Initial Empiric Antibiotic Therapy – For Patients With Late-Onset Disease or 
Risk Factors for MDR Pathogens 
Potential Pathogens
Recommended Antibiotic a
MDR Pathogens
Antipseudomonal cephalosporin 
(cefepime, ceftazidime) 
Pseudomonas aeruginosa 
Or
Klebsiella pneumoniae (Extended Spectrum 
Beta-Lactamase [ESBL]+)b
Antipseudomonal carbapenem 
Acinetobacter species b
(imipenem or meropenem) 
Or
-Lactam/-lactamase inhibitor 
(piperacillin–tazobactam) 
Plus
Antipseudomonal fluoroquinolone c
(ciprofloxacin or levofloxacin) 
Or
Aminoglycoside 
(amikacin) 
Plus
Methicillin-resistant Staphylococcus 
Linezolid or vancomycin d
aureus (MRSA) 
MDR = multidrug-resistant.
a – Proper/adequate initial doses noted in Table 2.  Initial antibiotic therapy should be adjusted or 
streamlined on the basis of microbiologic data and clinical response to therapy.
b – If an ESBL+ strain, such as K. pneumoniae,or an Acinetobacter species is suspected, a carbapenem is 
a reliable choice. 
c - The frequency of penicillin-resistant S. pneumoniae and multidrug-resistant S. pneumoniae is 
increasing; levofloxacin or moxifloxacin are preferred to ciprofloxacin and the role of other new 
quinolones, such as gatifloxacin, has not been established
d - If MRSA risk factors are present or there is a high incidence locally.
This table was modified from Table 4 of the 2005 ATS/IDSA Guidelines (5).


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8.4.1.1.3 Initial Intravenous, Adult Doses of Antibiotics
Table 2:  Initial Intravenous, Adult Doses of Antibiotics for Empiric Therapy
Antibiotic
Dosage a
Antipseudomonal cephalosporin 
Cefepime 
1–2 g every 8–12 h 
Ceftazidime 
2 g every 8 h 
Carbapenems 
Imipenem 
500 mg every 6 h or 1g every 8 h 
Meropenem 
1 g every 8 h 
-Lactam/-lactamase inhibitor 
Piperacillin–tazobactam 
4.5 g every 6 h 
Aminoglycosides 
Amikacin 
20 mg/kg per d b
Antipseudomonal quinolones 
Levofloxacin 
750 mg every d 
Ciprofloxacin 
400 mg every 8 h 
Vancomycin 
15 mg/kg every 12 h c
Linezolid 
600 mg every 12 h 
a - Dosages are based on normal renal and hepatic function.
b - Trough levels for amikacin should be less than 4–5 µg/mL.
c - Trough levels for vancomycin should be 15–20 µg/mL.
This table was reproduced from Table 5 of the 2005 ATS/IDSA Guidelines (5).
The armamentarium for treating Acinetobacter infections is limited because of resistance to 
many classes of antibiotics.  The most consistently effective antibiotics are the carbapenems 
(imipenem), the sulbactam component of ampicillin-sulbactam43 and the polymyxins.44  If 
susceptibility testing confirms the microbiological activity of the carbapenems, ampicillin-
sulbactam, or polymyxins (eg, colistin sulphomethate sodium) the IV dosage of these agents 
in adults with normal renal function is shown in Table 3.
Table 3:  Intravenous, Adult Doses of Antibiotics for Therapy of HAP, Including VAP, 
and HCAP in Patients With Acinetobacter species (adapted from ATS/IDSA 2005 [5])
Antibiotic
Dosage 
Carbapenem 
Imipenem
500 mg every 6 h or 1g every 8 h  
-Lactam/-lactamase inhibitor 
Ampicillin-sulbactam
1.5 g – 3.0 g q 6 h
Polymyxin 
Colistimethate for Injection
2.5 mg/kg – 5.0 mg/kg q 6-12 h 
8.4.1.1.4 Adjustment of Empiric Intravenous Antibiotic Therapy - amended
It is not uncommon for the initial empiric therapy recommendations to require adjustment 
once the results of respiratory tract and blood cultures become available.  Therapy can often 
be de-escalated (fewer antibiotics) or additional agents included based on the identity of 
specific pathogens, their susceptibility to specific antibiotics, and the patient’s clinical 
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With the exception of patients receiving combination therapy with IV amikacin (the only IV 
aminoglycoside permitted by protocol), an adjustment to empiric antibiotics is permitted 
under the following circumstances.
The following instructions are intended to provide the investigator with guidance on adjusting 
antibiotic therapy after the initiation of IV empiric therapy:  

Adjustment to initial, IV, empiric therapy should take place within the first 96 49
hours after the initiation of empiric therapy or as soon as initial culture and 
susceptibility results are available

Decisions on antibiotic(s) which should be added, continued or discontinued as part of 
maintenance therapy will be based on:
o
Organism(s) identified 
o
Results of susceptibility testing
o
An evaluation of the patient’s clinical signs and symptoms (eg, fever, white 
blood cell [WBC] count, tracheal secretions/purulence, chest radiograph, 
oxygenation) of pneumonia
o
An evaluation of the patient’s renal and hepatic function and the patient’s drug 
allergy history 
o
It is very possible that the dose of initial empiric therapy may need to be 
modified based an improving or worsening renal or hepatic function.  
Adjustment(s) in antibiotic dosing based on renal or hepatic function would 
not result in the patient being evaluated as a Clinical Failure

Further adjustments to maintenance antibiotic therapy are not permitted during the 
remaining treatment unless the patient is failing antibiotic treatment for pneumonia, in 
which case the patient would be considered a failure by the Investigator Assessment 
(not by the primary endpoint evaluation of Survival).50
Exception:  Patients receiving combination therapy with IV amikacin can have 
maintenance therapy adjusted a second time only to discontinue IV amikacin after 5 to 
7 days if the patient is responding to therapy (eg, temperature decreasing, WBC count 
decreasing, tracheal secretion volume/purulence decreasing, chest radiograph shows 
no progression of infiltrate, etc) and in the interest of patient safety (adapted from 
ATS Guidelines, 2005)

Refer to the Treatment Algorithm in Section 15.9 for further guidance on adjusting 
antibiotic therapy after the initiation of IV empiric therapy.  
                                                
49 Per Amendment 5
50 Per Amendment 6 and 8


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8.4.2
Identity of Investigational Products
For this study, BAY 41-6551 inhalation solution will be supplied to clinical sites as a 
preservative-free sterile solution, which has been labeled for clinical study use.
Active Ingredient:
Amikacin sulfate 1:1.8
Pharmacologic Class:
aminoglycoside antibiotic
Molecular Formula:
C22H43N5O13. 1.8 H2SO4
Molecular Weight:
762.15
Route of Administration:
aerosol/inhalation
Storage:
2°C to 8°C  (36°F to 46°F)
51The active ingredient will be obtained from ACS Dobfar (Bergamo, Italy) and the BAY 
41-6551 inhalation solution will be manufactured by Bayer AG (Leverkusen, Germany).  
Each single-use vial has a filling volume of 3.6 mL.  This fill volume of 3.6 mL is equivalent 
to the BAY 41-6551 solution containing 450 mg of amikacin free base at a concentration of 
125 mg/mL to ensure an extractable volume of 3.2 mL.  The 3.2 mL extractable volume is 
equivalent to 400 mg amikacin free base aerosolized.  BAY 41-6551 inhalation solution 
appears as a clear, colorless to slightly yellowish solution.  Other excipients or components of 
the solution include: hydrochloric acid, sodium hydroxide, water for injection, and nitrogen.
A placebo saline solution for inhalation was developed.  The saline solution contains water 
for injection and sodium chloride.
The formulations will be packaged in a 6-mL brown glass vial (type 1 glass) with a gray 
chlorobutyl teflon-coated stopper and have a filling volume of 3.6 mL.  A brown glass vial 
was chosen for light protection reasons.  Teflon-coated stoppers are inert and generally 
compatible with aqueous solutions. 
Medication will be labeled according to the requirements of local law and legislation.  Label 
text will be approved according to agreed Bayer procedures, and a copy of the labels will be 
made available to the study site upon request. 
All blinded medication will be labeled according to the concentration of amikacin free base 
(125 mg/ml) in BAY 41-6551 Solution (Amikacin Inhalation Solution).  Furthermore, all 
stated dosages of BAY 41-6551 will refer to the corresponding amikacin free base.
8.4.3
Method of Assigning Patients to Treatment Groups - amended
All patients who meet the enrollment criteria will be stratified based on geographic region (or 
country)52 and disease severity (as determined by the APACHE II score calculated at the time 
the patient is evaluated for entry into the study and a diagnosis of Gram-negative pneumonia 
is considered):

Stratum I: APACHE II score < 20 (mild to moderate disease severity)
                                                
51 Per Amendment 8
52 Per Amendment 5


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
Stratum II: APACHE II score ≥20 (severe disease)
Following stratification, patients will be randomized 1:1, in a blinded fashion, to receive 
either aerosolized BAY 41-6551 400 mg (amikacin as free base) every 12 hours as adjunctive 
therapy to IV antibiotics or aerosolized placebo (normal saline) every 12 hours as adjunctive 
therapy to IV antibiotics. 
8.4.4
Selection of Doses in the Study
The dose of study drug is 400 mg (amikacin as free base) BAY 41-6551 or 3.2 mL of placebo 
every 12 hours administered by inhalation (Section 5.4.2). 
8.4.5
Administration and Dosing Regimen - amended
Dosing of BAY 41-6551 by inhalation will be every 12 hours for ten full days according to 
Table 4.  All investigators should be aware that 400 mg every 12 hours dose of aerosolized 
BAY 41-6551 refers to the quantity of amikacin free base in BAY 41-6551 Solution 
(Amikacin Inhalation Solution) delivered from the extractable volume of 3.2 mL and that all 
blinded medication will be labeled according to the concentration of amikacin free base 
(125 mg/mL) in BAY 41-6551 Solution (Amikacin Inhalation Solution).  Aerosolized therapy 
will begin within 48 hours53 of the initiation of IV antibiotics for Gram-negative pneumonia.  
For the purposes of this study, a day is defined as a single 24-hour period, during which two 
consecutive study medication treatments are scheduled.  All study medication will be 
delivered to the ICU or the unit where the patient may be located in the hospital from the 
pharmacy/study staff and provided to the investigational staff in blinded vials containing an 
excess of liquid to ensure an extractable volume of 3.2 mL (400 mg, amikacin as free base).  
The staff will be instructed to remove the metal top from the vial and pour the contents of the 
vial into the PDDS reservoir per the Instruction Manual.  If a vial of medication is opened, 
the entire contents will be poured into the nebulizer at the patient’s bedside.  In turn, the 
nebulizer, when filled and the cap snapped shut, cannot be reopened and is leak resistant.  All, 
used and unused vials and any unused medication will be returned to the pharmacy/study staff 
for inventory.  The used and unused study medication will be stored by the investigator or 
designee until the inventory can be confirmed by the sponsor’s designee.  Study medication 
destruction will be performed according to normal standard practice in the local country.  
Study medication will be destroyed by the site or by the Bayer local affiliate or its designee.
Used devices identified on the random planned return list will be inventoried and returned to 
the sponsor or its designee.  Used devices not on the planned return list as well as unused 
devices will be inventoried and destroyed on site or returned to the sponsor or its designee 
where required by site SOP.54
                                                
53 Correction made with Amendment 6 (was erroneously 24 hours)
54 Paragraph revised per Amendment 6


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Table 4:  Study Drug Administration and Dosing Regimen
Group
Route
Study Drug and Dosea
Amount
Regimenb
Active
Inhalation
Active Drug:  400 mg
3.2 mL
q 12 h c
Placebo
Inhalation
Placebo
3.2 mL
q 12 h c
a - Administration of the aerosol dose of study drug in both groups will be observed to 
monitor tolerability.
b - Serum creatinine levels should be obtained once daily and the results available and 
reviewed prior to the next dose.
c - q 12 h – every 12 hours
The active treatment group will consist of patients randomized to receive a daily total 
aerosolized dose of 800 mg (amikacin as free base) BAY 41-6551 delivered in two equal 
doses per aerosol treatment.
The placebo treatment group will consist of patients randomized to receive a daily total 
aerosolized dose of 6.4 mL placebo delivered in two equal doses per aerosol treatment.
Dosing will be administered only after the investigator or a designated Sub-investigator has 
reviewed the patient’s serum creatinine levels (serum creatinine levels should be obtained 
once daily and the results available and reviewed prior to the next dose).
8.4.6
Dose Modification
8.4.6.1
Renal Impairment - amended
Dosing for both IV and aerosol treatments may require modification based on the patient’s 
renal function as measured by serum creatinine and urine output.  It may also be necessary to 
modify the dosage regimen of aerosol therapy if there is evidence of bronchospasm during 
administration of the aerosol drug.  Dosage modifications described are not considered 
protocol deviations and IV therapy should follow the recommendations set forth in the 
approved package labeling.
Serum creatinine levels should be obtained once daily and the results available and reviewed 
prior to the next dose. Patients with a serum creatinine 2 mg/dL (177 µmol/L), will not 
receive the aerosol study drug treatment.  Patients with a serum creatinine 2 mg/dL 
(177 µmol/L) and receiving continuous renal replacement therapy (CVVH and CVVH-D) 
or daily hemodialysis will receive aerosol study drug treatment.  Intravenous therapy should 
be modified according to the instructions in the manufacturer’s approved product label.  If the 
patient is receiving IV amikacin therapy, serum amikacin levels should be monitored with the 
objective of achieving trough serum concentrations no greater than 4-5 µg/mL.
Dosing of the aerosol therapy will be interrupted for patients with a urine output of 
< 0.5 mL/kg/h for two consecutive hours.  If urine output falls below this level, the serum 
creatinine should be (re)checked immediately.  Dosing of the aerosol therapy may be resumed 
after urine output is 0.5 mL/kg/h and the serum creatinine is 2 mg/dL (177 µmol/L).  
Patients on CVVH, CVVH-D or daily hemodialysis (HD) may not meet either the urine 


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output or the serum creatinine requirements, but should still receive their dose every 12 hours. 
55
If dosing is missed for two consecutive days (four doses of aerosol therapy) because of serum 
creatinine or urine output measurement results, the patient will be prematurely discontinued 
from study medication and followed through the late follow-up visit (Day 28-32) for safety 
only.
8.4.6.2
Bronchospasm
If, in the opinion of the investigator or sub-investigator(s), the patient experiences an acute 
onset of bronchospasm, the patient may be treated prophylactically with a bronchodilator 
according to clinical judgment prior to each subsequent dose of aerosol treatment, and the 
patient may remain on study medication.  If bronchospasm recurs with subsequent 
administrations, the patient will be prematurely discontinued from all study medication and 
followed through the late follow-up visit (Day 28-32) for safety only.
All episodes of bronchospasm must be documented on the AE page of the CRF noting the 
seriousness, start and stop date of the bronchospasm, severity, relationship to study drug and 
device, actions taken (including but not limited to study drug interruption or discontinuation 
and any concomitant [including but not limited to bronchodilators] medications used to treat 
the bronchospasm) and outcome of the event. 
8.5
Pulmonary Drug Delivery System (PDDS Clinical)
8.5.1
Identity of Device - amended
The PDDS Clinical is a single patient, single-dose drug delivery system, designed to deliver 
aerosolized medication for patients during mechanical ventilation and after extubation in the 
course of clinical investigation.  The PDDS Clinical will be used with the inline T-piece for 
use during mechanical ventilation of intubated patients (Section 15.2, Figure 1 and Figure 2) 
and in a handheld adaptor for use post-extubation (Section 15.2, Figure 3).  The PDDS 
Clinical nebulizer/reservoir contains Nektar’s Proprietary Aerosol Generator, which delivers 
a fine-particle aerosol. 
The PDDS Clinical control module is microprocessor-driven and utilizes a pressure 
transducer to monitor changes in airway pressure thus to identify inspiratory time.  The 
microprocessor delivers aerosol during the first 75% of the inspiration.  Limiting aerosol 
formation to the first 75% of the inspiratory cycle enhances efficiency of delivery and 
minimizes exhaled aerosol.  By contrast, the PDDS Clinical is designed to deliver 
approximately 50% of the nominal dose to the lungs, based on in vitro data for both the on-
ventilator and handheld (off-ventilator) configurations (data on file, Novartis Report No. 
IDD061A_TESTR_699-ProdSpecStudy_01, May 2012).  The dosing is approximately 20 to 
55 minutes for intubated and mechanically-ventilated patients, and approximately 10 to 25 
minutes in non-intubated patients.  Nebulization time can vary depending on the patient’s 
                                                
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minute ventilation and the nebulizer flow rate output.  Nebulization times not within this 
approximate window are not considered a protocol deviation. 56
The PDDS Clinical handheld configuration consists of a PDDS Clinical nebulizer reservoir, 
aerosol chamber, mouthpiece assembly (including an expiratory filter with a flow restrictor), 
system cable, and a control module to provide electrical signals to the nebulizer.  
The handheld configuration functions in the following ways:

The nebulizer is always on, pumping aerosol into the aerosol chamber where it 
accumulates until patient inspiration.

The patient can use the handheld with a mouth piece, self-sealing anesthesia mask, 
or adapted for a patient that is trached and is spontaneously breathing57

The base of the aerosol chamber serves as a collection chamber for oxygen (if 
necessary). 

The accumulated aerosol bolus is delivered to the patient upon inhalation.

Oxygen, if needed, enters the bottom of the aerosol chamber through the one-way 
inhalation valve followed by ambient air.

During exhalation, the one-way inhalation valve at the bottom of the aerosol 
chamber is forced closed and gas expired by the patient is routed through the flow 
restrictor and filtered prior to introduction into the environment.

Nebulized aerosol continues to collect in the aerosol chamber during exhalation.

If an inspiratory effort is not detected for 12 seconds, the aerosol generating unit 
shuts off, therefore further minimizing environmental exposure.
In vitro environmental exposure studies have demonstrated less than 3% of the nominal dose 
has been detected in the expiratory limb of the ventilator circuit in the On-Vent configuration 
and no amikacin was detected post expiratory filter on the handheld configuration (data on 
file, Nektar Report No. SB 987, Jul 2008).
The PDDS Clinical control module is identified by a unique serial number.
8.5.2
Ventilator Settings
The PDDS Clinical is designed for use with standard, adult ventilator settings.  An 
intermittent positive pressure ventilatory mode is required to activate the PDDS Clinical to 
deliver aerosol during inspiration (refer to the PDDS Clinical Instruction Manual).
A heat-moisture exchanger (HME) may not be used in the PDDS Clinical circuit during 
dosing, according to the PDDS Clinical Instruction Manual.
                                                
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8.5.3
Device Supply – amended
Prior to the first aerosolized dose of BAY 41-6551, one PDDS Clinical will be dispensed.  
The serial numbers for the PDDS Clinical control module and the lot number of the 
nebulizer/reservoir will be recorded in the dispensing log.  During the 10-day treatment 
period, one control module will be used per patient.  The nebulizer/reservoir will be 
dispensed after each dose and the lot number recorded.  
If the patient is extubated, a handheld adaptor kit will be dispensed, but the original control 
module will continue to be used. The patient number and dispensing date of the nebulizer 
reservoirs, handheld adapter kits, and On-Vent kits will also be recorded in the dispensing log 
at the time of dispensing. 
Used devices identified on the random planned return list will be inventoried and returned to 
the sponsor or sponsor’s designee.58  Used devices should be cleaned as instructed in the 
PDDS Clinical Instruction Manual before returning them to the sponsor or sponsor’s 
designee.  Unused devices will be inventoried and returned to the sponsor or its designee or 
be destroyed by the site or by the Bayer local affiliate or its designee.
8.5.4
Device Replacement
Devices for intubated and non-intubated patients may be replaced at any time if there is a 
suspicion of malfunction, but must be replaced if the investigator suspects the device is not 
performing optimally for any reason.
8.5.5
Device Malfunction or Failure
If any of the devices need to be replaced, the reason(s) will be documented in the patient’s 
device accountability record.  Additional PDDS Clinical devices are provided for this 
purpose.  The unique serial number of the new PDDS Clinical control module and lot number 
for the nebulizer/reservoir will be recorded in the patient’s device accountability record.
For PDDS Clinical device malfunction or complaints, the sponsor or the sponsor’s designee 
should be contacted as soon as possible and within 24 hours.
Failed devices will be inventoried and returned to the sponsor or sponsor’s designee.  Failed 
devices should be cleaned as per the PDDS Clinical Instruction Manual before returning them 
to the sponsor or sponsor’s designee.
8.6
Blinding/Unblinding - amended
The decision to unblind is the principal investigator’s.  The Medical Expert is available to 
discuss the need to unblind any patient, and can be contacted if needed.59
Unblinding should only occur in the event of an emergency.  Investigators should note that 
the occurrence of a serious adverse event (SAE) should not routinely precipitate the 
immediate unblinding of the label.  When knowledge of the study drug is essential for the 
                                                
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clinical management or welfare of the patient, the investigator may unblind a patient’s 
treatment assignment. In the event of emergency unblinding by the investigator, the sponsor 
must be informed as soon as possible.
For suspected, unexpected, serious adverse reactions (SUSAR) cases where the investigator 
has not broken the blind, the sponsor will break the blind in accordance to the Bayer 
HealthCare Global standard operating procedure before reporting to Health Authorities, 
IRBs/ECs and investigators if the SUSAR was related to the blinded treatment.  The 
information will be maintained in the Global Pharmacovigilance database.  
Any reported SAEs that refer to a failure of the expected pharmacological action, for example 
worsening of Gram-negative pneumonia, are not considered SUSAR cases and are therefore 
exempted from unblinding.60
8.7
Prior and Concomitant Medication
Patients are excluded if they have received another experimental drug within the previous 28 
days.
Concomitant or sequential use of IV, oral, or topical nephrotoxic products, particularly 
bacitracin, cisplatin, amphotericin B, cephaloridine, paramomycin, viomycin, polymyxin B,
colistin, vancomycin, or other aminoglycoside antibiotics, except amikacin, should be 
avoided when possible.  The investigator is referred to the Amikacin Sulfate for Injection 
product label for prescribing information for IV/IM amikacin administration and to the 
Investigators’ Brochure (IB).
Concomitant therapy with potent diuretics (such as ethacrynic acid or furosemide) should also 
be avoided if possible. 
Concomitant therapy with inhalational anesthetics (such as halothane) or neuromuscular 
blocking agents (such as d-tubocurarine, succinylcholine, decamethonium) should also be 
avoided if possible and especially in patients who are receiving aerosol therapy via the 
handheld device.
All other concomitant medications necessary for the health and well-being of the patient are 
permitted but should be recorded (using the generic name) on the CRF. 
8.8
Treatment Compliance
At all appropriate assessment periods or visits, the investigator or other study personnel will 
note in the CRF whether treatment has been administered, as directed in the protocol, during 
the preceding interval.  If not, the date and reason for each deviation must be recorded. 
All efforts will be made to ensure that the study will be conducted in compliance with the 
protocol and in accordance with Good Clinical Practice (GCP). 
                                                
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9.
Study Procedures
9.1
Schedule of Visits and Visit Specific Procedures and Assessments
9.1.1
Screening Period (48 Hours Prior to Randomization)
Potential study patients will be recruited by the study staff among hospitalized patients with a 
clinical diagnosis of pneumonia who have been intubated and mechanically-ventilated 
(patients who have had a tracheotomy may be considered as possible study participants). 
Written informed consent will be obtained from the patient or an authorized representative 
prior to performing screening assessments.  However, standard of care procedures may be 
used to pre-screen the patient for study eligibility provided that the appropriate evaluations 
are done within two days of beginning treatment with study medication.  
During the Screening Period the following assessments and procedures will be performed: 

Evaluate compliance with all inclusion and exclusion criteria 

Complete medical/surgical and medication history 

Complete physical examination, including vital signs (heart rate, blood pressure, 
respiratory rate, temperature), height and weight.  The daily maximum temperature 
will be recorded. 

Chest X-ray (CXR) 
NOTE:  the reading and interpretation of the CXR by the investigator and/or sub-
investigator(s) at the Screening Visit can be used to determine the patient's 
eligibility for inclusion; however, the radiology report (ie, the reading and 
interpretation of the CXR by the Radiologist) will be the "official" reading 
recorded on the CRF and used for the determination of evaluability.  The 
radiologist will remain blinded to the treatment assignment of the patient. 

Urine or serum -hCG pregnancy test for all women of child-bearing potential.  A 
negative test result must be received before study medication may be given.  Any 
patient with a positive pregnancy test result at screening will be excluded from the 
study.

Clinical laboratory evaluations (hematology, serum chemistry, and urinalysis) to 
be conducted at the local lab

Aerobic blood cultures obtained from two separate venipuncture sites 
(recommended) or according to local standards

Arterial blood gases or pulse oximetry (arterial blood gases preferred)

A respiratory specimen (eg, TA [Section 15.7, Guidance on Tracheal Aspirate 
Sampling Technique], BAL, mini-BAL, or PSB) will be obtained for Gram stain, 
semi-quantitative or quantitative culture, and susceptibility testing.  
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for culture if the Gram stain reveals > 10 squamous epithelial cells per low 
powered (100 x) field.42  

Pleural fluid cultures or cultures of any other material (repeated as necessary until 
negative), if clinically indicated

Calculated CPIS must be 6, (Section 15.3 - description of the CPIS used in this 
study and guidance on calculating a score)

Calculate the APACHE II score 

Assessment of clinical signs and symptoms of pneumonia

Concomitant medication use
If a patient meets all the eligibility criteria, the patient may be enrolled and randomized to 
study medication.  The Study Flow Chart and/or Schedule of Procedures is contained in 
Section 15.1.
9.1.2
Treatment Period (Day 1 to Day 10) - amended
Day 1 is defined as the day the initial dose of study medication (aerosolized BAY 41-6551 or 
aerosolized placebo61) is given.  Day 1 may be the same day as when the informed consent 
form (ICF) is signed, screening assessments are performed, and the patient is enrolled.

Prior to the first dose, each patient will receive a PDDS Clinical device consisting 
of a control module, T-piece adaptor, alternating current/direct current (AC/DC)
adaptor, air pressure feedback device, and cable (Section 8.5).

Patients will be started on aerosolized study medication within 48 hours62 of IV 
antibiotic therapy being initiated for Gram-negative pneumonia.  Patients will 
receive 3.2 mL of either BAY 41-6551 (400 mg [amikacin as free base]) or 
placebo solution every 12 hours (a window of ± 4 hours is acceptable) via the 
PDDS Clinical for 10 full calendar days (20 doses) (Section 8.2).  If a patient is 
extubated during the course of treatment or has a tracheostomy and is 
spontaneously breathing, aerosol administration will continue via the handheld 
adaptor for the remainder of the treatment period.
9.1.2.1
Assessments Performed Daily - amended
Patients will have the following assessments and procedures performed daily, unless 
otherwise indicated, during the treatment period:

A physical examination including vital signs

An assessment of clinical signs and symptoms of pneumonia 
                                                
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
Measurement of serum creatinine.  Serum creatinine levels should be obtained 
once daily and the results available and reviewed prior to the next dose.

Concomitant medications and AEs will be monitored and recorded.

Collection of ventilator parameters pre- and post-dose of study drug 63

Amikacin serum level monitoring
Serum amikacin levels will be obtained for those patients receiving IV amikacin 
therapy.  Serum level monitoring and/or dosage adjustments will be performed 
according to institutional guidelines or the standard of practice at the site.  A 
serum amikacin sample should also be sent to the Central Laboratory.  The Central 
Laboratory will not report serum amikacin levels to the investigator or sub-
investigator(s). 
Patients not receiving IV amikacin therapy but receiving aerosol treatment will 
have amikacin serum levels monitored through the Central Laboratory, therefore, a 
serum amikacin sample should be sent to the Central Laboratory.  However, 
because of low systemic exposure following aerosol treatment, amikacin serum 
levels will not be reported to the investigator or sub-investigator(s).  

Measurement of serum amikacin trough level 30 minutes (± 15 mins) 64 prior to 
each first aerosol dose of the day. 65
9.1.2.2
Assessments Performed on Days 1, 3, 5, and 7 - amended
65Patients will have the following assessments and procedures performed on Days 1, 3, 5, and 
7 during the treatment period as indicated:

CXR obtained 
NOTE:  the reading and interpretation of the CXR by the investigator and/or sub-
investigator(s) at the During Treatment Visits can be used for clinical decision-
making; however, the radiology report (ie, the reading and interpretation of the 
CXR by the radiologist) will be the "official" reading recorded on the CRF and 
used for the determination of evaluability.  The radiologist will remain blinded to 
the treatment assignment of the patient. 

Clinical laboratory evaluations (hematology, serum chemistry, and urinalysis) to 
be conducted at the local lab

Aerobic blood cultures obtained from two separate venipuncture sites 
(recommended) or according to local standards 
                                                
63 Per Amendment 5
64 Per Amendment 5
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
Arterial blood gases or pulse oximetry (arterial blood gases preferred)

A respiratory specimen (eg, TA [Section 15.7, Guidance on Tracheal Aspirate 
Sampling Technique], BAL, mini-BAL, or PSB) will be obtained for Gram stain, 
semi-quantitative or quantitative culture, and susceptibility testing.  
NOTE:  All respiratory specimens will be evaluated by Gram stain and rejected 
for culture if the Gram stain reveals > 10 squamous epithelial cells per low 
powered (100 x) field. 

Pleural fluid cultures or cultures of any other material (repeated as necessary until 
negative), if clinically indicated

Calculated CPIS (Section 15.3- description of the CPIS used in this study and 
guidance on calculating a score) 
9.1.3
Post-Treatment Period (Days 10-32)
9.1.3.1
End of Therapy Visit (Day 10) - amended
The end of therapy (EOT) visit will be conducted on Day 10 or within 24 hours after 
completion of study drug.  The Investigator Assessment of Patient Outcome will involve an 
evaluation of clinical signs and symptoms.66
Patients will have the following assessments and procedures performed during the EOT visit:

A physical examination including vital signs

CXR obtained
NOTE: the reading and interpretation of the CXR by the investigator and/or sub-
investigator(s) at the EOT visit can be used to determine the Investigator 
Assessment of Patient Outcome;67 however, the radiology report (i.e., the reading 
and interpretation of the CXR by the Radiologist) will be the “official” reading 
recorded on the CRF and used for the determination of evaluability.  The 
radiologist will remain blinded to the treatment assignment of the patient.

Clinical laboratory evaluations (hematology, serum chemistry, and urinalysis) to 
be conducted at the local lab

Arterial blood gas or pulse oximetry (arterial blood gases preferred)

A respiratory specimen (e.g., TA [Section 15.7, Guidance on Tracheal Aspirate 
Sampling Technique], BAL, mini-BAL, or PSB) will be obtained for Gram stain, 
semi-quantitative or quantitative culture, and susceptibility testing
NOTE: All respiratory specimens will be evaluated by Gram stain and rejected for 
                                                
66 Per Amendment 6
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culture if the Gram stain reveals > 10 squamous epithelial cells per low powered 
(100 X) field. 

Calculate CPIS (Section 15.3 – description of the CPIS used in this study and 
guidance on calculating a score)

Concomitant medication and AEs will be monitored and recorded. 
9.1.3.2
Test-of-Cure (TOC) Visit (Days 17 - 19) - amended
The TOC visit will be conducted on Days 17-19 of the study.  The Investigator Assessment of 
Patient Outcome will be determined by an assessment of clinical signs and symptoms.68
Patients will have the following assessments and procedures performed during the TOC visit:

Complete physical examination, including vital signs and weight.  In addition, the 
daily maximum temperature will be recorded. 

An assessment of clinical signs and symptoms of pneumonia 

CXR obtained
NOTE:  the reading and interpretation of the CXR by the investigator and/or sub-
investigator(s) at the TOC visit can be used to determine the Investigator 
Assessment of Patient Outcome;69 however, the radiology report (ie, the reading 
and interpretation of the CXR by the radiologist) will be the "official" reading 
recorded on the CRF and used for the determination of evaluability.  The 
radiologist will remain blinded to the treatment assignment of the patient. 

Clinical laboratory evaluations (hematology, serum chemistry, and urinalysis) to 
be conducted at the local lab

Aerobic blood cultures obtained from two separate venipuncture sites 
(recommended) or according to local standards 

Arterial blood gas 70

A respiratory specimen (eg, TA [Section 15.7, Guidance on Tracheal Aspirate 
Sampling Technique], BAL, mini-BAL, or PSB) will be obtained for Gram stain, 
semi-quantitative or quantitative culture, and susceptibility testing.  
NOTE:  All respiratory specimens will be evaluated by Gram stain and rejected 
for culture if the Gram stain reveals > 10 squamous epithelial cells per low 
powered (100 x) field. 
                                                
68 Per Amendment 6
69 Per Amendment 6
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
Calculated CPIS (Section 15.3 - description of the CPIS used in this study and 
guidance on calculating a score) 

Concomitant medications and AEs will be monitored and recorded
9.1.3.3
Late Follow-Up Visit (Days 28 - 32) - amended
The LFU visit will be conducted on Days 28 – 32 of the study.  Patients will be strongly 
encouraged to return to their study facility for their LFU visit.  However, if this is not feasible 
all obtainable information can be collected by telephone from the patient or the patient's care 
giver.
The following assessments should be performed:

Complete physical examination, including vital signs and weight.  In addition, the 
daily maximum temperature will be recorded.

Complete the Late Follow-Up Questionnaire (see Section 15.6)

An assessment of clinical signs and symptoms of pneumonia 

The Investigator Assessment of Patient Outcome will be determined by an 
assessment of clinical signs and symptoms71

Calculated CPIS (Section 15.3 - description of the CPIS used in this study and 
guidance on calculating a score)

Concomitant medications and AEs will be monitored and recorded

Clinical laboratory evaluations (hematology, serum chemistry, and urinalysis) to 
be conducted at the local lab
The following assessments should only be performed if clinically indicated.

CXR obtained

Aerobic blood cultures

Arterial blood gas or pulse oximetry (arterial blood gases are preferred)

A respiratory specimen (eg, TA [Section 15.7, Guidance on Tracheal Aspirate 
Sampling Technique], BAL, mini-BAL, or PSB) will be obtained for Gram stain, 
semi-quantitative or quantitative culture, and susceptibility testing.  
NOTE:  All respiratory specimens will be evaluated by Gram stain and rejected 
for culture if the Gram stain reveals > 10 squamous epithelial cells per low 
powered (100 x) field. 
                                                
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9.2
Completion of Study
A patient is considered to have completed the study when they have completed the treatment 
period and both post-treatment follow-up visits (eg, TOC and LFU visit).  
9.3
Follow-Up Assessments
Follow-up assessments will be obtained as needed to monitor any SAE until the event 
resolves or is considered to be stable and non-resolving. Hearing loss should be noted on the 
CRF.
9.4
Unscheduled Assessments or Visits
The investigator is responsible for monitoring patients for any treatment-related toxicity.  
Blood samples for clinical laboratory tests may be drawn at any time at the discretion of the 
investigator.
Samples obtained at unscheduled times will be sent to the local laboratory for analysis.
9.5
Premature Discontinuation / Early Withdrawal from Study - amended
Patients prematurely discontinuing or withdrawing early from the study, for whatever reason, 
will be asked to undergo the following evaluations at the time of discontinuation / 
withdrawal:

Complete physical examination, including vital signs; in addition the daily 
maximum temperature will be recorded  

CXR
NOTE:  the reading and interpretation of the CXR by the investigator and/or sub-
investigator(s) can be used to determine the Investigator Assessment of Patient 
Outcome;72 however, the radiology report (ie, the reading and interpretation of the 
CXR by the radiologist) will be the "official" reading recorded on the CRF. The 
radiologist will remain blinded to the treatment assignment of the patient. 

Clinical laboratory evaluations (hematology, serum chemistry, and urinalysis)

Aerobic blood cultures obtained from two separate venipuncture sites 
(recommended) or according to local standards

Arterial blood gas 73

Calculated CPIS (Section 15.3 - description of the CPIS used in this study and 
guidance on calculating a score) 

Assessment of clinical signs and symptoms of pneumonia
                                                
72 Per Amendment 6
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
A respiratory specimen (eg, TA [Section 15.7, Guidance on Tracheal Aspirate 
Sampling Technique], BAL, mini-BAL, or PSB) will be obtained for Gram stain, 
semi-quantitative or quantitative culture, and susceptibility testing.  
NOTE:  All respiratory specimens will be evaluated by Gram stain and rejected 
for culture if the Gram stain reveals >10 squamous epithelial cells per low 
powered (100 x) field. 

Pleural fluid cultures or cultures of any other material if clinically indicated

Concomitant medications and AEs will be monitored and recorded
9.6
Study Measurements
The objective of this study is to evaluate the efficacy and safety of adjunctive aerosolized 
BAY 41-6551 in the treatment of intubated and mechanically-ventilated adult patients with 
Gram-negative pneumonia.  
9.6.1
Efficacy Variables – amended
9.6.1.1
Primary Efficacy Variable:  Survival - amended
74The primary efficacy variable is Survival, which is determined by tabulating the cumulative 
mortality and survival through the LFU visit for each mITT patient. Survival (and mortality) 
is the only criteria evaluated for the primary endpoint, no other factors are considered other 
than survival status through the LFU visit.
9.6.1.2
Additional Analysis of Clinical Success - amended
75There are three additional analyses of clinical success. These three analyses are separate 
from the primary endpoint. The three analyses are (1) the FNIH recommendations for an 
endpoint based on mortality plus septic shock, (2) the Investigator’s assessment of Patient 
Outcome, and (3) the Composite Endpoint Evaluation (the previous Primary Endpoint).
9.6.1.2.1
FNIH Criteria - amended
76Clinical success using FNIH recommendations is defined as mITT patients who survived 
through the LFU visit and did not have septic shock. Patients will be designated as having a 
septic shock event based on the standard medical queries (SMQ) terms tabulated as adverse 
events.
                                                
74 Per Amendment 6 and 8
75 Added per Amendment 8
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9.6.1.2.2
Investigator Assessment of Patient Outcome - amended
77 The investigators will also assess patient outcome based on a composite endpoint. The 
Investigator Assessment of Patient Outcome is separate and different from the primary 
endpoint of Survival, which is done by using a computer algorithm based on collected data 
and specific criteria.  The Investigator Assessment of Patient Outcome is based on the 
following criteria:

CPIS assessed at baseline, Days 3, 5, 10, and the TOC visit

All-cause mortality assessed through the TOC visit

Systemic antibacterial use for the current episode of pneumonia beyond Day 10 (the 
EOT for aerosol administration)

Antibiotic adjustments made during therapy
9.6.1.2.2.1End of Therapy (Day 10)
78The Investigator Assessment of Patient Outcome will be evaluated at the EOT visit using 
the following terms and definition.  
Investigator Assessment of Patient Outcome - Cure:

Improvement or lack of progression of all abnormalities associated with 
pneumonia on chest radiograph;

Resolution towards normal of the following components of the CPIS - tracheal 
secretions (volume and purulence), temperature, blood leukocytes, oxygenation 
(PaO2/FiO2);
NOTE: “resolution towards normal”, as used in this definition, is intended to 
mean that the components of the CPIS may not be within normal limits (e.g., 
continuing low-grade fever or leukocytosis in an ICU patient); however, in the 
opinion of the investigator the measure is considered not to be clinically 
significant in the context of resolving pneumonia.

