Conditions: Pseudomonas Aeruginosa Pneumonia
Keywords: Pseudomonas aeruginosa pneumonia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 158
Healthy volunteers: no

Brief summary:
Prospective, double-blind, randomized assessment of the efficacy, safety and pharmacokinetic of Aerucin® as adjunct treatment (in addition to standard of care antibiotics) for pneumonia caused by P. aeruginosa.

Detailed description:
This is a double-blind, randomized, placebo-controlled study of the human monoclonal antibody (mAb) AR-105 for the adjunctive therapeutic treatment of P. aeruginosa pneumonia in mechanically ventilated subjects. Subjects who are randomized will be treated with either standard of care (SOC) antibiotics plus placebo or SOC antibiotics plus AR-105. The study is being conducted at approximately 100 clinical sites across 17 countries. Subjects who meet all of the inclusion criteria and none of the exclusion criteria are screened by the microbiological culture test and/or rapid diagnostic test of an endotracheal aspirate to confirm the presence of an active P. aeruginosa infection. Following eligibility confirmation, the subject will be randomized in a 1:1 ratio to one of two treatment groups.

Arms:
arm 1: One intravenous infusion of AR-105 20mg/'kg arm 2: Matching placebo

Interventions: intervention 1: AR-105 intervention 2: Placebo
Intervention descriptions: intervention 1: monoclonal antibody intervention 2: matching placebo (+ SOC antibiotics)

Protocol document:
Prot_000.pdf: 
 
 
CLINICAL STUDY PROTOCOL 
 
Study Title 
Placebo-controlled, double-blind, randomized study of Aerucin as 
adjunct therapy to antibiotics in the treatment of P. aeruginosa 
pneumonia 
 
Investigational Product: Aerucin® (aerubumab, AR-105) 
Protocol Number: AR-105-002 
EudraCT number: 2016-004261-10 
 
 
Sponsor: 
Aridis Pharmaceuticals, Inc. 
5941 Optical Court 
San Jose, CA 95138 
Phone: 408-385-1742 
Fax: 408-960-3822 
 
Protocol Version Number: 3.0 
Date: 09NOV2018 
 
 
 
 
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the written 
consent of Aridis Pharmaceuticals, Inc. except to the extent that disclosure would be required by 
law and for the purpose of evaluating and/or conducting a clinical study for Aridis 
Pharmaceuticals, Inc. You are allowed to disclose the contents of this document only to your 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) and study personnel 
directly involved with conducting this protocol. Persons to whom the information is disclosed must 
be informed that the information is confidential and proprietary to Aridis Pharmaceuticals, Inc. 
and that it may not be further disclosed to third parties. 




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INVESTIGATOR AGREEMENT 
By signing below, I agree that: 
I have read this protocol. I approve this document and I agree that it contains all necessary details 
for carrying out the study as described. I will conduct this study in accordance with the design and 
specific provision of this protocol and will make a reasonable effort to complete the study within 
the time designated. I will provide copies of this protocol and access to all information provided 
by Aridis Pharmaceuticals, Inc. to study personnel under my supervision. I will discuss this 
material with them to ensure they are fully informed about the study product and study procedures. 
I will let them know that this information is confidential and proprietary to Aridis Pharmaceuticals, 
Inc. and that it may not be further disclosed to third parties. I understand that the study may be 
terminated, or enrollment suspended at any time by Aridis Pharmaceuticals, Inc., with or without 
cause, or by me if it becomes necessary to protect the best interests of the study subjects. 
I agree to conduct this study in full accordance with Food and Drug Administration Regulations, 
Institutional Review Board/Ethic Committee Regulations and ICH Guidelines for Good Clinical 
Practices. 
 
 
 
 
 
 
______________________________________________  
____________________ 
Investigator’s Signature 
 
 
 
 
 
Date 
 
 
 
______________________________________________ 
Investigator’s Printed Name 
 
  


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VERSION HISTORY 
Version and Date 
Author 
Summary of changes 
1.2 
26-Dec-2016 
Paul-André de Lame, M.D. 
 
Original protocol 
1.3 - Taiwan 
07-Mar-2017 
Paul-André de Lame, M.D. 
 
Change to lower age limit from 18 
to 20 to comply with Taiwan 
regulations. 
1.4 - Germany 
28-Jul-2017 
Paul-André de Lame, M.D. 
Updated exclusion criteria # 10 to 
specific required contraception for 
women of childbearing potential 
and precautions required from male 
partners of such women. 
Added 
section 
12.2 
regarding 
criteria for study termination. 
Minor edits. 
1.5 
31-Aug-2017 
Paul-André de Lame. M.D. 
Integrates changes made in versions 
1.3 and 1.5. 
5.4: clarified PI free access to 
unblinding 
8.4: Clarified AE and SUSAR 
reporting per country regulations 
8.6: Clarified handling of SUSARs 
11.1: Specified that waivers and 
planned deviations form protocol 
are forbidden 
12.1: 
Clarified 
handling 
of 
amendments 
Minor edits 
2.0 
04-May-2018 
Alan Cohen, M.D. 
Please refer to separate Summary of 
Changes document 
3.0 
09-Nov-2018 
Wolfgang Dummer, M.D., Ph.D, 
Please refer to separate Summary of 
Changes document 


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SYNOPSIS 
TITLE:  Placebo-controlled, double-blind, randomized study of Aerucin as adjunct therapy to 
antibiotics in the treatment of P. aeruginosa pneumonia. 
PROTOCOL NUMBER:  AR-105-002 
INVESTIGATIONAL PRODUCT: Aerucin® (aerubumab, AR-105) 
PHASE:  2/3 
INDICATION(S): Aerucin is intended for use as adjunct therapy for treatment of ventilator-
associated pneumonia (VAP) due to Pseudomonas aeruginosa (P. aeruginosa) in combination 
with standard of care (SOC) antibiotic therapy. 
OBJECTIVES: 
Primary Clinical Efficacy Objective 
To assess the efficacy of Aerucin, administered as a single dose in addition to standard of care 
(SOC) antibiotic regimen on Clinical Cure rates (resolution of pneumonia) between SOC alone 
and SOC with Aerucin at Day 21. 
Primary Clinical Safety Objective 
To assess the clinical safety and tolerability of Aerucin in the study population. 
Secondary Clinical Efficacy Objectives 
To assess the effect of Aerucin, administered as a single dose in combination with SOC antibiotic 
regimen as an adjunct therapy of P. aeruginosa pneumonia, as compared to standard antibiotic 
therapy alone, on the following parameters: 
1. 
Clinical Cure rates at Day 28, 14 and 7, using the same criteria as for the primary efficacy 
objective.  
2. 
Time to Clinical Cure. 
3. 
Mortality and Pneumonia-related mortality post-treatment. 
4. 
Respiratory functional assessment: Time on mechanical ventilation (including if 
tracheostomy is in place). Time on supplemental oxygenation. Measures of respiratory health 
such as changes in PaO2/FiO2, using arterial blood gases and/or pulse oximetry measurements. 
5. 
Overall clinical status: Changes in sequential organ failure assessment (SOFA) score. 
6. 
Health economics: antibiotic utilization, duration of stay in the intensive care unit (ICU), 
duration of hospitalization, duration of intubation with ventilation or duration of mechanical 
ventilation if tracheostomy in place.  
Pharmacokinetics:  
To assess the PK Profile of Aerucin. 
Secondary Safety Objectives: To assess the immunogenicity of Aerucin. 


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Microbiological Efficacy Objectives 
To assess the effect of Aerucin, administered as a single dose in combination with SOC antibiotic 
regimen as an adjunct therapy of P. aeruginosa pneumonia, as compared to standard antibiotic 
therapy alone, on the following parameters 
1. Eradication of index P. aeruginosa at Day 21 and 28 post-treatment, 
2. Re-infection/new infection defined as a reoccurrence of pneumonia due to P. aeruginosa 
within the 28-day follow-up period, 
3. Reduction in bacterial load related to the index P. aeruginosa 
POPULATION: 
Persons of either gender who meet all of the following inclusion criteria and none of the exclusion 
criteria. 
Inclusion Criteria 
1. Written Informed Consent given by the patient or, if not possible, by a legally authorized 
representative and/or an independent physician as authorized by the competent ethics 
committee (EC) or independent review board (IRB) and local regulations. 
2. To be at least 18 years of age.  
Taiwan only: To be at least 20 years of age. 
South Korea only: To be at least 19 years of age. 
3. To be treated in an ICU at the time of enrollment. 
4. Endotracheal tube in place (tracheostomy is allowed). 
5. The patient is mechanically ventilated. 
6. Diagnosis of pneumonia based on the following criteria (a, b, and c, all must be met): 
a. One definitive chest X-ray diagnostic of pneumonia,  
                                                      or  
A sequence of at least 2 chest X-rays showing the presence of new or progressive 
infiltrate(s) suggestive of bacterial pneumonia. 
b. Hypoxemia based on at least one of the following measurements/criteria: 
i. 
PaO2/FiO2 < 250 mmHg (at sea level or equivalent for significant elevations above 
sea level) while intubated and mechanically ventilated, as one or more measures 
within  24 hours prior to randomization, or 
ii. 
PaO2 < 60 mmHg (at sea level or equivalent for significant elevations above sea level) 
while intubated and mechanically ventilated, as one or more measures 
within  24 hours prior to randomization, or 
iii. 
Respiratory failure necessitating intubation and mechanical ventilation. If 
tracheostomy is in place, the need for mechanical ventilation. 
c. At least one of the following signs:  


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i. 
Documented fever (e.g., body temperature greater than or equal to 38º Celsius). 
ii. 
Hypothermia (e.g., core body temperature less than or equal to 35º Celsius). 
iii. 
Total peripheral white blood cell (WBC) count greater than or equal to 10,000 cells/µL 
(or mm3). 
iv. 
Leukopenia with total WBC less than or equal to 4,500 cells/µL (mm3). 
v. 
Greater than 15 percent immature neutrophils (bands) noted on peripheral blood 
smear. 
7. Documented pulmonary infection with P. aeruginosa obtained by bronchoalveolar lavage 
(BAL), mini-BAL, protected endotracheal tube aspiration (ETA) (collectively ‘airway 
specimen’). For the study randomization, P. aeruginosa must be identified by one of the three 
methods below: 
a. An airway specimen culture positive by any method for P. aeruginosa of a specimen 
obtained less than 72 hours prior to randomization. A fresh airway specimen must be 
obtained prior to treatment initiation for baseline standard microbial culture by the local 
laboratory (including organism identification, quantitative/semi-quantitative culture and 
susceptibility testing); the corresponding culture results are NOT required prior to 
randomization. 
OR 
b. A rapid diagnostic test. In such case, the same sample must ALSO be used for standard 
microbial culture by the local laboratory (including organism identification, 
quantitative/semi-quantitative culture and susceptibility testing). The corresponding 
culture results are NOT required prior to randomization.  
OR 
c. A positive airway specimen culture by any method of P. aeruginosa from a specimen 
obtained at screening (quantitative, semi-quantitative). 
8. APACHE II score ≥ 10 and ≤ 35 within 24 hours once subject has consented. 
Exclusion Criteria 
1. The subject is moribund. Clinical judgment by the investigator that the subject is unlikely to 
survive the current illness/ICU-admission/treatment period despite delivery of adequate 
antibiotics for treatment of P. aeruginosa pneumonia. 
2. Effective antibacterial drug therapy for the index pneumonia administered continuously for 48 
hours or more prior to initiation of study treatment. Effective antibiotics would include those 
typically used to treat P. aeruginosa. 
3. Plasmapheresis (ongoing or planned) or any procedure that would remove/filter out the 
monoclonal antibody/study drug.  
4. Immunocompromised and at risk of infection by opportunistic pathogens including, but not 
limited to the following: 
a. HIV / AIDS who are not stable under medication and/or most recent CD4 < 200. 


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b. Expected neutropenia due to chemotherapy.  
c. Absolute neutrophil count less than 500/µL (mm3). 
d. Heart or lung transplant recipient within the past 6 months. 
5. Known hereditary complement deficiency. 
6. Liver dysfunction with a Child Pugh C score (Child Pugh score of A or B are acceptable at 
discretion of the Principal Investigator [PI]). 
7. Pulmonary disease that precludes evaluation of a therapeutic response (such as lung cancer 
resulting in bronchial obstruction or on the same side as the pneumonia, active tuberculosis, 
cystic fibrosis, granulomatous disease, fungal pulmonary infection, lung abscess, pleural 
empyema or post obstructive pneumonia). 
8. Patient has received intravenous (IV) immunoglobulin therapy within 3 months prior to the 
Screening Visit. 
9. Any woman of child-bearing potential (WOCBP) who does not have a negative pregnancy test 
result at Screening using SERUM or URINE testing based on Beta-subunit human chorionic 
gonadotropin (HCG) standard tests and methods from the local laboratory. Non-pregnant and 
non-lactating with confirmation via local laboratory testing is required. Women who are 
post-menopausal as evidenced by the absence of menstruation for at least 1 year are eligible; 
the date of last menstruation is to be recorded in the study files unless post-menopausal status 
is obvious due to age. 
10. Any sexually active subject who is unwilling to use acceptable methods of contraception for 
120 days after dosing. WOCBP must agree to use to an effective method of birth control (e.g., 
prescription oral contraceptives, contraceptive injections, contraceptive patch, intrauterine 
device, barrier methods, abstinence) or male partner sterilization alone for the duration of the 
study and for at least 120 days after dosing. Males with female partners of reproductive 
potential must agree to practice abstinence or to use a condom (male) plus an additional barrier 
method (female partner) of contraception for the duration of the study and for at least 120 days 
after dosing. 
11. Known lack of treatment compliance from prior studies or ongoing medical care based on 
medical records and PI’s judgment and/or the capacity of the patient to comply with all study 
requirements. 
12. Any medical, psychological, cognitive, social or legal conditions that would interfere in the 
ability to give an Informed Consent OR the absence of a legally valid representative of the 
patient or independent physician allowed and able to give consent on his/her behalf. 
13. Participation as a subject in another interventional study within 30 days prior to the first dose 
of study treatment, or planned participation in such a study during the study or within 30 days 
of its completion by the patient. Patients who participate in observational or epidemiological 
studies are eligible provided this does not interfere with their capacity or the capacity of the 
study staff to comply with all study requirements. 
STUDY DESIGN AND DURATION: 


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This study is an international, multicenter, prospective, double blind, randomized, 
placebo-controlled, parallel design protocol. It will be performed at multiple ICUs. 
Patients with a documented diagnosis of pneumonia, due to P. aeruginosa, and require ICU care, 
who are intubated (or have a tracheostomy tube in place) and are mechanically ventilated, are 
eligible for screening.  
Patients meeting all other eligibility requirements will be assessed for P. aeruginosa pulmonary 
infection on the basis of culture results (known from recent quantitative/semi-quantitative 
cultures) or on the basis of rapid diagnostic testing of a fresh airway specimen using methods 
available at the site (e.g. mass spectrometry, PCR, etc.), or using devices such as CE marked 
Cepheid’s GeneXpert® with “Investigational / Research Use Only” (IUO / RUO) PA Cartridge, or 
BioFire Diagnostics, LLC (a BioMerieux company)’s IUO FilmArray® LRTI Panel.  
Acceptable airway samples are BAL, mini-BAL, or ETA (ETA sample with < 10 squamous 
epithelial cells and >25 polymorphonuclear cells per low power field). It is expected that some 
subjects will have a positive rapid diagnostic test result that will not be confirmed by standard 
microbial culture (quantitative, or semi-quantitative). These subjects will be followed according 
to all the procedures described in this protocol but will not accrue toward the target 
microbiologically evaluable intent to treat population (micro-ITT). Subjects with a positive 
diagnosis of P. aeruginosa pulmonary infection will be randomized to receive either 
investigational product or matching placebo (more than one pathogen allowed, if P. aeruginosa is 
regarded a key pneumonia causing pathogen). In total, approximately 154 microbiologically 
evaluable subjects will be randomized 1-1 to be treated with placebo plus SOC or Aerucin 
(20 mg/kg) plus SOC in this Phase 2/3 study.  
The randomization procedure will account for the fact that many study sites will enroll only a few 
patients. Randomization will account for existence of sub-populations regarding oxygen status at 
baseline (PaO2/FiO2  200 or > 200). 
Study subjects will receive a single treatment dose (at Day 0) in addition to SOC antibiotic 
treatment, and then enter a safety, efficacy and PK follow-up study period for a total study duration 
of 28 days. The selection of SOC antibiotics is made in accordance with local best practices at the 
discretion of the investigator and should not exceed a duration of 14 days. 
The clinical course of pneumonia will be assessed daily by the investigator. Once Clinical Cure 
has been determined, the clinical status of the subject will be monitored to confirm continuation 
of Clinical Cure, re-infection (pneumonia due to P. aeruginosa), or new infection (pneumonia due 
to an unknown pathogen or a pathogen other than P. aeruginosa). “Clinical Cure” can be declared 
at any time during the study by the PI provided, that the required criteria are met either based on 
documented improvements in signs and symptoms, +/- changes documented by chest X-ray (if 
performed as part of SOC), as interpreted by the investigator.  
The assessment of Clinical Cure (resolution of pneumonia) by the site investigator will be used 
for the primary analysis. An adjudication committee will apply newly defined Clinical Cure 
criteria post hoc in a secondary analysis. “Clinical Cure” will be assessed for analytical purposes 
on Day 7, 14, 21 (primary efficacy endpoint) and 28.  


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Clinical safety assessments will be performed on an ongoing basis while predefined laboratory 
assessments will be performed at baseline, and thereafter at Day 4, 7, 14, 21, and 28. Test results 
obtained for medical reasons between these mandatory time points will be assessed for adverse 
events and documented accordingly.  
Secondary efficacy endpoints will be assessed in a similar manner during the 28-day period, when 
appropriate, daily when possible (e.g., time on mechanical ventilation including if tracheostomy 
is in place, time on supplemental oxygenation, measures of respiratory health such as changes in 
PaO2/FiO2 using arterial blood gases and/or pulse oximetry measurements), or upon occurrence 
(e.g., antibiotic utilization, duration of stay in the ICU, duration of hospitalization, duration of 
intubation with ventilation, or duration of mechanical ventilation if tracheostomy in place). 
Microbiological endpoints of eradication and re-infection/new infection will be determined based 
on quantitative/semi quantitative cultures performed by the local laboratory and testing of isolates 
performed by a central microbiology laboratory.  
Two PK analyses will be performed to assess the PK profile of Aerucin in the target patient 
population. The pharmacokinetics of Aerucin will be assessed using a population PK 
(compartmental modeling) approach as well as a non-compartmental analysis approach. A PK 
sub-study (“Full PK”) will be included, wherein more extensive sampling will be performed in a 
small number of patients (from select sites) who provide consent (i.e., 16 patients to obtain 8 
patients on active treatment). In the remaining patients, a sparse sampling strategy will be 
implemented with only a few samples obtained from each patient at varying time points (“Sparse 
PK”). A compartmental population PK model will be developed using the PK data collected from 
the sub-study and the sparse samples. PK parameters will be estimated as well as between-subject 
or inter-individual variability (IIV) and residual variability (RV). The effects of select factors 
describing the characteristics of sub-populations of interest (e.g. high or low bacterial load, cause 
of admission [trauma or non-trauma], and type of pneumonia) on the PK of Aerucin will be 
assessed via covariate analysis. In addition to the population PK evaluation, non-compartmental 
analysis of the PK sub-study data will be performed.  
The investigational therapy will be studied as an adjunct to antibiotic therapy as prescribed by the 
study investigator according to the SOC in his/her institution. The duration and nature of the initial 
and any subsequent antibiotic therapy related to the baseline pneumonia event and other infections 
will be recorded. Duration of antibiotic treatment for the index pneumonia should not exceed 14 
days. 
DOSAGE FORMS AND ROUTE OF ADMINISTRATION: 
Aerucin is provided as a sterile solution for intravenous infusion, in the amount of 4.5 mL in 
10 mL vials at a concentration of 27.5 mg/mL. 
STUDY ENDPOINTS:  
Primary Clinical Efficacy Endpoint 


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The proportion of patients with Clinical Cure at Day 21 in patients treated with Aerucin versus 
the placebo group as assessed by the investigator. The investigators’ assessment will be the 
primary analysis of the primary endpoint. 
Additionally, newly defined Clinical Cure criteria will be applied post-hoc by an independent 
adjudication committee: 
1. The subject must be alive through the index day visit 
2. The patient must have improved respiratory function evaluated at the index day, because:  
• The patient is now off the ventilator and extubated  
or 
• if the patient entered the study with mechanical ventilation due to reasons other than 
pneumonia and was assessed “likely ventilated beyond day 28” at screening, criteria #1 
(survival) and #3 (no signs and symptoms of pneumonia) are sufficient to establish 
Clinical Cure (presumed not ventilated) 
3. The subject must show no clinical signs and symptoms of bacterial pneumonia at the index 
day, which is determined by  
• Not receiving any antibiotic therapy active against the initial P. aeruginosa strain or 
against persisting pulmonary bacterial infection for 48 hours (antibiotic therapy for 
documented extra-pulmonary infection permitted) 
and 
• Resolution of signs and symptoms of bacterial pneumonia, as determined by the PI 
based on their clinical assessment. Parameters to be considered may include:  
o Fever > 38°C or hypothermia (< 35°C) attributable to the primary bacterial 
pneumonia 
o Tachypnea or shortness of breath (> 22 respirations/min) if off the ventilator 
and/or back to baseline respiratory rate 
o Tachycardia (> 100 bpm) or bradycardia (< 60 bpm) and/or back to baseline 
heart rate 
o Improvement of hypoxemia (ABG or PaO2/FiO2 > 200 or pulse 
oximetry > 90%) 
o If patient still produces sputum - negative P. aeruginosa culture from sputum, 
blood or pleural fluid 
Secondary Clinical Efficacy Endpoints 
1. 
Proportion of patients with Clinical Cure at Day 28 
2. 
Proportion of patients with Clinical Cure at Day 14 
3. 
All-cause mortality 
4. 
Pneumonia-related mortality 
5. 
Proportion of patients with Clinical Cure at Day 7 
6. 
Change from baseline in respiratory functional assessment: Time on mechanical ventilation 
(including if tracheostomy is in place). Time on supplemental oxygenation. Measures of 


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respiratory health such as changes in PaO2/FiO2, using arterial blood gases and/or pulse 
oximetry measurements. 
7. 
Mean change from baseline in overall clinical status measured by SOFA scores. 
8. 
Health economics: antibiotic utilization, duration of stay in the ICU, duration of 
hospitalization, duration of intubation with ventilation or duration of mechanical ventilation 
if tracheostomy is in place.  
Microbiological Endpoints 
Microbiological outcome of the index P. aeruginosa pneumonia based on the data provided by the 
local microbiology laboratory and central microbiology laboratory. 
Eradication of P. aeruginosa at Day 21 and 28. Eradication is considered as obtained when a 
specimen of respiratory secretions is obtained between the visit day and Day 28 and is negative. 
When no specimen is obtained within this time frame, microbiological outcome will be assessed 
as “Eradicated” only if the study subject is not receiving any antibiotic active against the initial 
strain after the study drug administration visit day and displays no signs and symptoms of 
pneumonia. 
Change in bacterial load related to the index P. aeruginosa on the basis of quantitative or 
semi-quantitative cultures by the local microbiological laboratory. 
Pharmacokinetic Endpoints 
Assessment of the PK parameters during full PK sub-study. 
Assessment of the PK parameters during sparse PK sub-study. 
Safety Endpoints: 
1. Assessment of clinical adverse events 
2. Assessment of clinical laboratory safety tests  
3. Assessment of immunogenicity to Aerucin 
 
STATISTICAL ANALYSES: 
Continuous data will be summarized by means, standard deviations, median, min, and max. 
Categorical data will be summarized by frequency and percentages.  
The primary endpoint of Clinical Cure rate at Day 21 will be analyzed using a stratified 
Cochran-Mantel-Haenszel (CMH) test. The CMH test will be stratified by baseline randomization 
strata. Time to Clinical Cure will be analyzed using a stratified log rank test. Other continuous 
endpoints will be analyzed using an Analysis of Covariance (ANCOVA), with treatment as a main 
effect, site, and baseline strata as covariates. Treatment by site interaction will be evaluated 
separately. Secondary endpoints will be analyzed using a sequential procedure in predefined order. 
Categorical variables will be analyzed using a stratified CMH test.  
The primary comparisons for all endpoints will be between the 20 mg/kg dose group and placebo 
and will be done at 0.05 level of significance. The details of the planned analyses will be provided 
in the Statistical Analysis Plan. 
Demographics, Baseline Characteristics, and Disposition 


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Demographics and baseline characteristics will be summarized by treatment group and overall. 
Disposition will be summarized by treatment group, and various outcomes (completed or 
discontinued the study, and reasons for discontinuation, etc.).  
Safety analysis 
Safety evaluations will include treatment emergent adverse events, vital signs, physical exam, and 
laboratory values. Safety will be summarized by treatment group. All treatment emergent adverse 
events, and serious adverse events, will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). Relationship to treatment, as well as severity will also be summarized. 
Changes in vital signs and physical exams will be summarized by group. Changes in laboratory 
values, as well as shifts (normal-> abnormal) will be summarized by treatment group. 
Pharmacokinetic analyses 
Two types of pharmacokinetic analyses will be performed to assess the PK hypothesis that the PK 
profile of Aerucin in the target patient population is similar to the profile observed in healthy 
human volunteers (HV). The first pharmacokinetic analysis will consist of a population PK 
(compartmental modeling) approach using the combined concentration data collected in the PK 
sub-study and the sparse concentration data, pooled with the available PK data from healthy 
volunteers (Study ARC-11-01). A compartmental population PK model will be developed and the 
effects of select intrinsic and extrinsic factors, including but not limited to patient status (e.g., HV 
versus patient with pneumonia), high or low bacterial load, and cause of admission [trauma or 
non-trauma]) on the PK of Aerucin will be evaluated via covariate analysis. The population PK 
model will be described by the estimation of mean structural model parameters, the magnitude of 
IIV in these parameters, and the magnitude of RV.  
The second pharmacokinetic analysis to be performed will be a non-compartmental analysis of the 
extensively sampled concentration-time data collected in the PK sub-study. The pharmacokinetic 
parameters to be derived from the individual concentration time profiles will include: the 
maximum observed plasma concentration (Cmax), the time of occurrence of Cmax (tmax), the area 
under the plasma concentration time curve from time 0 to Day 28 (AUC0-28), the terminal 
elimination rate constant (λz), and, if data permits, the terminal half-life (t1/2). Parameter estimates 
will be summarized and tabulated by individual and overall. Graphs of plasma concentration 
versus time profiles will be generated for each subject and graphs of mean ± SD profiles will be 
generated to compare patient and HV data. 