The patient never reached any of the early failure criteria AND

The patient survived through the EOT visit
NOTE: All four conditions listed above must be met in order for the Investigator Assessment 
of Patient Outcome to be a cure.
Investigator Assessment of Patient Outcome - Failure:

Rise in the CPIS by at least 2 points on Day 3;

Failure of the CPIS to drop at least 1 point on Day 5;
                                                
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
Failure of the CPIS to drop by at least 2 points on Day 10;

Continuation of systemic antibiotics (IV or PO) for pneumonia after Day 10; 

Any further change to the Gram-negative portion of the 79 antimicrobial regimen 
being used to treat pneumonia during the first 10 days, after the initial 
antimicrobial adjustment within the first 96 80 hours after the initiation of empiric 
therapy or as soon as initial culture and susceptibility results are available and 
excepting the discontinuation of aminoglycosides after 5-7 days, would be
considered a Clinical Failure; 
OR

All-cause mortality by the EOT visit. 
NOTE: If any one of the above conditions is met, the Investigator Assessment of Patient 
Outcome is a failure
9.6.1.2.2.2Test-of-Cure (TOC) Visit (Day 17-19) - amended
81The Investigator Assessment of Patient Outcome will be evaluated at the TOC visit using 
the following terms and definitions:
Investigator Assessment of Patient Outcome - Cure: 

Improvement or lack of progression of all abnormalities associated with  
pneumonia on chest radiograph;

Resolution towards normal of the following components of the CPIS - tracheal 
secretions (volume and purulence), temperature, blood leukocytes, oxygenation 
(PaO2/FiO2);
NOTE: “resolution towards normal”, as used in this definition, is intended to 
mean that the components of the CPIS may not be within normal limits (eg, 
continuing low-grade fever or leukocytosis in an ICU patient); however, in the 
opinion of the investigator, the measure is considered not to be clinically 
significant in the context of resolving pneumonia.

The patient never reached any of the early failure criteria;

The patient did not receive antibiotic therapy for pneumonia after 10 days; AND

The patient survived through the TOC visit. 
NOTE:  All five conditions listed above must be met in order for the Investigator Assessment 
of Patient Outcome to be a cure.
                                                
79 Per Amendment 5
80 Per Amendment 5
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Investigator Assessment of Patient Outcome - Failure: 

Rise in the CPIS by at least 2 points on Day 3;

Failure of the CPIS to drop at least 1 point on Day 5; 

Failure of the CPIS to drop by at least 2 points on Day 10; 

Continuation of systemic antibiotics (IV or PO) for pneumonia after Day 10;

Restarting systemic antibiotics (IV or PO) for pneumonia before the TOC (with a 
positive respiratory culture) visit; 

Any further change to the Gram-negative portion of the 82 antimicrobial regimen 
being used to treat pneumonia during the first 10 days, after the initial 
antimicrobial adjustment within the first 96 83 hours after the initiation of empiric 
therapy or as soon as initial culture and susceptibility results are available and 
excepting the discontinuation of aminoglycosides after 5-7 days, would be 
considered a Clinical Failure;
OR

All-cause mortality by the TOC visit.
NOTE:  If any one of the above conditions is met, the Investigator Assessment of Patient 
Outcome is a failure.
At Day 10 (End of Therapy), the criteria to determine whether IV antibiotics need to be 
continued will be an assessment of clinical signs and symptoms of pneumonia.  Specifically, 
this evaluation will consider temperature (oC or oF), blood leukocyte (WBC) count 
(cells/mm3) with differential (including % neutrophils), oxygenation (PaO2/FiO2) (mm Hg), 
volume and appearance of tracheal secretions (few, moderate, large, purulent) and chest 
radiography (no infiltrate, patchy or diffuse infiltrate, localized infiltrate).  
At Day 10, corresponding to the completion of 20 doses (EOT), patient outcome of failure 
will be defined as a failure to decrease the CPIS by 2 points.  There may be instances at Day 
10 where, if the CPIS falls by more than 2 points, there could still be reasons to continue IV 
antibiotic therapy and also instances where the score could fail to fall by more than 2 points 
and antibiotic therapy might be discontinued.  In both instances of such patient outcome 
failure, the reasons for continuing or discontinuing antibiotic therapy will be specified in the 
CRF.
A patient outcome of failure will be carried through the LFU visit evaluation.
                                                
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9.6.1.2.2.3Late Follow-up Visit (Days 28 – 32) – amended
84The Investigator Assessment of Patient Outcome will be evaluated at the LFU visit.  As 
mentioned previously, a patient evaluated at the TOC visit as a patient outcome failure will 
have that response carried forward to the LFU visit. 
For patients who were evaluated at the TOC visit as a patient outcome cure, their clinical 
response will be graded as:
Continued Investigator Assessment of Patient Outcome Cure: continued resolution of 
clinical signs and symptoms of pneumonia and continued improvement or lack of progression 
of all abnormalities on chest radiograph such that additional antibiotic therapy to treat 
pneumonia is not required. 
Relapse: reappearance of the signs and symptoms of pneumonia and worsening or 
progression of abnormalities on chest radiograph such that alternative antibiotic therapy is 
required.
9.6.1.2.2.4Premature Discontinuation Visit - amended
85A patient may not complete a full 10-day (20 doses) course of study drug treatment or may 
not reach the TOC visit (Days 17-19).  These patients may prematurely discontinue therapy 
because they are failing study treatment and alternative antibiotic therapy is required, while 
others may discontinue study medication because of an AE, protocol violation or other 
reasons as noted in Section 8.3.3.1.  Alternative antibiotic therapy may or may not be 
required.
For a patient outcome failure (ie, study drug therapy is discontinued because of a lack of 
therapeutic effect), the evaluation of the patient’s clinical condition should be based on the 
clinical signs and symptoms of pneumonia as well as objective evidence of failure (eg, 
persistent fever, rising WBC count, increasing tracheal secretions, poor oxygenation, 
progression of infiltrate on CXR) and a measure of their CPIS.  This information should be 
recorded on the CRF, as well as an evaluation of the patient’s clinical response to study drug.  
In most cases, the decision to evaluate the patient as a Clinical Failure will be made after at 
least 72 hours of study medication, but in rare instances, the clinical course of the illness may 
require that study medication be discontinued prior to three days treatment and alternative 
antibiotic therapy started.  Regardless of when the patient is prematurely discontinued, the 
clinical condition of the patient should be determined at the time of study drug 
discontinuation, recorded on the CRF, and a clinical response evaluation completed.
At the premature discontinuation visit, the patient’s outcome will be assessed according to the 
following terms and definitions.
                                                
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Investigator Assessment of Patient Outcome - Failure: 

Rise in the CPIS by at least 2 points on Day 3;

Failure of the CPIS to drop at least 1 point on Day 5; 

Failure of the CPIS to drop by at least 2 points on Day 10; 

Continuation of systemic antibiotics (IV or PO) for pneumonia after Day 10;

Restarting systemic antibiotics (IV or PO) for pneumonia before the TOC (with a 
positive respiratory culture) visit; 

Any further change to the antimicrobial regimen being used to treat pneumonia 
during the first 10 days, after the initial antimicrobial adjustment within the first 
72 hours after the initiation of empiric therapy or as soon as initial culture and 
susceptibility results are available and excepting the discontinuation of 
aminoglycosides after 5-7 days, would be considered a patient outcome failure; 
OR

All-cause mortality.
NOTE: At least one of the above conditions is necessary to consider a patient a patient
outcome failure.
In the case of the patient who has discontinued study drug for another reason (eg, AE, 
protocol violation, etc), the patient should be evaluated clinically to determine their response 
to treatment at the point they are discontinued.  This assessment would be recorded on the 
CRF and include a determination of their clinical signs and symptoms of pneumonia and a 
measure of their CPIS.
Clinical Improvement: reduction in the severity and/or number of clinical signs and 
symptoms of pneumonia and alternative antibiotic therapy is considered and may or may not 
be initiated.
Indeterminate:  not possible to determine clinical response to treatment (eg, withdrawal after 
less than three days of study drug therapy due to an AE).  The reason(s) for an indeterminate 
response must be recorded on the CRF.


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9.6.1.2.3
Composite Endpoint Evaluation:  - amended
86An evaluation of patient outcome based on 5 components is determined by using a 
computer algorithm based on collected data and specific criteria.  This assessment based on 5 
criteria is separate and different from the Primary Endpoint of Survival. For a patient to be 
evaluated as a Clinical Success for the Composite Endpoint Evaluation all the following 
criteria must be met:

Systemic antibiotics (IV or PO) for pneumonia must be stopped on or before the TOC 
visit 

Systemic antibiotics (IV or PO) for pneumonia must not be restarted after the TOC 
visit

The patient must survive through the LFU visit

The patient must not have a reported AE of lung abscess or empyema through the 
LFU visit 

The patient must have stable respiratory function evaluated at the TOC visit based on 
the P/F ratio (see below)
Stable respiratory function:
o
Patient is extubated at the TOC visit OR 
o
Patient is intubated at the TOC visit AND:

Patient has a P/F ratio > 200 at the TOC visit OR

Patient has a P/F ratio > 100 and ≤ 200 at the TOC visit AND: 

Patient had a P/F ratio ≤ 200 at baseline
Unstable respiratory function
o
Patient has a P/F ratio ≤ 100 at the TOC visit OR
o
Patient has a P/F ratio > 100 and ≤ 200 at the TOC visit AND: 

Patient had a P/F ratio > 200 at baseline
The outcome is Clinical Success if all 5 criteria are met.  If any one of the criteria is not met, 
then the patient is considered a Clinical Failure. Patients who do not have a clinical 
assessment of success due to missing data will be considered a Clinical Failure.
9.6.2
Safety Variables
All patients who have received at least one dose of the study drug(s) will be evaluated for 
safety in a descriptive manner.  The safety analysis will include tabulation of the type (using 
Medical Dictionary for Regulatory Activities [MedDRA] glossary) and frequency of all AEs.  
                                                
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Drug-related AEs, SAEs, premature discontinuations due to AEs will also be summarized, as 
well as AEs by severity, outcome, and action taken.
Incidence tables will be presented for all AEs up to seven days after the end of treatment and 
for SAEs, up to the Day 28 visit.
All laboratory data will be analyzed using descriptive statistics including identification of 
laboratory data outside normal ranges.
Rates of organ failure will also be summarized, by patient as well as by specific organ type.
87Mortality during the treatment period, Day 15 and Day 28 visit will be summarized (This is 
also the primary efficacy endpoint).
9.6.2.1
Clinical Laboratory Tests
The following clinical laboratory tests will be performed (Section 15.1):

Hematology:  hemoglobin, hematocrit, WBC with differential (%), red blood cell 
(RBC) count, platelet count

Chemistry:  alkaline phosphatase, alanine aminotransferase/serum glutamate 
pyruvate transaminase (ALT/SGPT), aspartate aminotransferase/serum glutamic 
oxalo-acetic transaminase (AST/SGOT), bicarbonate, bilirubin (total and direct), 
blood urea nitrogen (BUN),  calcium, chloride, cholesterol (total), creatinine, 
gamma-glutamyl transferase (GGT), glucose, lactate dehydrogenase (LDH), 
phosphorus, potassium, protein (total), sodium, triglycerides, and uric acid 

Urinalysis:  appearance, specific gravity, pH, protein, ketones, bilirubin, 
urobilinogen, blood, nitrite, microscopic examination of sediment. 
Serum creatinine levels should be obtained once daily and the results available and reviewed 
prior to the next dose.
The investigator will record on the laboratory report his/her medical opinion of the clinical 
significance of all laboratory values that are outside the laboratory reference range.  The 
investigator will sign and date each laboratory report form.  Clinically significant laboratory 
findings made after the start of study medication that meet the definition of an AE must be 
recorded on the CRF.
The investigator will provide the sponsor or sponsor’s designee with a copy of each 
laboratory’s certification and a tabulation of the normal ranges.
9.6.2.2
Bacteriological Response Assessments
Bacteriological response will be based on the results of the appropriate cultures taken before, 
during, and after therapy.  For infections caused by two or more pathogens, the response for 
each organism will be assessed separately.
                                                
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9.6.2.2.1 Test-of-Cure (TOC) Visit (Days 17-19)
The bacteriological response at the TOC visit will be graded as follows:

Eradication:  the absence of the original pathogen(s) at the post-treatment TOC 
culture of specimens from the original site of infection

Presumed eradication:  absence of appropriate culture material in a patient 
judged to be a clinical cure; he or she is unable to produce sputum and invasive 
procedures are not warranted

Persistence:  the presence of the original pathogen from the post-treatment TOC 
culture specimens from the original site of infection

Presumed persistence:  the absence of appropriate culture material in a patient 
judged to be a Clinical Failure and invasive procedures are not warranted

Superinfection:  the isolation of a new pathogen (not the original pathogen) from 
a specimen taken while the patient is on antibiotic therapy, signs and symptoms 
indicative of pneumonia are present, and there is a need for alternative 
antimicrobial therapy (Superinfections will not be considered microbiological 
failures, but will be assessed separately)

New infection:  the isolation of a new pathogen (not the original pathogen) from a 
specimen taken after the patient has completed antibiotic therapy, signs and 
symptoms indicative of pneumonia are present, and there is a need for alternative 
antimicrobial therapy

Indeterminate:  the bacteriological response to the study medication is not valid 
for any reason (eg, pre-treatment culture was negative or post-treatment culture 
was not obtained when material was available) 
9.6.2.2.2 Late Follow-up Visit (Days 28-32)
Continued Eradication: the absence of the original pathogen(s) at the post-treatment late 
follow-up culture of specimens from the original site of infection. 
Continued Presumed Eradication:  absence of appropriate culture material for evaluation 
because the patient’s pneumonia has resolved clinically, he or she is unable to produce 
sputum and invasive procedures are not warranted.
Recurrence:  the reappearance of the original pathogen(s) from a specimen taken after the 
TOC visit.
New infection:  the isolation of a new pathogen (not the original pathogen) from a specimen 
taken after the patient has completed antibiotic therapy, signs and symptoms indicative of 
pneumonia are present, and there is a need for alternative antimicrobial therapy.
Indeterminate:  the bacteriological response to the study medication is not valid for any 
reason (eg, pre-treatment culture was negative or post-treatment culture was not obtained 
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9.7
Data Quality
Monitoring and auditing procedures defined/agreed to by the sponsor will be followed, in 
order to comply with GCP guidelines.  Each center will be visited at regular intervals by a 
Monitor to ensure compliance with the study protocol, GCP and legal aspects.  This will 
include on-site checking of the CRF for completeness and clarity, cross-checking with source 
documents, and clarification of administrative matters.
9.8
Documentation
Entries made in the CRF must be either verifiable against source documents, or have been 
directly entered into the CRF, in which case the entry in the CRF will be considered as the 
source data.  The source data parameter to be verified and the identification of the source 
document must be documented.  The study file and all source data should be retained until 
notification given by the sponsor for destruction. 
10.
Ethical and Legal Aspects
10.1
Independent Ethics Committee (IEC) or Institutional Review Board 
(IRB)
Documented approval from appropriate IECs/IRBs will be obtained for all participating 
centers/countries prior to study start, according to GCP, local laws, regulations and 
organizations.  When necessary, an extension, amendment or renewal of the IEC/IRB 
approval must be obtained and also forwarded to the sponsor.  The IEC/IRBs must supply to 
the sponsor, upon request, a list of the IEC/IRB members involved in the vote and a statement 
to confirm that the IEC/IRB is organized and operates according to GCP and applicable laws 
and regulations. 
10.2
Ethical Conduct of the Study
The procedures set out in this protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the sponsor and investigator abide by 
GCP Guidelines and under the guiding principles detailed in the Declaration of Helsinki.  The 
study will also be carried out in keeping with applicable local law(s) and regulation(s).  This 
may include an inspection by the sponsor’s representatives and/or Regulatory Authority’s 
representatives at any time.  The investigator must agree to the inspection of study-related 
records by the Regulatory Authority/sponsor representatives, and must allow direct access to 
source documents to the Regulatory Authority/sponsor representatives.
The IRBs/IECs must approve the protocol prior to the start of the study.  Modifications to the 
study protocol will not be implemented by either the sponsor or the investigator without 
agreement by both parties.  However, the investigator or the sponsor may implement a 
deviation from, or a change of, the protocol to eliminate an immediate hazard(s) to the trial 
patients without prior IEC/IRB/sponsor approval/favorable opinion.  As soon as possible, the 
implemented deviation or change, the reasons for it and if appropriate the proposed protocol 
amendment should be submitted to the IEC/IRB/head of medical institution/sponsor.  Any 
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10.3
Regulatory Authority Approvals/Authorizations
Regulatory Authority approvals / authorizations / notifications, where required, must be in 
place and fully documented prior to study start. 
10.4
Patient Information and Consent - amended
A core information and ICF will be provided.  Prior to the beginning of the study, the 
investigator must have the IEC/IRB written approval/favorable opinion of the written ICF and 
any other written information to be provided to patients.  The written approval of the 
IEC/IRB together with the approved patient information / ICF must be filed in the study files.
Written informed consent must be obtained before any study specific procedure takes place.  
Participation in the study and date of informed consent given by the patient or an authorized 
representative should be documented appropriately in the patient’s files.  In the case where 
the patient is unable to provide consent, the patient’s legally authorized representative (LAR) 
(in accordance with applicable law) may provide consent for the patient.  In the absence of a 
LAR, the investigator must seek local legal and ethical guidance to ensure that, in such cases, 
consent is obtained for patients in accordance with local requirements.
Under these circumstances, if the patient becomes able during their participation in the trial, 
information about the trial should be given to the patient and their consent to remain in the 
clinical research study should be obtained as soon as possible.  The consent process for such 
patients should be clearly documented in the patient’s medical records.88
10.5
Insurance
All patients participating in the study will have insurance coverage by the sponsor, which is 
in line with applicable laws and/or regulations. 
10.6
Confidentiality
All records identifying the patient will be kept confidential and, to the extent permitted by the 
applicable laws and / or regulations, will not be made publicly available.
Patient names will not be supplied to the sponsor.  Only the patient number will be recorded 
in the CRF. If the patient name appears on any other document (eg, pathologist report), it 
must be obliterated before a copy of the document is supplied to the sponsor.  Study findings 
stored on a computer will be stored in accordance with local data protection laws.  The 
patients will be informed in writing that representatives of the sponsor, IEC/IRB, or 
Regulatory Authorities may inspect their medical records to verify the information collected, 
and that all personal information made available for inspection will be handled in strictest 
confidence and in accordance with local data protection laws.
If the results of the study are published, the patient’s identity will remain confidential.
The investigator will maintain a list to enable patients’ records to be identified.
                                                
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11.
Statistical Methods and Determination of Sample Size
11.1
Statistical and Analytical Plans
11.1.1
Analysis Populations - amended
The two populations used for analysis will be the mITT population and the ITT population.  
These populations will be comprised of patients recruited to this study and to study 13085 
(being conducted in different countries; the protocols are identical with the exception that 
study 13085 has a pharmacokinetic substudy).  The patients will be recruited competitively 
between studies 13084 and 13085; there are no minimum requirements for recruitment totals 
in either study.89  The mITT population is defined as all randomized patients with culture-
confirmed Gram-negative bacteria who have been treated with at least one dose of study drug 
and have an APACHE II score 10 at the time of diagnosis of pneumonia.  The ITT 
population is defined as all patients treated with at least one dose of study drug.
11.1.2
Analytical Plan - amended
The primary efficacy analysis will be conducted in the mITT population.  The primary 
analysis is on the combined database, no single study analyses will be performed as part of 
the primary analysis.90   Unless otherwise specified, all significance tests will be conducted 
using a two-sided alpha level of 0.05.
All variables collected in this study will be summarized with descriptive statistics at each 
assessment time.  Patient disposition and demographic and baseline characteristics will be 
summarized descriptively for each treatment group.  Demographic variables will be 
summarized for both the mITT and ITT populations.
Duration of treatment (the total number of doses) will be summarized descriptively by 
treatment group and delivery type (eg, on vent and handheld).  Overall duration and duration 
by device type will be provided for both the mITT and ITT populations.
All safety analyses will be provided only for the ITT population.
For continuous variables, descriptive statistics will include means, standard deviations, 
medians, minimums and maximums.  For categorical variables, frequency counts and 
percentages will be provided.
11.2
Determination of Sample Size - amended
91For this combined study (studies 13084 and 13085), a two group 2 test with a 0.05 two-
sided significance level will have 81% power to detect the difference between BAY 41-6551 
survival rate at LFU of 80% and Placebo survival rate at LFU of 69% when the sample size in 
each group is 254.  
                                                
89 Two sentences added per Amendment 6
90 Revised per Amendment 6
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Assuming approximately 30% of patients will not be eligible for the primary efficacy analysis 
(ie, will not have a pre-therapy Gram-negative organism) a total of 362 ITT patients per 
group (724 ITT overall) will be needed for the study, based on current surveillance.  Note that 
with this sample size, an observed treatment group difference of as low as 7.74% could 
provide a statistically significant result.
11.3
Methods for the Analysis of the Primary Efficacy Parameter (Survival) -
amended
92The primary efficacy variable is Survival through the LFU visit.  Survival is achieved when 
the patient is alive through the LFU visit. No other factors are considered in the evaluation of 
survival.
The primary analysis will compare the survival rates through LFU visit of patients in the 
BAY 41-6551 group versus patients in the placebo group, using the combined data from 
studies 13084 and 13085.
The null (H0) and the alternative (H1) hypothesis for this primary analysis is the following:

H0: p[BAY 41-6551] = p[placebo]

H1: p[BAY 41-6551] ≠ p[placebo]
where p is the true Survival rate.  
A Cochran-Mantel-Haenzel test of general association, adjusting for stratum and geographic 
region, will be performed as the primary efficacy analysis.  If the p-value from this test is less 
than 0.05, and the proportion of patients who survive is higher in the BAY 41-6551 group 
than in the placebo group, the study will have achieved its primary objective. 
In addition, as a supportive analysis, a 95% confidence interval will be calculated for the odds 
ratio.  This confidence interval will be generated from a logistic regression model with 
Survival as the primary variable, and treatment, stratum, and geographic region as the 
independent variables.  If the lower limit of the 95% confidence interval for the odds ratio 
(BAY 41-6551/placebo) is greater than 1, BAY 41-6551 will be demonstrated to be 
statistically superior to placebo. 
Tests will be performed using the SAS procedure FREQ, and the 95% confidence intervals 
for the odds ratios will be generated using PROC LOGISTIC. 
An unadjusted chi-squared test will also be performed as a supportive efficacy analysis.  In 
addition, a logistic regression model with only treatment as an independent variable will be 
performed, and the resulting 95% confidence interval for the odds ratio will be provided.  
These analyses will serve as sensitivity analyses to demonstrate consistency with the primary 
analysis. 
The Breslow-Day test will be used as a further supportive analysis to test for treatment by 
geographic region and treatment by stratum interaction.  If this test of the homogeneity of the 
                                                
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odds ratio indicates a significant interaction, exploratory analyses will attempt to define its 
source.  A Cochran-Mantel-Haenzel test of general association, adjusting for stratum and 
study protocol (ie, 13084 or 13085), will be performed to assess the effect of study protocol 
on the primary efficacy variable Survival.  Geographic region will not be included in this 
model as the 2 studies were conducted in different regions.
The primary efficacy analysis performed on the mITT population will be repeated for ITT 
population.
Exploratory descriptive summaries will be provided for the primary efficacy variable by 
treatment group and pre-determined subgroups of interest.  These subgroups will include:

Type of ventilator

Underlying diagnosis

Positive or negative blood culture

CPIS at pre-therapy (< 6, 6, 7, 8, 9, 10, 11)

APACHE II score (< 20, 20)

Age (<18, 18 to <45, 45 to < 65, 65 to <75, ≥75 years)

Sex

Race

Country

Geographic region

Latin America countries (Brazil, Colombia, Mexico)

Asia Pacific countries (Philippines, South Korea, Taiwan, Thailand, China, Japan)

Baseline Gram-negative antibiotic treatment taken by each patient (1, 2, ≥3)

Primary reason for intubation (Current pneumonia-related respiratory failure vs 
everything else)

Patients who received IV antibiotic for pneumonia ≥5 days after day of first 
intubation (Yes, No); 

Patients who received at least one dose of carbapenem during Days 1 through 10 
(Yes, No); 

Start time of amikacin from start time of IV antibiotic (0 to <12 hours, 12 to <24 
hours, >24 hours). 

Patients with confirmed MDR pathogens (MDR first detected at baseline, MDR 
first detected post-baseline, Not MDR); 

Patients with confirmed ESBL pathogens (ESBL first detected at baseline, ESBL 
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The last 2 subgroups above pertain to MDR designation which is described in detail in 
Appendix 9.1:

To be declared a MDR, a bacterial isolate at the same visit must be resistant using 
the central laboratory interpretation to at least 3 of the 7 drug classes on the 
susceptibility panel: aminoglycoside, β-lactam/β-lactamase inhibitor, cephams, 
carbapenam, tetracycline, folate pathway inhibitor, and quinolone. Once a patient 
has any MDR pathogen, he/she should be designated as a MDR patient no matter 
what the subsequent susceptibility tests show.

For the 3 cephams (ceftazidime, cefazolin, and cefpodoxime), resistance to any 
one of the 3 drugs in the panel counts as cepham resistance for the category.

An interpretation by central laboratory of “Not applicable” result will be 
considered as “susceptible” for purposes of MDR tabulation. This means that at 
least 3 results of “intermediate” or “resistant” are necessary for an MDR 
designation, and a “Not applicable” will not be included in the total. 
11.4
Methods for the Analysis of Secondary Efficacy Parameters - amended
93 If the null hypothesis for the primary efficacy variable is rejected, a formal hypothesis 
testing scenario will be applied for the secondary efficacy variables: 

Pneumonia-related mortality through the LFU visit (determined by blinded 
adjudication committee)

Early Clinical Response (based on CPIS, mortality, and certain AEs) assessed 
through Day 10 

The number of days on mechanical ventilation through the LFU visit

The number of days in the ICU through the LFU visit
The secondary efficacy variables will be formally tested for statistical significance of a 
difference between the BAY 41-6551 group versus the placebo group, only if the primary 
efficacy comparison is statistically significant at the two-sided 5% level.  A sequential testing 
procedure will be performed at the two-sided alpha level of 0.05 for these four secondary 
efficacy variables, strictly in the order listed above.
The null hypothesis of no difference between BAY 41-6551 and placebo in pneumonia –
related mortality and early clinical response will be tested using an unadjusted Chi-square 
test. Analysis of variance will be used to test the null hypothesis of no difference between 
BAY 41-6551 and placebo for the number of days on mechanical ventilation and in the ICU.
For the purpose of the sequential testing procedure, the only effect in the models will be 
treatment. As supportive analyses, additional models will be used with effects included for 
                                                
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geographic region for all secondary variables.  Non-parametric tests for treatment 
comparisons will be considered as sensitivity analyses.
The secondary endpoint of pneumonia-related mortality through the LFU visit will be 
examined further by subgroups listed for the primary analysis.  
All 4 secondary endpoints will be examined further by the following MDR subgroups:

Patients with confirmed MDR pathogens (MDR first detected at baseline, MDR first 
detected post-baseline, Not MDR); 

Patients with confirmed ESBL pathogens (ESBL first detected at baseline, ESBL first 
detected post-baseline, Not ESBL); 

Patients who received IV antibiotic for pneumonia ≥5 days after day of first intubation 
(Yes, No); 

Patients who received at least one dose of carbapenem during Day 1 through 10 (Yes, 
No); 

Start time of amikacin from start time of IV antibiotic (0 to <12 hours, 12 to <24 
hours, ≥24 hours).
94The other efficacy endpoints are:
1. The number of days in the hospital through LFU visit
2. Relapse rates at LFU
3. Total number of days of Gram-negative antibiotics
4. Change in component of CPIS score from baseline to TOC
5. Clinical response rates at EOT (Clinical cure, Clinical failure)
Analysis of variance will be used to test the null hypothesis of no difference between BAY 
41-6551 and placebo for the total number of days of Gram-negative antibiotics. The other 
four efficacy endpoints listed above will be summarized descriptively. 
.  .
11.5
Additional Analyses of Clinical Success - amended
95 The following endpoints will be analyzed as additional analyses of clinical success:
11.5.1
Foundation for the National Institute of Health Criteria - amended
Clinical success using FNIH recommendations is defined as mITT patients who survived 
through the LFU visit and did not have septic shock. Patients will be designated as having a 
                                                
94 Revised with Amendment 8
95 Section added per Amendment 8


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septic shock event based on the standard medical queries (SMQ) terms tabulated as adverse 
events. Descriptive analysis will be provided with 95% confidence intervals. Cochran-
Mantel-Haenszel test of general association adjusting for stratum and geographic region will 
also be performed.
11.5.2
Investigator Assessment of Patient Outcome - amended
Investigator Assessment of Patient Outcome is determined at the TOC visit. The outcomes of 
“success” or “failure” are based on the following criteria:

Improvement or lack of progression of all abnormalities on chest radiograph 

Resolution towards normal of the following CPIS components: tracheal secretions 
(volume and purulence), temperature, blood leukocytes, oxygenation (P/F ratio) 

Any further change to the Gram-negative portion of the antimicrobial regimen being used 
to treat pneumonia during the first 10 days, after the initial antimicrobial adjustment 
within the first 96 hours after the initiation of empiric therapy or as soon as initial culture 
and susceptibility results are available and excepting the discontinuation of 
aminoglycosides after 5-7 days, would be considered a Clinical Failure

Patient did not receive antibiotic therapy for pneumonia after  Day 10 (EOT)

Patient survived through the TOC visit
All 5 conditions listed above must be met to achieve Investigator’s Assessment of Patient 
Outcome to be a Success. At the LFU visit, an assessment of relapse will be considered to be 
Failure.
These endpoints will be summarized descriptively with 95% confidence interval. A Cochran-
Mantel-Haenszel test of general association adjusting for stratum and geographic region will 
be performed on the mITT patients. 
In addition, Kaplan-Meier curves will be provided for time to Investigator Assessment of 
Clinical Failure. Time to Clinical Failure is defined as the time from the first day of study 
drug intake to the first time at which clinical failure is assessed. Patients who do not fail will 
be censored at death date, their LFU visit or last visit.
11.5.3
Clinical Success (Former 5 Component Primary Endpoint) - amended
Clinical Success is achieved when the following criteria are met as listed in the order of 
medical relevance:

The patient must survive through the Late Follow-Up (LFU) visit

Systemic antibiotics (IV or PO) for pneumonia must be stopped on or before the TOC 
visit (Day 17-19), 

Systemic antibiotics (IV or PO) for pneumonia must not be restarted after the TOC 
visit through the LFU visit

The patient must have stable respiratory function evaluated at TOC or last visit based 
on the PaO2/FiO2 (P/F) ratio as outlined below (if P/F ratio is not available at the 
TOC, use the P/F ratio value from the closest previous visit), and 


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
The patient must not have a reported AE of lung abscess or empyema through the 
LFU visit
Stable respiratory function

Patient is extubated at the TOC visit or

Patient is intubated at the TOC and:
o
Patient has P/F ratio > 200 at the TOC visit or
o
Patient has P/F ratio > 100 and ≤ 200 at the TOC visit and:
o
Patient had a P/F ratio ≤ 200 at baseline
If ventilation status not explicitly known to be extubated for a patient at TOC or last visit, the 
status was assumed to be intubated for the determination of primary endpoint.
Unstable respiratory function

Patient has a P/F ratio ≤ 100 at the TOC visit or

Patient has a P/F ratio > 100 and ≤ 200 at the TOC visit and:

Patient has P/F ratio > 200 at baseline
The outcome is Clinical Success if all 5 criteria are met. If any one of the criteria is not met, 
then the patient is considered a Clinical Failure. Patients who do not have a clinical 
assessment of success due to missing data will be considered a Clinical Failure.
For patients who discontinue study drug (on vent or handheld) for reasons other than efficacy 
will be handled as described in the table below:                                                                                                       
Reason for Discontinuation of Aerosol 
Therapy
Outcome / Comments
No Gram-negative bacteria isolated from a pre-
therapy respiratory specimen
Patient is considered ITT analysis and not 
evaluated for efficacy analysis as mITT
Patient withdrew consent or refused handheld 
device
Evaluate for efficacy if all data for primary 
efficacy are available; if data are missing, 
then failure
Death
Failure
Adverse event
Failure
New therapy incompatible with aerosol therapy
Failure
Lost to follow-up
Failure
Any other reason/unknown reason
Failure


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Additional reasons for discontinuation may be included as failure after review of blinded 
data. The patient must have stable respiratory function evaluated at TOC or last visit based on 
the ventilation status and PaO2/FiO2 (P/F) ratio (if ventilation status or P/F ratio is not 
available at the TOC, use the respective ventilation status or P/F ratio value from the closest 
previous visit).  See Section Error! Reference source not found., Definition of Primary 
Efficacy Endpoint.
The analysis will compare the proportion of patients with Clinical Success in the BAY 41-
6551 group versus the patients in the placebo group, using the combined data from studies 
13084 and 13085. All assessments other than Clinical Success, which are failures, 
improvements, and missing (those patients who do not have a TOC assessment) will be 
grouped together in the Clinical Failure category for the purpose of this analysis. If a TOC 
assessment date is missing for determining the antibiotic criteria for a patient, the TOC 
assessment will be assumed to have occurred 17 days after the start of study drug.  
A Cochran-Mantel-Haenszel test of general association, adjusting for stratum and geographic 
region, will be performed as the primary efficacy analysis. If the p-value from this test is less 
than 0.05, and the proportion of patients with Clinical Success is higher in the BAY 41-6551 
group than in the placebo group, the study will have demonstrated superiority in this 
sensitivity analysis.
In addition, as a supportive analysis, a 95% confidence interval will be calculated for the odds 
ratio. This confidence interval will be generated from a logistic regression model with 
Clinical Success as the additional efficacy variable, and treatment, stratum, and geographic 
region as the independent variables. If the lower limit of the 95% confidence interval for the 
odds ratio (BAY 41-6551/placebo) is greater than 1, BAY 41-6551 will be demonstrated to 
be statistically superior to placebo.
Individual components of the composite endpoint will be analyzed using the Cochran-
Mantel-Haenszel test adjusting for stratum and geographic region. This is to assess the 
components are moving in the same general direction and which, if any, single component is 
driving the result. The analysis of individual components will be performed on the actual 
counts of each criterion, not ordered by medical relevance.
Tests will be performed using the SAS procedure FREQ, and the 95% confidence intervals 
for the odds ratios will be generated using PROC LOGISTIC.
An unadjusted chi-squared test will also be performed as a supportive efficacy analysis. In 
addition, a logistic regression model with only treatment as an independent variable will be 
performed, and the resulting 95% confidence interval for the odds ratio will be provided. 
The Breslow-Day test will be used as a further supportive analysis to test for treatment by 
geographic region and treatment by stratum interaction. If this test of the homogeneity of the 
odds ratio indicate significant interaction (P < 0.10), exploratory analyses will attempt to
define its source. 


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A Cochran-Mantel-Haenszel test of general association, adjusting for stratum and study 
protocol (i.e., 13084 or 13085), will be performed to assess the effect of study protocol on the 
Clinical Success as additional efficacy variable. Geographic region will not be included in 
this model as the 2 studies were conducted in different regions. 
Number and percent of patients meeting the each failure criteria will be summarized in the 
order of medical relevance as presented in Section 6.2.2. A patient with failure is counted 
only in the criteria with highest medical relevance in the order presented. Patients may not 
have any failure criteria, but not be included in the analysis due to missing data. To account 
for missing visits, the number of patients without failure criteria but has TOC visit and 
missing LFU visit will be presented. Additional summary of respiratory stability function will 
be given for components of stable respiratory function and unstable respiratory function for 
each treatment group.
.
11.6
Analysis of Device Performance
Device performance will be summarized descriptively as reported events, incidents, 
complaints and analysis of planned return units.  No inferential statistics will be provided.  
11.7
Analysis of Safety Data 
All analyses of safety endpoints will be descriptive only, and no inferential statistics will be 
provided.
The proportion of patients with organ failure will be summarized by treatment group.  The 
overall proportion of patients with any organ failure will be summarized, as well as the 
proportion of patients with each specific type of organ failure.
The incidence rates of treatment-emergent AEs, drug-related and device-related AEs, SAEs, 
drug-related and device-related SAEs, and premature discontinuations due to AEs will be 
presented by treatment group, MedDRA preferred term, and system organ class.
Mortality rates will be summarized during therapy, and at Day 15 and Day 28 by treatment 
group.  Ninety-five percent confidence intervals will also be provided for the difference 
between groups in mortality rates at these time points.  In addition, Kaplan-Meier curves will 
be provided for time to death.
Descriptive statistics for actual values and change from baseline values for clinical laboratory 
tests will be presented.  Incidence rates of treatment-emergent abnormally high or low clinical 
laboratory tests will also be provided.
11.8
Methods for the Analysis of the Microbiology Endpoints 
Summaries of microbiologic endpoints will only be provided for the mITT population.
By-patient and by-organism bacteriological eradication rates at the TOC visit will be 
provided for each treatment group.  In these summaries, eradication rates will be defined as 
the sum of eradications and presumed eradications divided by the sum of eradications, 
presumed eradications, persistence, presumed persistence, and indeterminate.


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Rates of emergent infections (new infections and superinfections) will be summarized 
separately, by treatment group.  By-patient and by-organism displays will be provided for 
each treatment group for each type of emergent infection.
12.
Adverse Events
12.1
Definitions
12.1.1
Adverse Event
An AE is any untoward undesirable experience associated with the use of a medicinal product 
or medical device in a patient.  The AE does not necessarily have to have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of an investigational product, whether or not considered related to the medicinal 
product.
Adverse events associated with the use of a drug in humans, whether or not considered drug 
related, include the following: 

An AE occurring in the course of the use of a drug product in professional 
practice.

An AE occurring from an overdose whether accidental or intentional.

An AE occurring from drug abuse.

An AE occurring from drug withdrawal. 

An AE where there is a reasonable possibility that the event occurred purely as a 
result of the patient’s participation in the study (eg, AE or SAE due to 
discontinuation of anti-hypertensive drugs during wash-out phase) must also be 
reported as an AE even if it is not related to the investigational product.
The clinical manifestation of any failure of expected pharmacological action is not recorded 
as an AE if it is already reflected as a data point captured in the CRF.  If, however, the event 
fulfills any of the criteria for an SAE, it must be recorded and reported as such.
12.1.2
Serious Adverse Event
An SAE is any untoward medical occurrence that at any dose: 

Results in death.

Is life-threatening.

Requires in-patient hospitalization or prolongation of existing hospitalization.

Results in persistent or significant disability or incapacity.

Is a congenital anomaly or birth defect.

Is a medically important event as judged by the investigator.


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Life-threatening: The term “life-threatening” in the definition of “serious” refers to an AE in 
which the patient was at risk of death at the time of the event. It does not refer to an AE 
which hypothetically might have caused death if it were more severe.
Hospitalization: Any AE leading to hospitalization or prolongation of hospitalization will be 
considered as serious, UNLESS at least one of the following exceptions is met:

The admission results in a hospital stay of less than 12 hours and is not otherwise 
associated with a medically important AE. 
OR

The admission is pre-planned (ie, elective or scheduled surgery arranged prior to 
the start of the study). 
OR

The admission is not associated with an AE (eg, social hospitalization for purposes 
of respite care).
However it should be noted that invasive treatment during any hospitalization may fulfill the 
criteria of ‘medically important’ and as such may be reportable as a serious AE dependent on 
clinical judgment.  In addition where local regulatory authorities specifically require a more 
stringent definition, the local regulation takes precedent.
Disability means a substantial disruption of a person’s ability to conduct normal life’s 
functions.
Important medical event: Any AE may be considered serious because it may jeopardize the 
patient and may require intervention to prevent another serious condition.  As guidance for 
determination of important medical events refer to the Eudravigilance Important Medical 
Event (IME) Terms List.  These terms either refer to or might be indicative of a serious 
disease state. 
Such reported events warrant special attention because of their possible association with a 
serious disease state and may lead to more decisive action than reports on other terms. 
12.1.3
Unexpected Adverse Event
An unexpected AE is any adverse drug event, the specificity or severity of which is not 
consistent with the current Investigator Brochure (or Package Insert for marketed products). 
Also, reports which add significant information on specificity or severity of a known, already 
documented AE constitute unexpected AEs.  For example, an event more specific or more 
severe than described in the Investigator Brochure would be considered “unexpected”.  
Specific examples would be; (a) acute renal failure as a labeled AE with a subsequent new 
report of interstitial nephritis and (b) hepatitis with a first report of fulminant hepatitis.
The expectedness of AEs, including the expectedness of AEs related to the medical device, 
will be determined by the sponsor according to the applicable reference document and 
according to all local regulations.


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12.1.4
Adverse Events of Special Safety Interest
Identified risks of parenteral (IV and IM) formulations of amikacin (eg, neurotoxicity, 
ototoxicity, and nephrotoxicity) should be monitored to assess the potential risk for 
aerosolized amikacin.  Adverse effects due to local exposure in the bronchopulmonary 
system, such as bronchospasm (see Section 8.4.6.2), coughing during or shortly after 
inhalation of aerosol, and hemoptysis should also be monitored.
12.1.5
Relationship of Adverse Event to Investigational Product
The assessment of the relationship of an AE to the administration of study drug is a clinical 
decision based on all available information at the time of the completion of the CRF.
An assessment of ‘No’ would include:
1. The existence of a clear alternative explanation eg, mechanical bleeding at surgical site.
OR
2. Non-Plausibility eg, the patient is struck by an automobile when there is no indication that 
the drug caused disorientation that may have caused the event; cancer developing a few days 
after the first drug administration. 
An assessment of ‘Yes’ indicates that there is a reasonable suspicion that the AE is associated 
with the use of the investigational drug.
Factors to be considered in assessing the relationship of the AE to study drug include: 

The temporal sequence from drug administration: The event should occur after the 
drug is given.  The length of time from drug exposure to event should be evaluated 
in the clinical context of the event.

Recovery on discontinuation (de-challenge), recurrence on reintroduction (re-
challenge): Patient’s response after drug discontinuation (de-challenge) or 
patient’s response after drug re-introduction (re-challenge) should be considered in 
the view of the usual clinical course of the event in question.

Underlying, concomitant, intercurrent diseases: Each report should be evaluated in 
the context of the natural history and course of the disease being treated and any 
other disease the patient may have.

Concomitant medication or treatment: The other drugs the patient is taking or the 
treatment the patient receives should be examined to determine whether any of 
them may be suspected to cause the event in question.

The pharmacology and pharmacokinetics of the test drug: The pharmacokinetic 
properties (absorption, distribution, metabolism and excretion) of the test drug(s), 
coupled with the individual patient’s pharmacodynamics should be considered.
12.1.6
Severity of the Adverse Event
The following classification should be used:
The severity of AEs should be graded as follows:


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Mild – usually transient in nature and generally not interfering with normal activities 
Moderate – sufficiently discomforting to interfere with normal activities 
Severe – prevents normal activities
12.1.7
Adverse Event Documentation
All AEs occurring after the patient has signed the informed consent until the completion of 
the end of study visit must be fully recorded in the patient’s CRF and transcribed to the 
electronic CRF (eCRF).
Documentation must be supported by an entry in the patient’s file.  A laboratory test 
abnormality considered clinically relevant, eg, causing the patient to withdraw from the 
study, requiring treatment or causing apparent clinical manifestations, or judged relevant by 
the investigator, should be reported as an AE.  Each event should be described in detail along 
with start and stop dates, severity, relationship to investigational product, action taken and 
outcome.
12.2
Reporting of Serious Adverse Events/Pregnancy
All investigators will be trained on all relevant aspects of the investigator’s reporting 
obligations for SAEs.  This information, including all relevant contact details, is summarized 
in the investigator site file.  This information will be updated as needed.
Serious AEs, including laboratory test abnormalities fulfilling the definition of serious, after 
signing the informed consent and during follow-up period must immediately (within 24 hours 
of the investigator’s awareness) be reported to the person detailed in the study file.  An SAE 
form must also be completed within 24 hours of the investigator awareness and forwarded to 
the designated person as detailed in the study file. Each SAE must be followed up until 
resolution or stabilization by submission of updated reports to the designated person.
When required, and according to local law and regulations, SAEs must be reported to the 
Ethics Committee and Regulatory Authorities.
Pregnancy occurring during a clinical investigation, although not considered an SAE, must be 
reported to Bayer within the same timelines as an SAE on a Pregnancy Monitoring Form. The 
outcome of a pregnancy should be followed up carefully and any abnormal outcome of the 
mother or the child should be reported. This also applies to pregnancies following the 
administration of the investigational product to the father prior to sexual intercourse.  Bayer 
usually does not gather information of drug exposure of the father, however, if those cases are 
reported, all efforts should be made to obtain similar information on course and outcome, 
subject to the partner’s consent.
12.2.1
Notification of the IECs/IRBs
Notification of the IECs/IRBs about all relevant events (eg, SAEs, SUSARs) will be 
performed by the sponsor or delegated to a CRO and/or by the investigator according to all 
applicable regulations.


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12.2.2
Notification of the Authorities
The processing and reporting of all relevant events (eg, SAEs, SUSARs) to the authorities 
will be done by the sponsor according to all applicable regulations.
12.2.3
Sponsor’s Notification of the Investigational Site
The sponsor or sponsor’s designee will inform all investigational sites about reported relevant 
events (eg, SUSARs) according to all applicable regulations.
12.3
Definition of an Incident
An incident is any malfunction or deterioration in the characteristics and/or performance of
the device, as well as any inadequacy in the labeling or the instructions for use, which directly 
or indirectly, might lead to or might have led to the death or to a serious deterioration in the 
state of health of a patient or user or of other persons. 
The following criteria apply in determining whether an incident has occurred:
A. An event has occurred or may occur if the same failure is repeated. 
An event could be among others:

Malfunction or deterioration in the characteristics or performance or

Unanticipated adverse reaction or unanticipated side effect or 

Interactions with other substances or products or 

Degradation / destruction of the device (e.g., fire) or 

Inappropriate therapy, or

Inaccuracy in the labeling, instructions for use including omissions or deficiencies.
B. The device is suspected to be a contributory cause of the event
C. The event led, or might have led, to one of the following outcomes:

Death of a patient or user or other person or

Serious deterioration in the state of health of a patient, user or other person
To determine whether an incident has occurred, criteria A, B, and C must be fulfilled.  All 
incidents will be reported to the respective national competent authorities, authorized 
representative, and as applicable, notified bodies according to local regulations and medical 
device regulations 93/42/EEC, MEDDEV 12.2, GHTF/SG2/N21R8:1999, and 21 Code of 
Federal Regulations (CFR) Part 803.
Incidents should be reported using a separate clinical investigations device complaint form.
12.3.1
Device Malfunction or Failure and Medical Device Reporting
Any device complaint, malfunction, or failure including use errors will be recorded by the 
clinical/investigational site, including all relevant device information using the clinical 
investigations device complaint form, and forwarded within 24 hours to the sponsor or 
sponsor’s designee for evaluation and investigation, regardless of whether or not a medical 


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event was associated with the device malfunction or failure.  There are three different 
situations, in which a medical device complaint form might need to be filled out by the 
investigator:
a) When an AE is recorded, the investigator needs to check if a device malfunction or 
failure might be associated with the recorded AE.
b) When a device malfunction or device failure occurs, the investigator needs to assess 
whether an AE might have occurred in relation to the device.
c) When a device malfunction, device failure, or use error occurs, without any associated 
AE, this also needs to be captured in the form and immediately forwarded to the 
sponsor for investigation.
The details of the malfunction and medical circumstances will be captured on a Device 
Complaint Form filled out by the investigator and then returned to the sponsor or sponsor’s 
designee.  The final determination of reportability is made by the sponsor and not the 
clinical/investigational site based on the medical circumstances surrounding the event.  
Novartis, the device manufacturer, may recommend reporting an incident based on 
investigations, but the final determination of reportability is made by the sponsor.
Investigator’s notification of the sponsor
All investigators will be instructed and trained on all relevant aspects of the investigator’s 
reporting obligations for device incidents and serious public health threats.  This information, 
including all relevant contact details, is summarized in the investigator site file. This 
information will be updated as needed.
The sponsor will inform the device manufacturer (Novartis) about any incident and Novartis 
will then perform an evaluation and investigation of the device, as necessary, and exchange 
any significant information with the sponsor.  Novartis will inform the sponsor about 
necessary trend reports and will provide the required documentation after completing the 
respective investigation and statistical analysis. The sponsor will then notify the authorities of 
any trend reports according to all applicable regulations.
All devices that have malfunctioned or failed will be inventoried and returned to the device 
manufacturer.  The devices should be stored in a hermetically sealed bag and labeled with the 
respective case reference.  In cases where an incident is recorded in connection with the 
device malfunction or failure, the device should be sent immediately per courier to the device 
manufacturer.  If any of the devices need to be replaced, the reason(s) will be documented.  
Additional PDDS Clinical devices are provided for this purpose. 
13.
Use of Data and Publication
All data and results and all intellectual property rights in the data and results derived from the 
study will be the property of the sponsor, who may utilize the data in various ways, such as 
for submission to government regulatory authorities or disclosure to other investigators.  The 
investigator, while free to utilize data derived from the study for scientific purposes, must 
discuss any publication with the sponsor prior to release and obtain written consent of the 
sponsor on the intended publication.  The sponsor recognizes the right of the investigator to 
publish the results upon completion of the study.  However, the investigator must send a draft 


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manuscript of the publication or abstract to the sponsor thirty days in advance of submission 
in order to obtain approval prior to submission of the final version for publication.  This will 
be reviewed promptly and approval will not be withheld unreasonably.  In case of a 
difference of opinion between the sponsor and the investigator(s), the contents of the 
publication will be discussed in order to find a solution which satisfies both parties. 


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14.
References - amended
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3. Palmer LB, Smaldone GC, Simon SR, et al.  Aerosolized antibiotics in mechanically-
ventilated patients: delivery and response.  Crit Care Med 1998;26:31-9.
4. Qanta A, Ahmed A, Niederman MS.  Respiratory infection in the chronically 
critically ill patient.  Clin Chest Med 2001;22(1):71-85.
5. American Thoracic Society and the Infectious Diseases Society of America.  
Guidelines for the management of adults with hospital-acquired, ventilator-associated, 
and healthcare-associated pneumonia.  Am J Respir Crit Care Med 2005;171:388-416.
6. American Thoracic Society.  Hospital-acquired pneumonia in adults:  diagnosis, 
assessment of severity, initial antimicrobial therapy, and preventative strategies:  A 
Consensus Statement.  Am J Respir Crit Care Med 1995;153:1711-25.
7. Chastre, J, Fagon JY.  Ventilator-associated pneumonia.  Am J Respir Crit Care Med 
2002;165:867-903.
8. Micek ST, Ward S, Fraser VJ, et al.  A randomized controlled study of an antibiotic 
discontinuation policy for clinically suspected ventilator-associated pneumonia.  
Chest 2004;125(5):1791-9.
9. Heyland DK, Cook DJ, Griffith L, et al. Canadian Critical Trials Group.  The 
attributable morbidity and mortality of ventilator-associated pneumonia in the 
critically ill patient.  Am J Resp Crit Care Med 1999;159:1249-56.
10. Richards M, Edwards JR, Culver DH, et al.  The national nosocomial infections 
surveillance system.  Nosocomial infections in medical intensive care units in the 
United States.  Crit Care Med 1999;27(5):887-92.
11. Dennesen P, van der Ven A, Kessels A, et al. Resolution of infectious parameters after 
antimicrobial therapy in patients with ventilator-associated pneumonia. Am J Resp 
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12. Singh N, Rogers P, Atwood C, et al. Short-course empiric antibiotic therapy for 
patients with pulmonary infiltrates in the intensive care unit. Am J Resp Crit Care 
Med 2000;162:505-11.
13. Chastre J, Wolff M, Fagon, J, et al. Comparison of 8 vs 15 days of antibiotic therapy 
for ventilator-associated pneumonia in adults. JAMA 2003;290:2588-98.


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14. Santré C, Georges H, Jacquier JM, et al.  Amikacin levels in bronchial secretions of 
10 pneumonia patients with respiratory support treated once daily versus twice daily.  
Antimicrob Agents Chemother 1995;39(1):264-7.
15. MacLusky IB, Gold R, Corey M, et al.  Long-term effects of inhaled tobramycin in 
patients with cystic fibrosis colonized with pseudomonas aeruginosa.  Pediatr 
Pulmonol 1989;7(1):42-8.
16. Smith AL, Ramsey BW, Hedges DL, et al.  Safety of aerosol tobramycin 
administration for 3 months to patients with cystic fibrosis.  Pediatr Pulmonol 
1989;7(4):256-71.
17. Fink JB, Dhand R.  Aerosol therapy in mechanically-ventilated patients:  recent 
advances and new techniques.  Semin Resp Critical Care Med 2000;21(3):183-201.
18. Smaldone GC, Palmer LB.  Aerosolized antibiotics:  current and future.  Respir Care 
2000;45(6):667-75.
19. Duarte AG, Fink JB.  Inhalation therapy during mechanical ventilation.  Resp Care 
Clin N Am 2001;7(2):233-60.
20. Langer M, Mosconi P, Cigada M, et al.  Long-term respiratory support and risk of 
pneumonia in critically ill patients.  Am Rev Respir Dis 1989;140(2):302-5.
21. Cook DJ, Walter SD, Cook RJ, et al.  Incidence of and risk factors for ventilator-
associated pneumonia in critically ill patients.  Ann Intern Med 1998;129(6):433-40.
22. Rello J, Torres A.  Microbial causes of ventilator-associated pneumonia.  Semin 
Respir Infect 1996;11(1):24-31.
23. Luna CM, Vujacich P, Niederman MS, et al.  Impact of BAL data on the therapy and 
outcome of ventilator-associated pneumonia.  Chest 1997;111(3):676-85.
24. Rello J, Diaz E.  Pneumonia in the intensive care unit.  Crit Care Med  
2003;31(10):2544-51
25. Goldstein I, Wallet F, Nicolas-Robin A, et al.  Lung deposition and efficiency of 
nebulized amikacin during Escherichia coli pneumonia in ventilated piglets.  Am J 
Resp Crit Care Med 2002;166:1375-81.  
26. Ferrari F, Goldstein I, Nieszkowszka A, et al.  Lack of lung tissue and systemic 
accumulation after consecutive daily aerosols of amikacin in ventilated piglets with 
healthy lungs.  Anesth 2003;98(4):1016-9.  
27. Wood GC, Boucher BA.  Aerosolized antimicrobial therapy in acutely ill patients.  
Pharmacotherapy 2000;20(2):166-81.
28. Lipworth BJ.  Pharmacokinetics of inhaled drugs.  Br J Clin Pharmacol 
1996;42(6):697-705.
29. Kondili E, Georgopoulos D.  Aerosol medications.  Respir Care Clin N Am 
2002;8(2):309-34.


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30. Dhand R.  Basic techniques for aerosol delivery during mechanical ventilation.  
Respir Care 2004;49(6):611-22.
31. Odio W, Van Laer E, Klastersky J.  Concentrations of gentamicin in bronchial 
secretions after intramuscular and endotracheal administration.  J Clin Pharmacol 
1975;15(7):518-24.
32. Dally MB, Kurrle S, Breslin AB.  Ventilatory effects of aerosol gentamicin.  Thorax 
1978;33(1):54-6.
33. Prober CG, Walson PD, Jones J. The Committee on Infectious Diseases and 
Committee on Drugs.  Technical report:  precautions regarding the use of aerosolized 
antibiotics.  Pediatrics 2000;106(6):1-6.
34. Flores RM, Starke B, Kramer T, et al.  Aerosolized antibiotics and microbial 
resistance in mechanically ventilated patients [abstract].  2001 Meeting of the 
American Thoracic Society; 2001; San Francisco, California.
35. Sorensen VJ, Horst HM, Obeid FN, et al.  Endotracheal aminoglycosides in 
Gram-negative pneumonia.  Am Surg 1986;52(7):391-4.
36. Faurisson F, Delatour F, Jelazko P.  A simple tool for monitoring nebulized amikacin 
treatments based on a single urine assay.  J Aerosol Med 2001;14(1):73-81.
37. Lancon JP, Caillard B, Manuelian M, et al.  Lung and serum amikacin concentrations 
after a single endotracheal dose in man.  Ann Fr Anesth Reanim  1991;10(3):230-4.
38. Faurisson F, Ghersi B, Chazalette JP.  Pharmacokinetics of aerosolized amikacin in 
cystic fibrosis.  Am Rev Respir Dis 1991;A294.
39. Faurisson F, Delatour F, Helyne D, et al.  Respiratory monitoring of inhalation 
increases the deposition of aerosolized amikacin (AMK) in healthy volunteers.  
Poster, 33rd Interscience Conf on Antimicrobial Agents & Chemotherapy 1993.
40. Standridge JB, Aliff CL.  Aerosolized amikacin in the treatment of pseudomonas 
pneumonia in the nursing home setting.  South Med J 2001;94(2):244-6.
41. Investigator’s Brochure, Amikacin Pulmonary Delivery System; Version 4.0: 
19 FEB 2015. 96
42. Morris A, Tanner D,  Reller L. Rejection criteria for endotracheal aspirates from 
adults.  Journal of Clinical Microbiology May 1993;31:1027-9.
43. Wood GC, Hanes SD.  Comparison of ampicillin-sulbactam and imipenem-cilastatin 
for the treatment of acinetobacter ventilator-associated pneumonia. Clinical Infectious 
Disease 2002;34:1425-30.
44. Garnacho-Montero J. et al. Treatment of multidrug-resistant acinetobacter baumannii 
ventilator-associated pneumonia (VAP) with intravenous colistin: A comparison with 
imipenem-susceptible VAP. Clinical Infectious Disease 2003; 36:1111-8.
                                                
96 Updated per Amendment 16.


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45. Luna CM, et al. Resolution of ventilator-associated pneumonia:  prospective 
evaluation of the clinical pulmonary infection score as an early clinical predictor of 
outcome.  Crit Care Med 2003;31(3):676-82.
46. Knaus WA, et al. APACHE II: A severity of disease classification system. Crit Care 
Med 1985;13(10):818-29.
47. Anon. Endotracheal suctioning of mechanically ventilated patients with artificial 
airways 2010. Respir Care 2010 Jun;55(6):758-64.
48. Kelman GR. Digital computer subroutine for the conversion of oxygen tension into 
saturation. J Appl Physiol 1966 Jul;21(4):1375-6. 


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15.
Appendices
15.1
Study Flow Chart and Schedule of Procedures - Amended
Day
Assessment
Screening
1
2
3
4
5
6
7
8
9
10 a
EOT
Premature 
D/C/Early 
Withdrawal
TOC 
Day 17 
to 19
Late Follow-Up
Day 28 to 32 b
In 
Person
By 
Phone
Informed Consent
X
Inclusion/Exclusion Criteria
X
Medical/Surgical/Medication Hx
X
Concomitant Medication c
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete Physical Exam/Vitals d
X
X
X
X
Brief Physical Exam/Vitals e
X
X
X
X
X
X
X
X
X
X
Assessment of clinical signs & 
symptoms of pneumonia
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chest X-Ray
X
X
X
X
X
X
X
X
Xr
Urine or Serum pregnancy testf
X
Hematology/Serum 
Chemistry/Urinalysis
X
X
X
X
X
X
X
X
X
Serum creatinine g
X
X
X
X
X
X
X
X
X
X
Aerobic blood culture h
X
Arterial blood gases/pulse 
oximetry 97
X
X
X
X
X
X
X s
X s
Xr
Collection of ventilator 
parameters pre- and post-dose 98
X
X
X
X
X
X
X
X
X
X99
Collect respiratory specimen for 
Gram stain and culture i
X
X
X
X
X
X
X
X
Xr
Pleural fluid culture j
X
                                                
97 Footnote s added with Amendment 6. 
98 Per Amendment 5
99 Added with Amendment 6 as it was erroneously omitted.


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CPIS k
X
X
X
X
X
X
X
X
X
APACHE II score
X
Randomization
X
Dispense PDDS Clinical Device
Xm
Dispense Study 
Medication/Nebulizer
Xn
X
X
X
X
X
X
X
X
X
Administer Study Medication
Xo
X
X
X
X
X
X
X
X
X
Serum amikacin trough level p
X
X
X
X
X
X
X
X
X
X
AEs
X q
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adjunct Therapy and Procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Investigator Assessment of 
Patient Outcome 100
X
X
X
X
X
Late Follow-Up Questionnaire
X
X
Notes:  Screening is within 48 hours prior to randomization.  AEs = adverse events; APACHE II = Acute Physiology and Chronic Health Evaluation 
II; BAL = bronchoalveolar lavage; CPIS = Clinical Pulmonary Infection Score; D/C = discontinuation; EOT = end of therapy; Hx = history; 
LFU = late follow-up; PBS = protected specimen brush; TA = tracheal aspirate; TOC = Test-of-Cure.
a - All assessments at Day 10 should be done after the last dose of aerosolized treatment that corresponds to the completion of 20 doses
b - Patients will be strongly encouraged to return to their study facility for their LFU.  This questionnaire needs to be completed whether in person or 
via a phone conversation with the patient, or the  patient’s advocate including recording concomitant medication and AEs.
c -  Include previous concomitant or post-therapy antibacterials, antifungals, and antivirals (within two weeks before start of treatment or during 
follow-up) 
d - Include weight, height (screening visit only), heart rate, blood pressure, respiratory rate, daily maximum temperature, and complete review of 
body systems
e - Include weight, heart rate, blood pressure, respiratory rate, daily maximum temperature, and review of body systems
f - Females of child-bearing potential only
g - Serum creatinine levels should be obtained once daily and the results available and reviewed prior to the next dose
h - Culture should be obtained from two separate venipuncture sites.  If the result is positive, repeat as needed (Days 1, 3, 5, 7, 10, TOC, LFU) until 
negative.
i - A respiratory specimen (eg, TA, BAL, mini-BAL, or PSB) will be obtained for Gram stain, semi-quantitative or quantitative culture, and 
susceptibility testing.  NOTE: All respiratory specimens will be evaluated by Gram stain and rejected for culture if the Gram stain reveals 10 
squamous epithelial cells per low powered (100 x) field.
j - Pleural fluid cultures should only be obtained for patients with evidence of a pleural effusion and if clinically indicated. Cultures from any other 
respiratory specimens should also be obtained if clinically indicated.  If the result is positive, repeat as needed if clinically indicated (Days 1, 3, 5, 
7,10, TOC, LFU) until negative.
k - CPIS must be greater than or equal to 6 for inclusion into study.
                                                
100 As per Amendment 6


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l – Footnote deleted per Amendment 6.
m - Prior to the first dose, each patient will receive a unique PDDS Clinical device consisting of a unique control module, T-piece adaptor, AC/DC 
adaptor, air pressure feedback device, and cable.
n - Prior to each dose, each patient will receive a one vial of study medication (either BAY 41-6551 or placebo) and one nebulizer/reservoir.101
o - Patients will be started on aerosolized study medication within 48 hours of systemic antibiotic therapy being initiated.  Patients will receive 
3.2 mL of either BAY 41-6551 (400 mg, amikacin as free base) or placebo every 12 hours via the PDDS Clinical for ten days (20 doses).  If a 
patient is extubated during the course of treatment or has had a tracheostomy and is spontaneously breathing, aerosol administration will continue 
via the handheld adaptor for the remainder of the treatment period. 102
p - Serum amikacin for trough level will be obtained 30 ± 15 minutes 103 prior to the first dose on each treatment day.   In addition, these trough 
levels should be obtained for all patients and be sent to the Central Laboratory.  If the site has mandated procedures for monitoring IV amikacin 
treatment, the site should perform these site-specific procedures in conjunction with the collection for serum Amikacin levels.
q – Adverse event reporting begins after the signing of the informed consent by the patient or their authorized representative.
r - Optional assessments
s – 104An arterial blood gas is needed at the TOC and premature discontinuation visits.
                                                
101 As per Amendment 6
102 As per Amendment 6 
103 “± 15” added with Amendment 6
104 Per Amendment 8


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15.2
Pulmonary Drug Delivery System (PDDS Clinical)
Figure 1: PDDS Clinical for Ventilator Application 


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Figure 2: PDDS Clinical on Vent Configuration


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Figure 3: PDDS Nebulizer/Reservoir Inserted Into the Handheld Adaptor


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15.3
Clinical Pulmonary Infection Score (CPIS) - amended
CPIS Points
0
1
2
Tracheal secretions
Few (purulent + 1)
Moderate (purulent + 1)
Large (purulent + 1)
Chest radiograph
No infiltrate
Patchy or Diffuse
Localized
Temperature (core), °C
105
36.5 and ≤ 38.4
38.5 and ≤ 38.9
39.0 or 36.4
Blood leukocytes, per 
mm3
4,000 and ≤ 11,000
4,000 or 11,000
--
Oxygenation PaO2 / 
FiO2, mm Hg
240 or presence of 
ARDS
--
240 and absence 
of ARDS
ARDS – acute respiratory distress syndrome
Guidance for Investigators for Calculating the CPIS 

Tracheal secretions: to assign a point score for the quantity and appearance of 
tracheal secretions observed in the last 24 hours106, consult the nursing/respiratory 
therapy notes for the best estimate  
o
Add 1 point, if the tracheal secretions are considered purulent (e.g., if the 
patient had “few” secretions but they were purulent, then the patient would 
have a score of 1 for this component of the score; or if the patient had a 
“large” amount of purulent secretions, then the score would be 3)

Chest radiograph (CXR): the most recent CXR taken within the previous 24 
hours106 (or sooner)

Temperature, oC: the maximal temperature taken within the previous 24 hours106
should be used for point assignment
o
For patients with hypothermia, the lowest temperature taken in the previous 
24 hours106 should be used for point assignment

Blood leukocytes (WBC) (cells/mm3): the maximal WBC count reported in the 
previous 24 hours106 should be used for point assignment
o
For patients with leukopenia, the lowest WBC count reported in the previous 
24 hours106 should be used for point assignment

Oxygenation PaO2 / FiO2, mm Hg: the most recently calculated P/F ratio obtained 
within the last 24 hours106 should be used for point assignment 
Note: If an arterial blood gas measurement is not obtained, a PaO2 value can be derived from 
pulse oximetry data according to the following method.
                                                
105 Row modified per Amendments 6 and 7
106 within 48 hours for the screening visit; within 24 hours for all other visits (added per Amendment 6)


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If using pulse oximetry, use the SaO2 to PaO2 Conversion Table48 as shown in Section 15.8. 

Patients who develop ARDS after initiation of study drug should have an oxygenation 
PaO2 / FiO2 score the same as when they developed ARDS 107

Patients on veno-arterial (V-A) ECMO prior to randomization should have their 
oxygenation PaO2 / FiO2 scored as 0; patients who initiate V-A ECMO after 
randomization should have their oxygenation PaO2 / FiO2 score maintained 
throughout as the same value at the time when they initiated V-A ECMO 108
                                                
107 Per Amendment 5
108 Per Amendment 5


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15.4
National Institute of Health Stroke Scale
Tested Item
Title
Scores and Responses
1A
Level of consciousness
0 – alert
1 – drowsy
2 – obtunded
3 – coma/unresponsive
1B
Orientation questions (2)
0 – answers both correctly
1 – answers one correctly
2 – answers neither correctly
1C
Response to commands (2)
0 – performs both tasks correctly
1 – performs one task correctly
2 – performs neither
2
Gaze
0 – normal horizontal movements
1 – partial gaze palsy
2 – complete gaze palsy
3
Visual fields
0 – no visual field defect
1 – partial hemianopia
2 – complete hemianopia
3 – bilateral hemianopia
4
Facial movements
0 – normal
1 – minor facial weakness
2 – partial facial weakness
3 – complete unilateral palsy
5
Motor function (arm)
a.
Left
b.
Right
0 – no drift
1 – drift before 5 seconds
2 – falls before 10 seconds
3 – no effort against gravity
4 – no movement
6
Motor function (leg)
a.
Left
b.
Right
0 – no drift
1 – drift before 5 seconds
2 – falls before 10 seconds
3 – no effort against gravity
4 – no movement
7
Limb ataxia
0 – no ataxia
1 – ataxia in 1 limb
2 – ataxia in 2 limbs
8
Sensory
0 – no sensory loss
1 – mild sensory loss
2 – severe sensory loss
9
Language
0 – normal
1 – mild aphasia
2 – severe aphasia
3 – mute or global aphasia
10
Articulation
0 – normal
1 – mild dysarthria
2 – severe dysarthria
11
Extinction of inattention
0 – absent
1 – mild (loss 1 sensory modality)
2 – severe (loss 2 modalities)
Instructions:  Administer stroke scale items in the order listed.  Record performance in each category after each subscale exam.  Scores 
should reflect what the patient does, not what the clinician thinks the patient can do.  The clinician should record answers while 
administering the exam and work quickly. Except where indicated, the patient should not be coached (ie, repeated requests to patient to 
make a special effort).The score should be assessed within 6 hours of the planned first administration of the study medication and should 
be compared retrospectively with the score derived following the same scoring system applied to patient’s neurological condition 2 days 
before.  Should there be an indication for deterioration - the patient should not be enrolled in the study.


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15.5
APACHE II Score / Glasgow Score - amended
The Acute Physiology and Chronic Health Evaluation II is a severity of disease classification 
system (Knaus et al, 1985)46, one of several ICU scoring systems.  After admission of a 
patient to an ICU, an integer score from 0 to 71 is computed based on several measurements; 
higher scores imply a more severe disease and a higher risk of death.
APACHE II was designed to measure the severity of disease for adult patients admitted to 
ICUs.  The lower age is not specified in the original article, but a good limit is to use 
APACHE II only for patients age 15 or older.
This scoring system is used in many ways:

Some procedures and some medicine is only given to patients with certain 
APACHE II score

APACHE II score can be used to describe the morbidity of a patient when 
comparing the outcome with other patients

Predicted mortalities are averaged for groups of patients in order to specify the 
group's morbidity.
Even though newer scoring systems, like Simplified Acute Physiology Score (SAPS) II have 
replaced APACHE II in many institutions, APACHE II continues to be used extensively 
because so much documentation is based on it.
The point score is calculated from 12 routine physiological measurements (such as blood 
pressure, body temperature, heart rate etc.). 109 The calculation method is optimized for paper 
schemas.  The resulting point score should always be interpreted in relation to the illness of 
the patient.
After the initial APACHE II score has been determined, no new score can be entered for this 
study during the hospital stay.110  If a patient is discharged from the ICU and readmitted, a 
new APACHE II score can be calculated.
The appendix of the document that originally described the APACHE II score describes how 
to calculate a predicted death rate for a patient.  In order to make this calculation of predicted 
mortality precise, the principal diagnosis leading to ICU admission was added as a category 
weight: the predicted mortality is computed based on the patient's APACHE II score and their 
principal diagnosis at admission.
                                                
109 Per Amendment 6
110 Per Amendment 6


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APACHE II Scoring Tool 
PHYSIOLOGIC VARIABLE
HIGH ABNORMAL RANGE
LOW ABNORMAL RANGE
+4
+3
+2
+1
0
+1
+2
+3
+4
1
Temperature rectal (°C)
= 41
39.0-40.9
38.5-38.9
36.0-38.4
34.0-35.9
32.0-33.9
30.0-31.9
= 29.9
2
Mean arterial pressure = (2 x diastolic+ 
systolic)/3
= 160
130-159
110-129
70-109
50-69
= 49
3
Heart rate (ventricular response)
= 180
140-179
110-139
70-109
55-69
40-54
= 39
4
Respiratory rate (non-ventilated or 
ventilated)
= 50
35-49
25-34
12-24
10-11
6-9
= 5
5
Oxygenation
A-aDO2 or PaO2 (mmHg) 
a)FiO2>0.5:record A-aDO2
= 500
350-499
200-349
< 200
b)FiO2 < 0.5,record only PaO2
> 70
61-70
55-60
< 55
6
Arterial pH 
If no ABGs, record serum HCO3 below
= 7.7
7.6-7.69
7.5-7.59
7.33-7.49
7.25-7.32
7.15-7.24
< 7.15
7
Serum Sodium
= 180
160-179
155-159
150-154
130-149
120-129
111-119
= 110
8
Serum Potassium
= 7.0
6.0-6.9
5.5-5.9
3.5-5.4
3.0-3.4
2.5-2.9
< 2.5
9
Serum Creatinine (mg/dl) Double Points 
for acute renal failure
= 3.5
2.0-3.4
1.5-1.9
0.6-1.4
<0.6
10
Hematocrit (%)
= 60
50-59.9
46-49.9
30-45.9
20-29.9
< 20
11
White Blood Count
= 40
20.0-39.9
15.0-19.9
3.0-14.9
1.0-2.9
< 1.0
12
Glasgow Coma Scale 
(Score = 15 minus actual GCS)
15-GCS=
A
Total Acute Physiology Score (APS)
Sum of the 12 individual variable points =
*
Serum HCO3 (venous-mMol/L) Not 
preferred, use only if no ABGs
< 52
41.0-51.9
32.0-40.9
22.0-31.9
18.0-21.9
15.0-17.9
< 15.0


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Glasgow Coma Scale
B Age 
Point
C 
Chronic Health Points 
APACHE II Score
(sum of A + B + C) 
A APS points
Eyes open 
Verbal – non-intubated 
Age 
Points 
If any of the 5 CHE categories is 
answered 
4 - spontaneously 
3 - to verbal 
5 - oriented and conversant 
4 - disoriented and talks 
< 44 
0
with yes give +5 points for non-operative 
or emergency postoperative patients 
with immunocompromised or severe 
organ insufficiency
+2 points for elective postoperative 
patient with immunocompromised or 
history of severe organ insufficiency 111
+ B Age points
2 - to painful 
stimuli 
3 -inappropriate words 
45-54 
2
Liver 
- Cirrhosis with PHT or encephalopathy 
+ C Chronic  Health 
Points
1 - no response 
Motor response 
2 -incomprehensible sounds 
1 - no response 
55-64 
65-74 
3
5
Cardiovascular 
Pulmonary 
- class IV angina or at rest or with 
minimal self care activities - chronic 
hypoxemia or hypercapnia or 
__________
6 - to verbal 
command 
Verbal - intubated 
> 75 
6
polycytaemia of PHT > 40mmHg 
= Total APACHE II
5 - localizes to 
pain 
5 -seems able to talk 
Kidney 
-chronic peritoneal or haemodialysis 
4 - withdraws to 
pain 
3 - decorticate 
3 -questionable ability to talk 
1 -generally unresponsive 
Age points = 
Immune 
- immune compromised host 
2 - decerebrate 
Chronic Health Points = 
1 - no response 
                                                
111 Per Amendment 6.


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15.6
Late Follow-Up Questionnaire
Patients will be strongly encouraged to return to their study facility for their LFU.  This 
questionnaire needs to be completed whether in-person (ie, face-to-face) or via phone contact 
with the patient, or the patient’s care giver including recording concomitant medication and 
AEs.  
1) Have you seen a doctor since your last visit or release from the hospital/clinic?
If yes:  Give reason and complete SAE, AE, and Concomitant Medication pages in the 
CRF (as applicable)
2) Have you been hospitalized since your initial release from the hospital/clinic?
If yes: Give reason and complete SAE, AE, and Concomitant Medication pages in the 
CRF
3) Have you been ill or experienced any unwanted health-related signs or symptoms 
since your last visit or release from the hospital/clinic?
If yes: Give illness and treatment and complete SAE, AE, and Concomitant 
Medication pages in the CRF
4) Since your last visit, what medications have you stopped, what medications have you 
started and what medications are you continuing  - include dose, reason for taking the 
medication, start and stop dates
5) Have you received antimicrobial medication for a pulmonary infection since your last 
visit?
NOTE: Complete the Clinical Response Assessment for the Late Follow-up Visit
15.7
Guidance on Tracheal Aspirate Sampling Technique
(Adapted from the American Association for Respiratory Care (AARC) Clinical Practice 
Guideline, 2010)47
Tracheal aspiration through a closed or open suction system for Gram-stain, bacterial culture, 
or amikacin levels will be performed according to the following instructions immediately 
prior to aspiration:

Hyperoxygenate the patient with 100% oxygen for greater than 30 seconds prior to 
the suctioning event by one of the following  procedures -
o
Give three to five breaths with the manual resuscitator bag:
o
For patients on greater than 5 centimeters (cm) H2O ensure the positive 
end-expiratory pressure (PEEP) level is maintained
o
Adjust the FiO2 setting on the mechanical ventilator


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
If secretions are thick you may instill normal saline (5 mL) into the artificial 
airway prior to the suctioning event according to your institution’s procedure (let 
the saline dwell for five seconds prior to suctioning)

Sterile technique should be employed

Suction pressure should be set according to your institution’s procedure

Place the secretion collection trap in line with the suction system to collect the 
specimen

Either through a closed or open suction system, insert the suction catheter until 
resistance is met, and withdraw 1 cm 

Apply suction for up to 15 seconds while withdrawing the catheter

Hyperoxygenate the patient with 100% oxygen for greater than 30 seconds prior to 
the suctioning event by one of the following  procedures:
o
Give three to five breaths with the manual resuscitator bag
o
For patients on greater than 5 cm H2O ensure the PEEP (positive end-
expiratory pressure) level is maintained
o
Adjust the FiO2 setting on the mechanical ventilator

Return patient to their normal ventilator settings

Seal and label the collection trap and send it to the clinical laboratory for analysis
15.8
SpO2 – Estimated PaO2 Conversion Table
SpO2
Pulse oximeter saturation 
(%)
Estimated PaO2
(mm Hg)
100
265
99
171
98
113
97
91
96
82
95
75
94
69
93
66
92
62
91
60
90
58
89
56
88
54
87
52
86
51
85
50


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Adapted from Kelman GR. Digital computer subroutine for the conversion of oxygen tension into saturation. 
J Appl Physiol 1966 Jul;21(4):1375-6


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15.9
Adjustment of Empiric IV Antibiotic Therapy (Treatment Algorithm) 
*Adjustment of Initial Empiric IV Antibiotic Therapy is based on the results of culture susceptibility data and/or microscopy, an evaluation of the patient’s 
clinical signs/symptoms of pneumonia (eg, temperature, WBC count with differential, oxygenation, volume and appearance of tracheal secretions, CXR), and 
other factors such as renal/hepatic function, drug allergy history.


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16.
Protocol amendments
16.1
Amendment 1
Amendment 1 can be found in integrated protocol version 2.0, dated 17-AUG-2009.
16.2
Amendment 2
Amendment 2 can be found in integrated protocol version 3.0, dated 14-JUN-2010.
16.3
Amendment 3
Amendment 3 can be found in integrated protocol version 4.0, dated 15-MAR-2011.
16.4
Amendment 4
Amendment 4 can be found in integrated protocol version 5.0, dated 31-OCT-2012.
16.5
Amendment 5
Amendment 5 can be found in integrated protocol version 6.0, dated 17 SEP 2014.
16.6
Amendment 6
16.6.1
Overview of Changes
To shorten the time required to develop data from the two Phase III clinical studies of the 
Amikacin Inhale program (BAY 41-6551/No. 13084 [Inhale 1] and BAY 41-6551/No. 13085 
[Inhale 2]) to sustain regulatory submission, Bayer decided that the results of both studies 
should be consolidated into a single report. This allowed the number of patients required to be 
reduced from approximately 1300 to approximately 724 in total from both studies.  
As there will be no second study to corroborate the findings in the consolidated report it was 
considered necessary to review the endpoints to ensure optimal clinical relevance. During a
blinded review of the data from 106 patients entered into the Phase III program it was found 
that there was an artificially high failure rate occasioned by the original antibiotic use rules. 
These failures did not correspond with data that are used as medical management tools and 
were considered spurious. Certain other elements of the original endpoint were also 
considered not to accurately reflect clinical benefit. This will require modifications a priority
of the statistical analysis plan, but will not require any alterations to patient management, 
modifications to data collection tools, or changes to the evaluations being performed at the 
clinic to assess Clinical Failure or Success. The aim is that the patient population recruited to 
the study and the management of the patients will be the same after the implementation of 
this amendment as it was before.
The changes to the protocol are summarized below:

Recruitment will continue in the two Phase III Amikacin Inhale studies until a total of 
approximately 724 patients have been enrolled. Enrollment will be competitive and 
both studies will be stopped when that number is reached.  The Synopsis and Section 
8.3 were revised.