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SAMPLE SIZE DETERMINATION: 
The primary efficacy endpoint is the proportion of subjects with Clinical Cure at Day 21. 
It is assumed that the proportion of subjects with Clinical Cure will be 65% in the placebo group, 
and 85% in the 20 mg/kg dose group. With 69 subjects per group, there will be > 90% power for 
a statistically significant difference at a two-sided 0.05 level of significance. Sample size 
calculation was performed based on Fisher’s Exact test using binomial enumerations (PASS 
version 14). Assuming a 10% drop-out rate, approximately 154 subjects (77 per group) will be 
randomized. 
SITES:  Approximately 120 sites worldwide. 
SPONSOR: 
Aridis Pharmaceuticals, Inc. 
5941 Optical Court 
San Jose, CA 95138 
Phone: 408-385-1742  
Fax: 408-960-3822 
 


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TABLE OF CONTENTS 
SIGNATURE PAGE ...............................................................................................................................2 
INVESTIGATOR AGREEMENT ..............................................................................................................3 
VERSION HISTORY ..............................................................................................................................4 
SYNOPSIS ...........................................................................................................................................5 
TABLE OF CONTENTS ........................................................................................................................ 15 
LIST OF TABLES ................................................................................................................................ 18 
LIST OF FIGURES ............................................................................................................................... 18 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ........................................................................ 19 
1 
INTRODUCTION AND BACKGROUND INFORMATION ................................................................. 22 
1.1 
RATIONALE ................................................................................................................................ 22 
1.2 
AERUCIN ..................................................................................................................................... 23 
1.3 
INDICATION ................................................................................................................................ 24 
1.4 
HYPOTHESES .............................................................................................................................. 24 
1.5 
RISK/BENEFIT ............................................................................................................................ 24 
1.5.1 Risks related to Aerucin ........................................................................................................... 24 
1.5.2 Risks related to the study design and required procedures ....................................................... 25 
2 
STUDY OBJECTIVES ................................................................................................................... 26 
2.1 
PRIMARY CLINICAL EFFICACY OBJECTIVE................................................................................ 26 
2.2 
PRIMARY CLINICAL SAFETY OBJECTIVE ................................................................................... 26 
2.3 
SECONDARY CLINICAL EFFICACY OBJECTIVES ......................................................................... 26 
2.4 
TO ASSESS THE PK PROFILE OF AERUCIN SECONDARY SAFETY OBJECTIVE ..................................... 27 
2.5 
MICROBIOLOGICAL EFFICACY OBJECTIVES .............................................................................. 27 
3 
STUDY DESCRIPTION ................................................................................................................ 28 
3.1 
SUMMARY OF STUDY DESIGN ................................................................................................... 28 
3.2 
STUDY INDICATION(S) ............................................................................................................... 29 
4 
SELECTION AND WITHDRAWAL OF SUBJECTS ............................................................................ 30 
4.1 
INCLUSION CRITERIA ................................................................................................................. 30 
4.2 
EXCLUSION CRITERIA ................................................................................................................ 31 
4.3 
WITHDRAWAL CRITERIA ........................................................................................................... 32 
5 
STUDY TREATMENTS ................................................................................................................ 34 
5.1 
TREATMENT GROUPS ................................................................................................................. 34 
5.2 
RATIONALE FOR DOSING ........................................................................................................... 34 
5.3 
RANDOMIZATION AND BLINDING .............................................................................................. 34 
5.4 
BREAKING THE BLIND ............................................................................................................... 34 
5.5 
DRUG SUPPLIES ......................................................................................................................... 35 
5.5.1 Formulation and Packaging ....................................................................................................... 35 
5.5.2 Study Drug Preparation and Dispensing .................................................................................... 35 


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5.5.3 Study Drug Administration ........................................................................................................ 36 
5.5.4 Treatment Compliance .............................................................................................................. 36 
5.5.5 Storage and Accountability ....................................................................................................... 36 
5.6 
PRIOR AND CONCOMITANT MEDICATIONS AND/OR PROCEDURES ............................................ 36 
5.6.1 Excluded Medications and/or Procedures ................................................................................. 36 
5.6.2 Restricted Medications and/or Procedures ............................................................................... 36 
5.6.3 Documentation of Prior and Concomitant Medication Use ...................................................... 36 
6 
STUDY PROCEDURES ................................................................................................................ 37 
6.1 
INFORMED CONSENT ................................................................................................................. 40 
6.1.1 Russia ......................................................................................................................................... 41 
6.2 
SCREENING AND ENROLLMENT (DAY-1) ................................................................................... 41 
6.3 
BASELINE AND RANDOMIZATION (DAY -1, PRIOR TO TREATMENT) .......................................... 44 
6.4 
TREATMENT (DAY 0, TIME 0) .................................................................................................... 45 
6.5 
DAILY FOLLOW-UP FOR EFFICACY AND SAFETY (DAY 1 TO 28) ................................................ 46 
6.6 
DAY 4, 7, 14, AND 21: REQUIRED FULL ASSESSMENTS .............................................................. 48 
6.7 
END OF STUDY (DAY 28) OR EARLY TERMINATION .................................................................. 49 
7 
EFFICACY ASSESSMENTS ........................................................................................................... 51 
7.1 
PRIMARY CLINICAL EFFICACY PARAMETER ............................................................................. 51 
7.2 
SECONDARY CLINICAL EFFICACY PARAMETERS ...................................................................... 51 
7.3 
MICROBIOLOGICAL ENDPOINTS ................................................................................................ 52 
7.4 
PHARMACOKINETIC MEASUREMENTS ....................................................................................... 52 
7.4.1 Full PK sub-study ........................................................................................................................ 52 
7.4.2 Sparse PK sub-study ................................................................................................................... 53 
8 
SAFETY ASSESSMENTS .............................................................................................................. 54 
8.1 
SAFETY PARAMETERS................................................................................................................ 54 
8.2 
CONTRACEPTIVE REQUIREMENTS AND PREGNANCY TESTING ................................................. 54 
8.3 
ADVERSE EVENTS ...................................................................................................................... 54 
8.3.1 Adverse (Drug) Reaction ............................................................................................................ 55 
8.3.2 Unexpected Adverse Drug Reaction .......................................................................................... 55 
8.3.3 Assessment of Adverse Events by the Investigator .................................................................... 55 
8.4 
SERIOUS ADVERSE EVENTS ....................................................................................................... 56 
8.5 
SERIOUS ADVERSE EVENT REPORTING − PROCEDURES FOR INVESTIGATORS .......................... 57 
8.6 
PREGNANCY REPORTING ........................................................................................................... 58 
8.7 
EXPEDITED REPORTING ............................................................................................................. 58 
8.8 
FOLLOW-UP PHONE CALLS ............................................................................................................... 59 
8.9 
CLINICAL SAFETY LABORATORY EVALUATIONS ...................................................................... 59 
8.9.1 Standard safety laboratory tests ............................................................................................... 59 
8.9.2 Immunogenicity (ADA) ............................................................................................................... 59 
8.9.3 Future biomarker samples will be collected, where applicable. ................................................ 60 
8.10 
VITAL SIGNS .............................................................................................................................. 60 
8.10.1 
Baseline, Treatment, and Daily in-ICU .............................................................................. 60 
8.11 
ELECTROCARDIOGRAMS .................................................................................................................. 60 
8.13 
CHEST X-RAYS ............................................................................................................................... 60 


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8.14 
AIRWAY SPECIMEN ......................................................................................................................... 60 
9 
STATISTICS ............................................................................................................................... 62 
9.1 
ANALYTICAL POPULATIONS ...................................................................................................... 62 
9.1.1 Safety Population (Safety) ......................................................................................................... 62 
9.1.2 Modified Intent-to Treat Population (mITT) .............................................................................. 62 
9.1.3 Microbiological Intent-to-Treat Population (micro-ITT) ............................................................ 62 
9.1.4 Per-protocol Population (PP) ..................................................................................................... 62 
9.2 
SAMPLE SIZE AND STATEMENT OF POWER ................................................................................ 62 
9.3 
STATISTICAL METHODS ............................................................................................................. 62 
9.3.1 Demographics, Baseline Characteristics, and Disposition ......................................................... 63 
9.3.2 Safety analysis ........................................................................................................................... 63 
9.3.3 Pharmacokinetic analyses ......................................................................................................... 63 
9.3.4 Interim Analysis ......................................................................................................................... 63 
9.3.5 Missing data .............................................................................................................................. 63 
9.4 
DATA MONITORING COMMITTEE (DMC) .................................................................................. 64 
9.5 
ADJUDICATION COMMITTEE ...................................................................................................... 64 
10 
DATA MANAGEMENT AND RECORD KEEPING ........................................................................... 65 
10.1 
DATA MANAGEMENT ................................................................................................................ 65 
10.1.1 
Data Handling ................................................................................................................... 65 
10.1.2 
Computer Systems ............................................................................................................ 65 
10.1.3 
Data Entry ......................................................................................................................... 65 
10.1.4 
Medical Information Coding ............................................................................................. 65 
10.1.5 
Data Validation ................................................................................................................. 65 
10.2 
RECORD KEEPING ...................................................................................................................... 66 
11 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL .......................................................... 67 
11.1 
ETHICAL CONDUCT OF THE STUDY ........................................................................................... 67 
11.2 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE ...................................... 67 
11.2.1 
United States of America .................................................................................................. 67 
11.2.2 
Europe and other non-US countries .................................................................................. 67 
11.3 
INFORMED CONSENT ................................................................................................................. 67 
11.3.1 
Russia ................................................................................................................................ 68 
11.4 
SUBJECT CARD........................................................................................................................... 68 
11.5 
STUDY MONITORING REQUIREMENTS ....................................................................................... 68 
11.6 
DISCLOSURE OF DATA ............................................................................................................... 68 
11.7 
RETENTION OF RECORDS ........................................................................................................... 69 
11.8 
PUBLICATION POLICY ................................................................................................................ 69 
11.9 
FINANCIAL DISCLOSURE ............................................................................................................ 69 
11.10 INSURANCE AND INDEMNITY ..................................................................................................... 69 
11.11 LEGAL ASPECTS ......................................................................................................................... 70 
12 
STUDY ADMINISTRATIVE INFORMATION .................................................................................. 71 
12.1 
PROTOCOL AMENDMENTS ......................................................................................................... 71 
12.2 
STUDY TERMINATION ................................................................................................................ 71 
12.3 
ADDRESS LIST............................................................................................................................ 71 


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12.3.1 
Sponsor ............................................................................................................................. 71 
12.3.2 
Contract Research Organization ....................................................................................... 71 
12.3.3 
Drug Safety ....................................................................................................................... 71 
12.3.4 
Biological Specimens ......................................................................................................... 72 
13 
APPENDIX A:  CLINICAL LABORATORY ANALYTICS ..................................................................... 73 
14 
APPENDIX B:  OTHER TRIAL SPECIFIC PROCEDURES ................................................................... 74 
14.1 
APACHE II SCORE .................................................................................................................... 74 
14.2 
SOFA SCORE ............................................................................................................................. 74 
14.3 
MICROBIOLOGICAL BASIS FOR RANDOMIZATION AND TREATMENT .......................................... 74 
14.3.1 
Culture ............................................................................................................................... 74 
14.3.2 
Rapid testing ..................................................................................................................... 74 
14.4 
QUANTITATIVE/SEMI-QUANTITATIVE MICROBIOLOGY .............................................................. 76 
15 
APPENDIX C:  CONVERSION TABLE FOR FIO2.............................................................................. 77 
16 
REFERENCES ............................................................................................................................ 78 
 
LIST OF TABLES 
TABLE 1-1 
SUMMARY OF RELATED AES ............................................................................................................................ 25 
TABLE 5-1 
COMPOSITION OF AERUCIN DRUG PRODUCT ..................................................................................................... 35 
TABLE 6-1 
SCHEDULE OF ASSESSMENTS ............................................................................................................................ 39 
TABLE 7-1 
 CRITERIA FOR CLINICAL CURE .......................................................................................................................... 51 
 
LIST OF FIGURES 
FIGURE 6-1 
 PROTOCOL OVERVIEW .............................................................................................................................. 38 
FIGURE 6-2:  
SCREENING AND RANDOMIZATION PROCESS .................................................................................................. 44 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
Abbreviation 
Definition 
ABG 
arterial blood gas 
ADA 
anti-drug antibody  
AE 
adverse event 
ALT 
Alanine transaminase 
ANCOVA 
analysis of covariance 
APACHE II 
acute physiology and chronic health evaluation II 
AST 
aspartate transaminase 
BAL 
broncho-alveolar lavage 
BOCF 
baseline observation carried forward 
BUN 
blood urea nitrogen 
CABP 
community-acquired bacterial pneumonia 
CF 
cystic fibrosis 
CIP 
Council of Independent Physicians 
CK 
creatine kinase 
CRA 
clinical research associate 
CTA 
clinical trial authorization 
CRP 
c-reactive protein 
CMH 
Cochran-Mantel-Haenszel 
DNA 
deoxyribonucleic acid 
DMC 
Data Monitoring Committee 
EC 
Ethics Committee 
ECG 
electrocardiography 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ETA 
endotracheal aspiration 
FA 
FilmArray 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practices 
GFR 
glomerular filtration rate 
HABP 
hospital-acquired bacterial pneumonia 
HAP 
hospital-acquired pneumonia 
HCAP 
healthcare-associated pneumonia 
HCABP 
healthcare associated bacterial pneumonia 
HCG 
human chorionic gonadotropin 
HCO³ 
Bicarbonate 
HIV/AIDS 
human 
immunodeficiency 
virus/acquired 
immunodeficiency 
syndrome 


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Abbreviation 
Definition 
HV 
human volunteers 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference of Harmonization 
ICU 
intensive-care units 
IEC 
Independent Ethics Committee 
IgG1 
immunoglobulin G1 
INR 
international normalized ratio 
IRB 
Institutional Review Board, Independent Review Board 
ITT 
Intent to Treat 
IUO 
investigational use only 
IV 
intravenous 
IWRS 
interactive web-based randomization system 
LDH 
lactate dehydrogenase 
LRTI 
lower respiratory tract infection 
LOCF 
Last Observation Carried Forward 
mAb 
monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
MDR 
multi-drug resistance 
mITT 
Modified Intent to Treat 
micro-ITT 
Microbiological Intent to Treat (microbiologically evaluable) 
MRSA 
methicillin-resistant Staphylococcus aureus 
NIMP 
Non-investigational Medical Product 
P. aeruginosa 
Pseudomonas aeruginosa 
PCR 
Polymerase Chain Reaction 
PD 
Pharmacodynamic(s) 
PEEP 
positive end-expiratory pressure 
PI 
Principal Investigator 
PK 
Pharmacokinetic(s) 
PO 
Per Os (orally) 
PP 
Per-protocol Population 
RBC 
red blood cell 
RUO 
research use only 
RV 
residual variability 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SOC 
standard of cure 
SOFA 
sequential organ failure assessment 
SUSAR 
suspected unexpected adverse reaction 


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Abbreviation 
Definition 
TOC 
Test of Cure 
VAP 
ventilator-associated pneumonia 
WBC 
white blood cell 
WOCBP 
Woman of Child-Bearing Potential 
 


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1 
INTRODUCTION AND BACKGROUND INFORMATION  
1.1 
Rationale 
Nosocomial infections such as hospital associated pneumonia (HAP) and particularly ventilator 
associated pneumonia (VAP) are a major problem for providers and payers [1,2]. Gram-negative 
bacteria are responsible for approximately 80% of cases of pneumonia in hospitalized patients (this 
contrasts with bloodstream infections, for example, which are mainly caused by Gram-positive 
bacteria, of which methicillin-resistant Staphylococcus aureus (MRSA) is the most prominent [3]. 
Pseudomonas aeruginosa (P. aeruginosa) causes the majority of multi-drug resistant (MDR) 
nosocomial infections. Pneumonia accounts for approximately 15% of all hospital-associated 
infections, and also 27% and 24% of all infections acquired in medical intensive-care units (ICU) 
and coronary care units, respectively, making it the second most common hospital-associated 
infection after urinary tract infections. Being intubated and attached to a mechanical ventilator are 
two of the most common risk factors for infection in ICU patients [4].  
Mortality for hospital-associated pneumonia and ventilator-associated pneumonia in particular, is 
high, e.g., for hospital-associated, pneumonia-attributed mortality rates of 20% to 33% have been 
reported and ventilator-associated pneumonia accounted for 60% of all deaths due to 
hospital-associated infections [1]. Direct mortality from HAP is ~50% with about 21% of all HAP 
caused by P. aeruginosa infections [2]. The unmet medical need in VAP treatment is even more 
acute than in cystic fibrosis (CF), as it is increasingly clear that mortality in VAP is high despite 
aggressive antibiotic therapies (up to 70%) [1], leading to expensive hospitalization costs 
(~$150,000 per patient) [4]. VAP patients are also at a high risk of MDR P. aeruginosa infection 
[1,3]. 
Given the rise in naturally occurring antibiotic resistance and the widening gap between the 
number of drug-resistant pathogens and the number of antibiotics under development within the 
past 3 decades, the development of new anti-infective is clearly of increased importance. Human 
monoclonal antibodies (mAbs) represent a promising class of anti-infective alternatives to 
antibiotics, exhibiting attractive attributes such as strong safety track records, long plasma half-life 
(e.g. 3-4 weeks for an IgG1), and thus require much less frequent dosing than antibiotics, 
differentiated immunological mechanisms that do not require transport across the 
membrane/capsule of the bacteria and thus not susceptible to common mechanisms of antibiotic 
resistance. A recognized binding target of some antibacterial mAbs is the capsule surface antigens 
of pathogens, such as extracellular polysaccharides. Aerucin is a fully human mAb that was 
discovered by screening B-cells of a volunteer that was immunized with P. aeruginosa 
extracellular polysaccharide alginate. 
Alginate (also called mucoid exopolysaccharide) is an ideal epitope because it is uniquely and 
ubiquitously expressed on P. aeruginosa. It consists of β-1, 4-linked D-mannuronic acid and 
L-glucuronic acid and confers resistance to antibiotics [5]. It is a key virulence associated factor 
with the absence of detectable escape mutants (alginate negative), and it is a conserved, polymeric, 
high-density and high-avidity cell surface target. Alginate expression is key to colonization, 
biofilm growth, virulence, and immune evasion. 


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In support of alginate as a clinically effective target, it has been observed that alginate production 
is the hallmark of progressive decline in lung function in CF patients [5,6] and P. aeruginosa 
persistence and virulence [7]. Additionally, a described subpopulation of older CF patients who 
were not colonized with P. aeruginosa produced alginate specific phagocytic antibodies [8]. 
Patients with opsonic antibodies had a lower rate of positive cultures for P. aeruginosa, while 
those lacking these antibodies were usually infected with P. aeruginosa [5,6,7]. One treatment 
approach is the use of vaccines to generate specific mAb against P. aeruginosa. Vaccines studies 
of P. aeruginosa, including alginate and alginate conjugate vaccines, have not resulted in data 
demonstrating the ability of vaccines to generate broadly protective antibodies in humans. Thus, 
an approach to overcome the potential problems of active vaccination is to produce human mAbs 
that can be administered passively; both for prophylactic (very early in life) and therapeutic (for 
patients with an existing P. aeruginosa infection) use. This approach formed the basis for the 
development of Aridis’ human mAb (Aerucin). 
1.2 
Aerucin 
Aerucin binds to the conserved epitope of P. aeruginosa, alginate, at the C6 carboxyl group of 
mannuronic acid and mediates complement dependent phagocytic killing of both mucoid and non-
mucoid P. aeruginosa. Our data show that alginate is present on >90% of clinical P. aeruginosa 
isolates tested, and that there is no non-specific binding of Aerucin against a panel of 40 normal 
human tissues. Opsonization is a key feature of Aerucin’s mechanism of action as demonstrated 
in vitro: phagocytic assays showed that enabling P. aeruginosa killing requires the presence of 
phagocytes (e.g., neutrophils, macrophages) and complement. Its binding target (alginate) is a 
common cell surface component of P. aeruginosa and is critically required for host colonization 
and pathogenicity. Indeed, if selection pressure resulted in down regulated expression of alginate 
(which is not known to occur naturally), P. aeruginosa would become unable to colonize the host 
and significantly more susceptible to conventional antibiotics. Aerucin offers additional features 
that may be advantageous compared to conventional small molecule antibiotics for use in 
pneumonia and in CF, including long systemic serum half-life of about 3 weeks, and thus requires 
much less frequent dosing than antibiotics. As a result, Aerucin offers a unique profile and an 
entirely new mode of action, with no direct competition from antibiotics.  
Aerucin has not yet been approved for human use. Cellular and animal studies conducted with 
Aerucin have confirmed the stability and efficacious quality of this antibody. Experimental tests 
were performed using a refrigerated stable liquid formulation of Aerucin. These in vitro and in 
vivo studies have demonstrated that: 1) Aerucin binds to more than 90% of P. aeruginosa strains 
tested, 2) Aerucin protected against and treated infection, and 3) the delivery modalities were 
efficient enough to deliver the required concentration of Aerucin to the target and to demonstrate 
efficacy in the animal model. Human tissue binding and mouse toxicology evaluations show no 
human tissue binding and no adverse toxic effects. 
A Phase 1 study in healthy volunteers showed that Aerucin has a favorable safety profile and a 
PK profile consistent with that of IgG immunoglobulins. The highest dose tested was 20 mg/kg, 
which is the dose selected for this study. 


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1.3 
Indication 
Aerucin is being developed as adjunct therapy in combination with antibiotics for the treatment 
of pneumonia caused by P. aeruginosa.  
1.4 
Hypotheses 
1. Treatment of P. aeruginosa pneumonia with Aerucin improves the rate of Clinical Cure 
of the index pneumonia. 
2. Treatment of P. aeruginosa pneumonia with Aerucin results in an increase in survival 
rate in the target population 
3. Treatment of P. aeruginosa pneumonia with Aerucin improves microbiological, 
functional and health economic outcomes overall. 
4. Aerucin at the proposed dose level is safe based on clinical observation, standard 
laboratory tests, and frequency and nature of related adverse events. 
5. Aerucin does not trigger an adverse immunogenic response (i.e., anti-Aerucin 
immunogenicity). 
1.5 
Risk/Benefit 
1.5.1 
Risks related to Aerucin 
Aerucin is a fully human monoclonal antibody. It has been shown in a phase 1 study (Protocol 
ARC-11-01) in healthy volunteers to be safe in doses of 2.0, 8.0, and 20.0 mg/kg, administered 
intravenously over 1 hour. In that phase 1 study, a total of 46 AEs was reported, with a frequency 
that was similar across all three treatment cohorts without any pattern indicating a possible dose-
related increase in frequency of the AEs or a specific safety issue. Most subjects (14/16, or 87.5%) 
experienced at least 1 AE. None of the reported AEs was serious. All AEs were mild in intensity.  
Out of the 46 AEs that were reported, 6 were deemed related, as summarized in Table 1-1 below. 
Again, there was no clear pattern of dose-dependent safety issues, and as noted above, all these 
events were mild in intensity. A decrease in diastolic blood pressure was observed in two separate 
subjects in the higher dose cohort. Both occurred close to the infusion of the investigational 
product, were mild, were deemed possibly related by the investigator, and promptly resolved 
without any medical intervention.  
The effectiveness of Aerucin has not been established. Therefore, no benefit should be expected. 


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Table 1-1 Summary of Related AEs 
System Organ Class 
    Preferred Term 
Aerucin 
2.0 mg/kg 
(N = 5) 
Aerucin 
8.0 mg/kg 
(N = 6) 
Aerucin 
20 mg/kg 
(N = 5) 
Total 
 
(N = 16) 
N AEs 
15 
15 
16 
46 
N Related AEs 
0 
2 
4 
6 
General disorders and administration site conditions 
 
 
 
 
    Infusion site edema 
0 
1 
0 
1 
Investigations 
 
 
 
 
    Blood pressure diastolic decreased 
0 
0 
2 
2 
Musculoskeletal and connective disuse disorders 
 
 
 
 
    Back pain 
0 
0 
1 
1 
Nervous system disorders 
 
 
 
 
    Headache 
0 
0 
1 
1 
    Somnolence 
0 
1 
0 
1 
1.5.2 
Risks related to the study design and required procedures 
Aerucin will be administered in addition to standard-of-care antibiotic therapy, as determined by 
the investigator on the exclusive basis of the medical needs of his/her patient. Therefore, 
participation in this study does not affect the chances of a positive clinical outcome in any given 
study subject, also taking into account the favorable safety profile of the investigational product. 
Except for blood sampling for PK and anti-drug antibody (ADA), and rapid testing of airway 
specimens for assessing the presence of P. aeruginosa, the procedures that are required for the 
study are all routine procedures, in nature and frequency, for this type of patients whose clinical 
status requires hospitalization in an ICU. Therefore, with the exceptions noted earlier, this study 
does not impose an unreasonable burden on the study subjects. 
Blood sampling for PK and ADA has been reduced to the minimum necessary by allowing sparse 
sampling for the majority of the study subjects, on the one hand, and by limiting the required 
sample volume to the minimum technically necessary for the assays, thus limiting the related 
burden as much as possible. 
Eligible study subjects will be randomized and treated either on the basis of culture results (known 
from recent cultures) or on the basis of rapid diagnostic testing of airway specimens using devices 
such as CE marked Cepheid’s GeneXpert® with Investigational / Research Use Only (IUO / RUO) 
PA Cartridge, BioFire Diagnostics, LLC (a BioMerieux company)’s IUO FilmArray® LRTI Panel 
(please refer to section 14.3). This approach is necessary to allow the study intervention to be 
implemented as early as possible in the course of the disease, as early treatment is a known driver 
of clinical outcomes. It is expected that the results of rapid testing will not be confirmed by 
standard microbial culture in a small number of subjects for various reasons including the 
possibility of rapid test false positive, inadequate samples, or sample cultures affected by an 
ongoing antibiotic treatment. This situation is not expected to occur in more than 5% of the 
randomized subjects. Considering the safety profile of Aerucin and of similar fully human anti-
infective mAbs, this risk is deemed acceptable in the context of this study protocol. 


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2 
STUDY OBJECTIVES 
2.1 
Primary Clinical Efficacy Objective 
To assess the efficacy of Aerucin, administered as a single dose in addition to standard of care 
(SOC) antibiotic regimen on Clinical Cure rates (resolution of pneumonia) between SOC alone 
and SOC with Aerucin at Day 21. 
2.2 
Primary Clinical Safety Objective 
To assess the clinical safety and tolerability of Aerucin in the study population. 
2.3 
Secondary Clinical Efficacy Objectives 
To assess the effect of Aerucin, administered as a single dose in combination with SOC antibiotic 
regimen as an adjunct therapy of P. aeruginosa pneumonia, as compared to standard antibiotic 
therapy alone, on the following parameters: 
1. Clinical Cure: 
- 
Clinical Cure rate at Day 28, 14 and 7, using the same criteria as for the primary efficacy 
objective at Day 21. 
- 
Time to Clinical Cure 
2. Mortality: 
- 
All-cause mortality  
- 
Pneumonia-related mortality post-treatment 
3. Respiratory functional assessment:  
- 
Mechanical ventilation parameters 
- 
Changes in PaO2/FiO2 ratio (e.g. by arterial blood gases), if available and whenever 
possible OR changes in non-invasive measures of oxygenation (e.g. by pulse oximetry) 
- 
Use of supplemental oxygen 
4. Overall clinical status:  
- 
Changes in sequential organ failure assessment (SOFA) score 
5. Health economics  
- 
Antibiotic utilization 
- 
Duration of stay in ICU 
- 
Duration of hospitalization 
- 
Duration of intubation with ventilation 
- 
Duration of mechanical ventilation if tracheostomy is in place 
6. Pharmacokinetics 


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2.4 
To assess the PK Profile of Aerucin Secondary Safety Objective 
To assess the immunogenicity of Aerucin 
2.5 
Microbiological Efficacy Objectives 
To assess the effect of Aerucin, administered as a single dose as adjunct therapy in addition to 
standard antibiotic therapy for P. aeruginosa pneumonia, as compared to standard antibiotic 
therapy alone, on the following parameters: 
1. Eradication of index P. aeruginosa at Day 21 and 28 post-treatment, 
2. Re-infection/new infection defined as a reoccurrence of pneumonia due to P. aeruginosa 
within the 28-day follow-up period, 
3. Reduction in bacterial load related to the index P. aeruginosa. 
 


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3 
STUDY DESCRIPTION 
3.1 
Summary of Study Design 
This study is an international, multicenter, prospective, double blind, randomized, 
placebo-controlled, parallel design protocol in patients with VAP caused by P. aeruginosa. It will 
be performed at multiple ICUs. 
Patients with a documented diagnosis of pneumonia due to P. aeruginosa, and require ICU care, 
and who are intubated (or have a tracheostomy tube in place) and are mechanically ventilated, are 
eligible for screening.  
Patients meeting all other eligibility requirements will be assessed for P. aeruginosa pulmonary 
infection on the basis of culture results (known from recent quantitative/semi-quantitative cultures) 
or on the basis of rapid diagnostic testing of a fresh airway specimen using methods available at 
the site (e.g., mass spectrometry, PCR, etc.), or using devices such as CE marked Cepheid’s 
GeneXpert® with IUO / RUO PA Cartridge, or BioFire Diagnostics, LLC (a BioMerieux 
company)’s IUO FilmArray® LRTI Panel (please refer to section 14.3). Acceptable samples are 
bronchoalveolar lavage (BAL), mini-BAL, or endotracheal tube aspiration (ETA, ETA sample 
with < 10 squamous epithelial cells and >25 polymorphonuclear cells per low power field). It is 
expected that a small number of subjects will have a positive rapid diagnostic test result that will 
not be confirmed by standard microbial culture (quantitative/semi-quantitative). These subjects 
will be followed according to all the procedures described in this protocol but will not accrue 
toward the target microbiologically evaluable intent to treat population (micro-ITT). Subjects with 
a positive diagnosis of P. aeruginosa pulmonary infection will be randomized to receive either 
investigational product or matching placebo (more than one pathogen allowed, if P. aeruginosa is 
regarded a key pneumonia causing pathogen). In total, approximately 154 microbiologically 
evaluable subjects will be randomized 1-1 to be treated with placebo plus SOC or Aerucin 
(20 mg/kg) plus SOC in this Phase 2/3 study.  
The randomization procedure will account for the fact that many study sites will enroll only a few 
patients. Randomization will account for existence of sub-populations regarding oxygen status at 
baseline (PaO2/FiO2  200 or > 200). 
Study subjects will receive a single treatment dose (at Day 0) in addition to SOC antibiotic 
treatment, and then enter a safety, efficacy and PK follow-up study period for a total study duration 
of 28 days. The selection of SOC antibiotics is made in accordance with local best practices at the 
discretion of the investigator and should not exceed the duration of 14 days. 
The clinical course of pneumonia will be assessed daily by the investigator. Once Clinical Cure 
has been determined, the clinical status of the subject will be monitored to confirm continuation 
of Clinical Cure, re-infection (pneumonia due to P. aeruginosa), or new infection (pneumonia due 
to an unknown pathogen or a pathogen other than P. aeruginosa). “Clinical Cure” will be declared 
at any time during the study by the PI, provided that the required criteria are met either based on 
documented improvements in signs and symptoms, +/- changes documented by chest X-ray (if 
performed as part of SOC), as interpreted by the investigator.  