Text was updated with the latest revision date of the Investigator’s Brochure.  
Sections 5.4.2 and 14 were revised.


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
Clarification was made with regards to the presence of Gram-negative organism as an 
inclusion criterion versus the mITT population evaluation criterion.  Section 8.3 was 
revised.

The primary efficacy endpoint has been modified so that the antibiotic rules better 
reflect clinical success or failure and the other variables are more clearly aligned with 
clinical response. The specific endpoints are as follows:

All-cause mortality to Day 28 (previously was to Day 17-19).  Pneumonia-related 
mortality will become an important secondary endpoint. 

Systemic antibiotic duration to the TOC visit (Day 17-19); all antibiotic 
adjustments to the TOC visit are allowed, extension or restarting of antibiotics for 
pneumonia beyond the TOC visit is not allowed.   

No AE of lung abscess or empyema reported through the LFU visit

Stable respiratory function at TOC (new).  The assessment will be based on the 
Berlin Criteria for ARDS, which categorizes severity based on P/F ratios.  (49)
The Synopsis, and Sections 5.1, 6, 8.2, 9.6.1, and 14 were revised.

Sections were moved for better comprehension.  The assessments previously referred 
to as Clinical Response Assessments (renamed as Investigator Assessment of Patient 
Outcome) were moved from Section 9.6.2.2 to Section 9.6.1.2.

Changes were made to the statistical sections due to the combining of data from study 
13084 and study 13085.  Sections 11.1.1, 11.1.2, 11.2, and 11.3 have been modified to 
reflect the changes to data management and analyses.  

The secondary variables have been revised.  Days in hospital and relapses rates have 
been removed, and pneumonia-related mortality added and speed of response based 
on CPIS success or failure has been added.  The secondary endpoints were changed 
due to the change in primary endpoints. CPIS, which mainly measures the speed of 
response, is now removed from consideration in the primary endpoint and has instead 
been added as an Early Clinical Response component to the secondary endpoints. In 
addition, pneumonia-related mortality was discussed and suggested as a possible 
secondary endpoint.  These two additions required the removal of the least relevant 
secondary endpoint.  Both relapse rate (success at TOC, but failure by LFU Day 28-
32) and hospital days were deemed as less likely to differentiate based on superior 
versus standard therapy.  The Synopsis and Sections 6 and 11.4 were revised.

An Adjudication Committee will be appointed: there will be 3 members one of whom 
will be appointed chairman. An Adjudication Committee Charter will be drawn up 
and guidelines produced that will determine the scope and methods to be applied by 
the committee.  A paragraph was added to Section 7 describing the role of the 
Adjudication Committee.  The Adjudication Committee was added to facilitate the 
evaluation of of mortality data from the different sites.  The Adjudication Committee 
will ensure a standardization of evaluation criteria.

The instructions for used and unused devices were revised in Sections 8.4.5 and 8.5.3.


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
The option of using pulse oximetry at the TOC and premature discontinuation visits 
was deleted.  An arterial blood gas is needed at these visits in order to calculate a 
PaO2/FiO2 ratio required by the new endpoint.  Sections 9.1.3.2, 9.5, and 15.1 were 
updated.

Missing text was added to the APACHE II Scoring Tool and clarification was added 
regarding scoring.  Section 15.5 was updated.

Minor editorial changes were made to improve clarity, corrections were made due to 
inconsistencies, text was revised to correct/clarify the timing of assessments, and 
terminology was revised for clarity and consistency.  The Synopsis, and Sections 4, 
5.1, 6, 7, 8.1, 8.2, 8.3.1, 8.3.3.1, 8.4.1, 8.4.5, 9.1.2, 9.1.2.1, 9.1.2.2, 15.1, and 15.3 
were revised. 

Lastly, the use of word “subject(s)” was replaced with “patient(s)” in this Phase III 
protocol.
16.6.2
Changes to the Protocol Text
In this section, all sections affected by this amendment are detailed; the sequence follows the 
structure of the most recent previous protocol version.  Deletions are crossed out and 
additions are underlined.  Minor editorial changes and corrections of typographical errors are 
not shown.
Synopsis
Old text:
Study objectives To evaluate the efficacy (superiority) and safety of BAY 41-6551 as 
measured by the comparison of the clinical cure rate of aerosolized 
BAY 41-6551, administered via the PDDS Clinical, versus placebo 
(normal saline) at the Test-of-Cure (TOC) visit in patients with 
microbiologically confirmed Gram-negative pneumonia. 
New text:
Study objectives The study objective is to demonstrate that as adjunctive therapy to 
IV antibiotics, BAY 41-6551 400 mg (amikacin as free base) 
administered as an aerosol by the 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 efficacy endpoint is Clinical Success as defined in 
Section 8.2. 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 ICU. 


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Added text:
Safety endpoints The safety endpoints are to compare (BAY 41-6551 vs aerosolized  
placebo, as adjunctive therapy to IV antibiotics in both arms) as 
measured by:

The frequency of adverse events (AEs)

The progression and incidence rates of organ failure

The all-cause mortality rate during therapy, at Day 15 and 
at Day 28
Old text:
Patient population Adult patients (age 18 years) with a microbiologically-confirmed 
pneumonia caused by Gram-negative organisms will be selected for 
this study.
New text:
Patient population Randomized, adult patients (age 18 years) with a 
microbiologically-confirmed pneumonia caused by Gram-negative 
organisms who received at least one dose of study drug and have an 
APACHE II score ≥ 10 at the time of diagnosis of pneumonia 
(modified Intent-to-Treat [mITT] population) will be analyzed in the 
primary efficacy analysis.
Old text:
Study design
This is a prospective, randomized, double-blind, placebo-controlled, 
multicenter study to evaluate the safety and efficacy of 10 calendar 
day (20 doses) course of aerosolized BAY 41-6551 400 mg 
(amikacin as free base) every 12 hours versus placebo (normal 
saline) as adjunctive therapy in intubated and mechanically-
ventilated patients with Gram-negative pneumonia.  All patients will 
receive parenteral antibiotics according to the 2005 ATS/IDSA 
guidelines for the management of HAP, VAP, or HCAP for 10 days. 
Patients who are extubated before completing the full course 
(10 calendar days if the first dose is administered in the AM or 
11 calendar days if the first dose is administered in the PM 
[20 doses]) of aerosol therapy will be continued on aerosolized 
therapy with the handheld adaptor. (Section 8.2)


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New text:
Study design
This is a prospective, randomized, double-blind, placebo-controlled, 
multicenter study to evaluate the safety and efficacy of 10 calendar 
day (20 doses) course of aerosolized BAY 41-6551 400 mg 
(amikacin as free base) every 12 hours versus aerosolized placebo 
(normal saline), as adjunctive therapy to IV antibiotics in both arms,
in intubated and mechanically-ventilated patients with known or 
suspected Gram-negative pneumonia.  All patients will receive 
parenteral antibiotics with consideration to include 2 antibiotics as 
per the 2005 ATS/IDSA guidelines for 10 days. Patients who are 
extubated before completing the full course (10 calendar days if the 
first dose is administered in the AM or 11 calendar days if the first 
dose is administered in the PM [20 doses]) of aerosol therapy will be 
continued on aerosolized therapy with the handheld adaptor. 
(Section8.2)
Old text:
Concurrent control Placebo aerosol solution
New text:
Concurrent control Aerosolized placebo 
Old text:
Methodology Seven to ten days after completing 10 days of aerosolized treatment, 
patients will be evaluated for clinical response, which will be 
assessed based on the results of chest x-rays, CPIS scores, use of 
antibiotic therapy, and survival. 
New text:
Methodology Eighteen to 22 days after completing 10 days of aerosolized 
treatment, patients will be evaluated for Clinical Success, which will 
be based on survival, the duration of antibiotic therapy, the absence 
of empyema or lung abscess, and stable respiratory function.


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Old text:
Efficacy variables The primary efficacy variable will be the clinical response at the 
TOC visit in the modified Intent-to-Treat (mITT; ie, ITT population 
plus a pre-therapy culture positive for a Gram-negative respiratory 
tract pathogen and an APACHE II score of 10) population.  The 
mITT population will be the primary analysis group.  
The secondary objectives are to evaluate the efficacy of BAY 
41-6551 (versus placebo) as measured by:

The number of days on mechanical ventilation 

The number of ICU days at Day 28

The total number of days of Gram-negative intravenous (IV) 
antibiotics per patient 

CPIS changes through TOC

The clinical relapse rates at Day 28 

The all-cause mortality rate during therapy at Day 15 and at 
Day 28

The number of hospital days at Day 28
New text:
Efficacy variables The primary efficacy variable will be Clinical Success in the mITT 
population (ie, the ITT population who prove to be culture positive 
for a Gram-negative pathogen and have an APACHE II score ≥ 10).   
Clinical Success is achieved when all of the following criteria are 
met:
1)  Systemic antibiotics (IV or by mouth [PO] for pneumonia must 
be stopped on or before the Test-of-Cure (TOC) visit (Day 17-19)
2)  Systemic antibiotics (IV or PO) for pneumonia must not be 
restarted after the TOC visit
3)  The patient must survive through the late follow-up (LFU) visit
3)  The patient must not have a reported AE of lung abscess or 
empyema through the LFU visit and 
4)  The patient must have stable respiratory function measured at the 
TOC visit   
The secondary objectives are to evaluate the efficacy of BAY 
41-6551 (versus aerosolized placebo), as adjunctive therapy to IV 
antibiotics in both arms, as measured by:

Pneumonia-related mortality to the LFU visit

Early Clinical Response based on CPIS scores, the presence of 
empyema or lung abscess, and all-cause mortality through Day 
10

The number of days on mechanical ventilation through the LFU 
visit (Day 28-32)

The number of ICU days assessed at the LFU visit (Day 28-32)
The investigator will assess patient signs and symptoms at the TOC 
visit (Day 17-19) for the Investigator Assessment of Patient 
Outcome, which is separate from the primary efficacy variable, 
Clinical Success.


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Old text:
Microbiology variables Secondary microbiological objectives will include comparisons 
(aerosolized BAY 41-6551 versus placebo) of the:

per pathogen microbiological response rates at the TOC visit

per patient microbiological response rate at the TOC visit

microbiological recurrence rates at the TOC and Day 28 visit

emergence of new respiratory pathogens during the treatment 
period 

emergence of resistance among baseline pathogens in those 
patients with persistent infection or colonization
New text:
Microbiology variables Secondary microbiological objectives will include comparisons 
(aerosolized BAY 41-6551 versus aerosolized placebo), as 
adjunctive therapy to IV antibiotics in both arms, of the:

per pathogen microbiological response rates at the TOC visit

per patient microbiological response rate at the TOC visit

microbiological recurrence rates at the TOC and LFU visits

emergence of new respiratory pathogens during the aerosol 
treatment period, Day 1-10

emergence of resistance among baseline pathogens in those 
patients with persistent infection or colonization
Old text:
Total number of patients
Approximately 662 patients will be randomized 1:1 to receive either 
400 mg BAY 41-6551 (amikacin as free base) every 12 hours or 
placebo every 12 hours in addition to ATS/IDSA guided IV 
antibiotic therapy to allow for completion of at least 430 evaluable 
patients in the primary efficacy analysis.
New text:
Total number of patients
Approximately a combined total of 724 ITT patients will be recruited 
to this study and to study 13085 (being conducted in different 
countries; the protocols are identical with the exception that study 
13085 has a pharmacokinetic substudy).  The 724 total patients will 
be recruited competitively between studies 13084 and 13085; there 
are no minimum requirements for recruitment totals in either study.  
The patients will be randomized 1:1 to receive either 400 mg BAY 
41-6551 (amikacin as free base) every 12 hours or aerosolized 
placebo every 12 hours in addition to ATS/IDSA guided IV 
antibiotic therapy to allow for completion of at least 472 evaluable 
mITT patients in the primary efficacy analysis.


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4.  Glossary and Abbreviations
Old text:
ICH
International Conference on Harmonization
PDDS Clinical
Pulmonary Drug Delivery System
New text:
ICH
International Council for Harmonization
PDDS 
Pulmonary Drug Delivery System
P/F
PaO2/FiO2
5.1  Background and Rationale
Old text: (last paragraph)
This clinical study will evaluate the clinical cure rate of adjunctive aerosolized amikacin, 
administered via PDDS Clinical, to that of placebo (normal saline solution) at the 
Test-of-Cure (TOC) visit in patients with microbiologically-confirmed Gram-negative 
pneumonia.  ….
New text: (last paragraph)
This clinical study will evaluate the Clinical Success rate of aerosolized amikacin, 
administered via PDDS Clinical, to that of aerosolized placebo (normal saline solution), as 
adjunctive therapy to IV antibiotics in both arms, in patients with microbiologically-
confirmed Gram-negative pneumonia.  ….
5.4.2  Human Studies
Deleted text:  (last paragraph)
Further details on the five clinical studies completed with BAY 41-6551 can be found in the 
Investigator’s Brochure (23-APR-2014 Ver. 3.0).
6.  Study Objectives
Old text:
6.1   Primary Objective
To evaluate the efficacy (superiority) and safety of BAY 41-6551 as measured by the 
comparison of the clinical cure rate of aerosolized BAY 41-6551, administered via the PDDS 


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Clinical, versus placebo (normal saline) at the TOC visit in patients with microbiologically 
confirmed Gram-negative pneumonia.
6.2   Secondary Objectives
The secondary objectives are to evaluate the efficacy of BAY 41-6551 (versus placebo) as 
measured by:

The number of days on mechanical ventilation 

The number of ICU days at Day 28

The total number of days of Gram-negative IV antibiotics per patient 

CPIS changes through TOC

The clinical relapse rates at Day 28 

The all-cause mortality rate during therapy, at Day 15 and at Day 28 

The number of hospital days at Day 28
6.3   Additional Objective
To determine that the PDDS Clinical device performs as intended.
6.4   Safety Endpoints 
The safety endpoints are to compare (BAY 41-6551 vs placebo) as measured by:

The frequency of AEs 

The progression and incidence rates of organ failure

The all-cause mortality rate during therapy, at Day 15 and at Day 28 
New text:
The study objective is to demonstrate that as adjunctive therapy to IV antibiotics, BAY 41-
6551 400 mg (amikacin as free base) administered as an aerosol by the 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 efficacy endpoint is Clinical Success as 
defined in Section 8.2.  The secondary objectives are to evaluate the superiority of 
aerosolized BAY 41-6551 versus aerosolized placebo in pneumonia-related mortality to the 
LFU visit, the Early Clinical Response at Day 10, the days on ventilation through the LFU 
visit, and the days in the ICU assessed at the LFU visit.
7.  Investigators and Other Study Participants
Old text:  (1st paragraph)
The 
  The role of the coordinating investigator has 
been assigned to Michael S. Niederman, MD, Winthrop University Hospital, 
PPD
PPD


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New text:  (1st paragraph)
The 
  The role of the coordinating investigator has 
been assigned to Michael S. Niederman, MD, New York-Presbyterian University Hospital of 
Columbia and Cornell, 
Added text:  (3rd paragraph)
Bayer will utilize an independent Adjudication Committee for the evaluation of the secondary 
variable, pneumonia-related mortality. The Adjudication Committee will be comprised of 3 
clinicians experienced in the field of clinical research and anti-infective drug products.  Each 
committee member will be screened for evidence of an absence of serious conflicts of 
interest. The operation of the Adjudication Committee will be governed by a charter.
Added text (after 3th paragraph)
In brief, the adjudication committee will review all deaths to determine the subset of deaths 
that are pneumonia-related. These pneumonia-related deaths should more likely be influenced 
by superior antibacterial treatment than pneumonia-unrelated deaths. The pneumonia-related 
death evaluation will be based on the death being plausibly related to:
(1) pulmonary infection (example pneumonia)
(2) spread (metastasis) of infection (example septicemia, septic shock)
(3) complications related to respiratory function. (example respiratory distress)
The AC will have a single binary decision: pneumonia-related death: yes/no
8.1   Study Design
Old text:
This is a Phase III, prospective, randomized, double-blind, placebo-controlled, multicenter, 
multinational study designed to show that aerosolized BAY 41-6551 400 mg (amikacin as 
free base) every 12 hours is more effective than placebo (aerosolized normal saline) as 
adjunctive therapy in intubated and mechanically-ventilated patients with Gram-negative 
pneumonia.  The safety and tolerability of aerosolized BAY 41-6551 and the microbiological 
endpoints will also be evaluated. Patients who are extubated before completing the full course 
(10 calendar days if the first dose is administered in the AM or 11 calendar days if the first 
dose is administered in the PM [20 doses, Section 8.2]) of aerosol therapy will be continued 
on aerosolized BAY 41-6551 with the handheld adaptor.  All patients will receive standard of 
care IV antibiotic therapy guided by the ATS/IDSA Guidelines for the management of adults 
with HAP, VAP, and HCAP. ….
New text:
This is a Phase III, prospective, randomized, double-blind, placebo-controlled, multicenter, 
multinational study designed to show that aerosolized BAY 41-6551 400 mg (amikacin as 
free base) every 12 hours is more effective than placebo (aerosolized normal saline), as 
adjunctive therapy to IV antibiotics in both arms, in intubated and mechanically-ventilated 
PPD
PPD


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patients with Gram-negative pneumonia.  The safety and tolerability of aerosolized BAY 41-
6551 and the microbiological endpoints will also be evaluated. Patients who are extubated 
before completing the full course (10 calendar days if the first dose is administered in the AM 
or 11 calendar days if the first dose is administered in the PM [20 doses, Section 8.2]) of 
aerosol therapy will be continued on aerosolized BAY 41-6551 with the handheld adaptor.  
All patients will receive standard of care IV antibiotic therapy with consideration to include 2 
antibiotics as per the ATS/IDSA Guidelines. ….
8.2   Study Plan
Old text:
The TOC visit will be conducted on Day 17-19 of the study or at the time the patient is 
considered a treatment failure and/or study drug is prematurely discontinued. The late follow-
up visit will be conducted on Day 28-32 of the study.  Clinical response will be evaluated at 
the TOC and late follow-up visits (Sections 9.6.1.2.2 and 9.6.1.2.3).  If available, respiratory 
secretions will be obtained, cultured, and evaluated for the emergence of resistance to study 
drug therapy among baseline organisms.  
The definition of Clinical Failure at the TOC visit will be

A rise in the CPIS by at least 2 points on Day 3

Failure of the CPIS to drop at least 1 point on Day 5 

Failure of the CPIS to drop by at least 2 points on Day 10 

Continuation of systemic antibiotics (IV or by mouth [PO]) for pneumonia after 
ten full days of aerosolized dosing

Restarting systemic antibiotics (IV or PO) for pneumonia before the TOC (with a 
positive respiratory culture) visit; 

One adjustment to the antimicrobial regimen is allowed when the initial culture 
result susceptibility results are available (typically 48-72 hours).  Any additional 
change to the antimicrobial regimen being used to treat pneumonia during the first 
10 days, after the initial antimicrobial adjustment of empiric therapy as soon as 
initial culture and susceptibility results are available, would be considered a 
Clinical Failure.  There are two exceptions where additional changes to the 
antimicrobial regimen are not considered Clinical Failures:  
o
1) discontinuation of IV administered aminoglycosides after 5-7 days or 
o
2) suitable de-escalation of therapy in patients who are doing well 
clinically.  Suitable de-escalation is either discontinuation or reduction in 
dose of an anti-infective drug.  The initial IV administered gram negative 
anti-infective therapy should be maintained for 10 to 12 days.
Patients who discontinue IV administered aminoglycosides after 5-7 days 
or who are suitably de-escalated are not considered Clinical Failures.  Any 


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introduction of a new anti-infective drug to treat the pneumonia after the 
initial adjustment will be considered a treatment failure.
OR

All-cause mortality
Note:  At least one of the above conditions is necessary to consider a patient a Clinical 
Failure. 
Local microbiology laboratories will perform Gram stains, identify organisms to genus and 
species (this information will be recorded in the case report form [CRF]) and when 
performing susceptibility testing will include amikacin in the sensitivity panel.  The local 
microbiology laboratories will send a slide (air dried, but not stained) of the clinical specimen 
(examples tracheal aspirate, sputum) to the Central Microbiology Laboratory. Instructions for 
preparing and shipping the slide will be provided in the investigator Manual for 
Microbiology.  …
New text:
The Test-of Cure (TOC) visit will be conducted on Day 17-19 of the study. The late follow-
up (LFU) visit will be conducted on Day 28-32 of the study.  Clinical Success will be 
evaluated at the TOC and LFU visits by programmed response criteria.   If available, 
respiratory secretions will be obtained, cultured, and evaluated for the emergence of 
resistance to study drug therapy among baseline organisms.  
The primary efficacy evaluation of the study is the Clinical Success in the mITT population, 
which is achieved when the following 5 criteria are met:  

Systemic antibiotics (IV or by mouth [PO]) for pneumonia must be stopped on or 
before the TOC visit 

Systemic antibiotics (IV or PO) for pneumonia must not be restarted after the TOC 
visit 

The patient must survive through the LFU visit 

The patient must not have a reported AE of lung abscess or empyema through the 
LFU visit 

The patient must have stable respiratory function at the TOC visit 
Stable or unstable respiratory function is determined based on the PaO2/FiO2 (P/F) 
ratio at TOC in the following manner:
Stable respiratory function:
o
Patient is extubated at the TOC visit OR
o
Patient is intubated at the TOC visit AND:

Patient has a P/F ratio > 200 at the TOC visit OR

Patient has a P/F ratio > 100 and ≤ 200 at the TOC visit AND:


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
Patient had a P/F ratio  ≤ 200 at baseline
Unstable respiratory function
o
Patient has a P/F ratio ≤ 100 at the TOC visit OR
o
Patient has a P/F ratio > 100 or ≤ 200 at the TOC visit AND:

Patient had a P/F ratio > 200 at baseline
The outcome is Clinical Success if all 5 criteria are met.  If any one of the criteria is not met, 
then the patient is considered a Clinical Failure.  Patients who do not have a clinical 
assessment of success due to missing data will be considered a Clinical Failure.
Local microbiology laboratories will perform Gram stains, identify organisms to genus and 
species (this information will be recorded in the case report form [CRF]) and when 
performing susceptibility testing will include amikacin in the sensitivity panel.  The local 
microbiology laboratories will send a slide (air dried and not stained) of the clinical specimen 
(examples tracheal aspirate, sputum) to the Central Microbiology Laboratory. Instructions for 
preparing and shipping the slide will be provided in the investigator Manual for 
Microbiology.  …
8.3  Selection of Study Population
Old text:
Patients of age 18 and older, who are hospitalized, have pneumonia suspected or confirmed to 
be caused by Gram-negative organisms, and who are intubated and mechanically-ventilated 
will be selected for this study.  In all patients where the pathogen is suspected of being Gram-
negative, it should be confirmed as soon as culture results are available.  Patients with 
microbiologically-confirmed pneumonia are those who have a Gram-negative organism 
cultured from an appropriate respiratory tract specimen collected prior to enrollment.  
The patient must meet all of the inclusion criteria and none of the exclusion criteria to 
participate in this study.  Approximately 662 patients will be randomized 1:1 to receive either 
BAY 41-6551 400 mg (amikacin as free base) aerosolized every 12 hours or aerosolized 
placebo every 12 hours in addition to ATS/IDSA-guided IV therapy to allow for completion 
of at least 430 evaluable patients in the primary efficacy analysis.
New text:
Patients of age 18 and older, who are hospitalized, have pneumonia suspected or confirmed to 
be caused by Gram-negative organisms, and who are intubated and mechanically-ventilated 
will be selected for this study.  In all patients where the pathogen is suspected of being Gram-
negative, it should be confirmed as soon as culture results are available.  Patients with 
microbiologically-confirmed pneumonia are those who have a Gram-negative organism
cultured from an appropriate respiratory tract specimen.  
The patient must meet all of the inclusion criteria and none of the exclusion criteria to 
participate in this study.  Approximately 724 patients will be randomized 1:1 in the 2 Phase 
III studies (13084 and 13085; study 13085 is being conducted in different countries; the 


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protocols are identical with the exception that study 13085 has a pharmacokinetic substudy)
to receive either BAY 41-6551 400 mg (amikacin as free base) aerosolized every 12 hours or 
aerosolized placebo every 12 hours in addition to ATS/IDSA-guided IV therapy to allow for 
completion of at least 472 evaluable patients (mITT) in the primary efficacy analysis.
8.3.1  Inclusion Criteria
Old text:
6) Impaired oxygenation (within 24 hours prior to screening):  a PaO2/FiO2
≤ 300 mmHg 
New text:
6) Impaired oxygenation (within 48 hours prior to screening):  a PaO2/FiO2
≤ 300 mmHg 
8.3.3.1  Reasons for Premature Discontinuation of the Study Drug
Added text:  (last sentence)
The disposition of patients who are prematurely discontinued is listed in Section 11.3.
8.4.1 Treatments to be Administered
Old text:
Treatment will consist of standard of care IV antibiotics for intubated patients with Gram-
negative pneumonia with consideration to include 2 antibiotics according to the 2005 
ATS/IDSA Guidelines, plus aerosolized BAY 41-6551 or aerosolized placebo (Section 8.2).  
If the patient develops a new infection, other than pneumonia, while on the aerosol treatment 
the patient will continue in the study as long as the study treatment for the new infection 
would not require an antibiotic course longer than the 10-12 full days of IV treatment 
required by the protocol.  Patients should continue aerosol study treatment.
Each inhalation or aerosol dose will be administered via the PDDS Clinical (instruction 
manual provided).  If a patient is subsequently extubated, the aerosol treatment will be 
continued via the handheld adaptor for the remainder of the 10 full days of treatment course.  
Extending the IV antibiotic therapy beyond the aerosolized therapy might be necessary if in 
the opinion of the investigator, the patient continues to have clinical signs and symptoms of 
pneumonia (ie, the patient is evaluated as a Clinical Failure).  The clinical signs and 
symptoms of pneumonia will be documented on the CRF as will the reason(s) for 
continuation of IV treatment past the treatment period allowed in the protocol.  Aerosol 
treatment will not extend beyond 10 full days corresponding to 20 doses (Section 8.2).
The administration of aerosolized antibiotics other than the aerosol study medication is 
prohibited.


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The use of an IV aminoglycoside during the treatment period will be permitted; however, the 
only aminoglycoside will be amikacin.  This will simplify aminoglycoside trough serum level 
monitoring, if an IV aminoglycoside is used with the aerosol study drug.  The monitoring of a 
single aminoglycoside (amikacin) will allow for safer use of IV therapy, if IV aminoglycoside 
therapy is required.  
….
New text: 
Treatment will consist of standard of care IV antibiotics for intubated patients with Gram-
negative pneumonia with consideration to include 2 antibiotics as per the 2005 ATS/IDSA 
Guidelines, plus aerosolized BAY 41-6551 or aerosolized placebo (Section 8.2).  If the 
patient develops a new infection, other than pneumonia, while on the aerosol treatment the 
patient will continue in the study.  
Each inhalation or aerosol dose will be administered via the PDDS Clinical (instruction 
manual provided).  If a patient is subsequently extubated, the aerosol treatment will be 
continued via the handheld adaptor for the remainder of the 10 full days of treatment course.  
Extending the IV antibiotic therapy beyond the aerosolized therapy might be necessary if in 
the opinion of the investigator, the patient continues to have clinical signs and symptoms of 
pneumonia.  The clinical signs and symptoms of pneumonia will be documented on the CRF 
as will the reason(s) for continuation of IV treatment past the treatment period.  Aerosol 
treatment will not extend beyond 10 full days corresponding to 20 doses (Section 8.2).
The administration of aerosolized antibiotics other than the aerosol study medication is 
prohibited.
The use of an IV aminoglycoside during the treatment period will be permitted; however, the 
only aminoglycoside allowed will be amikacin.  This will simplify aminoglycoside trough 
serum level monitoring, if an IV aminoglycoside is used with the aerosol study drug.  The 
monitoring of a single aminoglycoside (amikacin) will allow for safer use of IV therapy, if IV 
aminoglycoside therapy is required.  
….
Section 8.4.1.1.4  Adjustment of Empiric Intravenous Antibiotic Therapy
Added extra wording to the bullet on maintenance antibiotic therapy
Old text:
Further adjustments to maintenance antibiotic therapy are NOT permitted during the 
remaining treatment unless the patient is failing antibiotic treatment for pneumonia, (in which 
case the patient would be considered a failure).
New text:
Further adjustments to maintenance antibiotic therapy are not permitted during the remaining 
treatment unless the patient is failing antibiotic treatment for pneumonia, in which case the 


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patient would be considered a failure by the Investigator Assessment (not by the primary 
endpoint evaluation of Clinical Success).
Section 8.4.5  Administration and Dosing Regimen
Old text:
Dosing of BAY 41-6551 by inhalation will be every 12 hours for ten full days according to 
Table 4.  All investigators should be aware that 400 mg every 12 hours dose of aerosolized 
BAY 41-6551 refers to the quantity of amikacin free base in BAY 41-6551 Solution 
(Amikacin Inhalation Solution) delivered from the extractable volume of 3.2 mL and that all 
blinded medication will be labeled according to the concentration of amikacin free base 
(125 mg/mL) in BAY 41-6551 Solution (Amikacin Inhalation Solution).  Aerosolized therapy 
will begin within 24 hours of the initiation of IV antibiotics for Gram-negative pneumonia.  
…
Used devices will be inventoried and returned to the sponsor or its designee.  Unused devices 
will be inventoried and returned to the sponsor or its designee or be destroyed by the site or 
by the Bayer local affiliate or its designee.
New text:
Dosing of BAY 41-6551 by inhalation will be every 12 hours for ten full days according to 
Table 4.  All investigators should be aware that 400 mg every 12 hours dose of aerosolized 
BAY 41-6551 refers to the quantity of amikacin free base in BAY 41-6551 Solution 
(Amikacin Inhalation Solution) delivered from the extractable volume of 3.2 mL and that all 
blinded medication will be labeled according to the concentration of amikacin free base 
(125 mg/mL) in BAY 41-6551 Solution (Amikacin Inhalation Solution).  Aerosolized therapy 
will begin within 48 hours of the initiation of IV antibiotics for Gram-negative pneumonia.  
…
Used devices identified on the random planned return list will be inventoried and returned to 
the sponsor or its designee.  Used devices not on the planned return list as well as unused 
devices will be inventoried and destroyed on site or returned to the sponsor or its designee 
where required by site SOP.
8.5.3  Device Supply
Added text:  (3rd paragraph)
Used devices identified on the random planned return list will be inventoried and returned to 
the sponsor or sponsor’s designee. ….
Section 9.1.2   Treatment Period (Day 1 to Day 10) 
Added text: (1st paragraph)


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Day 1 is defined as the day the initial dose of study medication (aerosolized BAY 41-6551 or 
aerosolized placebo) is given.  Day 1 …
Old text: (second bullet)
Patients will be started on aerosolized study medication within 24 hours of IV antibiotic 
therapy being initiated for Gram-negative pneumonia.  Patients will …
New text: (second bullet)
Patients will be started on aerosolized study medication within 48 hours of IV antibiotic 
therapy being initiated for Gram-negative pneumonia.  Patients will …
Section 9.1.2.1   Assessments Performed Daily
Added text:
….
Patients not receiving IV amikacin therapy but receiving aerosol treatment will have amikacin 
serum levels monitored through the Central Laboratory, therefore, a serum amikacin sample 
should be sent to the Central Laboratory.  However, because of low systemic exposure 
following aerosol treatment, amikacin serum levels will not be reported to the investigator or 
sub-investigator(s).

Measurement of serum amikacin trough level 30 minutes (± 15 mins) prior to each 
first aerosol dose of the day.  
Section 9.1.2.2   Assessments Performed on Days 1, 3, 5, and 7
Deleted text: 

Measurement of serum amikacin trough level 30 minutes (± 15 mins) prior to each 
first aerosol dose of the day.  
NOTE:  The laboratory conducting the safety monitoring of serum amikacin 
trough levels will notify the investigator of the amikacin serum concentration only 
if the patient is receiving IV amikacin.
Section 9.1.3.1   End of Treatment (EOT) Visit (Day 10)
Old text:
The EOT visit will be conducted on Day 10 or within 24 hours after completion of study 
drug.  Clinical cure rates will be evaluated by an assessment of clinical signs and symptoms.
Patients will have the following assessments and procedures performed during the EOT visit:

A physical examination including vital signs


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
CXR obtained
NOTE: the reading and interpretation of the CXR by the investigator and/or sub-
investigator(s) at the EOT visit can be used to determine clinical response to 
therapy; however, the radiology report (i.e., the reading and interpretation of the 
CXR by the Radiologist) will be the “official” reading recorded on the CRF and 
used for the determination of evaluability.  The radiologist will remain blinded to 
the treatment assignment of the patient.
….
New text:
The EOT visit will be conducted on Day 10 or within 24 hours after completion of study 
drug.  The Investigator Assessment of Patient Outcome will involve an evaluation of clinical 
signs and symptoms.
Patients will have the following assessments and procedures performed during the EOT visit:

A physical examination including vital signs

CXR obtained
NOTE: the reading and interpretation of the CXR by the investigator and/or sub-
investigator(s) at the EOT visit can be used to determine the Investigator 
Assessment of Patient Outcome; however, the radiology report (i.e., the reading 
and interpretation of the CXR by the Radiologist) will be the “official” reading 
recorded on the CRF and used for the determination of evaluability.  The 
radiologist will remain blinded to the treatment assignment of the patient.
….
Section 9.1.3.2   Test-of-Cure (TOC) Visit (Days 17 – 19)
Old text:
The TOC visit will be conducted on Days 17-19 of the study.  Clinical cure rate will be 
evaluated by an assessment of clinical signs and symptoms.
….

NOTE:  the reading and interpretation of the CXR by the investigator and/or sub-
investigator(s) at the TOC visit can be used to determine clinical response to 
therapy; however, the radiology report (ie, the reading and interpretation of the 
CXR by the radiologist) will be the "official" reading recorded on the CRF and 
used for the determination of evaluability.  The radiologist will remain blinded to 
the treatment assignment of the patient. 
….

Arterial blood gas or pulse oximetry (arterial blood gases preferred)


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….
New text:
The TOC visit will be conducted on Days 17-19 of the study.  The Investigator Assessment of 
Patient Outcome will be determined by an assessment of clinical signs and symptoms.
….

NOTE:  the reading and interpretation of the CXR by the investigator and/or sub-
investigator(s) at the TOC visit can be used to determine the Investigator 
Assessment of Patient Outcome; however, the radiology report (ie, the reading and 
interpretation of the CXR by the radiologist) will be the "official" reading 
recorded on the CRF and used for the determination of evaluability.  The 
radiologist will remain blinded to the treatment assignment of the patient. 
….

Arterial blood gas 
….
Section 9.1.3.3   Late Follow-Up Visit (Days 28-32)
Old text:
….

Clinical response will be evaluated by an assessment of clinical signs and 
symptoms.
….
New text:
….

The Investigator Assessment of Patient Outcome will be determined by an 
assessment of clinical signs and symptoms.
….
Section 9.5   Premature Discontinuation / Early Withdrawal from Study
Old text:
….

NOTE:  the reading and interpretation of the CXR by the investigator and/or sub-
investigator(s) can be used to for clinical decision-making; however, the radiology 
report (ie, the reading and interpretation of the CXR by the radiologist) will be the 
"official" reading recorded on the CRF. The radiologist will remain blinded to the 
treatment assignment of the patient. 


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….

Arterial blood gas or pulse oximetry (arterial blood gases are preferred)
….
New text:
….

NOTE:  the reading and interpretation of the CXR by the investigator and/or sub-
investigator(s) can be used to determine the Investigator Assessment of Patient 
Outcome; however, the radiology report (ie, the reading and interpretation of the 
CXR by the radiologist) will be the "official" reading recorded on the CRF. The 
radiologist will remain blinded to the treatment assignment of the patient. 
….

Arterial blood gas 
….
Section 9.6.1   Efficacy Variables
Old text:
The primary efficacy variable will be the clinical response at the TOC visit in the modified 
Intent-to-Treat (mITT; ie, ITT population plus a pre-therapy culture positive for a Gram-
negative respiratory tract pathogen and an APACHE II score of 10) population.  The mITT 
population will be the primary analysis group.  
Secondary efficacy variables will include CPIS changes through the TOC visit and 
comparisons (aerosolized BAY 41-6551 versus placebo) of the:  

number of days on mechanical ventilation through the Day 28 visit

total number of days of Gram-negative IV antibiotics per patient 

number of ICU days at the Day 28 visit 

number of hospital days at the Day 28 visit

clinical relapse rates at the Day 28 visit
Secondary microbiological objectives will include comparisons (aerosolized BAY 41-6551 
versus placebo) of the:

per pathogen microbiological response rates at the TOC visit

per patient microbiological response rate at the TOC visit

microbiological recurrence rates at the TOC and Day 28 visits

emergence of new respiratory pathogens during the treatment period


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
emergence of resistance among baseline pathogens in those patients with 
persistent infection or colonization
New text:
9.6.1.1  Primary Efficacy Evaluation: Clinical Success 
The primary efficacy evaluation is the Clinical Success, which is determined by using a 
computer algorithm based on collected data and specific criteria.  For a patient to be 
evaluated as a Clinical Success, all the following criteria must be met: 

Systemic antibiotics (IV or PO) for pneumonia must be stopped on or before the 
TOC visit

Systemic antibiotics (IV or PO) for pneumonia must not be restarted after the 
TOC visit 

The patient must survive through the LFU visit 

The patient must not have a reported AE of lung abscess or empyema through the 
LFU visit 

The patient must have stable respiratory function evaluated at the TOC visit based 
on the P/F ratio (See Section 8.2)
9.6.1.2   Investigator Assessment of Patient Outcome 
The investigators will also assess patient outcome based on a composite endpoint. The 
Investigator Assessment of Patient Outcome is separate and different from the primary 
endpoint of Clinical Success, which is done by using a computer algorithm based on collected 
data and specific criteria.  The Investigator Assessment of Patient Outcome is based on the 
following criteria:

CPIS assessed at baseline, Days 3, 5, 10, and the TOC visit

All-cause mortality assessed through the TOC visit

Systemic antibacterial use for the current episode of pneumonia beyond Day 10 (the 
EOT for aerosol administration)

Antibiotic adjustments made during therapy
Old text:
9.6.2.2   Clinical Response Assessments
9.6.2.2.1   End of Therapy (EOT) (Day 10)
At the EOT visit, the investigators or the sub-investigators will evaluate the patient’s clinical 
response using the following terms and definition:
Clinical Cure:
….

The patient never reached any of the early failure criteria in Section 9.6.1.1; AND


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….
NOTE:  All four conditions listed above must be met in order for the patient to be considered 
a Clinical Cure.
Clinical Failure
….
NOTE:  At least one of the above conditions is necessary to consider a patient a Clinical
Failure.
….
New text:
9.6.1.2.1  End of Therapy (EOT) (Day 10)
The Investigator Assessment of Patient Outcome will be evaluated at the EOT visit using the 
following terms and definition.  
Investigator Assessment of Patient Outcome - Cure:
….