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The assessment of Clinical Cure (resolution of pneumonia) by the site investigator will be used for 
the primary analysis. An adjudication committee will apply newly defined Clinical Cure criteria 
post hoc in a secondary analysis. “Clinical Cure” will be assessed for analytical purposes on Day 
7, 14, 21 (primary efficacy endpoint) and 28.  
Clinical safety assessments will be performed on an ongoing basis while predefined laboratory 
assessments will be performed at baseline, and thereafter at Day 4, 7, 14, 21, and 28. Test results 
obtained for medical reasons between these mandatory time points will be assessed for adverse 
events and documented accordingly.  
Secondary efficacy endpoints will be assessed in a similar manner during the 28-day period when 
appropriate, daily when possible, (e.g., Time on mechanical ventilation including if tracheostomy 
is in place; Time on supplemental oxygenation; measures of respiratory health such as changes in 
PaO2/FiO2 using arterial blood gases and/or pulse oximetry measurements), or upon occurrence 
(e.g., antibiotic utilization, duration of stay in the ICU, duration of hospitalization, duration of 
intubation with ventilation, or duration of mechanical ventilation if tracheostomy in place). 
Microbiological endpoints of eradication and re-infection/new infection will be determined based 
on quantitative/semi-quantitative cultures performed by the local laboratory and testing of isolates 
performed by a central microbiology laboratory.  
Two PK analyses will be performed to assess the PK profile of Aerucin in the target patient 
population. The pharmacokinetics of Aerucin in patients will be assessed using a population PK 
(compartmental modeling) approach as well as a non-compartmental analysis approach. A PK 
sub-study (“Full PK”) will be included, wherein more extensive sampling will be performed in a 
small number of patients (from select sites) who provide consent (i.e., 16 patients to obtain 8 
patients on active treatment). In the remaining patients, a sparse sampling strategy will be 
implemented with only a few samples obtained from each patient at varying time points (“Sparse 
PK”). A compartmental population PK model will be developed using the PK data collected from 
the sub-study and the sparse samples. PK parameters will be estimated as well as between-subject 
or inter-individual variability (IIV) and residual variability (RV). The effects of select factors 
describing the characteristics of sub-populations of interest (e.g. high or low bacterial load, cause 
of admission [trauma or non-trauma], and type of pneumonia) on the PK of Aerucin will be 
assessed via covariate analysis. In addition to the population PK evaluation, non-compartmental 
analysis of the PK sub-study data will be performed.  
The investigational therapy will be studied as an adjunct to antibiotic therapy as prescribed by the 
study investigator according to the SOC in his/her institution. The duration and nature of the initial 
and any subsequent antibiotic therapy related to the baseline pneumonia event and other infections 
will be recorded. Antibiotic treatment of the index pneumonia should not exceed 14 days. 
3.2 
Study Indication(s) 
Aerucin is intended for use as adjunct therapy for the treatment of VAP due to P. aeruginosa in 
combination with SOC antibiotic therapy. 


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4 
SELECTION AND WITHDRAWAL OF SUBJECTS  
Subjects of either gender who meet all inclusion criteria and no exclusion criteria are eligible for 
participation in the study. 
4.1 
Inclusion Criteria 
1. Written Informed Consent given by the patient or, if not possible, by a legally authorized 
representative and/or an independent physician as authorized by the competent ethics 
committee (EC) or independent review board (IRB) and local regulations. 
2. To be at least 18 years of age.  
For Taiwan: To be at least 20 years of age. 
South Korea only: To be at least 19 years of age. 
3. To be treated in an ICU at the time of enrollment. 
4. Endotracheal tube in place (tracheostomy is allowed).  
5. The patient is mechanically ventilated. 
6. Diagnosis of pneumonia based on the following criteria (a, b, c, all must be met): 
a. One definitive chest X-ray diagnostic of pneumonia,  
                                           or  
A sequence of at least 2 chest X-rays showing the presence of new or progressive 
infiltrate(s) suggestive of bacterial pneumonia. 
b. Hypoxemia based on at least one of the following measurements/criteria: 
i. PaO2/FiO2 < 250 mmHg (at sea level or equivalent for significant elevations above 
sea level) while intubated and mechanically ventilated, as one or more measures 
within  24 hours prior to randomization, or 
ii. PaO2 < 60 mmHg (at sea level or equivalent for significant elevations above sea 
level) while intubated and mechanically ventilated, as one or more measures 
within  24 hours prior to randomization), or 
iii. Respiratory failure necessitating intubation and mechanical ventilation. If 
tracheostomy is in place, the need for mechanical ventilation. 
c. At least one of the following signs:  
i. Documented fever (e.g., body temperature greater than or equal to 38º Celsius). 
ii. Hypothermia (e.g., core body temperature less than or equal to 35º Celsius). 
iii. Total peripheral white blood cell (WBC) count greater than or equal to 10,000 
cells/µL (or mm3). 
iv. Leukopenia with total WBC less than or equal to 4,500 cells/µL (mm3). 
v. Greater than 15 percent immature neutrophils (bands) noted on peripheral blood 
smear. 


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7. Documented pulmonary infection with P. aeruginosa obtained by BAL, mini-BAL, protected 
ETA (collectively ‘airway specimen’). For the study randomization, P. aeruginosa must be 
identified by one of the three methods below: 
a. An airway specimen culture positive by any method for P. aeruginosa of a specimen 
obtained less than 72 hours prior to randomization. A fresh airway specimen must be 
obtained prior to treatment initiation for standard microbial culture by the local laboratory 
(including 
organism 
identification, 
quantitative/semi-quantitative 
culture 
and 
susceptibility testing); the corresponding culture results are NOT required prior to 
randomization. 
OR 
b. A rapid diagnostic test (see section 14.3 for acceptable methods). In such case, the same 
sample must ALSO be used for standard microbial culture by the local laboratory 
(including 
organism 
identification, 
quantitative/semi-quantitative 
culture 
and 
susceptibility testing). The corresponding culture results are NOT required prior to 
randomization.  
      OR 
c. A positive airway specimen culture by any method of P. aeruginosa from a specimen 
obtained at screening (quantitative, semi-quantitative). 
8. APACHE II score ≥ 10 and ≤ 35 within 24 hours once subject has consented. 
4.2 
Exclusion Criteria 
1. The subject is moribund. Clinical judgment by the investigator that the subject is unlikely to 
survive the current illness/ICU-admission/treatment period despite delivery of adequate 
antibiotics for treatment of P. aeruginosa pneumonia. 
2. Effective antibacterial drug therapy for the index pneumonia administered continuously for 48 
hours or more prior to initiation of study treatment. Effective antibiotics would include those 
typically used to treat P. aeruginosa. 
3. Plasmapheresis (ongoing or planned) or any procedure that would remove/filter out the 
monoclonal antibody/study drug. 
4. Immunocompromised and at risk of infection by opportunistic pathogens including, but not 
limited to the following: 
a. HIV / AIDS who are not stable under medication and/or most recent CD4 < 200. 
b. Expected neutropenia due to chemotherapy.  
c. Absolute neutrophil count less than 500/µL (mm3). 
d. Heart or lung transplant recipient within the past 6 months. 
5. Known hereditary complement deficiency. 
6. Liver dysfunction with a Child Pugh C score (Child Pugh score of A or B are acceptable at 
discretion of the Principal Investigator [PI]). 


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7. Pulmonary disease that precludes evaluation of a therapeutic response (such as lung cancer 
resulting in bronchial obstruction or on the same side as the pneumonia, active tuberculosis, 
cystic fibrosis, granulomatous disease, fungal pulmonary infection, lung abscess, pleural 
empyema or post obstructive pneumonia). 
8. Patient has received intravenous (IV) immunoglobulin therapy within 3 months prior to the 
Screening Visit.  
9. Any woman of child-bearing potential (WOCBP) who does not have a negative pregnancy test 
result at Screening using SERUM or URINE testing based on Beta-subunit human chorionic 
gonadotropin (HCG) standard tests and methods from the local laboratory. Non-pregnant and 
non-lactating with confirmation via local laboratory testing is required. Women who are 
post-menopausal as evidenced by the absence of menstruation for at least 1 year are eligible; 
the date of last menstruation is to be recorded in the study files unless post-menopausal status 
is obvious due to age.  
10. Any sexually active subjects who is unwilling to use acceptable methods of contraception for 
120 days after dosing. WOCBP must agree to use to an effective method of birth control (e.g., 
prescription oral contraceptives, contraceptive injections, contraceptive patch, intrauterine 
device, barrier methods, abstinence) or male partner sterilization alone for the duration of the 
study and for at least 120 days after dosing. Males with female partners of reproductive 
potential must agree to practice abstinence or to use a condom (male) plus an additional barrier 
method (female partner) of contraception for the duration of the study and for at least 120 days 
after dosing. 
11. Known lack of treatment compliance from prior studies or ongoing medical care based on 
medical records and PI’s judgment and/or the capacity of the patient to comply with all study 
requirements. 
12. Any medical, psychological, cognitive, social or legal conditions that would interfere in the 
ability to give an Informed Consent OR the absence of a legally valid representative of the 
patient or independent physician allowed and able to give consent on his/her behalf. 
13. Participation as subject in another interventional study within 30 days prior to the first dose of 
study treatment, or planned participation in such a study during the study or within 30 days of 
its completion by the patient. Patients who participate in observational or epidemiological 
studies are also eligible provided this does not interfere with their capacity or the capacity of 
the study staff to comply with all study requirements. 
4.3 
Withdrawal Criteria 
Participation of a subject in this clinical study may be discontinued, but not limited to, any of the 
following reasons: 
- 
The subject withdraws consent or formally requests discontinuation from the study for any 
reason; 
- 
The subject is lost to follow-up 
- 
Improvement of pneumonia and discharge from ICU should NOT be considered 
withdrawal. All assessments including Clinical Cure assessment should be collected 
through Day 28 


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- 
Termination of the study by the Sponsor or the regulatory authority. 
If a subject withdraws prematurely from the study due to the above criteria or any other reason, 
study staff should ensure that End of Study Visit data are recorded. The reason for subject 
withdrawal must be documented in the electronic case report form (eCRF). 
In the case of subjects lost to follow-up, attempts to contact the subject must be made and 
documented in the subject’s medical records, including whether the subject is alive at the time of 
contact. 
Withdrawn subjects will not be replaced.  


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5 
STUDY TREATMENTS 
5.1 
Treatment Groups 
After completing all screening procedures, eligible study subjects will be randomized to one of the 
following treatment groups: 
- 
Control group: placebo 
- 
Investigational Product group: Aerucin 20 mg/kg 
5.2 
Rationale for Dosing 
Aerucin was shown to be safe when administered in doses up to 20 mg/kg intravenously over 1 
hour in a phase 1 safety and PK study of 16 healthy volunteers. The 20 mg/kg dose, the highest 
dose then tested, was selected for this study because of the existence of a dose-response in animal 
studies, because of the severity of the target infection, and because the target for Aerucin is 
specific to P. aeruginosa, the amount of which may affect the PK profile of the product. 
5.3 
Randomization and Blinding 
This is a double-bind, placebo-controlled study.  
Study subjects will be first stratified as follows: 
- 
Stratum 1: VABP or non-VABP 
- 
Stratum 2: PaO2/FiO2 ≤200 or >200 
- 
Stratum 3: Americas, Eastern EU, Western EU and Asia 
Randomization will proceed in a 1:1 ratio, in blocks of 4, for the study overall.  
A computer-generated randomization schedule will be used to allocate study treatment according 
to the above randomization scheme. Upon confirmation of eligibility, the study personnel will be 
prompted to randomize the study subject using the electronic data capture (EDC) / interactive web-
based randomization system (IWRS) system.  
5.4 
Breaking the Blind 
The Investigator will be allowed to break the blind if, in his/her opinion, this is necessary to provide 
proper medical care to his/her patient. In general, study drug unblinding should not impact any 
necessary treatment decisions by the investigator. Prior to breaking the blind, the Investigator will 
confer with the Medical Monitor to confirm the necessity of such action. 
In the absence of the Investigator, the Medical Monitor may break the blind for a specific study 
subject under such urgent circumstances and after assessing the necessity of such action with a 
sub-investigator. 
Members of the Data Monitoring Committee (DMC) will be allowed to break the blind if it is 
deemed necessary to assess specific adverse events. 
The circumstances leading to breaking the blind will be fully documented in detail in a memo to 
file and as required, in the EDC system. 


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5.5 
Drug Supplies 
Aerucin is a fully human IgG1 lambda monoclonal antibody that binds to alginate on the surface 
of all P. aeruginosa cells and mediates complement-dependent phagocytic killing of both mucoid 
and non-mucoid P. aeruginosa. 
5.5.1 
Formulation and Packaging 
The Aerucin drug product is formulated at 27.5 mg/mL in 10 mM L-histidine, 150 mM sodium 
chloride, pH 6.0, and 0.02% w/v Polysorbate 20. Aerucin is a clear to slightly opalescent, 
colorless to pale yellow, sterile, preservative-free liquid for intravenous infusion. The composition 
of the Aerucin drug product is provided in the table below.  
The composition and formulation of the placebo is the same but for the absence of Aerucin. 
Table 5-1 Composition of Aerucin Drug Product 
Ingredient 
Amount/mL 
Function 
Aerucin 
27.5 mg/mL 
Active ingredient 
L-Histidine 
0.80 mg/mL 
Buffer 
L-Histidine (monohydrochloride, monohydrate) 
1.01 mg/mL 
Buffer 
Sodium chloride 
8.77 mg/mL 
Tonicity, Stabilizer 
Polysorbate 20 
0.2 mg/mL 
Stabilizer 
Water for Injection, USP 
q.s. 
Solvent 
Abbreviations: mg/mL = milligram(s) per milliliter; q.s. = quantum satis 
The study drug (investigational product or control) is provided in 10 mL glass vials with butyl 
rubber stoppers containing no less than 4.5 mL of extractable volume at an Aerucin concentration 
of 27.5 mg/mL. Each vial is labeled in the local language in compliance with local regulations. 
Each vial is identified with a unique vial number.  
The vials are packaged in individual cartons (one per vial), similarly labeled. 
5.5.2 
Study Drug Preparation and Dispensing 
Upon randomization, the number of vials of study drug based on subject’s weight required for 
treatment will be displayed by the EDC / IWRS system, and access will be given to the inventory 
corresponding to the treatment allocation of the subject.  
Study personnel will then select the specific vials required, up to a maximum of 20 vials from the 
inventory available on site. Subjects weighing over 120 kg will receive the amount of Aerucin or 
placebo corresponding to 120 kg, i.e. 20 vials. 
A Pharmacy Manual will describe the process in detail. In summary, to prepare the study drug for 
use, the corresponding volume of liquid from the study drug must first be extracted from a 100 mL 
normal saline infusion bag, and then the content of the selected vials must be transferred into this 
bag using sterile technique. 


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When ready for use, the infusion bag should be marked with the study subject number, the date 
and time of preparation, and the number of vials used, and a list of the vial numbers that were used 
for verification against the list assigned using the EDC / IWRS system should be provided. 
5.5.3 
Study Drug Administration 
The entire content of the bag must then be administered intravenously at room temperature in 
approximately 2 hours. An in-line 0.2 µm pore filter should be used. 
5.5.4 
Treatment Compliance 
The study drug will be administered once, intravenously, in a strictly monitored setting. 
Compliance will be recorded by confirming the start and stop dates and times of the infusion to 
show that the study drug was administered per the amount indicated by the EDC / IWRS system. 
5.5.5 
Storage and Accountability 
The study drug must be kept refrigerated between 2 and 8º C (35.6 and 46.4º F). Storage 
temperature is to be monitored and the corresponding records kept on file. 
Availability and usage of study drug by the study sites will be recorded using the EDC / IWRS & 
Inventory system.  
5.6 
Prior and Concomitant Medications and/or Procedures 
5.6.1 
Excluded Medications and/or Procedures 
Administration of monoclonal antibodies is forbidden for the duration of the study. Patients who 
received intravenous immunoglobulins (IVIG) within the last 90 days are excluded from the study. 
5.6.2 
Restricted Medications and/or Procedures 
None. 
5.6.3 
Documentation of Prior and Concomitant Medication Use 
All concomitant therapies which are ongoing at the time of Informed Consent signature and/or 
administered during the course of study through 28 days after study treatment will be recorded in 
the EDC. This includes both prescription and non-prescription drugs. 
In addition to reporting period above, antibiotic therapies administered within 48 hours of study 
treatment should also be recorded in the EDC, even if they were administered prior to Informed 
Consent Signature. 


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6 
STUDY PROCEDURES 
An overview of the study is provided below (Figure 6-1). Day-by-day details are provided in 
(Table 6-1). In summary, any patient with VAP, who is intubated, older than 18 years (at least 20 
years of age in Taiwan and at least 19 years of age in South Korea) and who signed an informed 
consent, will enter a screening phase dedicated to identifying any pathogen that is present, and in 
particular, verifying whether P. aeruginosa is present. This screening phase is critical to ensuring 
that no potentially eligible patient is missed. Therefore, the related activities should be organized 
and managed proactively. Participation of key hospital staff is very important, including personnel 
involved in managing infectious diseases in the institution, the local microbiology department, and 
any relevant personnel.  
If a culture from a valid airway specimen (BAL, mini-BAL or ETA) obtained within 72 hours of 
randomization is positive for P. aeruginosa, the subject can be randomized on this sole basis 
provided that all eligibility criteria are met, and that a new valid airway specimen is obtained prior 
to treatment. This baseline airway specimen will be sent to the site’s local microbiology laboratory 
for quantitative/semi-quantitative culture. These baseline culture results are not required prior to 
randomization. 
The sites will obtain airway specimens for culture prior to treatment (baseline), as medically 
indicated, at time of extubation, and at Day 28 (if not extubated prior to Day 28). Airway specimen 
cultures will be sent to the local microbiology laboratory for culture, including identification of 
genus and species, quantification and susceptibility testing as outlined in the microbiology 
laboratory manual.  
Isolates of unique organisms from airway specimen cultures will be sent to the central lab. The 
central microbiology laboratory will confirm identification and perform standardized antibiotic 
quantitative/semi-quantitative culture, susceptibility testing and serotyping on target pathogens as 
outlined in the microbiology laboratory manual. 
If the results of an airway specimen obtained within 72 hours of randomization are not available, 
a valid airway specimen (BAL, mini-BAL or ETA) should be obtained and tested using rapid 
diagnostic testing (see section 14.3) if available at site and approved to use by the Regulatory  
Authorities (RA) / Independent Ethics Committee (IEC). If such rapid testing is positive for P. 
aeruginosa, the subject can be randomized on this sole basis.  
The same airway specimen used for rapid testing will be assessed at the site’s local laboratory for 
baseline culture including identification of genus and species, quantitative/semi-quantitative 
culture and susceptibility testing as outlined in the laboratory procedure manual. These baseline 
culture results are not required prior to randomization.  
Isolates of unique organisms will be sent to the central lab. The central microbiology laboratory 
will confirm identification, perform the standardized antibiotic susceptibility testing, and 
serotyping.  
If no rapid diagnostic test is available and no culture within 72 hours of randomization has been 
taken, the site should make all possible efforts to have an airway specimen (BAL, mini-BAL or 
ETA) collected and sent to their local microbiology lab as soon as possible. The randomization 
cannot be done in this case until the microbiology results of a positive P. aeruginosa culture have 
been confirmed.  


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As soon as P. aeruginosa is confirmed on a valid airway specimen and all other inclusion and 
exclusion criteria are met, the subject should be randomized and treated (more than one pathogen 
allowed, if P. aeruginosa is regarded a key pneumonia causing pathogen). The study personnel 
will randomize the subject using the EDC / IWRS system to either Aerucin 20 mg/kg or placebo.  
Upon randomization, PK evaluations will be initiated as detailed in section 7.4.  
Following treatment, all patients will be assessed daily for overall clinical status, as detailed below 
(see Section 6.5), based on information collected as medically required. In addition, complete 
assessments will be performed on Day 4, 7, 14, 21 and 28, as detailed below (see Section 6.6). 
Methods are described in detail in the Laboratory Manual. 
Figure 6-1 
Protocol Overview 
Study Design: Protocol AR-105-002 
 
 


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Table 6-1 
Schedule of Assessments 
Visit 
Screening, 
Baseline, and 
Randomization 
Treatment 
Follow-up 
(Daily until 
index 
pneumonia is 
considered 
resolved) 
Follow-up  
Any 
setting 
End of Study14 or 
Early Termination17 
Day 
-1 
0 
1 to 28 
Daily 
 
4, 7, 14, 
21 
28 or 
Day of Termination 
Informed Consent 
X 
 
 
 
 
Eligibility 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Type of Pneumonia10 
X 
 
 
 
 
Medical history 
X 
 
 
 
 
Surgical History 
X 
 
 
 
 
Case history 
X 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
Physical exam 
X 
 
 
X 
X 
Vital signs11 
X 
X 
X 
X 
X 
12-lead ECG 
X 
 
 
 
 
Safety laboratory tests 
X 
 
X1 
X 
X 
Sampling: ADA 
X3 
 
 
 
X 
Sampling: Future Biomarkers 
(where applicable)  
 
 
 
X 
X 
Sampling: PK 
X4 
X5,6 
X5,6 
X5,6 
X5,6 
Microbiology: rapid testing 
X 
 
 
 
 
Microbiology: classic 
X 
 
X1 
X1 
X1 
Sampling: microbiology 
X 
 
X1 
X1 
X1 
Respiratory data 
X 
X2 
X1 
X 
X 
Arterial 
gases 
or 
pulse 
oximetry16 
X 
X 
 
X 
X 
PaO2/FiO2 ratio  
X 
X 
X 
X 
X 
APACHE II 
X 
 
 
 
 
SOFA 
X 
X 
X2 
 
 
Randomization 
X7 
 
 
 
 
Treatment 
 
X 
 
 
 
Assessment of Clinical Cure 
 
 
X8 
X 
X 
Adverse events 
 
X 
X 
X 
X 
Chest X-Rays 
X12 
 
 
 
 
Pregnancy Test  
(Urine or Serum) 
X13 
 
 
 
 
Discharge data 
 
 
 
 
X9 
Study Follow-Up Phone Call 
 
 
 
X15 
X15 


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Visit 
Screening, 
Baseline, and 
Randomization 
Treatment 
Follow-up 
(Daily until 
index 
pneumonia is 
considered 
resolved) 
Follow-up  
Any 
setting 
End of Study14 or 
Early Termination17 
Day 
-1 
0 
1 to 28 
Daily 
 
4, 7, 14, 
21 
28 or 
Day of Termination 
1. 
To be performed if medically necessary. Follow-up airway specimens to be obtained as medically necessary and 
prior to extubation and at Day 28 (if not extubated prior to then) for quantitative or semi-quantitative culture.  
2. 
SOFA and respiratory data to be collected on Day 0, 12 hours after treatment initiation and on Day 4, 7, 14, 21, 28 
while intubated and mechanically ventilated. Parameters for SOFA score calculation should not be older than 72 
hours. 
3. 
ADA only at screening / baseline and Day 28, or at early termination. 
4. 
Pre-dose PK sample to be obtained prior to treatment initiation. 
5. 
PK samples to be obtained for the FULL PK sub-study at the following times after initiation of treatment: 2 hours 
(end of infusion), 4h, 12h, and 24 hours and 1 sample at each of the following visits: Day 4, 7, 14, 21, and 28.  
6. 
PK samples for the SPARSE PK sub-study at the following times after initiation of treatment: 1 sample at 2 hours 
(end of infusion), 1 sample at either 4h, 12h, or 24 hours post-treatment initiation (inclusive) and 1 sample at any of 
the following visits: Day 4, 7, 14, 21, or 28.  
7. 
Eligible subjects are randomized on Day -1, Treatment day is Day 0 for the purpose of monitoring and collecting 
the required samples over the first 24 hours. 
8. 
Clinical Cure will be assessed at Day 7, 14, 21, 28 for the analytical purposes.  
9. 
Discharge data to be obtained when discharge occurs or Day 28, whichever occurs first. 
10. Patients with pneumonia who are intubated are eligible for screening regardless of the type of pneumonia, which 
will be recorded at the time of screening for all study subjects. 
11. Vital signs will be recorded at baseline prior to treatment (time 0) and then at 1, 2, 4, 12, and 24 hours post treatment. 
Vital signs will also be recorded daily thereafter. 
12. In addition to the screening timepoint, chest x-ray(s) are to be taken at any time as medically indicated. 
13. Women of child bearing potential must take a urine or serum pregnancy test at the time of Screening. 
14. For subjects with early discharge, effort must be made to perform all protocol defined procedures outlined for End 
of Study/Early Termination. 
15. Subjects who decide to discontinue study assessments prior to Day 28 will receive a study exit safety follow-up 
phone call on key days (Day 4, 7, 14, 21, 28) until Day 28 (+7 days) to assess Clinical Cure, survival and the status 
of any adverse events. 
16. Changes in PaO2/FiO2 ratio (e.g. by arterial blood gases), if available and whenever possible OR changes in non-
invasive measures of oxygenation (e.g. by pulse oximetry) 
17. A few days before or after the specified date is acceptable ( 2 days) 
6.1 
Informed Consent 
Informed consent will be obtained prior to any study-related procedure or data collection according 
to the regulations applicable at the study site where the patient is being enrolled. Depending upon 
such regulations, informed consent may be given by the study subject, a legally authorized 
representative, an independent physician or a council of independent physicians. The informed 
consent process will be duly documented in the subject’s study file.  
Prior to signing this document, the patient and/or his/her representative must have an opportunity 
to read it thoroughly, ask any questions, and do so under no pressure. The Informed Consent Form 
(ICF) should be provided to the patients as soon as possible before the first study procedures, so 
that time is allowed for each patient or his/her representative to review the documents and discuss 
them at his/her leisure.  