The patient never reached any of the early failure criteria; AND

The patient survived through the EOT visit
….
NOTE: All four conditions listed above must be met in order for the Investigator Assessment 
of Patient Outcome to be a cure.
Investigator Assessment of Patient Outcome - Failure:
….

All-cause mortality by the EOT visit. 
NOTE:  If any one of the above conditions is met, the Investigator Assessment of Patient 
Outcome is a failure.
Old text:
9.6.2.2.2   Test-of-Cure (TOC) Visit (Day 17-19)
At the TOC visit, the investigator and/or sub-investigator(s) will evaluate the patient’s 
clinical response using the following terms and definitions:
Clinical Cure: 
….
NOTE:  All five conditions listed above must be met in order for the patient to be considered 
a Clinical Cure.


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Clinical Failure:
….
NOTE:  At least one of the above conditions is necessary to consider a patient a Clinical 
Failure.
….
At Day 10, corresponding to the completion of 20 doses (EOT), Clinical Failure will be 
defined as a failure to decrease the CPIS by 2 points.  There may be instances at Day 10 
where, if the CPIS falls by more than 2 points, there could still be reasons to continue IV 
antibiotic therapy and also instances where the score could fail to fall by more than 2 points 
and antibiotic therapy might be discontinued.  In both instances of such Clinical Failure, the 
reasons for continuing or discontinuing antibiotic therapy will be specified in the CRF.
Clinical failures will be carried through the LFU visit evaluation
New text:
9.6.1.2.2  Test-of-Cure (TOC) Visit (Day 17-19)
The Investigator Assessment of Patient Outcome will be evaluated at the TOC visit using the 
following terms and definitions:
Investigator Assessment of Patient Outcome - Cure: 
….
NOTE:  All five conditions listed above must be met in order for the Investigator Assessment 
of Patient Outcome to be a cure.
Investigator Assessment of Patient Outcome - Failure:
….

All cause mortality by the TOC visit
NOTE:  If any one of the above conditions is met, the Investigator Assessment of Patient 
Outcome is a failure.
…. 
At Day 10, corresponding to the completion of 20 doses (EOT), patient outcome of failure 
will be defined as a failure to decrease the CPIS by 2 points.  There may be instances at Day 
10 where, if the CPIS falls by more than 2 points, there could still be reasons to continue IV 
antibiotic therapy and also instances where the score could fail to fall by more than 2 points 
and antibiotic therapy might be discontinued.  In both instances of such patient outcome
failure, the reasons for continuing or discontinuing antibiotic therapy will be specified in the 
CRF.
A patient outcome of failure will be carried through the LFU visit evaluation.


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Old text:
9.6.2.2.3   Late Follow-up Visit (Days 28 - 32)
At the LFU visit, the investigator and/or sub-investigator(s) will evaluate the patient’s clinical 
response.  As mentioned previously, a patient evaluated at the TOC visit as a Clinical Failure
will have that clinical response carried forward to the LFU visit. 
For patients who were evaluated at the TOC visit as a Clinical Cure, their clinical response 
will be graded as:
Continued Clinical Cure: ….
New text:
9.6.1.2.3 Late Follow-up Visit (Days 28 – 32)
The Investigator Assessment of Patient Outcome will be evaluated at  the LFU visit.  As 
mentioned previously, a patient evaluated at the TOC visit as a patient outcome failure will 
have that response carried forward to the LFU visit. 
For patients who were evaluated at the TOC visit as a patient outcome cure, their clinical 
response will be graded as:
Continued Investigator Assessment of Patient Outcome Cure:…
Old text:
9.6.2.2.4   Premature Discontinuation Visit 
….
In the case of a patient who is evaluated as a Clinical Failure (ie, study drug therapy is 
discontinued because of a lack of therapeutic effect), the evaluation of their clinical condition 
should be based on the clinical signs and symptoms of pneumonia as well as objective 
evidence of failure (eg, persistent fever, rising WBC count, increasing tracheal secretions, 
poor oxygenation, progression of infiltrate on CXR) and a measure of their CPIS.  This 
information should be recorded on the CRF, as well as an evaluation of the patient’s clinical 
response to study drug.  In most cases, the decision to evaluate the patient as a Clinical 
Failure will be made after at least 72 hours of study medication, but in rare instances, the 
clinical course of the illness may require that study medication be discontinued prior to three 
days treatment and alternative antibiotic therapy started.  Regardless of when the patient is 
prematurely discontinued, the clinical condition of the patient should be determined at the 
time of study drug discontinuation, recorded on the CRF, and a clinical response evaluation 
completed.
At the premature discontinuation visit, the investigator and/or sub-investigator should 
evaluate the patient’s clinical response according to the following terms and definitions.
Clinical Failure: 
….


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
Any further change to the antimicrobial regimen being used to treat pneumonia during 
the first 10 days, after the initial antimicrobial adjustment within the first 72 hours 
after the initiation of empiric therapy or as soon as initial culture and susceptibility 
results are available and excepting the discontinuation of aminoglycosides after 5-7 
days, would be considered a Clinical Failure;
….
NOTE: At least one of the above conditions is necessary to consider a patient a Clinical 
Failure.
….
At the premature discontinuation visit, the investigator and/or sub-investigator(s) will 
evaluate the patient’s clinical response.
….
New text:
9.6.1.2.4  Premature Discontinuation Visit
….
For a patient outcome failure (ie, study drug therapy is discontinued because of a lack of 
therapeutic effect), the evaluation of the patient’s clinical condition should be based on the 
clinical signs and symptoms of pneumonia as well as objective evidence of failure (eg, 
persistent fever, rising WBC count, increasing tracheal secretions, poor oxygenation, 
progression of infiltrate on CXR) and a measure of their CPIS.  This information should be
recorded on the CRF, as well as an evaluation of the patient’s clinical response to study drug.  
In most cases, the decision to evaluate the patient as a Clinical Failure will be made after at 
least 72 hours of study medication, but in rare instances, the clinical course of the illness may 
require that study medication be discontinued prior to three days treatment and alternative 
antibiotic therapy started.  Regardless of when the patient is prematurely discontinued, the 
clinical condition of the patient should be determined at the time of study drug 
discontinuation, recorded on the CRF, and a clinical response evaluation completed.
At the premature discontinuation visit, the patient’s outcome response will be assessed
according to the following terms and definitions.
Investigator Assessment of Patient Outcome - Failure: 
….

Any further change to the antimicrobial regimen being used to treat pneumonia during 
the first 10 days, after the initial antimicrobial adjustment within the first 72 hours 
after the initiation of empiric therapy or as soon as initial culture and susceptibility 
results are available and excepting the discontinuation of aminoglycosides after 5-7 
days, would be considered a patient outcome failure; 
….


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NOTE: At least one of the above conditions is necessary to consider a patient a patient 
outcome failure.
11.1.1   Analysis Populations
Added text:
The two populations used for analysis will be the mITT population and the ITT population.  
These populations will be comprised of patients recruited to this study and to study 13085 
(being conducted in different countries; the protocols are identical with the exception that 
study 13085 has a pharmacokinetic substudy).  The patients will be recruited competitively 
between studies 13084 and 13085; there are no minimum requirements for recruitment totals 
in either study.  The mITT population is defined as all randomized patients with culture-
confirmed Gram-negative bacteria who have been treated with at least one dose of study drug 
and have an APACHE II score 10 at the time of diagnosis of pneumonia.  The ITT 
population is defined as all patients treated with at least one dose of study drug.
11.1.2   Analytical Plan
Old text:
The primary efficacy analysis will be conducted in the mITT population.  Supportive efficacy 
analyses will be provided for the ITT population.  Unless otherwise specified, all significance 
tests will be conducted using a two-sided alpha level of 0.05
New text:
The primary efficacy analysis will be conducted in the mITT population.  The primary 
analysis is on the combined database, no single study analyses will be performed as part of 
the primary analysis. Unless otherwise specified, all significance tests will be conducted 
using a two-sided alpha level of 0.05.


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11.2   Determination of Sample Size
Old text:
For this study, a sample size of 215 patients per treatment group will provide 85% power to 
obtain a statistically significant result at a two-sided alpha level of 0.05, assuming true 
clinical cure rates at TOC of 55% for placebo and 69% for BAY 41-6551.  Assuming 35% of 
patients will not be eligible for the primary efficacy analysis (ie, will not have a pre-therapy 
Gram-negative organism) a total of 331 patients per group (662 overall) will be needed for 
the study, based on current surveillance.  If the actual rate of ineligible patients is different 
than 35%, the overall enrollment will be adjusted to ensure that 430 patients with Gram-
negative organisms are enrolled.  Note that with this sample size, an observed treatment 
group difference of as low as 9.3% could provide a statistically significant result.
New text:
For this combined study (studies 13084 and 13085), a sample size of 236 mITT patients per 
treatment group will provide 92% power to obtain a statistically significant result at a two-
sided alpha level of 0.05, assuming true Clinical Success rates at LFU of 54% for placebo and 
69% for BAY 41-6551.  Assuming 35% of patients will not be eligible for the primary 
efficacy analysis (ie, will not have a pre-therapy Gram-negative organism) a total of 362 ITT 
patients per group (724 ITT overall) will be needed for the study, based on current 
surveillance.  If the actual rate of ineligible patients is different than 35%, the overall 
enrollment will be adjusted to ensure that 472 patients with Gram-negative organisms are 
enrolled.  Note that with this sample size, an observed treatment group difference of as low as 
8.9% could provide a statistically significant result.
11.3   Methods for the Analysis of the Primary Efficacy Parameter
Old text:
The primary efficacy variable is clinical response at the TOC visit.  The primary analysis will 
compare the proportion of patients with cures in the BAY 41-6551 group versus the 
proportion in the placebo group.  All assessments other than cure - failures, improvements, 
indeterminates, and missings (those patients who do not have a test of cure assessment) will 
be grouped together in a non-cure category for the purposes of this analysis.
The null (H0) and the alternative (H1) hypothesis for this primary analysis is the following:

H0: p[BAY 41-6551] = p[placebo]

H1: p[BAY 41-6551] ≠ p[placebo]
where p is the true cure rate.  
A Cochran-Mantel-Haenzel test of general association, adjusting for stratum and geographic 
region, will be performed as the primary efficacy analysis.  If the p-value from this test is less 
than 0.05, and the proportion of patients with cures is higher in the BAY 41-6551 group than 
in the placebo group, the study will have achieved its primary objective. 
In addition, as a supportive analysis, a 95% confidence interval will be calculated for the odds 
ratio.  This confidence interval will be generated from a logistic regression model with 


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clinical response as the primary variable, and treatment, stratum, and geographic region as the 
independent variables.  If the lower limit of the 95% confidence interval for the odds ratio 
(BAY 41-6551/placebo) is greater than 1, BAY 41-6551 will be demonstrated to be 
statistically superior to placebo. 
….
The Breslow-Day test will be used as a further supportive analysis to test for treatment by 
geographic region and treatment by stratum interaction.  If this test of the homogeneity of the 
odds ratio indicates a significant interaction, exploratory analyses will attempt to define its 
source.
….
In addition, an analysis of clinical response will be conducted that excludes patients who 
received anti-microbial therapy considered to be effective against Gram-negative organisms, 
for infections other than the underlying pneumonia.  Patients will only be excluded from this 
analysis if the additional anti-microbial therapy was administered before the TOC visit and 
the patient was not a Clinical Failure.
…
New text:
The primary efficacy variable is Clinical Success.  Clinical Success is achieved when all of 
the following criteria are met:
1)  Systemic antibiotics (IV or PO) for pneumonia must be stopped on or before the TOC 
visit
2)  Systemic antibiotics (IV of PO) for pneumonia must not be restarted after the TOC visit
3)   The patient must survive through the LFU visit
4)  The patient must not have a reported AE of lung abscess or empyema through the LFU 
visit 
5)  The patient must have stable respiratory function evaluated at the TOC visit based on the 
P/F ratio as outline below (if the P/F ratio is not available at the TOC, use the P/F ratio value 
from the closest previous visit):
Stable respiratory function

Patient is extubated at the TOC visit OR

Patient is intubated at the TOC visit AND:

Patient has a P/F ratio > 200 at the TOC visit OR

Patient has a P/F ratio > 100 and ≤ 200 at the TOC visit AND:

Patient had a P/F ratio ≤ 200 at baseline
Unstable respiratory function

Patient has a P/F ratio ≤ 100 at the TOC visit OR


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
Patient has a P/F ratio > 100 and ≤ 200 at the TOC visit AND: 
o
Patient had a P/F ratio > 200 at baseline
The outcome is Clinical Success if all 5 criteria are met.  If any one of the criteria is not met, 
then the patient is considered a Clinical Failure.  Patients who do not have a clinical 
assessment of success due to missing data will be considered a Clinical Failure.
Patients who are discontinued from aerosol therapy will be evaluated as follows:
Reason for Discontinuation of Aerosol Therapy
Outcome/Comments

No Gram-negative bacteria isolated from a pre-
therapy respiratory specimen

Patient is considered ITT 
and not evaluated for 
efficacy

Patient withdrew consent or refused handheld 
device

Evaluate for efficacy if all 
data are available; if data are 
missing, then failure

Death

Failure

Adverse event, abnormal laboratory value (elevated 
creatine, etc)

Failure

New therapy incompatible with aerosol therapy

Failure

Discharged/lost to follow-up

Failure

Any other reason/unknown reason

Failure
The primary analysis will compare the proportion of patients with Clinical Success in the 
BAY 41-6551 group versus the proportion in the placebo group, using the combined data 
from studies 13084 and 13085.  All assessments other than Clinical Success - failures, 
improvements, and missings (those patients who do not have a TOC assessment) will be 
grouped together in the Clinical Failure category for the purposes of this analysis.
The null (H0) and the alternative (H1) hypothesis for this primary analysis is the following:

H0: p[BAY 41-6551] = p[placebo]

H1: p[BAY 41-6551] ≠ p[placebo]
where p is the true Clinical Success rate.  
A Cochran-Mantel-Haenzel test of general association, adjusting for stratum and geographic 
region, will be performed as the primary efficacy analysis.  If the p-value from this test is less 
than 0.05, and the proportion of patients with Clinical Success is higher in the BAY 41-6551 
group than in the placebo group, the study will have achieved its primary objective. 
In addition, as a supportive analysis, a 95% confidence interval will be calculated for the odds 
ratio.  This confidence interval will be generated from a logistic regression model with 
Clinical Success as the primary variable, and treatment, stratum, and geographic region as the 
independent variables.  If the lower limit of the 95% confidence interval for the odds ratio 
(BAY 41-6551/placebo) is greater than 1, BAY 41-6551 will be demonstrated to be 
statistically superior to placebo. 


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The individual components of the composite endpoint will be analyzed using Mantel-
Haenszel adjusting for stratum and geographic region.  This is to assess if the components are 
moving in the same general direction and which, if any, single component is driving the 
result.
….
The Breslow-Day test will be used as a further supportive analysis to test for treatment by 
geographic region and treatment by stratum interaction.  If this test of the homogeneity of the 
odds ratio indicates a significant interaction, exploratory analyses will attempt to define its 
source.  A Cochran-Mantel-Haenzel test of general association, adjusting for stratum and 
study protocol (ie, 13084 or 13085), will be performed to assess the effect of study protocol 
on the primary outcome Clinical Success.  Geographic region will not be included in this 
model as the 2 studies were conducted in different regions.
….
In addition, an analysis of Clinical Success will be conducted that excludes patients who 
received anti-microbial therapy considered to be effective against Gram-negative organisms, 
for infections other than the underlying pneumonia.  Patients will only be excluded from this 
analysis if the additional anti-microbial therapy was administered before the TOC visit and 
the patient was not a Clinical Failure.
11.4   Methods for the Analysis of Secondary Efficacy Parameters
Old text:
If the null hypothesis for the primary efficacy variable is rejected, a formal hypothesis testing 
scenario will be applied for 4 secondary efficacy variables.  These four are: 

the number of days on mechanical ventilation

the number of days in the ICU

the number of days in the hospital

relapse rates
For the first three variables, the counting of the totals will begin on the first day of study drug 
therapy and continue through Day 28.  
Holm’s sequentially rejective testing procedure will be used for these four secondary 
endpoints.  With this approach, the p-values from the tests of the four variables are ordered 
from lowest to highest.  If the lowest p-value is 0.0125 (0.05/4), none of the null hypotheses 
of treatment equality for these variables will be rejected, and no more comparisons will be 
performed.  If the lowest p-value is 0.0125, the null hypothesis for that variable will be 
rejected, and the next lowest p-value will then be compared to 0.0167 (0.05/3).  The tests will 
continue until the first time at which the null hypothesis is not rejected; all null hypotheses 
from that point on are also not rejected.


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Analysis of variance will be used to test the null hypothesis of no difference between 
BAY 41-6551 and placebo for the three secondary variables counting number of days in the 
sequentially rejective testing approach.  For the purpose of the sequentially rejective testing 
procedure, the only effect in the model will be treatment and the p-values from the treatment 
effect will be used to compare to the Holm boundaries.  The null hypothesis of no difference 
between BAY 41-6551 and placebo in clinical relapse rates will be tested using an unadjusted 
Chi-square test.
As supportive analyses, additional models will be used with effects included for geographic 
region for all four of these secondary variables.  Non-parametric tests for treatment 
comparisons will be considered as sensitivity analyses.
Analysis of variance will be used to test the null hypothesis of no difference between 
BAY 41-6551 and placebo for the total number of days of Gram-negative antibiotics.
The remaining secondary endpoints –total number of days of Gram-negative antibiotics, 
clinical response rates at end of therapy, change in component of CPIS score from baseline to 
TOC, and microbiological eradication rates, will be summarized descriptively.  In addition, 
Kaplan-Meier curves will be provided for time to Clinical Failure. 
New text:
If the null hypothesis for the primary efficacy variable is rejected, a formal hypothesis testing 
scenario will be applied for the secondary efficacy variables: 

Pneumonia-related mortality through the LFU visit

Early Clinical Response (based on CPIS, mortality, and certain AEs) assessed through 
Day 10

The number of days on mechanical ventilation through the LFU visit

The number of days in the ICU through the LFU visit
The secondary efficacy variables will be formally tested for statistical significance of a 
difference between the BAY 41-6551 group versus the placebo group, only if the primary 
efficacy comparison is statistically significant at the two-sided 5% level.  A sequential testing 
procedure will be performed at the two-sided alpha level of 0.05 for these four secondary 
efficacy variables, strictly in the order listed above.
The null hypothesis of no difference between BAY 41-6551 and placebo in pneumonia –
related mortality and early clinical response will be tested using an unadjusted Chi-square 
test. Analysis of variance will be used to test the null hypothesis of no difference between 
BAY 41-6551 and placebo for the number of days on mechanical ventilation and in the ICU.  
For the purpose of the sequentially rejective testing procedure, the only effect in the model 
will be treatment.  As supportive analyses, additional models will be used with effects 
included for geographic region for all secondary variables.  Non-parametric tests for 
treatment comparisons will be considered as sensitivity analyses.
The other endpoints – total number of days of Gram-negative antibiotics, clinical response 
rates at end of therapy, change in component of CPIS score from baseline to TOC, 


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microbiological eradication rates, the number of days in the hospital, and relapse rates will be 
summarized descriptively, however for the total number of days of Gram-negative antibiotics, 
analysis of variance will be used to test the null hypothesis of no difference between BAY 41-
6551 and placebo.  In addition, Kaplan-Meier curves will be provided for time to Clinical 
Failure.  The Investigator Assessment of Patient Outcome will be analyzed as sensitivity 
analysis.
14.  References
Old text:
41. Investigator’s Brochure, Amikacin Pulmonary Delivery System; Version 3.0: 
23-Apr-2014.
New text:
41. Investigator’s Brochure, Amikacin Pulmonary Delivery System; Version 4.0: 
19 FEB 2015.
49. The ARDS Definition Task Force.  Acute respiratory distress syndrome. The Berlin 
definition.  JAMA 2012;307(23):2526-33.


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15.1.  Study Flow Chart and Schedule of Procedures
Old text:
Day
Assessment
Screening
1
2
3
4
5
6
7
8
9
10 a
EOT
Premature 
D/C/Early 
Withdrawal
TOC 
Day 17 
to 19
Late Follow-Up
Day 28 to 32 b
In 
Person
By 
Phone
….
Arterial blood gases/pulse 
oximetry
X
X
X
X
X
X
X
X
Xr
….
APACHE II score l
X
….
Collection of ventilator 
parameters pre- and post-dose 
X
X
X
X
X
X
X
X
X
…
Evaluation of Clinical 
Response
X
X
X
X
X
….
l - APACHE II score for the 24 hours immediately preceding the first dose of study medication
….
n - Prior to each dose, each patient will receive a carton containing one vial of study medication (either BAY 41-6551 or placebo) and one nebulizer/reservoir.
o - Patients will be started on aerosolized study medication within 24 hours of systemic antibiotic therapy being initiated.  Patients will receive 3.2 mL of either 
BAY 41-6551 (400 mg, amikacin as free base) or placebo solution every 12 hours via the PDDS Clinical for ten days (20 doses).  If a patient is extubated 
during the course of treatment or has had a tracheostomy and is spontaneously breathing, aerosol administration will continue via the handheld adaptor for 
the remainder of the treatment period.
p - Serum amikacin for trough level will be obtained 30 minutes  prior to the first dose on each treatment day.   In addition, these trough levels should be 
obtained for all patients and be sent to the Central Laboratory.  If the site has mandated procedures for monitoring IV amikacin treatment, the site should 
perform these site-specific procedures in conjunction with the collection for serum Amikacin levels.
….


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New text:
Day
Assessment
Screening
1
2
3
4
5
6
7
8
9
10 a
EOT
Premature 
D/C/Early 
Withdrawal
TOC 
Day 17 
to 19
Late Follow-Up
Day 28 to 32 b
In 
Person
By 
Phone
….
Arterial blood gases/pulse 
oximetry
X
X
X
X
X
X
X s
X s
Xr
….
APACHE II score 
X
….
Collection of ventilator 
parameters pre- and post-dose 
X
X
X
X
X
X
X
X
X
X
….
Investigator Assessment of 
Patient Outcome
X
X
X
X
X
….
….
l – Footnote deleted per Amendment 6.
….
n - Prior to each dose, each patient will receive a one vial of study medication (either BAY 41-6551 or placebo) and one nebulizer/reservoir.
o - Patients will be started on aerosolized study medication within 48 hours of systemic antibiotic therapy being initiated.  Patients will receive 3.2 mL of either 
BAY 41-6551 (400 mg, amikacin as free base) or placebo every 12 hours via the PDDS Clinical for ten days (20 doses).  If a patient is extubated during the 
course of treatment or has had a tracheostomy and is spontaneously breathing, aerosol administration will continue via the handheld adaptor for the 
remainder of the treatment period.
p - Serum amikacin for trough level will be obtained 30 ± 15 minutes  prior to the first dose on each treatment day.   In addition, these trough levels should be 
obtained for all patients and be sent to the Central Laboratory. If the site has mandated procedures for monitoring IV amikacin treatment, the site should 
perform these site-specific procedures in conjunction with the collection for serum Amikacin levels.
.….
s – Pulse oximetry not required at the premature discontinuation/early withdrawal and TOC visits.


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15.3.  Clinical Pulmonary Infection Score (CPIS)
Old text:
CPIS Points
0
1
2
Tracheal secretions
Few (purulent + 1)
Moderate (purulent + 1)
Large (purulent + 
1)
Chest radiograph
No infiltrate
Patchy or Diffuse
Localized
Temperature (core), °C
36.5 and ≤ 38.4
38.5 and ≤ 38.9
39.0 or 36.0
Blood leukocytes, per 
mm3
4,000 and ≤ 11,000
4,000 or 11,000
--
Oxygenation PaO2 / 
FiO2, mm Hg
240 or presence of 
ARDS
--
240 and 
absence of ARDS
ARDS – acute respiratory distress syndrome
*CPIS for Screening/Randomization purposes is calculated from the 5 components.  
Guidance for Investigators for Calculating the CPIS

Tracheal secretions: to assign a point score for the quantity and appearance of 
tracheal secretions observed in the last 24 hours, consult the nursing/respiratory 
therapy notes for the best estimate  
o
Add 1 point, if the tracheal secretions are considered purulent (e.g., if the 
patient had “few” secretions but they were purulent, then the patient would 
have a score of 1 for this component of the score; or if the patient had a 
“large” amount of purulent secretions, then the score would be 3)

Chest radiograph (CXR): the CXR taken within the previous 24 h (or sooner)

Temperature, oC: the maximal temperature taken within the previous 24 hours 
should be used for point assignment
o
For patients with hypothermia, the lowest temperature taken in the previous 
24 hours should be used for point assignment

Blood leukocytes (WBC) (cells/mm3): the maximal WBC count reported in the 
previous 24 hours should be used for point assignment
o
For patients with leukopenia, the lowest WBC count reported in the previous 
24 hours should be used for point assignment

Oxygenation PaO2 / FiO2, mm Hg: the most recently calculated P/F ratio obtained 
within the last 24 hours should be used for point assignment 


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New text:
CPIS Points
0
1
2
Tracheal secretions
Few (purulent + 1)
Moderate (purulent + 1)
Large (purulent 
+ 1)
Chest radiograph
No infiltrate
Patchy or Diffuse
Localized
Temperature (core), °C
36.1 and ≤ 38.4
38.5 and ≤ 38.9
39.0 or 36.0
Blood leukocytes, per 
mm3
4,000 and ≤ 11,000
4,000 or 11,000
--
Oxygenation PaO2 / FiO2, 
mm Hg
240 or presence of 
ARDS
--
240 and 
absence of 
ARDS
ARDS – acute respiratory distress syndrome
  
Guidance for Investigators for Calculating the CPIS

Tracheal secretions: to assign a point score for the quantity and appearance of 
tracheal secretions observed in the last 24 hours97, consult the nursing/respiratory 
therapy notes for the best estimate  
o
Add 1 point, if the tracheal secretions are considered purulent (e.g., if the 
patient had “few” secretions but they were purulent, then the patient would 
have a score of 1 for this component of the score; or if the patient had a 
“large” amount of purulent secretions, then the score would be 3)

Chest radiograph (CXR): the most recent CXR taken within the previous 24 hours97
(or sooner)

Temperature, oC: the maximal temperature taken within the previous 24 hours97
should be used for point assignment
o
For patients with hypothermia, the lowest temperature taken in the previous 
24 hours97 should be used for point assignment

Blood leukocytes (WBC) (cells/mm3): the maximal WBC count reported in the 
previous 24 hours97 should be used for point assignment
o
For patients with leukopenia, the lowest WBC count reported in the previous 
24 hours97 should be used for point assignment

Oxygenation PaO2 / FiO2, mm Hg: the most recently calculated P/F ratio obtained 
within the last 24 hours97 should be used for point assignment 
97within 48 hours for the screening visit; within 24 hours for all other visits
15.5.  APACHE II Score / Glasgow Score
Old text:
….


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During the first 24 hours after admission, the point score is calculated from 12 routine 
physiological measurements (such as blood pressure, body temperature, heart rate etc.) during 
the first 24 hours after admission, information about previous health status and other 
information obtained at admission (such as age).  The calculation method is optimized for 
paper schemas.  The resulting point score should always be interpreted in relation to the 
illness of the patient.
After the initial APACHE II score has been determined, no new score can be calculated
during the hospital stay.  If a patient is discharged from the ICU and readmitted, a new 
APACHE II score can be calculated.
….
New text:
….
The point score is calculated from 12 routine physiological measurements (such as blood 
pressure, body temperature, heart rate etc.).  The calculation method is optimized for paper 
schemas.  The resulting point score should always be interpreted in relation to the illness of 
the patient.
After the initial APACHE II score has been determined, no new score can be entered for this 
study during the hospital stay.  If a patient is discharged from the ICU and readmitted, a new 
APACHE II score can be calculated.
….


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Added text:
Glasgow Coma Scale
B 
Age 
Point
C 
Chronic Health Points 
APACHE II Score 
(sum of A + B + C) 
A APS points 
Eyes open 
Verbal – non-intubated 
Age 
Points 
If any of the 5 CHE categories is 
answered 
4 - spontaneously 
3 - to verbal 
5 - oriented and 
conversant 
4 - disoriented and talks 
< 44 
0
with yes give +5 points for non-operative 
or emergency postoperative patients 
with immunocompromised or severe 
organ insufficiency
+2 points for elective postoperative 
patient with immunocompromised or 
history of severe organ insufficiency
+ B Age points 
2 - to painful 
stimuli 
3 -inappropriate words 
45-54 
2
Liver 
- Cirrhosis with PHT or encephalopathy 
+ C Chronic  Health 
Points
1 - no response 
Motor response 
2 -incomprehensible 
sounds 
1 - no response 
55-64 
65-74 
3
5
Cardiovascular 
Pulmonary 
- class IV angina or at rest or with 
minimal self care activities - chronic 
hypoxemia or hypercapnia or 
__________ 
6 - to verbal 
command 
Verbal - intubated 
> 75 
6
polycytaemia of PHT > 40mmHg 
= Total APACHE II 
5 - localizes to 
pain 
5 -seems able to talk 
Kidney 
-chronic peritoneal or haemodialysis 
4 - withdraws to 
pain 
3 - decorticate 
3 -questionable ability to 
talk 1 -generally 
unresponsive 
Age points = 
Immune 
- immune compromised host 
2 - decerebrate 
Chronic Health Points = 
1 - no response 


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16.7
Amendment 7
16.7.1
Overview of Change
A correction has been made in the temperature criterion for the calculation of CPIS points.  
This correction accurately reflects the programming that has been used in the eCRF by the 
investigators to calculate the CPIS score throughout the study, ie, it does not represent a 
change in the conduct of the study.
16.7.2
Changes to the Protocol Text
In this section, deleted text is crossed out and added text is underlined.  
15.3.  Clinical Pulmonary Infection Score (CPIS)
Old text:
CPIS Points
0
1
2
Tracheal secretions
Few (purulent + 1)
Moderate (purulent + 1)
Large (purulent + 1)
Chest radiograph
No infiltrate
Patchy or Diffuse
Localized
Temperature (core), °C
36.1 and ≤ 38.4
38.5 and ≤ 38.9
39.0 or 36.0
Blood leukocytes, per 
mm3
4,000 and ≤ 11,000
4,000 or 11,000
--
Oxygenation PaO2 / 
FiO2, mm Hg
240 or presence of 
ARDS
--
240 and absence 
of ARDS
ARDS – acute respiratory distress syndrome
  
New text:
CPIS Points
0
1
2
Tracheal secretions
Few (purulent + 1)
Moderate (purulent + 1)
Large (purulent + 
1)
Chest radiograph
No infiltrate
Patchy or Diffuse
Localized
Temperature (core), °C
36.5 and ≤ 38.4
38.5 and ≤ 38.9
39.0 or 36.4
Blood leukocytes, per 
mm3
4,000 and ≤ 11,000
4,000 or 11,000
--
Oxygenation PaO2 / FiO2, 
mm Hg
240 or presence of 
ARDS
--
240 and absence 
of ARDS
ARDS – acute respiratory distress syndrome
  
16.8
Amendment 8
This is a global amendment to Protocol 13084, Version 8.0 (dated 30 AUG 2016), and will be 
included as part of the integrated global protocol.
Minor changes to the protocol include editorial changes, correction of typographical errors, 
and minor revisions of language to ensure clarity and consistency throughout the document.  


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16.8.1
Overview of Change
This section provides a conceptual overview of all modifications to the original protocol 
Version 8.0, as introduced by this amendment.  The associated changes to the protocol text 
are detailed in Section 16.8.2.
During a blinded review of the data from 454 mITT patients entered into the Phase III 
program it was found that there was an artificially high failure rate occasioned by the 
antibiotic duration criteria. These failures did not correspond with data that are used as 
medical management tools and were considered spurious. Certain other elements of the 
endpoint related to the TOC date were also considered not to accurately reflect clinical 
benefit.
These data necessitated a change in the primary endpoint. It was decided to narrow the 
primary endpoint to all-cause mortality alone through the LFU visit (days 28-32). This 
primary endpoint is in alignment with current FDA draft guidance for ventilated pneumonia. 
All-cause mortality through the LFU visit will be the sole criteria for evaluation.
The changes to the protocol are summarized below:

The primary efficacy endpoint has been modified to all-cause mortality through the 
LFU visit. 

Name of sponsor’s medical responsible persons

The Signature of the sponsor’s medically responsible persons, Synopsis, and Sections 
5.1, 6, 8.1, 8.2, 8.4.1.1.4, 9.6.1.1, 9.6.1.2, 11.2, 11.3, 11.4, 11.5 and 15.1 were revised.
16.8.2
Changes to the Protocol Text
In this section, all sections affected by this amendment are detailed; the sequence follows the 
structure of the most recent previous protocol version.  Deletions are crossed out and 
additions are underlined.  Minor editorial changes and corrections of typographical errors are 
not shown.
Signature of the sponsor’s medically responsible persons
Old Text 
Name:
   
Role:
Signature:
Date:
Name:
   
Role:
Signature:
Date:
PPD
PPD
PPD
PPD


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New Text
Name:
   
Role:
Signature:
Date:
Synopsis
Old Text
Diagnosis and main criteria for 
inclusion/exclusion 
Patients of age 18 and older, who are hospitalized, have pneumonia 
suspected or confirmed to be caused by Gram-negative organisms, 
and who are intubated and mechanically-ventilated will be selected 
for this study.  In all patients where the pathogen is suspected of 
being Gram-negative, it should be confirmed as soon as culture 
results are available.  Patients with microbiologically-confirmed 
pneumonia are those who have a Gram-negative organism cultured 
from an appropriate respiratory tract specimen collected prior to 
enrollment.  The main inclusion criteria are:
New Text
Diagnosis and main criteria for 
inclusion/exclusion 
Patients of age 18 and older, who are hospitalized, have pneumonia 
suspected or confirmed to be caused by Gram-negative organisms, 
and who are intubated and mechanically-ventilated will be selected 
for this study.  In all patients where the pathogen is suspected of 
being Gram-negative, it should be confirmed as soon as culture 
results are available.  Patients with microbiologically-confirmed 
pneumonia are those who have a Gram-negative organism cultured 
from an appropriate respiratory tract specimen.  The main inclusion 
criteria are:
Old Text
Study objectives The study objective is 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 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 efficacy endpoint is Clinical Success as 
defined in Section 8.2.  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 ICU.
PPD
PPD


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New Text
Study objectives The study objective is 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 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 primary efficacy variable is Survival as 
defined in Section 8.2.  The secondary 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 ICU.
Old text:
Safety endpoints
The safety endpoints are to compare (BAY 41-6551 vs aerosolized 
placebo, as adjunctive therapy to IV antibiotics in both arms) as 
measured by:

The frequency of adverse events (AEs)

The progression and incidence rates of organ failure

The all-cause mortality rate during therapy, at Day 15 and at 
Day 28
New text
Safety endpoints 
The safety endpoints are to compare (BAY 41-6551 vs aerosolized 
placebo, as adjunctive therapy to IV antibiotics in both arms) as 
measured by:

The frequency of adverse events (AEs)

The progression and incidence rates of organ failure

The all-cause mortality rate during therapy, at Day 15 and at 
Day 28 (also the primary efficacy endpoint)
Old Text
Methodology Eighteen to 22 days after completing 10 days of aerosolized 
treatment, patients will be evaluated for Clinical Success, which will 
be based on survival, the duration of antibiotic therapy, the absence 
of empyema or lung abscess, and stable respiratory function.
New Text
Methodology Eighteen to 22 days after completing 10 days of aerosolized 
treatment, patients will be evaluated for Survival. Patients who 
survive through the late follow up visit are considered a success, 
patients who suffer mortality for any reason on or before the LFU 
visit are considered a failure.


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Old Text
Efficacy variables The primary efficacy variable will be Clinical Success in the mITT 
population (ie, the ITT population who prove to be culture positive 
for a Gram-negative pathogen and have an APACHE II score ≥ 10).  
Clinical Success is achieved when all of the following criteria are 
met: 
1)  Systemic antibiotics (IV or by mouth [PO]) for pneumonia must 
be stopped on or before the Test-of-Cure (TOC) visit (Day 17-19) 
2)  Systemic antibiotics (IV or PO) for pneumonia must not be 
restarted after the TOC visit
3)  The patient must survive through the late follow-up (LFU) visit
4) The patient must not have a reported AE of lung abscess or 
empyema through the LFU visit and 
5)  The patient must have stable respiratory function measured at the 
TOC visit.  

…
The investigator will assess patient signs and symptoms at the 
TOC visit (Day 17-19) for the Investigator Assessment of Patient 
Outcome, which is separate from the primary efficacy variable, 
Clinical Success.
New Text
Efficacy variables The primary efficacy variable will be Survival in the mITT 
population (ie, the ITT population who prove to be culture positive 
for a Gram-negative pathogen and have an APACHE II score ≥ 10).  
Survival is achieved when the patient is documented as alive through 
the LFU visit.
…
Three additional analysis of clinical success will be conducted.

Clinical success using Foundation for the National Institute of 
Health (FNIH) recommendations is defined as mITT patients 
who survived through the LFU visit and did not have septic 
shock.

Investigator Assessment of Patient Outcome will be 
determined at the TOC visit (Day17-19). The investigator will 
assess patient signs and symptoms at the TOC visit.

Clinical Success will be evaluated using 5 component criteria, 
which were the former primary end point for this study.
5.1 Background and Rationale – amended


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Old Text
Old Text
Inhalation delivery of BAY 41-6551 (amikacin solution for inhalation) offers an attractive 
addition to IV or IM delivery.  Inhalation administration minimizes systemic exposure while 
delivering drug directly to the site of infection.  Bayer HealthCare is investigating the use of 
aerosolized BAY 41-6551 for the treatment of serious bacterial respiratory infections in 
intubated and mechanically-ventilated patients using a proprietary high efficiency Pulmonary 
Drug Delivery System (PDDS Clinical).
…
This clinical study will evaluate the Clinical Success rate of aerosolized amikacin, 
administered via PDDS Clinical, to that of aerosolized placebo (normal saline solution), as 
adjunctive therapy to IV antibiotics in both arms, in patients with microbiologically-
confirmed Gram-negative pneumonia. The PDDS Clinical is expected to be a more efficient 
way of delivering aerosolized medication than a conventional pneumatic system.  The study 
will also provide information on the safety and tolerability of aerosolized amikacin.
New Text
Inhalation delivery of BAY 41-6551 (amikacin solution for inhalation) offers an attractive 
addition to IV or IM delivery.  Inhalation administration minimizes systemic exposure while 
delivering drug directly to the site of infection.  Bayer is investigating the use of aerosolized 
BAY 41-6551 for the treatment of serious bacterial respiratory infections in intubated and 
mechanically-ventilated patients using a proprietary high efficiency Pulmonary Drug 
Delivery System (PDDS Clinical).
…
This clinical study will evaluate the Survival rate of patients treated with aerosolized 
amikacin, administered via PDDS Clinical, to that of aerosolized placebo (normal saline 
solution), as adjunctive therapy to IV antibiotics in both arms, in patients with 
microbiologically-confirmed Gram-negative pneumonia. The PDDS Clinical is expected to be 
a more efficient way of delivering aerosolized medication than a conventional pneumatic 
system.  The study will also provide information on the safety and tolerability of aerosolized 
amikacin.
6. Study Objectives – amended


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Old Text
The study objective is to demonstrate that as adjunctive therapy to IV antibiotics, BAY 41-
6551 400 mg (amikacin as free base) administered as an aerosol by the 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 efficacy endpoint is Clinical Success as 
defined in Section 8.2.  The secondary objectives are to evaluate the superiority of 
aerosolized BAY 41-6551 versus aerosolized placebo in pneumonia-related mortality to the 
LFU visit, the Early Clinical Response at Day 10, the days on ventilation through the LFU 
visit, and the days in the ICU assessed at the LFU visit.
New Text
The study objective is to demonstrate that as adjunctive therapy to IV antibiotics, BAY 41-
6551 400 mg (amikacin as free base) administered as an aerosol by the 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 primary efficacy variable is Survival as defined 
in Section 8.2.  The secondary objectives are to evaluate the superiority of aerosolized BAY 
41-6551 versus aerosolized placebo in pneumonia-related mortality to the Late Follow-up
(LFU) visit, the Early Clinical Response at Day 10, the days on ventilation through the LFU 
visit, and the days in the ICU assessed at the LFU visit.
8.1 Study Design – amended
Old Text
This is a Phase III, prospective, randomized, double-blind, placebo-controlled, multicenter, 
multinational study designed to show that aerosolized BAY 41-6551 400 mg (amikacin as 
free base) every 12 hours is more effective than placebo (aerosolized normal saline), as 
adjunctive therapy to IV antibiotics in both arms, in intubated and mechanically-ventilated 
patients with Gram-negative pneumonia.  
New Text
This is a Phase III, prospective, randomized, double-blind, placebo-controlled, multicenter, 
multinational study designed to show that aerosolized BAY 41-6551 400 mg (amikacin as 
free base) every 12 hours is more effective than placebo (aerosolized normal saline), as 
adjunctive therapy to IV antibiotics, in intubated and mechanically-ventilated patients with 
Gram-negative pneumonia.  
8.2 Study Plan – amended
Old Text
The Test-of-Cure (TOC) visit will be conducted on Day 17-19 of the study. The late follow-
up (LFU) visit will be conducted on Day 28-32 of the study.  Clinical Success will be 


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evaluated at the TOC and LFU visits by programmed response criteria. If available, 
respiratory secretions will be obtained, cultured, and evaluated for the emergence of 
resistance to study drug therapy among baseline organisms.  
The primary efficacy evaluation of the study is the Clinical Success in the mITT population, 
which is achieved when the following 5 criteria are met:

Systemic antibiotics (IV or by mouth [PO]) for pneumonia must be stopped on or 
before the TOC visit

Systemic antibiotics (IV or PO) for pneumonia must not be restarted after the TOC 
visit

The patient must survive through the LFU visit 

The patient must not have a reported AE of lung abscess or empyema through the 
LFU visit 

The patient must have stable respiratory function at the TOC visit 
Stable or unstable respiratory function is determined based on the PaO2/FiO2 (P/F) 
ratio at TOC in the following manner:
Stable respiratory function:
o
Patient is extubated at the TOC visit OR 
o
Patient is intubated at the TOC visit AND:

Patient has a P/F ratio > 200 at the TOC visit OR

Patient has a P/F ratio > 100 and ≤ 200 at the TOC visit AND: 

Patient had a P/F ratio ≤ 200 at baseline
Unstable respiratory function
o
Patient has a P/F ratio ≤ 100 at the TOC visit OR
o
Patient has a P/F ratio > 100 and ≤ 200 at the TOC visit AND: 

Patient had a P/F ratio > 200 at baseline
The outcome is Clinical Success if all 5 criteria are met.  If any one of the criteria is not met, 
then the patient is considered a Clinical Failure. Patients who do not have a clinical 
assessment of success due to missing data will be considered a Clinical Failure.
New Text
The Test-of-Cure (TOC) visit will be conducted on Day 17-19 of the study. The late follow-
up (LFU) visit will be conducted on Day 28-32 of the study.  Survival will be evaluated 
through the LFU visit. If available, respiratory secretions will be obtained, cultured, and 
evaluated for the emergence of resistance to study drug therapy among baseline organisms.  
The primary efficacy variable of the study is Survival in the mITT population through the 
LFU visit.


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Section 8.4.1.1.4 Adjustment of Empiric Intravenous Antibiotic Therapy -
amended
Old Text
Further adjustments to maintenance antibiotic therapy are not permitted during the remaining 
treatment unless the patient is failing antibiotic treatment for pneumonia, in which case the 
patient would be considered a failure by the Investigator Assessment (not by the primary 
endpoint evaluation of Clinical Success).
New Text
Further adjustments to maintenance antibiotic therapy are not permitted during the remaining 
treatment unless the patient is failing antibiotic treatment for pneumonia, in which case the 
patient would be considered a failure by the Investigator Assessment (not by the primary 
endpoint evaluation of Survival).
Section 8.4.2 Identity of Investigational Products
Old Text
The active ingredient will be obtained from ACS Dobfar (Bergamo, Italy) and the BAY 
41-6551 inhalation solution will be manufactured by Bayer HealthCare AG (Leverkusen, 
Germany).  Each single-use vial has a filling volume of 3.6 mL.  This fill volume of 3.6 mL is 
equivalent to the BAY 41-6551 solution containing 450 mg of amikacin free base at a 
concentration of 125 mg/mL to ensure an extractable volume of 3.2 mL.  The 3.2 mL 
extractable volume is equivalent to 400 mg amikacin free base aerosolized.  BAY 41-6551 
inhalation solution appears as a clear, colorless to slightly yellowish solution.  Other 
excipients or components of the solution include: hydrochloric acid, sodium hydroxide, water 
for injection, and nitrogen.
New Text
The active ingredient will be obtained from ACS Dobfar (Bergamo, Italy) and the BAY 
41-6551 inhalation solution will be manufactured by Bayer AG (Leverkusen, Germany).  
Each single-use vial has a filling volume of 3.6 mL.  This fill volume of 3.6 mL is equivalent 
to the BAY 41-6551 solution containing 450 mg of amikacin free base at a concentration of 
125 mg/mL to ensure an extractable volume of 3.2 mL.  The 3.2 mL extractable volume is 
equivalent to 400 mg amikacin free base aerosolized.  BAY 41-6551 inhalation solution 
appears as a clear, colorless to slightly yellowish solution.  Other excipients or components of 
the solution include: hydrochloric acid, sodium hydroxide, water for injection, and nitrogen.
Section 9.6.1.1 Primary Efficacy Variable:  Survival – amended


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Old Text
Primary Efficacy Evaluation:  Clinical Success - amended
The primary efficacy evaluation is the Clinical Success, which is determined by using a 
computer algorithm based on collected data and specific criteria.  For a patient to be 
evaluated as a Clinical Success, all the following criteria must be met:

Systemic antibiotics (IV or PO) for pneumonia must be stopped on or before the 
TOC visit 

Systemic antibiotics (IV or PO) for pneumonia must not be restarted after the TOC 
visit

The patient must survive through the LFU visit

The patient must not have a reported AE of lung abscess or empyema through the 
LFU visit 

The patient must have stable respiratory function evaluated at the TOC visit based 
on the P/F ratio (see Section 8.2)
New Text
Primary Efficacy Variable:  Survival - amended
The primary efficacy variable is Survival, which is determined by tabulating the cumulative 
mortality and survival through the LFU visit for each mITT patient. Survival (and mortality) 
is the only criteria evaluated for the primary endpoint, no other factors are considered other 
than survival status through the LFU visit.
Section 9.6.1.2 Additional Analysis of Clinical Success - amended
Added Text
9.6.1.2 Additional Analysis of Clinical Success - amended
There are three additional analyses of clinical success. These three analyses are separate from 
the primary endpoint. The three analyses are  (1) the FNIH recommendations for an endpoint 
based on mortality plus septic shock, (2) the Investigator’s assessment of Patient Outcome, 
and (3) the Composite Endpoint Evaluation (the previous Primary Endpoint).
9.1.6.2.1 FNIH Criteria - amended
Clinical success using FNIH recommendations is defined as mITT patients who survived
through the LFU visit and did not have septic shock. Patients will be designated as having a 
septic shock event based on the standard medical queries (SMQ) terms tabulated as adverse 
events.


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Section 9.6.1.2.2 Investigator Assessment of Patient Outcome - amended
Old Text
The investigators will also assess patient outcome based on a composite endpoint. The 
Investigator Assessment of Patient Outcome is separate and different from the primary 
endpoint of Clinical Success, which is done by using a computer algorithm based on collected 
data and specific criteria.  The Investigator Assessment of Patient Outcome is based on the 
following criteria:
New Text
The investigators will also assess patient outcome based on a composite endpoint. The 
Investigator Assessment of Patient Outcome is separate and different from the primary 
endpoint of Survival, which is done by using a computer algorithm based on collected data 
and specific criteria.  The Investigator Assessment of Patient Outcome is based on the 
following criteria:
9.6.1.2.3 Composite End Point Evaluation:  - amended
Added Text
An evaluation of patient outcome based on 5 components is determined by using a computer 
algorithm based on collected data and specific criteria.  This assessment based on 5 criteria is 
separate and different from the Primary End point of Survival. For a patient to be evaluated as 
a Clinical Success for the Composite End point Evaluation all the following criteria must be 
met:

Systemic antibiotics (IV or PO) for pneumonia must be stopped on or before the 
TOC visit 

Systemic antibiotics (IV or PO) for pneumonia must not be restarted after the TOC 
visit

The patient must survive through the LFU visit

The patient must not have a reported AE of lung abscess or empyema through the 
LFU visit 

The patient must have stable respiratory function evaluated at the TOC visit based 
on the P/F ratio (see below)
Stable respiratory function:
o
Patient is extubated at the TOC visit OR 
o
Patient is intubated at the TOC visit AND:

Patient has a P/F ratio > 200 at the TOC visit OR

Patient has a P/F ratio > 100 and ≤ 200 at the TOC visit AND: 

Patient had a P/F ratio ≤ 200 at baseline


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Unstable respiratory function
o
Patient has a P/F ratio ≤ 100 at the TOC visit OR
o
Patient has a P/F ratio > 100 and ≤ 200 at the TOC visit AND: 

Patient had a P/F ratio > 200 at baseline
The outcome is Clinical Success if all 5 criteria are met.  If any one of the criteria is not met, 
then the patient is considered a Clinical Failure. Patients who do not have a clinical 
assessment of success due to missing data will be considered a Clinical Failure.
9.6.2 Safety Variables
Old Text
Mortality during the treatment period, Day 15 and Day 28 visit will be summarized.
New Text
Mortality during the treatment period, Day 15 and Day 28 visit will be summarized (This is 
also the primary efficacy endpoint).
Section 11.2 Determination of Sample Size – amended
Old Text
For this combined study (studies 13084 and 13085), a sample size of 236 mITT patients per 
treatment group will provide 92% power to obtain a statistically significant result at a two-
sided alpha level of 0.05, assuming true Clinical Success rates at LFU of 54% for placebo and 
69% for BAY 41-6551. Assuming 35% of patients will not be eligible for the primary 
efficacy analysis (ie, will not have a pre-therapy Gram-negative organism) a total of 362 ITT 
patients per group (724 ITT overall) will be needed for the study, based on current 
surveillance.  If the actual rate of ineligible patients is different than 35%, the overall 
enrollment will be adjusted to ensure that 472 patients with Gram-negative organisms are 
enrolled.  Note that with this sample size, an observed treatment group difference of as low as 
8.9% could provide a statistically significant result.
New Text
For this combined study (studies 13084 and 13085), a two group 2 test with a 0.05 two-
sided significance level will have 81% power to detect the difference between BAY 41-6551 
survival rate at LFU of 80% and Placebo survival rate at LFU of 69% when the sample size in 
each group is 254.  
Assuming approximately 30% of patients will not be eligible for the primary efficacy analysis 
(ie, will not have a pre-therapy Gram-negative organism) a total of 362 ITT patients per 
group (724 ITT overall) will be needed for the study, based on current surveillance.  Note that 
with this sample size, an observed treatment group difference of as low as 7.74% could 
provide a statistically significant result.


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Section 11.3 Methods for the Analysis of the Primary Efficacy Parameter 
(Survival) – amended
Old Text
The primary efficacy variable is the Clinical Success.  Clinical Success is achieved when all 
of the following criteria are met:
1)  Systemic antibiotics (IV or PO) for pneumonia must be stopped on or before the TOC 
visit
2)  Systemic antibiotics (IV or PO) for pneumonia must not be restarted after the TOC visit
3)  The patient must survive through the LFU visit
4)  The patient must not have a reported AE of lung abscess or empyema through the LFU 
visit  
5)  The patient must have stable respiratory function evaluated at the TOC visit based on the 
P/F ratio as outline below (if the P/F ratio is not available at the TOC, use the P/F ratio value 
from the closest previous visit):
Stable respiratory function

Patient is extubated at the TOC visit OR 

Patient is intubated at the TOC visit AND:
o
Patient has a P/F ratio > 200 at the TOC visit OR
o
Patient has a P/F ratio > 100 and ≤ 200 at the TOC visit AND: 

Patient had a P/F ratio ≤ 200 at baseline
Unstable respiratory function

Patient has a P/F ratio ≤ 100 at the TOC visit OR

Patient has a P/F ratio > 100 and ≤ 200 at the TOC visit AND: 
o
Patient had a P/F ratio > 200 at baseline
The outcome is Clinical Success if all 5 criteria are met.  If any one of the criteria is not met, 
then the patient is considered a Clinical Failure.  Patients who do not have a clinical 
assessment of success due to missing data will be considered a Clinical Failure.
Patients who are discontinued from aerosol therapy will be evaluated as follows:


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Reason for Discontinuation of Aerosol Therapy
Outcome/Comments

No Gram-negative bacteria isolated from a pre-
therapy respiratory specimen

Patient is considered ITT 
and not evaluated for 
efficacy

Patient withdrew consent or refused handheld 
device

Evaluate for efficacy if all 
data are available; if data are 
missing, then failure

Death

Failure

Adverse event, abnormal laboratory value 
(elevated creatine, etc)

Failure

New therapy incompatible with aerosol therapy

Failure

Discharged/lost to follow-up

Failure

Any other reason/unknown reason

Failure
The primary analysis will compare the proportion of patients with Clinical Success in the 
BAY 41-6551 group versus the proportion in the placebo group, using the combined data 
from studies 13084 and 13085. All assessments other than Clinical Success - failures, 
improvements, and missings (those patients who do not have a TOC assessment) will be 
grouped together in the Clinical Failure category for the purposes of this analysis.
The null (H0) and the alternative (H1) hypothesis for this primary analysis is the following:

H0: p[BAY 41-6551] = p[placebo]

H1: p[BAY 41-6551] ≠ p[placebo]
where p is the true Clinical Success rate.  
A Cochran-Mantel-Haenzel test of general association, adjusting for stratum and geographic 
region, will be performed as the primary efficacy analysis.  If the p-value from this test is less 
than 0.05, and the proportion of patients with Clinical Success is higher in the BAY 41-6551 
group than in the placebo group, the study will have achieved its primary objective. 
In addition, as a supportive analysis, a 95% confidence interval will be calculated for the odds 
ratio.  This confidence interval will be generated from a logistic regression model with 
Clinical Success as the primary variable, and treatment, stratum, and geographic region as the 
independent variables.  If the lower limit of the 95% confidence interval for the odds ratio 
(BAY 41-6551/placebo) is greater than 1, BAY 41-6551 will be demonstrated to be 
statistically superior to placebo. 
The individual components of the composite endpoint will be analyzed using Mantel-
Haenszel adjusting for stratum and geographic region.  This is to assess if the components are 
moving in the same general direction and which, if any, single component is driving the 
result.
Tests will be performed using the SAS procedure FREQ, and the 95% confidence intervals 
for the odds ratios will be generated using PROC LOGISTIC. 


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An unadjusted chi-squared test will also be performed as a supportive efficacy analysis.  In 
addition, a logistic regression model with only treatment as an independent variable will be 
performed, and the resulting 95% confidence interval for the odds ratio will be provided.  
These analyses will serve as sensitivity analyses to demonstrate consistency with the primary 
analysis. 
The Breslow-Day test will be used as a further supportive analysis to test for treatment by 
geographic region and treatment by stratum interaction.  If this test of the homogeneity of the 
odds ratio indicates a significant interaction, exploratory analyses will attempt to define its 
source.  A Cochran-Mantel-Haenzel test of general association, adjusting for stratum and 
study protocol (ie, 13084 or 13085), will be performed to assess the effect of study protocol 
on the primary outcome Clinical Success.  Geographic region will not be included in this 
model as the 2 studies were conducted in different regions.
Exploratory descriptive summaries will be provided for the primary efficacy variable by 
treatment group and pre-determined subgroups of interest.  These subgroups will include:

Type of ventilator

Underlying diagnosis

Positive or negative blood culture

CPIS (at pre-therapy)

APACHE II score (< 20, 20)

Age (< 45, 45-64, 65)

Sex

Race

Country

Body mass index (BMI) (< 25, 25 - < 30, 30)

Baseline Gram-negative antibiotic treatment regimen (to be determined by actual 
baseline antibiotic usage; antibiotic groups will be determined before unblinding)
In addition, an analysis of Clinical Success will be conducted that excludes patients who 
received anti-microbial therapy considered to be effective against Gram-negative organisms, 
for infections other than the underlying pneumonia.  Patients will only be excluded from this 
analysis if the additional anti-microbial therapy was administered before the TOC visit and 
the patient was not a Clinical Failure.
An additional descriptive exploratory analysis will be performed to compare the baseline 
characteristics of the patients who have the following TOC clinical responses:

Cure or failure

Indeterminate

Missing


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Baseline characteristics will be shown by each of the three groups (cure/failure, 
indeterminate, missing).  If the number of patients with indeterminate or missing responses is 
low, these groups will be combined.
New Text
The primary efficacy variable is Survival through the LFU visit.  Survival is achieved when 
the patient is alive through the LFU visit. No other factors are considered in the evaluation of 
survival.
The primary analysis will compare the survival rates through LFU visit of patients in the 
BAY 41-6551 group versus patients in the placebo group, using the combined data from 
studies 13084 and 13085.
The null (H0) and the alternative (H1) hypothesis for this primary analysis is the following:

H0: p[BAY 41-6551] = p[placebo]

H1: p[BAY 41-6551] ≠ p[placebo]
where p is the true Survival rate.  
A Cochran-Mantel-Haenzel test of general association, adjusting for stratum and geographic 
region, will be performed as the primary efficacy analysis.  If the p-value from this test is less 
than 0.05, and the proportion of patients who survive is higher in the BAY 41-6551 group 
than in the placebo group, the study will have achieved its primary objective. 
In addition, as a supportive analysis, a 95% confidence interval will be calculated for the odds 
ratio.  This confidence interval will be generated from a logistic regression model with 
Survival as the primary variable, and treatment, stratum, and geographic region as the 
independent variables.  If the lower limit of the 95% confidence interval for the odds ratio 
(BAY 41-6551/placebo) is greater than 1, BAY 41-6551 will be demonstrated to be 
statistically superior to placebo. 
Tests will be performed using the SAS procedure FREQ, and the 95% confidence intervals 
for the odds ratios will be generated using PROC LOGISTIC. 
An unadjusted chi-squared test will also be performed as a supportive efficacy analysis.  In 
addition, a logistic regression model with only treatment as an independent variable will be 
performed, and the resulting 95% confidence interval for the odds ratio will be provided.  
These analyses will serve as sensitivity analyses to demonstrate consistency with the primary 
analysis. 
The Breslow-Day test will be used as a further supportive analysis to test for treatment by 
geographic region and treatment by stratum interaction.  If this test of the homogeneity of the 
odds ratio indicates a significant interaction, exploratory analyses will attempt to define its 
source.  A Cochran-Mantel-Haenzel test of general association, adjusting for stratum and 
study protocol (ie, 13084 or 13085), will be performed to assess the effect of study protocol 
on the primary efficacy variable Survival.  Geographic region will not be included in this 
model as the 2 studies were conducted in different regions.


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The primary efficacy analysis performed on the mITT population will be repeated for ITT 
population.
Exploratory descriptive summaries will be provided for the primary efficacy variable by 
treatment group and pre-determined subgroups of interest.  These subgroups will include:

Type of ventilator

Underlying diagnosis

Positive or negative blood culture

CPIS at pre-therapy (< 6, 6, 7, 8, 9, 10, 11)

APACHE II score (< 20, 20)

Age (<18, 18 to <45, 45 to < 65, 65 to <75, ≥75 years)

Sex

Race

Country

Geographic region

Latin America countries (Brazil, Colombia, Mexico)

Asia Pacific countries (Philippines, South Korea, Taiwan, Thailand, China, Japan)

Baseline Gram-negative antibiotic treatment taken by each patient (1, 2, ≥3)

Primary reason for intubation (Current pneumonia-related respiratory failure vs 
everything else)

Patients who received IV antibiotic for pneumonia ≥5 days after day of first 
intubation (Yes, No); 

Patients who received at least one dose of carbapenem during Days 1 through 10 
(Yes, No); 

Start time of amikacin from start time of IV antibiotic (0 to <12 hours, 12 to <24 
hours, >24 hours). 

Patients with confirmed MDR pathogens (MDR first detected at baseline, MDR 
first detected post-baseline, Not MDR); 

Patients with confirmed ESBL pathogens (ESBL first detected at baseline, ESBL 
first detected post-baseline, Not ESBL); 
The last 2 subgroups above pertain to MDR designation which is described in detail in 
Appendix 9.1:

To be declared a MDR, a bacterial isolate at the same visit must be resistant using 
the central laboratory interpretation to at least 3 of the 7 drug classes on the 
susceptibility panel: aminoglycoside, β-lactam/β-lactamase inhibitor, cephams, 


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carbapenam, tetracycline, folate pathway inhibitor, and quinolone. Once a patient 
has any MDR pathogen, he/she should be designated as a MDR patient no matter 
what the subsequent susceptibility tests show.

For the 3 cephams (ceftazidime, cefazolin, and cefpodoxime), resistance to any 
one of the 3 drugs in the panel counts as cepham resistance for the category.

An interpretation by central laboratory of “Not applicable” result will be 
considered as “susceptible” for purposes of MDR tabulation. This means that at 
least 3 results of “intermediate” or “resistant” are necessary for an MDR 
designation, and a “Not applicable” will not be included in the total. 
Section 11.4 Methods for the Analysis of Secondary Efficacy Parameters –
amended
Old Text
If the null hypothesis for the primary efficacy variable is rejected, a formal hypothesis testing 
scenario will be applied for the secondary efficacy variables:

Pneumonia-related mortality through the LFU visit
…
For the purpose of the sequential testing procedure, the only effect in the models will be 
treatment. As supportive analyses, additional models will be used with effects included for 
geographic region for all secondary variables.  Non-parametric tests for treatment 
comparisons will be considered as sensitivity analyses.
The other endpoints –total number of days of Gram-negative antibiotics, clinical response 
rates at end of therapy, change in component of CPIS score from baseline to TOC, 
microbiological eradication rates, the number of days in the hospital, and relapse rates will be 
summarized descriptively, however for the total number of days of Gram-negative antibiotics 
analysis of variance will be used to test the null hypothesis of no difference between BAY 41-
6551 and placebo.  In addition, Kaplan-Meier curves will be provided for time to Clinical 
Failure.  The Investigator Assessment of Patient Outcome will be analyzed as sensitivity 
analysis.
New Text
If the null hypothesis for the primary efficacy variable is rejected, a formal hypothesis testing 
scenario will be applied for the secondary efficacy variables:

Pneumonia-related mortality through the LFU visit (determined by blinded 
adjudication committee)
…
For the purpose of the sequential testing procedure, the only effect in the models will be 
treatment. As supportive analyses, additional models will be used with effects included for 


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geographic region for all secondary variables.  Non-parametric tests for treatment 
comparisons will be considered as sensitivity analyses.
The secondary endpoint of pneumonia-related mortality through the LFU visit will be 
examined further by subgroups listed for the primary analysis.  
All 4 secondary endpoints will be examined further by the following MDR subgroups:

Patients with confirmed MDR pathogens (MDR first detected at baseline, MDR 
first detected post-baseline, Not MDR); 

Patients with confirmed ESBL pathogens (ESBL first detected at baseline, ESBL 
first detected post-baseline, Not ESBL); 

Patients who received IV antibiotic for pneumonia ≥5 days after day of first 
intubation (Yes, No); 

Patients who received at least one dose of carbapenem during Day 1 through 10 
(Yes, No); 

Start time of amikacin from start time of IV antibiotic (0 to <12 hours, 12 to <24 
hours, ≥24 hours).
The other efficacy endpoints are:
1. The number of days in the hospital through LFU visit
2. Relapse rates at LFU
3. Total number of days of Gram-negative antibiotics
4. Change in component of CPIS score from baseline to TOC
5. Clinical response rates at EOT (Clinical cure, Clinical failure)
Analysis of variance will be used to test the null hypothesis of no difference between BAY 
41-6551 and placebo for the total number of days of Gram-negative antibiotics. The other 
four efficacy endpoints listed above will be summarized descriptively. 
Section 11.5 Additional Analyses of Clinical Success  - amended
Added Text
11.5 Additional Analyses of Clinical Success - amended
The following endpoints will be analyzed as additional analyses of clinical success:
11.5.1 Foundation for the National Institute of Health Criteria - amended
Clinical success using FNIH recommendations is defined as mITT patients who survived
through the LFU visit and did not have septic shock. Patients will be designated as having a 
septic shock event based on the standard medical queries (SMQ) terms tabulated as adverse 


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events. Descriptive analysis will be provided with 95% confidence intervals. Cochran-
Mantel-Haenszel test of general association adjusting for stratum and geographic region will 
also be performed. 
11.5.2 Investigator Assessment of Patient Outcome - amended
Investigator Assessment of Patient Outcome is determined at the TOC visit. The outcomes of 
“success” or “failure” are based on the following criteria:

Improvement or lack of progression of all abnormalities on chest radiograph 

Resolution towards normal of the following CPIS components: tracheal secretions 
(volume and purulence), temperature, blood leukocytes, oxygenation (P/F ratio) 

Any further change to the Gram-negative portion of the antimicrobial regimen being used 
to treat pneumonia during the first 10 days, after the initial antimicrobial adjustment 
within the first 96 hours after the initiation of empiric therapy or as soon as initial culture 
and susceptibility results are available and excepting the discontinuation of 
aminoglycosides after 5-7 days, would be considered a Clinical Failure

Patient must not receive antibiotic therapy for pneumonia after  Day 10 (EOT)

Patient must survive through the TOC visit
All 5 conditions listed above must be met to achieve Investigator’s Assessment of Patient 
Outcome to be a Success. At the LFU visit, an assessment of relapse will be considered to be 
Failure.
These endpoints will be summarized descriptively with 95% confidence interval. A Cochran-
Mantel-Haenszel test of general association adjusting for stratum and geographic region will 
be performed on the mITT patients. 
In addition, Kaplan-Meier curves will be provided for time to Investigator Assessment of 
Clinical Failure. Time to Clinical Failure is defined as the time from the first day of study 
drug intake to the first time at which clinical failure is assessed. Patients who do not fail will 
be censored at death date, their LFU visit or last visit.
11.5.3 Clinical Success (Former 5 Component Primary Endpoint) -
amended
Clinical Success is achieved when the following criteria are met as listed in the order of 
medical relevance:

The patient must survive through the Late Follow-Up (LFU) visit

Systemic antibiotics (IV or PO) for pneumonia must be stopped on or before the TOC 
visit (Day 17-19), 

Systemic antibiotics (IV or PO) for pneumonia must not be restarted after the TOC 
visit through the LFU visit

The patient must have stable respiratory function evaluated at TOC or last visit based 
on the PaO2/FiO2 (P/F) ratio as outlined below (if P/F ratio is not available at the 
TOC, use the P/F ratio value from the closest previous visit), and 


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
The patient must not have a reported AE of lung abscess or empyema through the 
LFU visit
Stable respiratory function

Patient is extubated at the TOC visit or

Patient is intubated at the TOC and:
o
Patient has P/F ratio > 200 at the TOC visit or
o
Patient has P/F ratio > 100 and ≤ 200 at the TOC visit and:
o
Patient had a P/F ratio ≤ 200 at baseline
If ventilation status not explicitly known to be extubated for a patient at TOC or last visit, the 
status was assumed to be intubated for the determination of primary endpoint.
Unstable respiratory function

Patient has a P/F ratio ≤ 100 at the TOC visit or

Patient has a P/F ratio > 100 and ≤ 200 at the TOC visit and:

Patient has P/F ratio > 200 at baseline
The outcome is Clinical Success if all 5 criteria are met. If any one of the criteria is not met, 
then the patient is considered a Clinical Failure. Patients who do not have a clinical 
assessment of success due to missing data will be considered a Clinical Failure.
For patients who discontinue study drug (on vent or handheld) for reasons other than efficacy 
will be handled as described in the table below:                                                                                                        
Reason for Discontinuation of Aerosol 
Therapy
Outcome / Comments
No Gram-negative bacteria isolated from a pre-
therapy respiratory specimen
Patient is considered ITT analysis and not 
evaluated for efficacy analysis as mITT
Patient withdrew consent or refused handheld 
device
Evaluate for efficacy if all data for primary 
efficacy are available; if data are missing, 
then failure
Death
Failure
Adverse event
Failure
New therapy incompatible with aerosol therapy
Failure
Lost to follow-up
Failure
Any other reason/unknown reason
Failure


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Additional reasons for discontinuation may be included as failure after review of blinded 
data. The patient must have stable respiratory function evaluated at TOC or last visit based on 
the ventilation status and PaO2/FiO2 (P/F) ratio (if ventilation status or P/F ratio is not 
available at the TOC, use the respective ventilation status or P/F ratio value from the closest 
previous visit).  See Section 6.2.1.1, Definition of Primary Efficacy Endpoint.
The analysis will compare the proportion of patients with Clinical Success in the BAY 41-
6551 group versus the patients in the placebo group, using the combined data from studies 
13084 and 13085. All assessments other than Clinical Success, which are, failures, 
improvements, and missing (those patients who do not have a TOC assessment) will be 
grouped together in the Clinical Failure category for the purpose of this analysis. If a TOC 
assessment is missing for determining the antibiotic criteria for a patient, the TOC assessment 
will be assumed to have occurred 17 days after the start of study drug.  
A Cochran-Mantel-Haenszel test of general association, adjusting for stratum and geographic 
region, will be performed as the primary efficacy analysis. If the p-value from this test is less 
than 0.05, and the proportion of patients with Clinical Success is higher in the BAY 41-6551 
group than in the placebo group, the study will have demonstrated superiority in this 
sensitivity analysis.
In addition, as a supportive analysis, a 95% confidence interval will be calculated for the odds 
ratio. This confidence interval will be generated from a logistic regression model with 
Clinical Success as the additional efficacy variable, and treatment, stratum, and geographic 
region as the independent variables. If the lower limit of the 95% confidence interval for the 
odds ratio (BAY 41-6551/placebo) is greater than 1, BAY 41-6551 will be demonstrated to 
be statistically superior to placebo.
Individual components of the composite endpoint will be analyzed using the Cochran-
Mantel-Haenszel test adjusting for stratum and geographic region. This is to assess the 
components are moving in the same general direction and which, if any, single component is 
driving the result. The analysis of individual components will be performed on the actual 
counts of each criterion, not ordered by medical relevance.
Tests will be performed using the SAS procedure FREQ, and the 95% confidence intervals 
for the odds ratios will be generated using PROC LOGISTIC.
An unadjusted chi-squared test will also be performed as a supportive efficacy analysis. In 
addition, a logistic regression model with only treatment as an independent variable will be 
performed, and the resulting 95% confidence interval for the odds ratio will be provided. 
The Breslow-Day test will be used as a further supportive analysis to test for treatment by 
geographic region and treatment by stratum interaction. If this test of the homogeneity of the 
odds ratio indicate significant interaction (P < 0.10), exploratory analyses will attempt to 
define its source. 
A Cochran-Mantel-Haenszel test of general association, adjusting for stratum and study 
protocol (i.e., 13084 or 13085), will be performed to assess the effect of study protocol on the


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Clinical Success as additional efficacy variable. Geographic region will not be included in 
this model as the 2 studies were conducted in different regions. 
Number and percent of patients meeting the each failure criteria will be summarized in the 
order of medical relevance as presented in Section 6.2.2. A patient with failure is counted 
only in the criteria with highest medical relevance in the order presented. Patients may not 
have any failure criteria, but not be included in the analysis due to missing data. To account 
for missing visits, the number of patients without failure criteria but has TOC visit and 
missing LFU visit will be presented. Additional summary of respiratory stability function will 
be given for components of stable respiratory function and unstable respiratory function for 
each treatment group.
Section 15.1
Old Text
….
Late Follow-Up Questionnaire
X
X
Notes:
….
s – Pulse oximetry not required at the premature discontinuation/early withdrawal and TOC visits.
New Text
….
Late Follow-Up Questionnaire
X
X
Notes:
….
s – An arterial blood gas is needed at the TOC and premature discontinuation visits.

SAP_001.pdf: 
 
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 
NCT number: 
NCT01799993 and NCT00805168 
Document date: 
03 NOV 2017 
 


Combined Statistical Analysis Plan  
PH-39322 
03 NOV 2017 
BAY 41-6551 IMPACT number 13084/13085 
Page 1 of 44
 
Statistical Analysis Plan Final Version 6.0 
Reference Number: RD-OI-0119 Supplement Version: 8 
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 
INHALE 1&2 
BSP study drug: 
BAY 41-6551 (Amikacin Solution for Inhalation and the Pulmonary 
Drug Delivery System [PDDS Clinical])   
 
Study purpose: 
Confirmatory for registration   
Clinical study 
phase: 
III 
Date: 3 November 2017 
 
Study No.: 
 
13084 & 13085 
Version: 6 
 
Author: 
   
 
 
 
 
Confidential 
The information provided in this document is strictly confidential and is intended solely 
for the guidance of the clinical investigation.  Reproduction or disclosure of this 
document, whether in part or in full, to parties not associated with the clinical 
investigation or its use for any other purpose without the prior written consent of the 
sponsor is not permitted. 
Throughout this document, symbols indicating proprietary names (®, TM) are not displayed.  Hence, the 
appearance of product names without these symbols does not imply that these names are not protected. 
This Statistical Analysis Plan is produced on a word-processing system and bears no signatures. 
The approval of the Statistical Analysis Plan is documented in a separate Signature Document. 
PPD


Combined Statistical Analysis Plan  
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BAY 41-6551 IMPACT number 13084/13085 
Page 2 of 44
 
Statistical Analysis Plan Final Version 6.0 
Reference Number: RD-OI-0119 Supplement Version: 8 
Table of Contents 
Table of Contents ....................................................................................................................... 2 
Table of Tables .......................................................................................................................... 3 
Abbreviations ............................................................................................................................. 4 
1. 
Introduction ........................................................................................................................ 5 
2. 
Study Objectives ................................................................................................................. 5 
3. 
Study Design ...................................................................................................................... 5 
3.1 
Design Overview ......................................................................................................... 5 
3.2 
Schedule of Procedures – amended ............................................................................. 7 
3.3 
Determination of Sample Size ................................................................................... 11 
4. 
General Statistical Considerations .................................................................................... 11 
4.1 
General Principles ..................................................................................................... 11 
4.2 
Handling of Dropouts ................................................................................................ 11 
4.3 
Handling of Missing Data ......................................................................................... 11 
4.4 
Interim Analyses and Data Monitoring ..................................................................... 12 
4.5 
Data Rules ................................................................................................................. 12 
4.6 
Validity Review ......................................................................................................... 13 
5. 
Analysis Sets .................................................................................................................... 13 
5.1 
Assignment of analysis sets ....................................................................................... 13 
6. 
Statistical Methodology .................................................................................................... 14 
6.1 
Population characteristics .......................................................................................... 14 
6.1.1 
Disposition of patients .................................................................................... 14 
6.1.2 
Demographic and Baseline Characteristics .................................................... 14 
6.1.3 
Medical History .............................................................................................. 15 
6.1.4 
Concomitant Medications .............................................................................. 16 
6.1.5 
Study Medication Exposure ........................................................................... 16 
6.2 
Efficacy ..................................................................................................................... 16 
6.2.1 
Primary Efficacy Endpoints ........................................................................... 16 
6.2.2 
Secondary Efficacy Endpoints ....................................................................... 19 
6.2.3 
Other Efficacy Analysis ................................................................................. 21 
6.2.4 
Additional Analysis of Clinical Success ........................................................ 21 
6.2.5 
Microbiological Analysis ............................................................................... 25 
6.3 
Mortality .................................................................................................................... 28 
6.4 
Pharmacokinetics / pharmacodynamics .................................................................... 28 
6.5 
Safety ......................................................................................................................... 29 
6.5.1 
Adverse Events ............................................................................................... 29 
6.5.2 
Device Events ................................................................................................. 32 
6.5.3 
Laboratory Data.............................................................................................. 32 
6.5.4 
Vital Signs ...................................................................................................... 33 
6.5.5 
ECG Data ....................................................................................................... 33 
6.6 
Additional analyses ................................................................................................... 33 
7. 
Document history and changes in the planned statistical analysis ................................... 33 
8. 
References ........................................................................................................................ 36 


Combined Statistical Analysis Plan  
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Statistical Analysis Plan Final Version 6.0 
Reference Number: RD-OI-0119 Supplement Version: 8 
9. 
Appendices ....................................................................................................................... 36 
9.1 
Appendix A: MDR Subgroup Analysis Plan ............................................................ 37 
9.2 
Appendix B: Definition of organ failure ................................................................... 41 
9.3 
Appendix C: Definition of bronchial hyperreactivity ............................................... 43 
9.4 
Appendix D: Definition of toxic-septic shock conditions ......................................... 44 
 
Table of Tables 
Table 3–1 Schedule of Procedures - amended ........................................................................... 7 
Table 3–2 Sampling scheme of the PK substudy..................................................................... 10 
Table 4–1 Assignment of visits................................................................................................ 13 
Table 6–1 Outcome of patients who discontinue study drug ................................................... 23 
Table 6–2 Safety topics of special interest .............................................................................. 32 
Table 7–1 Document history and changes in the planned statistical analysis ......................... 33 
Table 9–1 MDR Subgroup Analysis Plan ................................................................................ 37 
Table 9–2 MDR designation .................................................................................................... 40 
Table 9–3 Preferred terms for "organ failure" under MedDRA v20.0 .................................... 41 
 


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Statistical Analysis Plan Final Version 6.0 
Reference Number: RD-OI-0119 Supplement Version: 8 
Abbreviations 
AE 
Adverse events 
AESI 
Adverse event of special interest 
APACHE II 
Acute Physiology and Chronic Health Evaluation II 
ATC 
Anatomic Therapeutic Chemical Classification System 
BAL 
Bronchoalveolar lavage 
BMI 
Body Mass Index 
CPIS 
Clinical Pulmonary Infection Score 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EOT 
End of treatment 
ESBL 
Extended Spectrum Beta-Lactamase 
FNIH 
Foundation for the National Institute of Health 
H0 
Null hypothesis 
H1 
Alternative hypothesis 
ICU 
Intensive Care Unit 
ITT 
Intent to treat 
IV 
Intravenous 
IVRS 
Interactive Voice Response System 
LFU 
Late Follow-up 
MDR 
Multidrug resistant 
MedDRA 
Medical dictionary for regulatory activities 
MIC 
Minimum inhibitory concentration 
mITT 
Modified Intent to treat 
MLG 
MedDRA labeling groupings 
N 
Number 
PDDS Clinical 
Pulmonary Drug Delivery System 
PaO2/FiO2 (P/F) 
Ratio of arterial oxygen partial pressure to fractional inspired oxygen 
PT 
Preferred Term 
SAE 
Serious adverse event 
SAP 
Statistical Analysis plan 
SAS 
Statistical Analysis System 
SD 
Standard deviation 
SI 
International System of Units 
SOC 
System Organ Class 
TA 
Tracheal aspirate 
TEAE 
Treatment-emergent adverse event 
TEAESI 
Treatment-emergent adverse event of special interest 
TOC 
Test of cure 
WBC 
White blood cells 
WHO-DD 
World Health Organization-Drug Dictionary 
 
 


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Statistical Analysis Plan Final Version 6.0 
Reference Number: RD-OI-0119 Supplement Version: 8 
1. Introduction 
This statistical analysis plan describes the study objectives, study design, study population, 
efficacy and safety variables, statistical analysis methods, and study tables to be used in this 
study.  
This version is based on study protocol 13084 amendment 8.0, version 9.0, dated 29 August 
2017 and 13085 amendment 19, version 8.0, dated 29 August 2017 . 
Inhaled amikacin as an adjunctive therapy to intravenously (IV) or intramuscularly (IM) 
(guideline directed) standard therapy for patients with gram-negative pneumonia may have 
potential to improve survival. Inhalation administration minimizes systemic exposure while 
delivering drug directly to the site of infection. This study will investigate the use of inhaled 
amikacin for the treatment of serious bacterial respiratory infections in intubated and 
mechanically-ventilated patients using a proprietary Pulmonary Drug Delivery System 
(PDDS Clinical). 
2. Study Objectives 
The study objective is to demonstrate that as adjunctive therapy to IV antibiotics, BAY 
41-6551 400 mg (amikacin as free base) administered as an aerosol by the 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 efficacy endpoint is 
Survival as defined in protocol Section 8.2 and in Section 6.2.1.1 of this document. The 
secondary objectives are to evaluate the superiority of aerosolized BAY 41-6551 versus 
aerosolized placebo in clinical success rate, pneumonia-related mortality, the Early Clinical 
Response at Day 10, the days on ventilation, and the days in the ICU. 
3.  Study Design 
3.1 Design Overview 
This is a Phase III, prospective, randomized, double-blind, placebo controlled, multicenter, 
multinational study designed to show that aerosolized BAY 41-6551 400 mg (amikacin as 
free base) every 12 hours is more effective than placebo (aerosolized normal saline), as 
adjunctive therapy to IV antibiotics in both arms, in intubated and mechanically-ventilated 
patients with Gram-negative pneumonia. The safety and tolerability of aerosolized BAY 
41-6551 and the microbiological endpoints will also be evaluated. All patients will receive 
standard of care IV antibiotic therapy with consideration to include 2 antibiotics as per the 
ATS/IDSA guidelines. Patients who are extubated before completing the full course (10 
calendar days if the first dose is administered in the AM or 11 calendar days if the first dose 
is administered in the PM [20 doses]) of aerosol therapy will be continued on aerosolized 
therapy with the handheld adaptor.  
A combined total of approximately 724 intent to treat (ITT) patients will be recruited to study 
13084 and to study 13085 (being conducted in different countries; the protocols are identical 


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Statistical Analysis Plan Final Version 6.0 
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with the exception that study 13085 has a pharmacokinetic substudy). The 724 total patients 
will be recruited competitively between studies 13084 and 13085; there are no minimum 
requirements for recruitment totals in either study. The patients will be randomized in 1:1 
ratio to receive either 400 mg BAY 41-6551 (amikacin as free base) every 12 hours or 
aerosolized placebo every 12 hours in addition to ATS/IDSA guided IV antibiotic therapy to 
allow for completion of at least 472 evaluable modified intent to treat (mITT) patients in the 
primary efficacy analysis. The studies will be conducted at approximately 256 centers in 
North America, South America, Asia Pacific, Australia and Europe. 
The duration of antibiotic therapy (both intravenous and aerosol) will be 10-12 full days; 
patients will be followed up to 28-32 Days after start of study drug. The end of the study for 
regulatory purposes is the date the last randomized patient completed the end of study visit.  
Patients will be stratified by disease severity using the Acute Physiology and Chronic Health 
Evaluation (APACHE II) score (stratum I:  APACHE II < 20, stratum II:  APACHE II ≥ 20) 
by geographic region (or country). The APACHE II score that will be used to stratify the 
patient is the score calculated at the time the patient is evaluated for entry into the study. 
Values used to calculate the APACHE II score (e.g. temperature, WBC counts, etc.) may be 
obtained at any time during the 48-hour screening period.  
Once stratified, patients will be randomized in a double-blind fashion using a 1:1 allocation 
of patients to BAY 41-6551 versus placebo through the Interactive Voice Response System 
(IVRS). 
No interim analysis is planned. 