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If for any reason, the Informed Consent Form can only be read to the patient prior to his/her 
signing, a witness must sign, together with the patient, to guarantee that the document has been 
read to and understood by the patient prior to his/her signature. 
The Investigator is responsible for obtaining the Informed Consent. If this task is delegated to other 
study personnel, the Investigator remains responsible for ensuring that the Informed Consent 
process has been followed and clearly documented.  
6.1.1 
Russia 
Subject, legally authorized representative (LAR), or council of independent physicians (CIP) has 
provided written informed consent. 
6.2 
Screening and Enrollment (Day-1) 
Please refer to Figure 6-2 for a detailed flowchart of the screening and randomization process. 
All patients who are at least 18 years of age (at least 20 years of age in Taiwan) for whom an 
informed consent has been obtained, who are diagnosed with pneumonia based on the 
requirements in the inclusion criteria, and who are intubated will be considered for the study. 
Additionally to the exclusion criteria, by way of clarification, if the subject: 
a. is unlikely to survive for the study duration despite delivery of adequate antibiotics 
and supportive care for treatment;  
b. has a diagnosis of liver dysfunction with a Child Pugh C score > 9; 
c. is a WOCBP and has not agreed to use an effective method of birth control or is not 
post-menopausal as evidenced by the absence of menstruation for at least 1 year prior 
to Screening Visit; 
d. is not receiving/has not received interventional study drug (e.g. placebo) or 
medications/procedures except for SOC within the timeframe described (subject can 
be included, if he/she received placebo); 
he/she will be excluded from / not be enrolled in the study. 
The following information will be recorded: 
- 
Demographics 
- 
Screening data and reason(s) for screen failure in such case 
- 
Microbiology and Rapid Diagnostic Test for P. aeruginosa 
- 
All subjects who have given consent, have pneumonia and are intubated will enter the 
screening phase. 
Subjects for whom a culture from a valid airway specimen (BAL, mini-BAL or ETA) 
obtained within 72 hours of randomization is positive for P. aeruginosa can be 
randomized on this sole basis provided that all eligibility criteria are met, and that a 
new valid baseline airway specimen is obtained prior to treatment. This baseline airway 
specimen will be sent to the site’s local microbiology laboratory for culture including 
identification of genus and species, quantitative/semi-quantitative culture and 
susceptibility testing as outlined in the microbiology laboratory manual. These baseline 
culture results are not required prior to randomization. Isolates of unique organisms 


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will be sent to a central lab. The central microbiology laboratory will perform 
confirmation of identification, standardized antibiotic susceptibility testing and 
serotyping on target pathogens as outlined in the microbiology laboratory manual. Such 
culture results are not required prior to randomization. 
For subjects in whom a culture from a valid airway specimen (BAL, mini-BAL or ETA) 
obtained within 72 hours of randomization is NOT available, such valid airway 
specimen will be obtained and tested using rapid diagnostic testing (see section 14.3). 
If such rapid testing is positive for P. aeruginosa, the subject can be randomized on 
this sole basis and should be treated. The same airway specimen will be sent to the 
site’s local microbiology laboratory for culture including identification of genus and 
species, quantitative/semi-quantitative culture and susceptibility testing as outlined in 
the microbiology laboratory lab manual. These baseline culture results are not required 
prior to randomization. Isolates of unique organisms will be sent to a central lab. The 
central microbiology laboratory will perform confirmation of identification, 
standardized antibiotic susceptibility testing and serotyping on target pathogens as 
outlined in the microbiology laboratory manual.  
If NO rapid diagnostic test is available and NO culture within 72 hours of 
randomization has been taken, the site should make all possible efforts to have an 
airway specimen (BAL, mini-BAL or ETA) collected and sent to their local 
microbiology lab as soon as possible. The randomization cannot be done in this case 
until the microbiology results of a positive P. aeruginosa culture have been confirmed.  
- 
Acceptable airway specimen sampling methods are BAL, mini-BAL, and ETA for both 
rapid testing and standard microbial culture (quantitative or semi-quantitative). 
Aliquots should be reserved for assessing bioavailability. Make sure that blood urea 
nitrogen (BUN) or urea is recorded on or about the same time a BAL or mini-BAL 
sample is obtained. 
- 
The same airway specimens will be processed by the local microbiology laboratory for 
identification and quantification (quantitative/semi-quantitative cultures). Isolates of 
all the target pathogens obtained from the culture performed at the local lab will be sent 
to the central microbiology lab for confirmation of identification, susceptibility testing 
and serotyping. 
- 
The nature, quantity and antibiotic susceptibility of all pathogens identified by the local 
microbiology laboratory, and an assessment of the probability that the identified 
pathogen(s) are responsible for the index pneumonia will be recorded using the EDC 
system. 
- 
Record type of pneumonia based on the following criteria: 
a. Hospital-acquired bacterial pneumonia (HABP) 
Pneumonia occurring in a patient hospitalized for more than 48 hours or developing 
within 7 days of discharge from a hospital or a similar institution (e.g., long-term care 
facility).  
b. VAP 
Pneumonia (as defined below) occurring in a patient mechanically ventilated for at least 
48 hours. 


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c. Healthcare-associated bacterial pneumonia (HCABP) 
Pneumonia occurring in a patient who was in a hospital or a similar institution (e.g., 
long-term care facility) more than 7 days and less than 90 days prior to developing 
pneumonia  
d. Community-acquired bacterial pneumonia (CABP) 
Pneumonia occurring outside of any of the conditions described in points a, b and c. 
- 
For any subject who has a positive culture for P. aeruginosa, promptly assess all remaining 
eligibility criteria.  


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Figure 6-2:  Screening and Randomization Process 
 
6.3 
Baseline and Randomization (Day -1, prior to treatment)  
- 
Confirm eligibility and collect corresponding source documents.  


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- 
Medical and surgical history 
- 
Concomitant medications 
- 
To include current antibiotic therapy, its duration and whether or not effective against 
the P. aeruginosa assumed to be responsible of the pneumonia. 
- 
History of current condition (case history) 
- 
Reason for admission 
- 
Date and time of diagnosis of pneumonia, including the supporting evidence (see 
Section 4.1). 
- 
Pregnancy testing if woman of child bearing potential (urine or serum) 
- 
Severity status, including date and time. “Severe” is defined as PaO2/FiO2  200. 
- 
Physical exam 
- 
Vital signs 
- 
12-lead electrocardiography (ECG) 
- 
Laboratory tests. For details, please refer to the Section 8.9 for a list of the required tests, and 
to the Laboratory Manual for the corresponding procedures. 
- 
Standard safety tests 
- 
Baseline ADA sample 
- 
Future biomarker samples (where applicable) 
- 
Compute baseline scores (APACHE II, SOFA) and collect source data as instructed. Please 
refer to Section 14 (Appendix B) and to the EDC / IWRS manual. 
- 
Obtain respiratory data: 
- 
Mechanical ventilation parameters 
- 
Changes in PaO2/FiO2 (e.g. by arterial blood gases) OR changes in non-invasive 
measures of oxygenation (e.g. by pulse oximetry) 
- 
Use of supplemental oxygen 
- 
As soon as P. aeruginosa is confirmed on a valid airway specimen, all eligibility criteria are 
met, and baseline assessments are completed, the subject should be randomized and treated at 
once. Please refer to section 5.3 and the EDC / IWRS Manual for details. 
6.4 
Treatment (Day 0, Time 0) 
- 
Pre-dose (baseline) PK sample prior to dose administration.  
- 
Treatment administration. Please refer to Section 5.5 for details. 
- 
PK sample at end of infusion (i.e., 2 hours after treatment initiation) and the other Day 0 
PK samples as required depending upon participation in the Full or Sparse PK sub-
studies. 


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- 
Adverse Events. Monitor for 24 hours from treatment initiation for signs or symptoms 
including procedure-related complications, such as injection-site pain, swelling, 
bruising, or redness, infusion reactions, such as fever, chills, or diaphoresis, 
anaphylactoid reactions (e.g. urticaria, angioedema), anaphylaxis, and cardiovascular 
instability. 
- 
Concomitant Medications 
- 
Vital signs prior to treatment (time 0) and at 1, 2, 4, 12 and 24 hours after treatment 
initiation. 
- 
Safety laboratory tests  
- 
For subjects participating in the FULL PK sub-study, additional PK samples at 4, 12, 
and 24 hours after treatment initiation. For subjects participating in the SPARSE PK 
sub-study, 1 sample at 4h, 12h or 24h after treatment initiation (inclusive). Time of 
sampling to be recorded. 
- 
Compute SOFA score 12 hours following treatment initiation and collect source data 
on the corresponding worksheet.  
- 
Obtain respiratory data 12 hours post treatment initiation: 
- 
Mechanical ventilation parameters 
- 
Changes in PaO2/FiO2 (e.g. by arterial blood gases) possible OR changes in 
non-invasive measures of oxygenation (e.g. by pulse oximetry) 
- 
Use of supplemental oxygen 
6.5 
Daily follow-up for efficacy and safety (Day 1 to 28) 
These assessments are required daily for as long as the index pneumonia has not been deemed 
resolved by the investigator. 
- 
Clinical status including Clinical Cure of pneumonia 
- 
Note date and time of extubation and obtain a last airway specimen prior to 
extubation.  
- 
If Clinical Cure, record/collect full documentation of assessment, including a 
chest X-ray if performed as part of SOC. 
- 
As soon as P. aeruginosa is confirmed on a valid airway specimen, all 
eligibility criteria are met, and baseline assessments are completed, the subject 
should be randomized and treated at once. 
- 
Document Clinical Cure, persistence or re-infection/new infection of index 
pneumonia 
- 
Clinical Cure status to be analyzed on Day 7, 14, 21, 28. 
- 
Respiratory health: 
– Mechanical ventilation parameters 


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– PaO2/FiO2 ratio (e.g. by arterial blood gases), OR changes in non-
invasive measures of oxygenation (e.g. by pulse oximetry) 
– Use of supplemental oxygen 
- 
SOFA scores on Day 4, 7, 14, 21, 28 for the duration of stay in the ICU and/or while 
intubated and mechanically ventilated. 
- 
Adverse events 
- 
Concomitant Medications 
- 
Safety laboratory tests as available from medically indicated assessments. Key 
parameters of interest include white blood cells, neutrophils and CRP. Additional 
parameters should be recorded in the EDC system if available. 
- 
Microbiology:  
- 
Airway specimens are to be obtained: 
– At any time when as medically indicated 
- 
At the least, a valid airway specimen (BAL, mini-BAL or ETA) is 
to be obtained just prior to extubation. Ideally, an ETA specimen 
would be preferred for the airway culture. If BAL or mini-BAL, 
make sure that either BUN or urea is collected at or about the same 
time as sampling.  
- 
An aliquot (i.e. half of the specimen) is to be reserved for assessing 
bioavailability (refer to microbiology lab manual for instructions).  
- 
If not obtained on Day 7, 14, and 21, the nearest specimen collected 
will be used to assess microbiological outcome. 
- 
Obtain airway specimens (by BAL, mini-BAL, or protected ETA) for 
quantitative/semi-quantitative culture by the local microbiology laboratory. 
Other sampling methods, including sputum, are acceptable after extubation. 
- 
The local microbiology laboratory will perform culture including identification 
of genus and species, quantitative/semi-quantitative culture and susceptibility 
testing as outlined in the microbiology laboratory manual. 
- 
The local microbiology laboratory will obtain isolates of unique organisms 
from airway specimen cultures and send them to the central laboratory. The 
central microbiology laboratory will perform confirmation of organism 
identification, susceptibility testing and serotyping on target organisms as 
outlined in the microbiology laboratory manual. 
- 
Record microbiological assessments from the local laboratory in the EDC 
system, including:  
– Assessment of the quality of the sample 
– Organism identification (genus and species) 
– Quantification 


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– Any organisms identified 
– The corresponding antibiotic susceptibility profile for each pathogen as 
determined by the local microbiology laboratory 
– An assessment of microbiological outcome 
- 
Chest X-Rays at any time as medically indicated. 
6.6 
Day 4, 7, 14, and 21: Required full assessments 
- 
All daily assessments as detailed above are required whether the subject is in the ICU 
or has been transferred out of the ICU. 
- 
Perform full assessment of the clinical status of pneumonia 
- 
Document Clinical Cure, persistence or re-infection/new infection of index pneumonia 
using the daily assessments described above. 
- 
Microbiology:  
- 
 Airway specimens are to be obtained: 
– At any time when as medically indicated 
– At the least, a valid airway specimen (BAL, mini-BAL or ETA) is 
to be obtained just prior to extubation. Ideally, an ETA specimen 
would be preferred for the airway culture. If BAL or mini-BAL, 
make sure that either BUN or urea is collected at or about the same 
time of sampling.  
– An aliquot (i.e. half of this specimen) is to be reserved for assessing 
bioavailability (refer to microbiology lab manual for instructions). 
– If not obtained on Day 4, 7, 14, and 21, the nearest specimen 
collected will be used to assess microbiological outcome. 
- 
Obtain airway specimens for local and central laboratory assessment (by BAL, 
mini-BAL, or protected endotracheal tube aspiration) for standard microbial 
culture (quantitative, semi-quantitative). Other sampling methods, including 
sputum, are acceptable after extubation. 
- 
Obtain isolates for assessment by the central laboratory. 
- 
Record microbiological assessments from the local laboratory in the EDC 
system, including:  
– Assessment of the quality of the sample 
– Organism identification (genus and species) 
– Quantification 
– Any organisms identified,  
– The corresponding antibiotic susceptibility profile for each pathogen as 
determined by the local microbiology laboratory 


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– An assessment of microbiological outcome 
- 
Physical exam 
- 
Vital signs 
- 
Adverse Events  
- 
Concomitant Medications  
- 
Respiratory health: 
– Mechanical ventilation parameters 
– PaO2/FiO2 ratio (e.g. by arterial blood gases), if available and whenever 
possible OR changes in non-invasive measures of oxygenation (e.g. by 
pulse oximetry) 
– Use of supplemental oxygen 
- 
Laboratory tests. 
- 
Standard safety tests (required on these days regardless of medical need) 
- 
For subjects participating in the FULL PK sub-study, PK samples at Day 4, 
Day 7, Day 14, and Day 21. For subjects participating in the SPARSE PK sub-
study, 1 sample at any of the following visits: Day 4, 7, 14 or 21. Instructions 
for scheduling such sampling will be provided on a per-subject basis. 
- 
Future biomarker samples (where applicable) 
- 
Chest X-Rays at any time as medically indicated 
6.7 
End of study (Day 28) or Early Termination 
- 
Perform full assessment of the status of pneumonia 
- 
Document final clinical outcome of the index pneumonia  
- 
Airway specimens are to be obtained: 
- 
At any time when as medically indicated 
- 
At the least, a valid airway specimen (BAL, mini-BAL or ETA) is 
to be obtained just prior to extubation. Ideally, an ETA specimen 
would be preferred for the airway culture. If BAL or mini-BAL, 
make sure that either BUN or urea is collected at or about the same 
time as sampling.  
- 
An aliquot (i.e. half of the specimen) is to be reserved for assessing 
bioavailability (refer to microbiology lab manual for instructions).  
- 
If not obtained on Day 28, the nearest specimen collected will be 
used to assess microbiological outcome. 
- 
Obtain airway specimens for local and central laboratory assessment (by BAL, 
mini-BAL, or protected endotracheal tube aspiration) for standard microbial 
culture (quantitative, semi-quantitative). Other sampling methods, including 
sputum, are acceptable after extubation. 