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Statistical Analysis Plan Final Version 6.0 
Reference Number: RD-OI-0119 Supplement Version: 8 
3.2 Schedule of Procedures – amended 
 
Table 3–1 Schedule of Procedures - amended 
 
 
Day 
Prematu
re D/C/ 
Early 
Withdra
wal 
TOC 
Day 
17 
to 
19 
Late Follow-
Up 
Day 28 to 32b 
 
Assessment 
 
Screeni
ng 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
8 
 
9 
 
10a 
(EO
T) 
In  
Perso
n 
By 
Phon
e 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical/Medication History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medicationc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete Physical Exam/Vitalsd 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
Brief Physical Exam/Vitalse 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Assessment of clinical signs and 
symptoms of pneumonia 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Chest X-Ray 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
Xr 
 
Urine or Serum pregnancy testf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology/ 
Serum Chemistry/Urinalysis 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
X 
 
Serum creatinineg 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Aerobic blood cultureh 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Arterial blood gases/pulse oximetry1 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
Xs 
Xs 
Xr 
 
Collection of ventilator parameters pre- 
and post-dose2 
 
X 
X 
X 
X 
X 
X 
X 
X 
X3 
X4 
 
 
 
 
                                                 
1 Footnote s added with Protocol 13084 Amendment 6 and Protocol 13085 Amendment 16. 
2 Per Protocol 13084 Amendment 5 and Protocol 13085 Amendment 11 
3 Added with Protocol 13084 Amendment 6 and Protocol 13085 Amendment 16 as it was erroneously omitted. 
4 Added with Protocol 13084 Amendment 6 and Protocol 13085 Amendment 16 as it was erroneously omitted. 


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Statistical Analysis Plan Final Version 6.0 
Reference Number: RD-OI-0119 Supplement Version: 8 
 
 
Day 
Prematu
re D/C/ 
Early 
Withdra
wal 
TOC 
Day 
17 
to 
19 
Late Follow-
Up 
Day 28 to 32b 
 
Assessment 
 
Screeni
ng 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
8 
 
9 
 
10a 
(EO
T) 
In  
Perso
n 
By 
Phon
e 
Collect respiratory specimen for Gram 
stain and culturei 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
Xr 
 
Pleural fluid culturej 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CPISk 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
X 
 
APACHE II score  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense PDDS Clinical Device 
 
Xm 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense Study Medication/Nebulizer 
 
Xn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Administer Study Medication 
 
Xo 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Serum amikacin trough levelp 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
AEs 
Xq 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adjunct Therapy and Procedures 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Investigator Assessment of Patient 
Outcome5 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Late Follow-Up Questionnaire 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Notes:  Screening is within 48 hours prior to randomization; AEs = adverse events; APACHE II = Acute Physiology and Chronic Health 
Evaluation II; BAL = bronchoalveolar lavage; CPIS = Clinical Pulmonary Infection Score; D/C = discontinuation; EOT = end of therapy; LFU = 
late follow-up; PBS = protected specimen brush; TA = tracheal aspirate; TOC = Test-of-Cure. 
a - All assessments at Day 10 should be done after the last dose of aerosolized treatment that corresponds to the completion of 20 doses. 
b - Patients will be strongly encouraged to return to their study facility for their LFU.  This questionnaire needs to be completed whether in 
person or via a phone conversation with the patient, or the patient’s advocate including recording concomitant medication and AEs. 
c - Include previous concomitant or posttherapy antibacterials, antifungals, and antivirals (within 2 weeks before start of treatment or during 
follow-up).  
d - Include weight, height (screening visit only), heart rate, blood pressure, respiratory rate, daily maximum temperature, and complete review of 
body systems 
e - Include weight, heart rate, blood pressure, respiratory rate, daily maximum temperature, and review of body systems 
f - Females of child-bearing potential only 
                                                 
5 Per Protocol 13084 Amendment 6 and Protocol 13085 Amendment 16 


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Day 
Prematu
re D/C/ 
Early 
Withdra
wal 
TOC 
Day 
17 
to 
19 
Late Follow-
Up 
Day 28 to 32b 
 
Assessment 
 
Screeni
ng 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
8 
 
9 
 
10a 
(EO
T) 
In  
Perso
n 
By 
Phon
e 
g - Serum creatinine levels should be obtained once daily and the results available and reviewed prior to the next dose. 
h - Culture should be obtained from 2 separate venipuncture sites.  If the result is positive, repeat as needed (Days 1, 3, 5, 7, 10, TOC, LFU) 
until negative. 
i - A respiratory specimen (e.g., TA, BAL, mini-BAL, or PSB) will be obtained for Gram stain, semi-quantitative or quantitative culture, and 
susceptibility testing.  NOTE: All respiratory specimens will be evaluated by Gram stain and rejected for culture if the Gram stain reveals >10 
squamous epithelial cells per low powered (100 x) field. 
j - Pleural fluid cultures should only be obtained for patients with evidence of a pleural effusion and if clinically indicated.  Cultures from any 
other respiratory specimens should also be obtained if clinically indicated.  If the result is positive, repeat as needed if clinically indicated (Days 
1, 3, 5, 7, 10, TOC, LFU) until negative. 
k - CPIS must be greater than or equal to 6 for inclusion into study. 
l – Footnote deleted per Amendment 16 
m - Prior to the first dose, each patient will receive a unique PDDS Clinical device consisting of a unique control module, T-piece adaptor, 
AC/DC adaptor, air pressure feedback device, and cable. 
n - Prior to each dose, each patient will receive one vial of study medication (either BAY 41-6551 or placebo) and one nebulizer/reservoir.6 
o - Patients will be started on aerosolized study medication within 48 hours of systemic antibiotic therapy being initiated.  Patients will receive 
3.2 mL of either BAY 41-6551 (400 mg, amikacin as free base) or placebo every 12 hours via the PDDS Clinical for 10 days (20 doses).  If a 
patient is extubated during the course of treatment or has had a tracheostomy and is spontaneously breathing, aerosol administration will 
continue via the handheld adaptor for the remainder of the treatment period.7 
p - Serum amikacin for trough level will be obtained 30 ± 15 minutes8 prior to the first dose on each treatment day.   In addition, these trough 
levels should be obtained for all patients and be sent to the Central Laboratory.  If the site has mandated procedures for monitoring IV amikacin 
treatment, the site should perform these site-specific procedures in conjunction with the collection for serum amikacin levels 
q - AE reporting begins after the signing of the informed consent by the patient or their legally authorized representative. 
r - Optional assessments 
s – Pulse oximetry not required at the premature discontinuation/early withdrawal and TOC visits. 
                                                 
6 Per Protocol 13084 Amendment 6 and Protocol 13085 Amendment 16 
7 Per Protocol 13084 Amendment 6 and Protocol 13085 Amendment 16  
8 “± 15” added with Protocol 13084 Amendment 6 and Protocol 13085 Amendment 16 


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In addition to the procedures listed above, pharmacokinetic sampling for BAY 41-6551 
concentrations in tracheal aspirates, serum, and urine is performed in study #13085. The 
sampling scheme is outlined below. 
 
Table 3–2 Sampling scheme of the PK substudy 
Collection time on Day 1a, 3 and 10e [hr] 
Blood 
Urine 
Tracheal aspirateb 
(30 minutes before first dose) 
X 
Xc 
X 
0.25 ± 0.25 (after end of inhalation) 
X 
 
X 
1.0 ± 0.5 (after end of inhalation) 
X 
 
X 
2.0 ± 0.5 (after end of inhalation) 
X 
 
X 
4.0 ± 1.5 (after end of inhalation 
X 
 
X (optional) 
8.0 ± 2.0 (after end of inhalation) 
X 
 
 
12.0 ± 2.0 (trough) (after end of inhalation)d 
X 
 
X 
Abbreviations:  hr = hour(s). 
a  blood sampling 
b  if feasible, (e.g. before patients are extubated) 
c  on Day 1 only: Urine samples should be taken from 0 to 12hr(s) and from 12 to 24hr(s) 
d  The blood sample for 12 hrs after the end of the inhalation must be collected before second dose 
e  Samples on Day 10 are optional but should be collected in case patients were switched to the hand-
held inhalation device 
Note: The first collection after end of inhalation is done after 30 minutes for China and EU and 15 
minutes after for Japan. 
 


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3.3 Determination of Sample Size 
For this combined study (studies 13084 and 13085), a two group 2 test with a 0.05 two-sided 
significance level will have 81% power to detect the difference between BAY 41-6551 
survival rate at LFU of 80% and Placebo survival rate at LFU of 69% when the sample size in 
each group is 254. Assuming approximately 30% of patients will not be eligible for the 
primary efficacy analysis (i.e., will not have a pre-therapy Gram-negative organism) a total of 
362 ITT patients per group (724 overall) will be needed for the study, based on current 
surveillance. Note that with this sample size, an observed treatment group difference of as 
low as 7.74% could provide a statistically significant result. 
4. General Statistical Considerations 
4.1 General Principles 
The statistical evaluation will be performed by using the software package SAS release 9.1 or 
higher (SAS Institute Inc., Cary, NC, USA). Unless otherwise stated, all variables will be 
analyzed by descriptive statistical methods. The number of data available and missing data, 
mean, standard deviation, minimum, quartiles, median, and maximum will be calculated for 
continuous data. Frequency tables will be generated for categorical data. 
All analyses are based on data from both studies 13084 and 13085 combined. 
4.2 Handling of Dropouts 
Premature discontinuations from study drug will be summarized by treatment group, both for 
any type of discontinuation, and for each specific reason for discontinuation. For the overall 
discontinuation rate, a chi-squared test will be used to test the null hypothesis of no 
differences in the discontinuation rates between treatment groups. 
4.3 Handling of Missing Data 
In order to achieve the goal of a well conducted clinical trial according to Good Clinical 
Practice (GCP), every effort should be made to collect all data. However, despite best efforts, 
it may be inevitable that missing or incomplete data are reported.  
All missing or partial data will be presented in the patient data listings as they are recorded on 
the eCRF. Except as noted, missing data will not be imputed or carried forward in any 
statistical analysis. Missing responses for the secondary endpoints or additional analysis of 
clinical success will be included in the failure category. Missing responses can occur when 
the patients do not have a respiratory function assessment, and are not prematurely 
discontinued due to early treatment failure. Patients with missing data such that the primary 
endpoint assessment cannot be made are considered failures. This will also be the case for the 
secondary variable of early Clinical Response at the end of treatment (EOT) visit. 
For the secondary and other efficacy endpoint variables related to duration of mechanical 
ventilation/intensive care unit (ICU)/in the hospital, the following approach will be used. If 


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the complete stop date of mechanical ventilation/ ICU/antibiotic therapy is not known, 28 
days will be used for the calculation of the number of days. 
For the Clinical Pulmonary Infection Score (CPIS) variable, a last observation carried 
forward (LOCF) approach will be used for patients with missing value at Days 3, 5, 10/EOT, 
TOC and LFU visits. The LOCF is being used as a conservative imputation, since the 
evaluations of CPIS early in the course of disease are generally worse than subsequent 
assessments later in the course of the disease. This LOCF method will be used for any 
missing individual components of the score. The CPIS will then be calculated using the 
available values, plus the carried-forward value(s) in place of the missing value(s). 
For adverse events and concomitant medications, rules for handling missing or partial 
information will be implemented so as not to exclude patient data from analyses due to 
missing or missing or partially complete data. The general principle is as follows: 
If an adverse event start date is completely missing or partially missing, then it assumed that 
the start date occurs at the earliest time on-treatment whenever possible.  
If concomitant medication start date is completely missing, then the date is not imputed. 
Otherwise, if the concomitant medication start date is partially missing, then it is assumed 
that the start date occurs at the earliest time on-treatment whenever possible.  
If a concomitant medication or adverse event stop date is completely missing or partially 
missing, then the stop date is imputed to maximize the duration of the event or concomitant 
treatment. It should be noted that imputation of stop dates only applies to concomitant 
medications that are not ongoing and adverse events that are not ongoing (i.e. outcome is not 
resolved).  
4.4 Interim Analyses and Data Monitoring 
No interim analyses for the purposes of evaluating efficacy are planned. A Data Monitoring 
Committee will be used to monitor safety findings. Only negative safety findings would result 
in stopping the trial early, and Bayer personnel will remain blinded. 
4.5 Data Rules 
Generally, for each date stored in database a set of organizational variables will be derived in 
order to describe the temporal context of that date in the specific study: Phase of treatment 
(pre, during or post study treatment), day relative to the start of study treatment, day relative 
to the end of study treatment. 
Unless otherwise specified, baseline is defined as the last available value prior to the first 
dose of study treatment. Day 1 is assumed to be pre-dose if assessment time is not available.  
If assessment time is available, it will be used to determine pre-dose. 
For the determination of visit of premature discontinuation, assignment of visits were based 
on the study day related to the corresponding scheduled visits. 
 


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Table 4–1 Assignment of visits 
Study day 
Visit (AVISIT) 
< 1 
Screening 
1 to 9, inclusive 
Day 1, 2, 3, 4, 5, 6, 7, 8, 9, respectively 
10, 11 
Day 10 / End of Treatment 
17 to 19, inclusive 
Test of Cure 
28 to 32, inclusive 
Late Follow-up 
Refer to Section 4.3 for handling on missing data, as well as to Section 6.2, where for specific 
endpoints data rules are described, for example censoring subjects or definition of treatment-
emergent AEs. 
The countries will be pooled into the following geographical regions for purposes of 
subgroup and stratified analysis: 
 North America – United States, Canada, and Australia 
 Latin America –  Brazil, Colombia, and Mexico 
 Asia Pacific – Philippines, South Korea, Taiwan, Thailand, China, and Japan 
 Europe – Czech Republic, Turkey, Belgium, Netherlands, France, Greece, Spain, 
Israel, Portugal, Hungary, Poland, Russia, and Ukraine. 
The analysis described in this statistical analysis plan (SAP) will be performed for all 
geographical regions. A separate set of tables, figures and listings will be produced for each 
country requiring country analysis report (CAR).  
4.6 Validity Review 
The main concern of the validity review is to make sure that the mITT population, that is ITT 
population with a documented gram negative pathogen and have an APACHE II score ≥ 10, 
is well identified in the study. The results of the validity review meeting will be documented 
in the Validity Review Report and may comprise decisions and details relevant for statistical 
evaluation. Any changes to the statistical analysis prompted by the results of the validity 
review meeting will be documented in a supplement to this SAP, if applicable, or in the 
Clinical Study Report. 
5. Analysis Sets 
5.1 Assignment of analysis sets 
The primary population for all efficacy analyses is the modified intent-to-treat (mITT) 
population, defined as all randomized patients with culture-confirmed Gram-negative bacteria 
who have been treated with at least one dose of study medication, and have an APACHE II 
score ≥ 10 at the time of diagnosis of pneumonia. Patients in the mITT population will be 
analyzed in the treatment group assigned. The ITT population is defined as all patients treated 
with at least one dose of study drug. 


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For efficacy analyses, patients in the ITT population will be analyzed in the treatment group 
assigned.  
ITT for Safety population will be defined as ITT patients who will be analyzed as treated for 
safety analyses. Safety analysis will also be performed on mITT patients who will be 
analyzed as treated. 
Pharmacokinetic dataset (PKS) includes ITT patients from whom a valid PK sample was 
obtained. This includes PK data from any of the 4 specimen types (tracheal aspirate, BAL, 
serum, urine) from both studies (13084 and 13085), i.e. also trough samples. Valid PK 
sample is determined by PK validity assessment. 
These will be the only analysis populations in the study. No per protocol population is 
planned. 
Invalid patients: only patients who do not receive any study medication will be considered 
invalid for this study.  
Final decisions regarding the assignment of patients to analysis sets will be made during the 
Validity Review Meeting and documented in the Validity Review Report (see Section 4.6). 
6. Statistical Methodology 
6.1 Population characteristics 
6.1.1 
Disposition of patients 
The number of patients enrolled will be tabulated by center and treatment group. Patient 
validity and primary reasons for exclusion from analysis will be summarized by treatment 
group.  
A summary table will also be presented by the primary reason for discontinuation from 
screening for enrolled patients and at end of study for the randomized patients. Overview of 
patient disposition will be tabulated for all enrolled patients. As stated in Section 4.2, for the 
overall discontinuation rate, a chi-squared test will be used to test the null hypothesis of no 
differences in the discontinuation rates between treatment groups. 
Protocol deviations by center will be tabulated. 
6.1.2 
Demographic and Baseline Characteristics 
Demographic variables and baseline characteristics will be summarized descriptively for each 
treatment group separately and for all patients, in both the mITT and ITT populations. For 
continuous variables such as age, summary statistics will include N (number of patients 
contributing information), arithmetic mean, standard deviation (SD), median, minimum and 
maximum values. For categorical variables such as sex, frequency counts and percentages 
will be provided.  
The following demographic data will be summarized: 


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 Age (year), Age category ((<18, 18 to <45, 45 to < 65, 65 to <75, ≥75) 
 Sex 
 Race and ethnicity 
 Geographical regions (North America, Latin America, Asia Pacific, Europe) 
 Latin America countries (Brazil, Colombia, Mexico) 
 Asia Pacific countries (Philippines, South Korea, Taiwan, Thailand, China, Japan) 
The following baseline characteristics will be summarized: 
 Height (cm) 
 Weight (kg) 
 BMI (kg/m2), BMI group (<25, 25 to <30, ≥30) 
 APACHE II score (< 20, ≥ 20) 
 CPIS at pre-therapy (< 6, 6, 7, 8, 9, 10, 11) 
 Type of tracheal device ((Endotracheal tube, Tracheostomy) 
 Type of pneumonia (hospital acquired pneumonia; health-care associated pneumonia; 
ventilator associated pneumonia; community acquired pneumonia) 
 Respiratory culture organisms also present in blood culture (Yes, No); 
 Patients with confirmed multidrug resistant (MDR) pathogens (MDR first detected at 
baseline, MDR first detected post-baseline, Not MDR);  
 Patients with confirmed ESBL pathogens (ESBL first detected at baseline, ESBL first 
detected post-baseline, Not ESBL);  
 Patients who received IV antibiotic for pneumonia ≥ 5 days after day of first 
intubation (Yes, No);  
 Patients who received at least one dose of carbapenem during Days 1 through 10 
(Yes, No);  
 Start time of amikacin from start time of IV antibiotic (0 to < 12 hours, 12 to < 24 
hours, 24 to < 36 hours, 36 to ≥ 48 hours and missing). 
The frequency of patients with baseline gram negative pathogens based on central laboratory 
results will be tabulated for ITT and mITT populations. Additionally, the proportion of ESBL 
pathogens from MIC testing will be tabulated.   
6.1.3 
Medical History 
Medical histories will be tabulated by treatment group using Medical Dictionary for 
Regulatory Activities (MedDRA) version 18.0 or higher version if available, summary 
statistics (frequency and percentage) will be provided by system organ class (SOC) and 


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preferred term (PT) for ITT and mITT populations. Clinical assessment of pneumonia at 
screening will be tabulated. 
6.1.4 
Concomitant Medications 
Prior and concomitant medications will be coded using WHO-DD version 2005/Q3. Prior and 
concomitant medications will be tabulated by anatomical class and chemical level for the ITT 
and mITT populations.  For the antibiotic medications, the coded medications will be 
reviewed by the project physician for appropriate mapping.  Particular attention will be given 
to mapping of Gram negative antibiotics and to indication for current episode of pneumonia. 
Prior and concomitant antibiotics will be tabulated by indication and treatment group.  
6.1.5 
Study Medication Exposure 
Study medication (total number of days; total number of doses; number of patients with one 
or more dose interruption and reasons) will be summarized descriptively by treatment group 
for ITT and mITT populations. Overall number of doses by administration device type will 
also be provided. Additionally, frequency of adjunctive therapy will be tabulated by treatment 
group. Duration will be calculated from the date of first study drug administration and 
continues through the last study drug administration. Medication interruptions will not be 
included. If a patient was extubated and re-intubated, the ventilator-free days will not be 
included in the calculation of the number of days on study drug via on-vent configuration. 
6.2 Efficacy 
The primary efficacy analysis will be conducted in the mITT population. The primary 
analysis is on the combined database, no single study analyses will be performed as part of 
the primary analysis. Supportive efficacy analysis will be provided for the ITT population. 
Unless otherwise specified, all significance tests will be conducted using a two-sided alpha 
level of 0.05. 
6.2.1 
Primary Efficacy Endpoints 
6.2.1.1 
Definition of Primary Efficacy Endpoint 
The primary efficacy variable is Survival through the LFU visit. Survival is achieved when 
the patient is alive through the LFU visit. No other factors are considered in the evaluation of 
survival. 
6.2.1.2 
Primary Efficacy Analysis 
The primary analysis will compare the survival rates through LFU visit of patients in the 
BAY 41-6551 group versus the patients in the placebo group, using the combined data from 
studies 13084 and 13085. 
The null (H0) and the alternative (H1) hypothesis for this primary analysis is the following: 
H0: p [BAY 41-6551] = p[placebo] 


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H1: p [BAY 41-6551] ≠ p[placebo] 
where p is the true Survival rate.  
A Cochran-Mantel-Haenszel test of general association, adjusting for stratum and geographic 
region, will be performed as the primary efficacy analysis. If the p-value from this test is less 
than 0.05, and the proportion of patients who surviveis higher in the BAY 41-6551 group 
than in the placebo group, the study will have achieved its primary objective. 
In addition, as a supportive analysis, a 95% confidence interval will be calculated for the odds 
ratio. This confidence interval will be generated from a logistic regression model with 
Survival as the primary variable, and treatment, stratum, and geographic region as the 
independent variables. If the lower limit of the 95% confidence interval for the odds ratio 
(BAY 41-6551/placebo) is greater than 1, BAY 41-6551 will be demonstrated to be 
statistically superior to placebo. 
Tests will be performed using the SAS procedure FREQ, and the 95% confidence intervals 
for the odds ratios will be generated using PROC LOGISTIC. 
An unadjusted chi-squared test will also be performed as a supportive efficacy analysis. In 
addition, a logistic regression model with only treatment as an independent variable will be 
performed, and the resulting 95% confidence interval for the odds ratio will be provided. 
These analyses will serve as sensitivity analyses to demonstrate consistency with the primary 
analysis. 
The Breslow-Day test will be used as a further supportive analysis to test for treatment by 
geographic region and treatment by stratum interaction. If this test of the homogeneity of the 
odds ratio indicate significant interaction (P < 0.10), exploratory analyses will attempt to 
define its source.  
A Cochran-Mantel-Haenszel test of general association, adjusting for stratum and study 
protocol (i.e., 13084 or 13085), will be performed to assess the effect of study protocol on 
primary outcome, Survival. Geographic region will not be included in this model as the 2 
studies were conducted in different regions.  
The primary efficacy analysis performed on the mITT population will be repeated for ITT 
population. 
6.2.1.3 Subgroup Analysis 
Exploratory descriptive summaries will be provided for the primary efficacy variable 
(survive, death, and missing) by treatment group and pre-determined subgroups of interest, 
provided there is sufficient number of events in total within the subgroup across the treatment 
arms. These subgroups will include: 
 type of ventilation (mechanical; mechanical and hand-held)  
 underlying diagnosis (hospital acquired pneumonia; health-care associated 
pneumonia; ventilator associated pneumonia; community acquired pneumonia) 


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 Blood culture (positive = presence of GN pathogen at screening or baseline; negative 
= absence of GN pathogen at screening or baseline) 
 CPIS at pre-therapy (< 6, 6, 7, 8, 9, 10, 11) 
 APACHE II score at pre-therapy (< 20; ≥ 20) 
 Age (< 18, 18 to < 45, 45 to < 65, 65 to < 75, ≥ 75 years) 
 Sex  
 Race  
 Body mass index (BMI) (< 25; 25-< 30; ≥ 30 kg/m2) 
 Geographic region 
 Latin America countries (Brazil, Colombia, Mexico) 
 Asia Pacific countries (Philippines, South Korea, Taiwan, Thailand, China, Japan) 
 Baseline Gram-negative antibiotic treatment taken by each patient (1, 2, ≥ 3) 
 Primary reason for intubation (Current pneumonia-related respiratory failure vs 
everything else) 
 Patients who received IV antibiotic for pneumonia ≥ 5 days after day of first 
intubation (Yes, No);  
 Patients who received at least one dose of carbapenem during Days 1 through 10 
(Yes, No);  
 Start time of amikacin from start time of IV antibiotic (0 to < 12 hours, 12 to < 24 
hours, ≥ 24 hours).  
 Patients with confirmed MDR pathogens (MDR first detected at baseline, MDR first 
detected post-baseline, Not MDR);  
 Patients with confirmed ESBL pathogens (ESBL first detected at baseline, ESBL first 
detected post-baseline, Not ESBL);  
The last 2 subgroups above pertain to MDR designation which is described in detail in 
Appendix A: 
 To be declared a MDR, a bacterial isolate at the same visit must be resistant using the 
central laboratory interpretation to at least 3 of the 6 drug classes on the susceptibility 
panel: aminoglycoside, β-lactam/β-lactamase inhibitor, cephams, carbapenam, 
tetracycline, folate pathway inhibitor, and quinolone. Once a patient has any MDR 
pathogen, he/she should be designated as a MDR patient no matter what the 
subsequent susceptibility tests show. 
 For the 3 cephams (ceftazidime, cefazolin, and cefpodoxime), resistance to any one of 
the 3 drugs in the panel counts as cepham resistance for the category. 


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 An interpretation by central laboratory of “Not applicable” result will be considered as 
“susceptible” for purposes of MDR tabulation. This means that at least 3 results of 
“intermediate” or “resistant” are necessary for an MDR designation, and a “Not 
applicable” will not be included in the total.  
6.2.2 
Secondary Efficacy Endpoints 
The following secondary endpoints will be tested sequentially in the order listed if the null 
hypothesis for the primary endpoint is rejected. 
 Adjudicated pneumonia-related mortality through LFU visit as determined by blinded 
adjudication committee 
 Early Clinical Response (based on CPIS, mortality, and presence of empyema or 
pulmonary abscess through the EOT visit) 
 The number of days on mechanical ventilation through the LFU visit 
 The number of days in the ICU through the LFU visit 
Early Clinical Response will be determined by the following: 
1) CPIS scoring at days 3, 5, and 10 compared to baseline as follows: 
 On Day 3, CPIS increase from baseline by at least 2 points is considered a failure 
 On Day 5, CPIS decrease from baseline of at least 1 point is not a failure. CPIS of no 
change from baseline is considered a failure. Any CPIS increase from baseline is a 
failure.  
 On Day 10, CPIS decrease from baseline of at least 2 points is not a failure. CPIS 
decrease of only 1 point is a failure. CPIS of no change is considered a failure. Any 
CPIS increase from baseline is a failure.  
A failure at any one of the three CPIS evaluations on days 3, 5 or 10 makes the patient a 
failure for the early clinical response. 
2) All-cause mortality through the EOT visit is a failure. 
3) The development of empyema or lung abscess through the EOT visit is a failure. 
The Early Clinical Response is a success if all three of the CPIS determinations are not 
failures, and the all-cause mortality and empyema and lung abscess variables are absent. If 
any one of the Early Clinical Response evaluations is a failure, then the patient is a failure for 
Early Clinical Response. 
The number of days on mechanical ventilation and the number of days in ICU are calculated 
from the date of first study drug administration and continue through the LFU visit. If a 
patient was extubated and re-intubated during the 28 day study period, the ventilator free days 
will not be included. If the complete date of stop date of mechanical ventilation/ICU is not 
known for a patient, the 28 days will be used for the number of days. For patients who died, 


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the number of days on ventilation will be censored at 28 days. For patients who lived through 
LFU visit, the ventilation days are 28 days. 
6.2.2.1 Secondary Efficacy Analysis  
The secondary efficacy endpoint variables will be formally tested for statistical significance 
of a difference between the BAY 41-6551 group versus the placebo group, only if the primary 
efficacy comparison is statistically significant at the two-sided 5% level in the mITT and ITT 
populations, except as noted below. A sequential testing procedure will be performed at the 
two-sided alpha level of 0.05 for the four secondary efficacy variables, strictly in the order 
listed above.  
The null hypothesis of no difference between BAY 41-6551 and placebo in adjudicated 
pneumonia-related mortality and early clinical response will be tested using an unadjusted 
Chi-square test in the mITT population. 
Analysis of variance will be used to test the null hypothesis of no difference between BAY 
41-6551 and placebo for the number of days on mechanical ventilation and the number of 
days in the ICU.  
For the purpose of the sequential testing procedure, the only effect in the model will be 
treatment. As supportive analyses, additional models will be used with effects included for 
geographic region for all secondary variables. Non-parametric tests for treatment comparison 
will be considered as sensitivity analyses.  
The secondary endpoint of pneumonia-related mortality through the LFU visit will be 
examined further by subgroups listed for the primary analysis in Section 6.2.1.3.  All 4 
secondary endpoints will be examined further by the following MDR subgroups: 
 Patients with confirmed MDR pathogens (MDR first detected at baseline, MDR first 
detected post-baseline, Not MDR);  
 Patients with confirmed ESBL pathogens (ESBL first detected at baseline, ESBL first 
detected post-baseline, Not ESBL);  
 Patients who received IV antibiotic for pneumonia ≥ 5 days after day of first 
intubation (Yes, No);  
 Patients who received at least one dose of carbapenem during Days 1 through 10 
(Yes, No);  
 Start time of amikacin from start time of IV antibiotic (0 to <12 hours, 12 to <24 
hours, ≥24 hours). 
Number of days on mechanical ventilator will be summarized by descriptive statistics.  
Duration will be defined as the number of days from the date of first study drug through the 
LFU visit. For patients who lived through the LFU visit, the ventilation days are actual days 
on ventilation with a maximum value of 28 days. For patients who died after Day 28, but on 
or before their LFU visit, the days on ventilator is censored at 28 days. For patients who died 
or discontinued off-ventilation, the number of days on ventilation is actual days on ventilation 


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with a maximum value of 28 days.  For patients who died or discontinued on-ventilation, the 
number of days on ventilation will be 28 days. Further analysis of the number of days on 
mechanical ventilator will be performed with censoring at Day 28 for subset of patients on 
ventilation without censoring. 
Patient status at the LFU visit will also be summarized, where the status will be dead, 
ventilated and in ICU, off-ventilation in ICU, and off ventilation in hospital (not ICU). 
Number of days on ICU will be summarized by descriptive statistics.  Duration will be 
defined as the number of days from the date of first study drug through the LFU visit. For 
patients who lived in ICU through the LFU visit, the ICU days are actual days in ICU with a 
maximum value of 28 days. For patients who died after Day 28, but on or before their LFU 
visit, the days in ICU is censored at 28 days. For patients who died or discontinued in ICU, 
the number of days in ICU will be 28 days. Further analysis of the number of days in ICU 
will be performed with censoring at Day 28 for subset of patients on ventilation and without 
censoring. 
6.2.3 
Other Efficacy Analysis 
The other efficacy endpoints are: 
1. The number of days in the hospital through LFU visit 
2. Relapse rates at LFU 
3. Total number of days of Gram-negative antibiotics 
4. Change in component of CPIS score from baseline to TOC 
5. All cause mortality rates at EOT 
Analysis of variance will be used to test the null hypothesis of no difference between BAY 
41-6551 and placebo for the total number of days of Gram-negative antibiotics. Other 
secondary endpoints will be summarized descriptively.  
6.2.4 
Additional Analysis of Clinical Success 
6.2.4.1 Foundation for the National Institute of Health (FNIH) Criteria 
Clinical success using FNIH recommendation will be defined as mITT patients who survived 
through the LFU visit and did not have septic shock.  Patients will be designated as having a 
septic shock event based on the standard medical queries (SMQ) terms tabulated as adverse 
events. Descriptive analysis will be provided with 95% confidence intervals. Cochran-
Mantel-Haenszel test of general association adjusting for stratum and geographic region will 
also be performed. 
6.2.4.2 Investigator Assessment of Patient Outcome 
Investigator Assessment of Patient Outcome is determined at the TOC visit. The outcomes of 
“success” or “failure” are based on the following criteria: 


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 Improvement or lack of progression of all abnormalities on chest radiograph  
 Resolution towards normal of the following CPIS components: tracheal secretions 
(volume and purulence), temperature, blood leukocytes, oxygenation (P/F ratio)  
 Any further change to the Gram-negative portion of the antimicrobial regimen being 
used to treat pneumonia during the first 10 days, after the initial antimicrobial 
adjustment within the first 96 hours after the initiation of empiric therapy or as soon 
as initial culture and susceptibility results are available and excepting the 
discontinuation of aminoglycosides after 5 to7 days, would be considered a Clinical 
Failure 
 Patient did not receive antibiotic therapy for pneumonia after  Day 10 (EOT) 
 Patient survived through the TOC visit 
All 5 conditions listed above must be met to achieve Investigator’s Assessment of Patient 
Outcome to be a success. At the LFU visit, an assessment of relapse will be considered to be 
failure. 
This endpoint will be summarized descriptively with 95% confidence interval. A Cochran-
Mantel-Haenszel test of general association adjusting for stratum and geographic region will 
be performed on the mITT patients.  
In addition, Kaplan-Meier curves will be provided for time to Investigator Assessment of 
clinical failure. Time to clinical failure is defined as the time from the first day of study drug 
intake to the first time at which clinical failure is assessed. Patients who do not fail will be 
censored at death date, their LFU visit or last visit. 
6.2.4.3 Clinical Response Endpoint - 5 component endpoint 
Clinical Success is achieved when the following criteria are met as listed in the order of 
medical relevance: 
 The patient must survive through the Late Follow-Up (LFU) visit 
 Systemic antibiotics (IV or PO) for pneumonia must be stopped on or before the TOC 
visit (Day 17-19),  
 Systemic antibiotics (IV or PO) for pneumonia must not be restarted after the TOC 
visit through the LFU visit 
 The patient must have stable respiratory function evaluated at TOC or last visit based 
on the PaO2/FiO2 (P/F) ratio as outlined below (if P/F ratio is not available at the 
TOC, use the P/F ratio value from the closest previous visit), and  
 The patient must not have a reported AE of lung abscess or empyema through the 
LFU visit 
Stable respiratory function 
 Patient is extubated at the TOC visit or 


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 Patient is intubated at the TOC and: 
o Patient has P/F ratio > 200 at the TOC visit or 
o Patient has P/F ratio > 100 and ≤ 200 at the TOC visit and 
o Patient had a P/F ratio ≤ 200 at baseline 
If ventilation status not explicitly known to be extubated for a patient at TOC or last visit, the 
status was assumed to be intubated for the determination of primary endpoint. 
Unstable respiratory function 
 Patient has a P/F ratio ≤ 100 at the TOC visit or 
 Patient has a P/F ratio > 100 and ≤ 200 at the TOC visit and: 
o Patient has P/F ratio > 200 at baseline 
The outcome is Clinical Success if all 5 criteria are met. If any one of the criteria is not met, 
then the patient is considered a Clinical Failure. Patients who do not have a clinical 
assessment of success due to missing data will be considered a Clinical Failure. 
For patients who discontinue study drug (on vent or handheld) for reasons other than efficacy 
will be handled as described in the table below:                                                                                                        
 
Table 6–1 Outcome of patients who discontinue study drug 
Reason for Discontinuation of Aerosol Therapy 
Outcome / Comments 
No Gram-negative bacteria isolated from a pre-
therapy respiratory specimen 
Patient is considered ITT analysis and not 
evaluated for efficacy analysis as mITT 
Patient withdrew consent or refused handheld 
device 
Evaluate for efficacy if all data for primary 
efficacy are available; if data are missing, then 
failure 
Death 
Failure 
Adverse event 
Failure 
New therapy incompatible with aerosol therapy 
Failure 
Lost to follow-up 
Failure 
Any other reason/unknown reason 
Failure 
 
Additional reasons for discontinuation may be included as failure after review of blinded 
data. The patient must have stable respiratory function evaluated at TOC or last visit based on 
the ventilation status and PaO2/FiO2 (P/F) ratio (if ventilation status or P/F ratio is not 
available at the TOC, use the respective ventilation status or P/F ratio value from the closest 
previous visit).   
The analysis will compare the proportion of patients with Clinical Success in the BAY 41-
6551 group versus the patients in the placebo group, using the combined data from studies 
13084 and 13085. All assessments other than Clinical Success, that is, failures, 
improvements, and missings (those patients who do not have a TOC assessment) will be 
grouped together in the Clincial Failure category for the purpose of this analysis. If a TOC 


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assessment is missing for determining the antibiotic criteria for a patient, the TOC assessment 
will be assumed to have occurred 17 days after the start of study drug.   
A Cochran-Mantel-Haenszel test of general association, adjusting for stratum and geographic 
region, will be performed as additional analysis of success. If the p-value from this test is less 
than 0.05, and the proportion of patients with Clinical Success is higher in the BAY 41-6551 
group than in the placebo group, the study will have demonstrated superiority in this 
sensitivity analysis. 
In addition, as a supportive analysis, a 95% confidence interval will be calculated for the odds 
ratio. This confidence interval will be generated from a logistic regression model with 
Clinical Sucess as the additional analysis of success and treatment, stratum, and geographic 
region as the independent variables. If the lower limit of the 95% confidence interval for the 
odds ratio (BAY 41-6551/placebo) is greater than 1, BAY 41-6551 will be demonstrated to 
be statistically superior to placebo. 
Individual components of the composite endpoint will be analyzed using the Cochran-
Mantel-Haenszel test adjusting for stratum and geographic region. This is to assess the 
components are moving in the same general direction and which, if any, single component is 
driving the result. The analysis of individual components will be performed on the actual 
counts of each criterion, not ordered by medical relevance.  
Tests will be performed using the SAS procedure FREQ, and the 95% confidence intervals 
for the odds ratios will be generated using PROC LOGISTIC. 
An unadjusted chi-squared test will also be performed as a supportive efficacy analysis. In 
addition, a logistic regression model with only treatment as an independent variable will be 
performed, and the resulting 95% confidence interval for the odds ratio will be provided.  
The Breslow-Day test will be used as a further supportive analysis to test for treatment by 
geographic region and treatment by stratum interaction. If this test of the homogeneity of the 
odds ratio indicate significant interaction (P < 0.10), exploratory analyses will attempt to 
define its source.  
A Cochran-Mantel-Haenszel test of general association, adjusting for stratum and study 
protocol (i.e., 13084 or 13085), will be performed to assess the effect of study protocol on the 
Clinical Success as additional efficacy variable. Geographic region will not be included in 
this model as the 2 studies were conducted in different regions.  
Number and percent of patients meeting the each failure criteria will be summarized in the 
order of medical relevance as presented in Section 6.2.2. A patient with failure is counted 
only in the criteria with highest medical relevance in order presented. Patients may not have 
any failure criteria, but not be included in the analysis due to missing data. To account for 
missing visits, the number of patients without failure criteria but has TOC visit and missing 
LFU visit will be presented. Additional summary of respiratory stability function will be 
given for components of stable respiratory function and unstable respiratory function for each 
treatment group. 


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6.2.5 
Microbiological Analysis 
Organism identifications generated by the central laboratory will be used as the primary 
source for microbiological endpoints. Local laboratory results will not be used for analysis. 
Microbiology related endpoints:  
There are 7 microbiology related endpoints. All of these are secondary endpoints.  
Secondary microbiological objectives will include comparisons (aerosolized BAY 41-6551 
versus aerosolized placebo), as adjunctive therapy in the mITT population in the following 
analysis: 
1. Microbiological response by pathogen at the TOC and LFU visit 
2. Microbiological response by patient at the TOC and LFU visit  
3. Clinical response by pathogen and patient at the LFU visit 
4. Emergence of new respiratory pathogens during the aerosol treatment period, Days 1-
10 
5. Amikacin resistance among pathogens by patient (baseline, EOT, TOC, LFU) 
6. Clinical Response by MIC value of amikacin by patient and pathogen 
7. Clinical response in Monomicrobic versus polymicrobic infections 
By-patient and by-pathogen bacteriological eradication rates at the TOC visit will be provided 
by treatment group in the mITT population. 
Microbiological responses are based on culture results from the central laboratory and utilize 
the following terms: 
 Eradication:  the absence of the original pathogen(s) at the post-treatment TOC or 
LFU culture of specimens from the original site of infection (tracheal aspirate/sputum) 
 Presumed eradication:  no culture results available/culture not taken in a patient 
judged to be a Clinical Success (survival); [patient is unable to produce sputum and 
invasive procedures are not warranted] 
 Persistence:  the presence of the original pathogen from the post-treatment TOC or 
LFU culture specimens from the original site of infection 
 Presumed persistence:  no culture results available/culture not taken in a patient 
judged to be a Clinical Failure (mortality) and invasive procedures are not warranted 
 Indeterminate:  the bacteriological response to the study medication is not valid for 
any reason (e.g., pre-treatment culture was negative or post-treatment culture was not 
obtained when material was available)  


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6.2.5.1 
Microbiological response by baseline pathogen from respiratory 
sample at the TOC and LFU visit. 
For microbiological responses by pathogen, the percentage of patients with microbiological 
response for each pathogen among the total number of patients with baseline pathogen 
isolates for each pathogen will be determined. If a patient has 3 pathogens, all 3 are tabulated.  
Bacteriological eradication rate is defined as (eradication and presumed eradication) 
divided by the sum of (eradication + presumed eradication + persistence + presumed 
persistence + indeterminate (all total outcomes)).  Similarly, other microbiological response 
rates will be calculated.  
The data is displayed for each bacterial genus/species. 
Baseline pathogen is defined as pathogens tested at screening and Day 1 visit by central 
laboratory. 
6.2.5.2 
Microbiological response by patient at the TOC and LFU visit. 
For microbiological responses by patient, the percentage of patients with microbiological 
response among mITT patients will be determined 
 The responses of eradication, presumed eradication are tabulated for each patient.  
 All pathogen isolates from an individual patient must be eradicated (or presumed 
eradicated) to tabulate an eradicated (or presumed eradicated) response.  
If one or more pathogen persists (or presumed persists), all isolates from a patient are 
tabulated as “persistence” (or presumed persistence). Bacteriological eradication rate is 
defined as (eradication and presumed eradication) divided by the sum of (eradication + 
presumed eradication + persistence + presumed persistence + indeterminate (i.e. all total 
outcomes)). Similarly, other microbiological response rates will be calculated. 
The data is displayed for each individual bacterial genus/species. 
6.2.5.3 
Clinical response by pathogen and patient at the LFU visit. 
In addition to the microbiological response by pathogen, the clinical response by pathogen 
and patient is displayed. This evaluation uses the same clinical response criteria (survival) as 
the primary end point  on the mITT population subdivided by pathogen. This evaluation can 
only be done on the LFU visit, since that is when the primary clinical response is evaluated. 
The percentage of patients with indicated baseline isolate tabulated as Clinical Success 
among the total number of patients with the indicated baseline pathogen isolates will be 
determined. 
6.2.5.4 
Emergence of new respiratory pathogens after start of study drug 
Rates of emergent of new bacterial species (superinfection) after start of study drug will be 
summarized by treatment group. This will include a summary of new bacterial genus/species 


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which occur after start of study drug. By patient and by-organism displays will be provided 
for each treatment group for each type of emergent infection. 
6.2.5.5 
Amikacin resistance among pathogens by patient (baseline, EOT, 
TOC, LFU). 
Resistance to Amikacin is determined for the bacterial isolates by using a standardized 
microbiology laboratory test that generates a minimum inhibitory concentration (MIC) for 
amikacin and bacterial isolate. For the INHALE trials, the MIC values of amikacin are 
important in tracking resistance. Fortunately, the same microbiology resistance standard is 
used for all bacteria tested against amikacin. 
Resistant bacteria have a MIC value of 64 µg/mL or greater. Percentages of resistance are 
calculated based on the percentage of patients infected with pathogens resistant to amikacin at 
the different trial points (baseline, EOT, TOC, LFU). Resistance as determined by central 
laboratory is displayed for each bacterial genus/species. Rates of baseline pathogens at the 
baseline MIC with microbiological assessment at TOC visit of eradicated or presumed 
eradicated (or persistent or presumed persistent) among the total number of pathogens for the 
MIC at baseline will be determined for the amikacin group. 
6.2.5.6 
 
Clinical Response by MIC value by patient and pathogen  
Results of pre-therapy Amikacin sensitivity testing by baseline genus/species and primary 
clinical response (survival/mortality at LFU) will be presented for each baseline pathogen 
from respiratory sample collection displayed by MIC at baseline for Clinical Success and 
failures. For each pathogen, the percentage of baseline pathogen at the MIC with Clinical 
Success or Clinical Failure among the total number of pathogen for the MIC will be 
displayed.  
6.2.5.7 
Clinical response for monomicrobic versus polymicrobic infections at 
LFU. 
 Patients with 1 pathogen at baseline considered monomicrobic 
 Patients with >1 baseline pathogen considered polymicrobic 
The Clinical Success response for monomicrobial and polymicrobial infections is displayed. 
This evaluation uses the same clinical response criteria as the primary end point on the mITT 
population subdivided by monomicrobial and polymicrobial infections. This evaluation can 
only be done on the LFU visit, since that is when the primary clinical response is evaluated. 
The clinical response is displayed for each bacterial genus/species. 
6.2.5.8 
Additional microbiological analysis 
Additional analyses include the following: 
 Summary of clinical response for Gram negative and mixed infections,   


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 Summary of treatment-emergent resistance to amikacin displays the number of 
patients who had specific pathogen that was susceptible to amikacin in pre-treatment 
period and resistant or indeterminate to amikacin in treatment or post-treatment period 
or patients who had indeterminate in pre-treatment period and resistant in treatment or 
post-treatment period.   
 Summary of new pulmonary pathogens include the number of patients with new 
pathogen (not the original pathogen) from a specimen after the patient has completed 
antibiotic therapy.   
6.3 Mortality 
Mortality rates will be summarized through the LFU visit, through the TOC visit, during 
therapy, through day 15 and through day 28 by treatment group for the ITT and mITT 
populations. 95% confidence intervals will also be provided for the difference between 
groups in mortality rates at these time points. Normal approximations to the binomial 
distribution will be used to generate the confidence intervals.  
Time to death will be provided for observed time for patients who died. Kaplan-Meier curves 
will be provided for time to death for all patients. Time to death is defined as the time from 
the first day of study drug intake to death. Patients alive during the study are censored at LFU 
visit or last visit date Causes of death will be summarized through the LFU visit, through the 
TOC visit, during therapy, through day 15 and through day 28.  If a patient did not have TOC 
visit, day 17 will be used as a cut-point for determining mortality at TOC visit. If a patient did 
not have EOT visit, day 10 will be used as a cut-point for determining mortality at EOT. 
6.4 Pharmacokinetics / pharmacodynamics 
PK summary statistics 
Summary statistics of valid concentrations of amikacin from serum, tracheal aspirate, and 
urine samples in the PKS population will be provided for each assessment time point. All 
patients had PK assessment at trough (pre-dose) only, whereas patients in the PK substudy 
had PK assessments at all time points. Separate summaries will be provided for patients who 
received amikacin by inhalation only, patients who received amikacin by inhalation with 
amikacin IV as concomitant medication, and as those who received amikacin IV as 
concomitant medication only. Plot of geometric mean and geometric SD of trough serum 
concentration of amikacin over the entire study duration will be provided. Means at any time 
will only be calculated if at least 2/3 of the individual data were measured and were above the 
lower limit of quantification (LLOQ). For the calculation of the mean value a data point 
below LLOQ will be substituted by one half of this limit. In tables showing mean values, 
where values below LLOQ are included in the calculation of mean values, these means willbe 
flagged.  
PK analysis for blood, serum and urine samples 
Exploratory population PK and pharmacokinetic/pharmacodynamic (PK/PD) modeling will 
be performed to describe amikacin pharmacokinetics using population approaches (e.g. 


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NONMEM). This analysis will include an investigation of potential inter-ethnic differences in 
the pharmacokinetics of amikacin. The influence of relevant patient covariables such as age, 
gender, or body weight, or potentially relating parameters of clinical efficacy response to 
amikacin serum concentrations will also be evaluated.  
Population PK for TA and respiratory secretions 
PK/PD modeling using population approach, e.g. NONMEM, will be performed to describe 
PK/PD including potential influence of relevant patient co-variables (e.g. inter-ethnic 
differences, age, gender, etc.) 
The corresponding investigations for serum, urine, bronchoalveolar lavage (BAL), and 
tracheal aspirate (TA) will be described and reported under separate cover.  
6.5 Safety 
All analyses of safety endpoints will be descriptive only; no formal testing will be performed. 
All safety tabulations will be produced for the ITT for Safety population grouped as treated, 
as well as for the mITT population as treated. 
6.5.1 
Adverse Events 
An assessment of the safety of treatment will be conducted based on the comparison of 
treatment groups for the ITT for Safety population grouped as treated, and the mITT 
population grouped as treated with respect to the incidence of all treatment-emergent adverse 
events and, separately, all drug-related and device-related treatment-emergent adverse events. 
All AEs will be coded using the MedDRA dictionary Version 18 or higher.  
AE and serious AE (SAE) will be considered treatment-emergent if they occur any time after 
the first dose of therapy, through 7 days after the end of treatment. The incidence of AEs will 
be described by SOC and preferred term (PT) within the SOC. Additionally, SAEs up to LFU 
(Day 28 visit) will be presented by SOC and PT. 
A table will summarize the overall number and percentage of patients with at least 1 of the 
following AEs, where patients with more than 1 AE in a particular category are counted only 
once in that category for the ITT for Safety population grouped as treated and the mITT 
population grouped as treated: 
 Any AE 
 Any study drug-related AE 
 Any SAE 
 Any study drug-related SAE 
For each of the above AE category - 
 AE by intensity 
 AE by worst outcome 


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 Any AEs leading to study drug discontinuation 
 Any SAEs leading to study drug discontinuation 
 Any device-related AE 
 Any device-related SAE 
 Any device related serious AE 
 Any study procedure-related AE 
 Any study procedure-related SAE 
Similar overall table will be summarized for TEAE for the ITT for Safety population grouped 
as treated, and the mITT population grouped as treated. 
For the summary by intensity, patient with multiple occurrences of the same event will be 
counted once at their maximum intensity within a SOC and PT.  
The number and percentage of patients reporting each AE and TEAE will be summarized by 
SOC and PT for the ITT for Safety population and the mITT population as specifed. Tables 
will be sorted alphabetically by SOC. PTs will be sorted by descending overall total. The 
following summaries will be produced: 
 AE by SOC and PT for ITT and mITT 
 SAE by SOC and PT for ITT and mITT 
 AE leading to drug withdrawal by SOC and PT for ITT and mITT 
 AE resulting in death by SOC and PT for ITT and mITT 
 AE by maximum intensity, SOC and PT for ITT and mITT 
 Serious AE by maximum intensity, SOC and PT for ITT and mITT 
 AE by worst outcome, SOC and PT for ITT and mITT 
 Serious AE by worst outcome, SOC and PT for ITT and mITT 
 TEAE by SOC and PT for ITT and mITT 
 Drug-related TEAE by SOC and PT for ITT 
 Device-related TEAE by SOC and PT for ITT 
 Study procedure-related TEAE by SOC and PT for ITT 
 Serious TEAE by SOC and PT for ITT and mITT 
 Drug-related serious TEAE by SOC and PT for ITT 
 Device-related serious TEAE by SOC and PT for ITT 
 Study procedure-related serious TEAE by SOC and PT 


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 TEAE leading to drug withdrawal by SOC and PT for ITT and mITT 
 TEAE resulting in death by SOC and PT for ITT and mITT 
 TEAE by maximum intensity, SOC and PT for ITT and mITT 
 Serious TEAE by maximum intensity, SOC and PT for ITT and mITT 
 Drug-related TEAE by maximum intensity, SOC and PT for ITT 
 TEAE by worst outcome, SOC and PT for ITT and mITT 
 Serious TEAE by worst outcome, SOC and PT for ITT and mITT 
Tables will be produced displaying the incidences of AE or TEAE, drug-related TEAE, 
device-related TEAE and study procedure-related TEAE by MedDRA labeling groupings 
(MLG), i.e. sponsor defined groupings of MedDRA preferred terms by primary SOC. A 
separate overview table will be created showing the PTs belonging to all MLGs. 
The overall proportion of patients with any TEAE identified as organ failure will be 
summarized, as well as the proportion of patients in each specific type of organ failure by 
SOC and PT for ITT and mITT for safety population. Similar display will be summarized for 
AE identified as organ failure. Organ failure is defined by organ type, by a collection of 
MedDRA preferred terms determined by the Bayer clinical team and listed in Appendix B of 
this document.  
The overall proportion of patients with bronchial hyperreactivity will be compared with 
patients without bronchial hyperreactivity. Bronchial hyperreactivity was defined by the 
clinical team and listed in Appendix C of this document. Overall summary tables as well as 
summaries by SOC and PT for TEAE, serious TEAE, study drug-related TEAE, and drug-
related serious TEAE will be provided.  
Adverse events of special safety interest (AESI) are those identified as risks of parenteral (IV 
and IM) formulations of the study treatment (e.g., neurotoxicity, ototoxicity, and 
nephrotoxicity). AEs due to local exposure in the bronchopulmonary system, such as 
bronchospasm, coughing during or shortly after inhalation of aerosol, and hemoptysis are also 
considered AESI. An overview table will be provided listing PTs belonging to sponsor 
defined MedDRA term groupings for each topic of special interest for ITT and mITT for 
safety group. TEAE of special interest (TEAESI) will be summarized by safety topic and PT: 
 TEAESI by safety topic and PT 
 TEAESI by maximum intensity  
 TEAESI by worst outcome. 
 


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Statistical Analysis Plan Final Version 6.0 
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Table 6–2 Safety topics of special interest 
Topic 
Adverse events of special safety interest 
Localized adverse effects to 
the respiratory tract (excluding 
bronchospasm) 
PBMQ  ‘Localized adverse effects to the respiratory tract (Amikacin 
Inhale)’  (SMQ code=SMQ_1610) excluding ‘Bronchospasm 
(Amikacin Inhale)’ (SMQ code = SMQ_1608)  but including MLG 
‘Respiratory tract hemorrhage’  (SMQ code=SMQ_0163) 
Bronchospasm 
PBMQ ‘Bronchospasm (Amikacin Inhale)’  (SMQ code = SMQ_1608)  
Device-related events   
All AEs that were reported as device-related by the investigator 
Nephrotoxicity 
SMQ ‘Acute renal failure (SMQ)’  (SMQ code=20000003) 
Hypersensitivity/Anaphylactic 
reactions 
PBMQ ‘Hypersensitivity type I and IV and anaphylactic reactions 
(Amikacin Inhale)’  (SMQ code = SMQ_1607)  
Ototoxicity/Vestibular toxicity 
SMQ ‘Hearing impairment (SMQ)’  (SMQ code=20000171) 
SMQ ‘Vestibular disorders (SMQ)’ (SMQ code=20000172) 
Neuromuscular Blockade / 
Neurotoxicity   
PBMQ ‘Peripheral neurotoxicity and neuromuscular blockade 
(Amikacin/Aminoglycosides)’ (SMQ code = SMQ_1612)  
 
Patient listings of all AE as well as subset listings of device-related AEs, treatment-related 
AEs, SAEs with outcome of death, SAEs, device-related AEs, SAEs resulting in study drug 
discontinuation, procedure-related SAEs, and drug related SAEs will be provided. 
6.5.2 
Device Events 
Device evaluation results as reported in the eCRF will be summarized by device event 
category and treatment group. The incident evaluation (incident, near incident, non-incident, 
missing, and associated with AE/SAE) of device events among the ITT for safety population 
will be presented by the number of study drug dose and treatment group. Percentage of event 
category (device malfunction, use error or handling difficulty, and other device event) for 
each incident evaluations will be presented. Additionally, the number of patients with at least 
one event will be summarized in each category. 
6.5.3 
Laboratory Data 
Laboratory data will be analyzed descriptively for the ITT population and mITT population 
grouped as treated using International System of Units (SI). The absolute values and changes 
from baseline will be summarized for each treatment group using N (number of patients 
contributing information), arithmetic mean, standard deviation (SD), median, minimum and 
maximum values for each visit. If multiple assessments are made during a treatment visit, the 
last scheduled or unscheduled assessment will be included in the summary. For analysis 
purposes, values preceded by a “>”sign (i.e. those above the limits of quantification) will be 
considered equal to the upper limit of quantification. Values preceded by a “<” sign (below 
the limits of quantification) will be substituted with ½ the limit of quantification for the 
calculation of descriptive statistics.  Urinalysis tests will be summarized by frequency of 
categorical results at each visit. 
Creatinine clearance is calculated using Modifications of Diet in Renal Disease (MDRD) 
method, where GFR = 175 x serum creatinine ** -1.154 x age ** (-0.203) x (1.212 if Black) x 
(0.742 if female).  


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Statistical Analysis Plan Final Version 6.0 
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Number of patients with acute kidney injury (AKI) will be summarized for patients with 
baseline APACHE II score of No for acute renal failure. For patients with normal serum 
creatinine at baseline, AKI is defined as an increase of 0.3 mg/dL in creatinine from baseline. 
For patients with abnormal baseline serum creatinine, AKI is defined as an increase of 50% 
from baseline. 
Additionally, a summary of number of patients with treatment emergent abnormally low 
values and treatment emergent abnormally high values will be provided by laboratory test. 
Pregnancy information was summarized by treatment group. 
6.5.4 
Vital Signs 
Vital sign data will be analyzed descriptively for the ITT population and the mITT population 
grouped as treated. The absolute values and changes from baseline will be summarized for 
each treatment group using N (number of patients contributing information), arithmetic mean, 
standard deviation (SD), median, minimum and maximum values for each visit. Baseline 
values will be defined as the last pre-dose assessment. Mean of the assessment will not be 
used. If multiple assessments are made during a treatment visit, the last scheduled or 
unscheduled assessment will be included in the summary. 
6.5.5 
ECG Data 
ECG data will not be collected in this study. 
6.6 Additional analyses 
Not Applicable. 
7. Document history and changes in the planned statistical analysis 
 
Table 7–1 Document history and changes in the planned statistical analysis 
Document Version / Date 
Changes 
Reason of Changes 
Version 1.0 / 16 March 2011 
Combined SAP for both studies 
13084 and 13085 
Not applicable 
Version 2.0 / 10 Feb 2015 for 
13084 only 
Sample size change from 650 to 
662; patients in mITT 
populations changed from 520 to 
430. 
Changes based on the protocol 
amendment dated 17 
September 2014 
Version 2.0 / 10 Feb 2015 for 
13084 only 
Geographic region (or country) 
added as a randomization 
stratification factor. 
Changes based on the protocol 
amendment dated 17 
September 2014 
Version 2.0 / 10 Feb 2015 for 
13084 only 
Regional definitions modified to 
reflect different countries 
included in the study. 
Changes based on the protocol 
amendment dated 17 
September 2014 
Version 2.0 / 10 Feb 2015 for 
13084 and 13085 
Odds ratio analysis clarified to 
be a supportive analysis only. 
 
Changes based on the protocol 
amendment dated 17 
September 2014 
Version 2.0 / 10 Feb 2015 for 
Variables in the formal 
Changes based on the protocol 


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Statistical Analysis Plan Final Version 6.0 
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Document Version / Date 
Changes 
Reason of Changes 
13084 only 
secondary analysis hypothesis 
testing algorithm modified – 
relapse rates and hospital days 
added, number of antibiotic days 
and change in CPIS removed. 
 
amendment dated 17 
September 2014 
Version 2.0 / 10 Feb 2015 for 
13084 only 
Treatment emergent AE 
definition clarified. 
 
Changes based on the protocol 
amendment dated 17 
September 2014 
Version 4 / 19 Feb 2016 
Study Objectives revised to 
match wording in the protocol. 
Changes based on the protocol 
amendment 6, Version 7.0 8 
February 2016. 
Version 4 / 19 Feb 2016 
Study Design Overview revised 
reflects combined study 13084 
and 13085. Sample size change 
from 662 to 724 ITT; patients in 
mITT populations changed from 
430 to 472. 
Changes based on the protocol 
amendment 6, Version 7.0 8 
February 2016. 
Version 4 / 19 Feb 2016 
Schedule of Procedures added. 
Changes based on the protocol 
amendment 6, Version 7.0 8 
February 2016. 
Version 4 / 19 Feb 2016 
Sample size recalculated for 
combined study. 
Changes based on the protocol 
amendment 6, Version 7.0 8 
February 2016. 
Version 4 / 19 Feb 2016 
Handling of Dropouts 
Added details. 
Version 4 / 19 Feb 2016 
Handling of Missing Data 
Added details  
Version 4 / 19 Feb 2016 
Data Rules geographical regions 
were revised 
Changes based on the protocol 
amendment 6, Version 7.0 8 
February 2016. 
Version 4 / 19 Feb 2016 
Disposition of Patients section 
added. 
Added details. 
Version 4 / 19 Feb 2016 
Sections on Demographic and 
Baseline Characteristics; 
Medical History, Concomitant 
Medication, Study Medication 
Exposure, Adverse Events, 
Laboratory Data, Vital Signs 
Added details. 
Version 4 / 2 Mar 2016 
Efficacy sections 
Changes based on study 
protocol 13084 amendment 6.0, 
version 7.0, dated 29 February 
2016 and 13085 amendment 
16, version 6.0, dated 29 
February 2016. 
Version 5 / 19 May 2016 
Efficacy sections 
Changes based on study 
protocol 13084 amendment 7.0, 
version 7.0, dated 16 May 2016 
and 13085 amendment 16, 
version 6.0, dated 16 May 2016 
Version 6 / 3 April 2017 
Study Design. 
 
Clarified stratification as country 
rather than region. 
Version 6 / 3 April 2017 
Data Rules 
 
Clarified baseline definition and 
deleted a sentence on country-


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Statistical Analysis Plan Final Version 6.0 
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Document Version / Date 
Changes 
Reason of Changes 
specific analysis. 
Version 6 / 3 April 2017 
Demographic and Baseline 
Characteristics 
Revised subgroups for 
respiratory culture organisms 
and added 5 subgroups 
pertaining to MDR. 
Version 6 / 3 April 2017 
Concomitant medications 
Clarified coding of concomitant 
medications and antibiotics. 
Version 6 / 3 April 2017 
Study Medication Exposure 
Added details of analysis. 
Version 6 / 3 April 2017 
Efficacy 
Ordered primary efficacy criteria 
by medical relevance. 
Added ventilation status 
assumption. 
Added handling of missing TOC 
visit for endpoint criteria 
regarding systemic antibiotics. 
Added details on additional 
efficacy analyses. 
Added subgroups for MDR and 
details of derivation of MDR 
patients for primary and 
secondary analyses. 
Added details on secondary 
efficacy analyses. 
Added exploratory analysis of 
primary efficacy endpoint. 
Version 6 / 3 April 2017 
Microbiological Analysis 
Clarified analysis and added 
descriptions of additional 
analyses 
Version 6 / 3 April 2017 
Mortality 
Added details of analysis 
Version 6 / 21 April 2017 
Adverse events 
Added condition for TEAE. 
Added details of analyses. 
Added summary by MLG. 
Added analysis by bronchial 
hyperreactivity. 
Added table defining AE of 
special interest. 
Version 6 / 21 April 2017 
Laboratory Data 
Added urinalysis summary. 
Added definition of creatinine 
clearance. 
Added AKI. 
Version 6 / 21 April 2017 
Appendices 
Added list of terms for organ 
failure. 
Added list of terms for bronchial 
hyperreactivity 
Version 6 / 21 April 2017 
Device events 
Added details for device event 
analysis: summary by event/no. 
of doses; summary by event / 
no. of patients; summary by 
category; summary by event; 
summary by event related to 
AE/SAE 
Version 6 / 28 June 2017 
Header 
Revised study number and 


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Statistical Analysis Plan Final Version 6.0 
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Document Version / Date 
Changes 
Reason of Changes 
header format to be consistent 
with CSR header. 
Version 6 / 28 July 2017 
Efficacy 
Changes based on the protocol 
amendment 6, Version 7.0 8 
February 2016. 
New primary endpoint added 
Moved previous primary 
endpoint to Additional Efficacy 
Endpoint Analysis 
Version 6 / 2 Aug 2017 
6.5.4 Vital Signs 
Clarified definition of baseline 
Version 6 / 2 Aug 2017 
4.5 Data Rules 
Clarified the assignment of visit 
for discontinuation 
Clarified the definition of 
baseline 
Version 6 / 16 Oct 2017 
 
Amended according to the new 
primray endpoint described in 
protocol amendment. 
Version 6 / 20 Oct 2017 
 
Added AE and TEAE 
summaries for mITT population 
grouped as treated. 
Version 6 / 3 Nov 2017 
Introduction 
Fixed 13084 amendment and 
version numbers. 
Version 6 / 3 Nov 2017 
6.5.1 Adverse events 
Deleted duplicate bullet lines. 
Added mITT to organ failure 
and AE of special interest 
8. 
References 
None. 
9. 
Appendices 


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Statistical Analysis Plan Final Version 6.0 
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9.1 Appendix A: MDR Subgroup Analysis Plan 
Table 9–1 MDR Subgroup Analysis Plan 
Subgroups 
Groups defined as 
Analysis to be provided 
Patients with confirmed MDR pathogens 
See next page for definitions.  
 
MDR first detected at baseline 
 
MDR first detected post baseline 
 
Not MDR 
a) Descriptive statistics 
b) Survival 
c) Pneumonia-related mortality 
d) Early clinical response 
e) Vent days 
f) 
ICU days 
Patients with confirmed ESBL 
pathogens (identified by Covance 
microbiology lab) 
 
See next page for definitions.  
 
ESBL first detected at baseline 
 
ESBL first detected post baseline 
 
Not ESBL 
a) Descriptive statistics 
b) Survival 
c) Pneumonia-related mortality 
d) Early clinical response 
e) Vent days 
f) 
ICU days 
Late onset of infection on the vent: >d5 
If a patient was intubated on multiple 
dates, use the earliest occurrence of 
start of intubation. If intubation date or 
antibiotic start date is completely 
missing, the date will not be imputed and 
the response will be No. If partial 
intubation date, impute to earlier of first 
study drug date, 1st of month (if dd is 
missing), 1JAN (if dd and mmm is 
missing). 
If patient received antibiotic on multiple 
dates, use the earliest occurrence after 
intubation. 
Patients who received IV antibiotic for pneumonia 5 or 
more days after day of intubation. 
 
Yes 
 
No (includes those with < 5 days and no IV 
antibiotics for pneumonia) 
a) Descriptive statistics 
b) Survival 
c) Pneumonia-related mortality 
d) Early clinical response 
e) Vent days 
f) 
ICU days 


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Statistical Analysis Plan Final Version 6.0 
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Subgroups 
Groups defined as 
Analysis to be provided 
Cochrane review on VAP 2016 showed 
only carbapenem-use shows a 
difference in clinical cure: All patients 
that were NOT treated with with IV-
carbapenems  
CMATC01 (ATC Code 01) = 
CARBAPENEMS 
Patients who received at least one dose of carbapenem 
during Days 1 through 10  
 
Yes 
 
No 
a) Descriptive statistics 
b) Survival 
c) Pneumonia-related mortality 
d) Early clinical response 
e) Vent days 
f) 
ICU days 
Start time of amikacin from start time of 
earliest IV antibiotic taken 
Use the latest start time of antibiotic 
before of study drug. 
If IV antibiotic start time is missing, the 
time is not imputed. (Slot to ≥24 hours) 
For partial start time of antibiotic, impute 
to later of start time of study drug, hh:59 
minute (if minute is missing), 23:mm (if 
hour is missing). 
For missing or partial start time of 
amikacin, use the earliest time possible 
for the start date: 00:00 if hour is 
missing; hh:00 is minute is missing. 
 
0 to <12 hours 
 
12 to <24 hours 
 
> 24 hours 
a) Descriptive statistics 
b) Survival 
c) Pneumonia-related mortality 
d) Early clinical response 
e) Vent days 
f) 
ICU days 


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Statistical Analysis Plan Final Version 6.0 
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MDR designation 
 To be declared a MDR, a bacterial isolate must be resistant to at least 3 (3 or more) of 
the 6 drug classes on the susceptibility panel below. Resistance must be to 3 or more 
drug classes from the same isolate at the same visit. 
 Once a patient has any MDR pathogen, he/she should be designated as a MDR patient 
no matter what the subsequent susceptibility tests show. 
 There can be 3 classes of patients based on MDR and timing of first detection of 
MDR in a patient: 
o MDR first detected at baseline 
o MDR first detected post baseline   
o Not MDR 
 For the 3 cephams, resistance to any one of the 3 drugs in the panel counts as cepham 
resistance for the category. 
 For consistency, consider a “NA” result as a “susceptible” for purposes of MDR 
tabulation. This means that 3+ results of “intermediate” or “resistant” are needed for 
MDR designation, and a “NA” does not count towards this total. 
 CCLS interpretation of drug resistance will be used to determine MDR. 
The efficacy table format would then be showing the primary endpoint and the 4 secondary 
endpoints for these 3 patient groups. 
The modified listing for classifying MDR gram negatives should count intermediates as “non-
susceptible”;  therefore for the gram negatives the following criteria are used (with the 
addition of Levofloxacin as the quinolone). Previously,  only true resistance designations 
were counted; the census is to also count the intermediates as “resistant” Adjustments are 
highlighted; drugs with an intermediate designation had that value moved into the resistant 
column.


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Statistical Analysis Plan Final Version 6.0 
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Table 9–2 MDR designation 
Drug Class 
Drugs in panel 
Resistance criteria 
Susceptible 
Aminoglycoside 
Amikacin (AN) 
32, 64, 128, 256 
16,8,4,…0.12 
β-lactam/β-lactamase inhibitor 
Amox/Clav (AmC) 
16/8, 32/16, 64/32 
8/4, ….<=0.03/ 0.015 
Cephams 
Ceftazidime. (CAZ) 
Cefazolin, (CZ) 
Cefpodoxime (CPD) 
8, 16, 32, 64 
32, 64  
 4, 8, 16, 32, 64 
4,2,…</= 0.03 
16,8,4…</= 0.03 
2,1…</= 0.03 
Carbapenam 
Imipenem (IPM) 
2, 4, 8, 16, 32 
1,0.5,…</= 0.015 
Tetracycline 
Tetracycline (TE) 
8, 16, 32, 64 
4,2,…</= 0.03 
Folate pathway inhibitor 
Trimethoprim-sulfamethoxazole (SXT) 
4/76, 8/152, 16/304, 32/608 2/38, 1/19, …..</=0.03/0.6 
Quinolone 
Levofloxacin 
4,8,16… 
2,1,0.5 
 


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Statistical Analysis Plan Final Version 6.0 
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9.2 Appendix B: Definition of organ failure 
The preferred terms  “Organ failure” under MedDRA version 20.0 are: 
Table 9–3 Preferred terms for "organ failure" under MedDRA v20.0 
Preferred term (aeptnam) 
PT code (aeptcd) 
Multiple organ dysfunction syndrome 
10077361 
Acute on chronic liver failure 
10077305 
Acute left ventricular failure 
10063081 
Acute right ventricular failure 
10063082 
Cardiac failure 
10007554 
Cardiac failure acute 
10007556 
Cardiac failure congestive 
10007559 
Cardiogenic shock 
10007625 
Cardiopulmonary failure 
10051093 
Cardiorenal syndrome 
10068230 
Cor pulmonale acute 
10010969 
Left ventricular failure 
10024119 
Low cardiac output syndrome 
10024899 
Ventricular failure 
10060953 
Acute hepatic failure 
10000804 
Hepatorenal failure 
10019845 
Hepatorenal syndrome 
10019846 
Subacute hepatic failure 
10056956 
Septic shock 
10040070 
Toxic shock syndrome 
10044248 
Acute kidney injury 
10069339 
Renal failure 
10038435 
Acute respiratory failure 
10001053 
Respiratory failure 
10038695 
Circulatory collapse 
10009192 
Distributive shock 
10070559 
Hypovolaemic shock 
10021138 
Neurogenic shock 
10058119 
Shock 
10040560 
Shock haemorrhagic 
10049771 
Respiratory arrest 
10038669 
Acute respiratory distress syndrome 
10001052 
Hepatic encephalopathy 
10019660 
Purpura fulminans 
10037556 
Hepatic necrosis 
10019692 
Brain injury 
10067967 
Encephalopathy 
10014625 


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Statistical Analysis Plan Final Version 6.0 
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Preferred term (aeptnam) 
PT code (aeptcd) 
Coma 
10010071 
Coma hepatic 
10010075 
Coma acidotic 
10049037 
Coma uraemic 
10010082 
Pancreatic failure 
10079281 
Cardiac arrest 
10007515 
Cerebral circulatory failure 
10008097 
Hepatic failure 
10019663 
Organ failure 
10053159 
Peripheral circulatory failure 
10034567 
Right ventricular failure 
10039163 
Postoperative renal failure 
10056675 
 
 


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Statistical Analysis Plan Final Version 6.0 
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9.3 
Appendix C: Definition of bronchial hyperreactivity 
MedDRA HLT: Bronchospasm and obstruction 
The preferred terms with primary or secondary path through MedDRA HLT “Bronchospasm 
and obstruction” under MedDRA version 19.1 are: 
PT: Acute post asthmatic amyotrophy 
PT: Airway remodelling 
PT: Aspirin-exacerbated respiratory disease 
PT: Asthma 
PT: Asthma exercise induced 
PT: Asthma late onset 
PT: Asthma-chronic obstructive pulmonary disease overlap syndrome 
PT: Asthmatic crisis 
PT: Bronchial hyperreactivity 
PT: Bronchial obstruction 
PT: Bronchial oedema 
PT: Bronchitis chronic 
PT: Bronchospasm 
PT: Bronchospasm paradoxical 
PT: Bronchostenosis 
PT: Chronic obstructive pulmonary disease 
PT: Cystic fibrosis 
PT: Cystic fibrosis lung 
PT: Infantile asthma 
PT: Infective exacerbation of chronic obstructive airways disease 
PT: Infective pulmonary exacerbation of cystic fibrosis 
PT: Obliterative bronchiolitis 
PT: Obstructive airways disorder 
PT: Occupational asthma 
PT: Reactive airways dysfunction syndrome 
PT: Reversible airways obstruction 
PT: Severe asthma with fungal sensitisation 
PT: Status asthmaticus 
PT: Unilateral bronchospasm 
PT: Wheezing 
 
 


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9.4 Appendix D: Definition of toxic-septic shock conditions 
 
[SMQ] Toxic-septic shock conditions (SMQ)[V20] 
PT: Acute kidney injury 
PT: Acute prerenal failure 
PT: Acute respiratory failure 
PT: Anuria 
PT: Blood pressure immeasurable 
PT: Cerebral hypoperfusion 
PT: Circulatory collapse 
PT: Distributive shock 
PT: Endotoxic shock 
PT: Grey syndrome neonatal 
PT: Hepatic congestion 
PT: Hepatojugular reflux 
PT: Hepatorenal failure 
PT: Hypoperfusion 
PT: Jugular vein distension 
PT: Myocardial depression 
PT: Neonatal anuria 
PT: Neonatal multi-organ failure 
PT: Neonatal respiratory failure 
PT: Organ failure 
PT: Prerenal failure 
PT: Propofol infusion syndrome 
PT: Renal failure 
PT: Renal failure neonatal 
PT: Respiratory failure 
PT: Septic shock 
PT: Shock 
PT: Shock symptom 
PT: Toxic shock syndrome