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- 
Obtain isolates for assessment by the central laboratory. 
- 
Record microbiological assessments from the local laboratory in the EDC 
system, including:  
– Assessment of the quality of the sample 
– Organism identification (genus and species) 
– Quantification 
– Any organisms identified 
– The corresponding antibiotic susceptibility profile for each pathogen as 
determined by the local microbiology laboratory 
– An assessment of microbiological outcome 
- 
Respiratory health: 
– Mechanical ventilation parameters 
– PaO2/FiO2 ratio (e.g. by arterial blood gases), if available and whenever 
possible OR changes in non-invasive measures of oxygenation (e.g. by 
pulse oximetry) 
– Use of supplemental oxygen 
- 
Physical exam 
- 
Vital signs 
- 
Chest X-Rays at any time when as medically indicated 
- 
All-cause mortality 
- 
Adverse Events  
- 
Concomitant Medications  
- 
Laboratory tests 
- 
Standard safety tests (required on these days regardless of medical need) 
- 
For subjects participating in the FULL PK sub-study, PK sample is to be 
obtained on Day 28. For subjects participating in the SPARSE PK sub-study, 
a PK sample is to be obtained on Day 28 if it has not been collected previously 
at any of the following visits: Day 4, 7, 14, or 21. 
- 
ADA sample 
- 
Future biomarker sample, where applicable. 
- 
Ensure that outcomes of all recorded adverse events are known, final and recorded. 
- 
If early termination, reason(s) for early study termination and date thereof. Death is a 
possible reason for early termination. 
- 
Date of discharge from the ICU (when applicable) 
- 
Date of discharge from the hospital (when applicable) 


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7 
EFFICACY ASSESSMENTS 
7.1 
Primary Clinical Efficacy Parameter 
The proportion of patients with Clinical Cure at Day 21 in patients treated with Aerucin versus 
the placebo group as assessed by the investigator. The investigators’ assessment will be the 
primary analysis of the primary endpoint. 
Additionally, newly defined Clinical Cure (Table 7-1) and will be applied post-hoc by an 
independent adjudication committee. 
Table 7-1  
Criteria for Clinical Cure 
1. The subject must be alive through the index day visit  
2. The patient must have improved respiratory function evaluated at the index day, because:  
• The patient is now off the ventilator and extubated  
or 
3. if the patient entered the study with mechanical ventilation due to reasons other than 
pneumonia and was assessed “likely ventilated beyond day 28” at screening, criteria #1 
(survival) and #3 (no signs and symptoms of pneumonia) are sufficient to establish Clinical 
Cure (presumed not ventilated) 
4. The subject must show no clinical signs and symptoms of bacterial pneumonia at the 
index day, which is determined by  
• Not receiving any antibiotic therapy active against the initial P. aeruginosa strain or 
against persisting pulmonary bacterial infection for 48 hours (antibiotic therapy for 
documented extra-pulmonary infection permitted) 
and 
• Resolution of signs and symptoms of bacterial pneumonia, as determined by the PI 
based on their clinical assessment. Parameters to be considered may include:  
o Fever > 38°C or hypothermia (< 35°C) attributable to the primary bacterial 
pneumonia 
o Tachypnea or shortness of breath (> 22 respirations/min) if off the ventilator 
and/or back to baseline respiratory rate 
o Tachycardia (> 100 bpm) or bradycardia (< 60 bpm) and/or back to baseline 
heart rate 
o Improvement of hypoxemia (ABG or PaO2/FiO2 > 200 or pulse 
oximetry > 90%) 
o If patient still produces sputum - negative P. aeruginosa culture from 
sputum, blood or pleural fluid  
7.2 
Secondary Clinical Efficacy Parameters 
1. 
Proportion of patients with Clinical Cure at Day 28 
2. 
Proportion of patients with Clinical Cure at Day 14 
3. 
All-cause mortality  
4. 
Pneumonia-related mortality 
5. 
Proportion of patients with Clinical Cure at Day 7 


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6. 
Change from baseline in respiratory functional assessment: Time on mechanical 
ventilation (including if tracheostomy is in place). Time on supplemental oxygenation. 
Measures of respiratory health such as changes in PaO2/FiO2, using arterial blood gases 
and/or pulse oximetry measurements. 
7. 
Mean change from baseline in overall clinical status measured by:  
a. SOFA scores 
8. 
Health economics: antibiotic utilization, duration of stay in the ICU, duration of 
hospitalization, duration of intubation with ventilation or duration of mechanical 
ventilation if tracheostomy in place 
7.3 
Microbiological Endpoints 
1. 
Microbiological outcome of the index P. aeruginosa pneumonia based on the data 
provided by the local microbiology laboratory and central microbiology laboratory. 
2. 
Eradication of P. aeruginosa at Day 21 and 28. Eradication is considered as obtained 
when a specimen of respiratory secretions is obtained between the visit day and Day 28 
and is negative. When no specimen is obtained within this time frame, microbiological 
outcome will be assessed as “Eradicated” only if the study subject is not receiving any 
antibiotic active against the initial strain after the study drug administration visit day and 
displays no signs and symptoms of pneumonia. 
3. 
Change in bacterial load related to the index P. aeruginosa on the basis of quantitative 
or semi-quantitative cultures by the local microbiological laboratory. 
An antibiotic susceptibility profile will be obtained locally in order to confirm the effectiveness of 
the concomitant antibiotic regimen prior to enrollment and thereafter, as medically indicated.  
Quantitative and semi-quantitative cultures will be performed locally prior to treatment (baseline), 
as medically indicated, just prior to extubation, and at Day 28 (if not extubated prior to Day 28). 
Organism identification and antibiotic susceptibility profiles will be confirmed by the central 
microbiology laboratory for the purpose of confirming the infecting pathogen(s), and the adequacy 
of the concomitant antibiotic regimen.  
Serotyping will be performed by the central microbiology laboratory. 
7.4 
Pharmacokinetic Measurements 
Blood samples for determination of Aerucin concentration will be collected at specified times 
from all subjects. A sub-set of 16 subjects will contribute to a Full PK sub-study. All other subjects 
will contribute to a Sparse PK sub-study. 
At each sampling time, a primary and a back-up sample of 3 mL each will be obtained. The detailed 
handling, storing and shipping procedures are detailed in the Laboratory Manual. 
7.4.1 
Full PK sub-study 
For each patient participating in the FULL PK sub-study, a total of ten (10) PK samples will be 
obtained. Sampling times are as follows: 
Prior to the beginning of infusion (pre-dose, time 0) 
2 hours (end of infusion), 


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4 hours,  
12 hours,  
24 hours,  
96 hours (Day 4 visit), 
168 hours (Day 7 visit),  
336 hours (Day 14 visit),  
504 hours (Day 21 visit),  
672 hours (Day 28 visit). 
A non-compartmental analysis will be performed to characterize the PK of Aerucin for the FULL 
PK sub-study. 
7.4.2 
Sparse PK sub-study 
For subjects participating in the SPARSE PK sub-study, four (4) PK samples will be obtained for 
each at the following times: 
Prior to the beginning of infusion (pre-dose, time 0) 
2 hours (end of infusion),  
at any one of the following timepoints:  4h 12h, or 24h post-dose initiation (inclusive),  
at any of the following visits:  Day 4, 7, 14, 21, or 28.  
A population PK approach will be used to characterize the PK of Aerucin for the SPARSE PK 
population. 


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8 
SAFETY ASSESSMENTS 
8.1 
Safety Parameters 
1. 
Assessment of clinical adverse events, 
2. 
Assessment of clinical laboratory safety tests, 
3. 
Assessment of immunogenicity to Aerucin 
8.2 
Contraceptive Requirements and Pregnancy Testing 
Females of child bearing potential must agree to use at least 2 effective methods of birth control 
(e.g., prescription oral contraceptives, contraceptive injections, contraceptive patch, intrauterine 
device, barrier methods, abstinence) or male partner sterilization alone for the duration of the 
study and for at least 120 days after dosing. Males with female partners of reproductive potential 
must agree to practice abstinence or to use a condom (male) plus an additional barrier method 
(female partner) of contraception for the duration of the study and for at least 120 days after 
dosing. 
WOCBP must have a negative pregnancy test result at Screening (serum or urine) to meet the 
eligibility criteria for enrollment. Women who are post-menopausal as evidenced by the absence 
of menstruation for at least 1 year prior to Screening Visit are eligible; the date of the last 
menstruation is to be recorded in the study file unless postmenopausal status is obvious due to 
age. 
8.3 
Adverse Events 
An adverse event is defined as any untoward medical occurrence in a clinical investigation subject 
administered a pharmaceutical product, which does not necessarily have a causal relationship with 
this treatment. An adverse event can therefore be any unfavorable and/or unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an investigational medicinal product, whether or not related to the investigational medicinal 
product. All adverse events, including observed or volunteered problems, complaints, or 
symptoms, are to be recorded on the appropriate electronic case report form (eCRF). 
Adverse events, which include clinical laboratory test variables, will be monitored and 
documented from the time of randomization until 28 days after last dose. Subjects should be 
instructed to report any adverse event that they experience to the Investigator. Beginning at Day 0, 
Investigators should make an assessment for adverse events at each visit and record the adverse 
event on the appropriate eCRF using the EDC system.  
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified by the Investigator and recorded on the eCRF using the EDC 
system. However, if an observed or reported sign or symptom is not considered a component of a 
specific disease or syndrome by the Investigator, it should be recorded as a separate adverse event. 
Additionally, the condition that led to a medical or surgical procedure (e.g., surgery, endoscopy, 
tooth extraction, or transfusion) should be recorded as an adverse event, not the procedure.  
Any medical condition already present prior to Day 0 should be recorded as a pre-existing 
condition in the Medical History, and not be reported as an adverse event. However, should the 
medical condition or signs or symptoms present at baseline change in severity or seriousness at 


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any time after randomization or during the study, an adverse event should be reported (worsening 
of pre-existing condition). 
Clinically significant abnormal laboratory or other examination (e.g. electrocardiogram) findings 
independent from the underlying medical condition that are detected during the study or are present 
at prior to Day 0 and significantly worsen during the study should be reported as adverse events. 
The Investigator will exercise his or her medical and scientific judgment in deciding whether an 
abnormal laboratory finding, or other abnormal assessment is clinically significant. Clinically 
significant abnormal laboratory values occurring during the clinical study will be followed until 
repeat tests return to normal, stabilize, or are no longer clinically significant. Any abnormal test 
that is determined to be an error does not require reporting as an adverse event. 
Worsening of the index infection due to insufficient therapeutic effect of study drug is captured as 
an efficacy measure (i.e., clinical failure) and in general will not be considered an AE. However, 
if the worsening of the index infection meets seriousness criteria (see Section 8.3), the event will 
be deemed an SAE. 
8.3.1 
Adverse (Drug) Reaction 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered an adverse drug reaction. “Responses” to a medicinal product means that a causal 
relationship between a medicinal product and an adverse event is at least a reasonable possibility, 
i.e. the relationship cannot be ruled out. 
8.3.2 
Unexpected Adverse Drug Reaction 
An Unexpected Adverse Drug Reaction is defined as an adverse reaction, the nature or severity of 
which is not consistent with the applicable product information. For Aerucin, the reference safety 
information is included in 7.1 of the Investigator’s Brochure currently in force. The reference 
safety information will be reviewed yearly, and the periodicity of the review will be harmonized 
with the reporting period of the Development Safety Update Report. 
8.3.3 
Assessment of Adverse Events by the Investigator 
Unless an adverse event is considered serious and meets SAE criteria, progression or worsening 
of the index infection due to insufficient effect of study drug should not be deemed an AE or 
deemed related to study drug. 
The Investigator will assess the severity (intensity) of each adverse event as mild, moderate, or 
severe, and will also categorize each adverse event as to its potential relationship to study drug 
using the categories of “yes” or “no”. 
Assessment of Severity: 
Mild – An event that is easily tolerated and generally not interfering with normal daily activities. 
Moderate – An event that is sufficiently discomforting to interfere with normal daily activities. 
Severe – An event that is incapacitating with inability to work or perform normal daily activities. 
Causality Assessment: 
The relationship of an adverse event to the administration of the study drug is to be assessed 
according to the following definitions: 


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No (unrelated, not related, no relation) – The time course between the administration of study drug 
and the occurrence or worsening of the adverse event rules out a causal relationship and another 
cause (concomitant drugs, therapies, complications, etc.) is suspected. 
Yes (related) – The time course between the administration of study drug and the occurrence or 
worsening of the adverse event is consistent with a causal relationship and no other cause 
(concomitant drugs, therapies, complications, etc.) can be identified. 
The definition implies a reasonable possibility of a causal relationship between the event and the 
study drug. This means that there are facts (evidence) or arguments to suggest a causal relationship. 
The following factors should also be considered: 
- 
The temporal sequence from study drug administration: The event should occur during or after 
the study drug is administered. The length of time from study drug exposure to event should be 
evaluated in the clinical context of the event. 
- 
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 subject 
may have. 
- 
Concomitant drug: The other drugs the subject is taking or the treatment the subject receives 
should be examined to determine whether any of them might be recognized to cause the event 
in question. 
- 
Known response pattern for this class of study drug: Clinical and/or preclinical data may 
indicate whether a particular response is likely to be a class effect. 
- 
Exposure to physical and/or mental stresses: The exposure to stress might induce adverse 
changes in the recipient and provide a logical and better explanation for the event. 
- 
The pharmacology and pharmacokinetics of the study drug: The known pharmacologic 
properties (absorption, distribution, metabolism, and excretion) of the study drug should be 
considered. 
8.4 
Serious Adverse Events 
An adverse event or adverse reaction is considered serious if, in the view of either the Investigator 
or Sponsor, it results in any of the following outcomes: 
- 
Death, 
- 
A life-threatening adverse event, 
- 
NOTE: An adverse event or adverse reaction is considered “life-threatening” if, in view of 
either the Investigator or Sponsor, its occurrence places the subject at immediate risk of 
death. It does not include an event that, had it occurred in a more severe form, might have 
caused death. 
- 
Requires hospitalization or prolongation of existing hospitalizations, 
- 
NOTE: Any hospital admission with at least one overnight stay will be considered an 
inpatient hospitalization. An emergency room visit without hospital admission will not be 
recorded as a serious adverse event (SAE) under this criterion, nor will hospitalization for 
a procedure scheduled or planned before signing of informed consent. However, unexpected 


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complications and/or prolongation of hospitalization that occur during elective surgery 
should be recorded as adverse events and assessed for seriousness. Admission to the hospital 
for social or situational reasons (i.e., no place to stay, live too far away to come for hospital 
visits) will not be considered inpatient hospitalizations.  
- 
A persistent or significant disability/incapacity or substantial disruption of the ability to conduct 
normal life functions, 
- 
A congenital anomaly or birth defect,  
- 
An important medical event. 
- 
NOTE: Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed above. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasia or convulsions that do not result in inpatient hospitalizations, or the development 
of drug dependency. 
8.5 
Serious Adverse Event Reporting − Procedures for Investigators 
Initial Reports 
Serious adverse events will be reported in compliance with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority IRB/EC and investigators. 
All SAEs occurring from randomization until 28 days following the last administration of study 
drug must be reported to the Contact Research Organization (CRO) Clinical Safety within 24 hours 
of the knowledge of the occurrence (this refers to any adverse event that meets any of the 
aforementioned serious criteria). All SAEs that the Investigator considers related to study drug 
occurring after the 28-day follow-up period must be reported to the Aridis Pharmaceuticals Inc. 
To report the SAE, complete the SAE form electronically in the EDC system for the study. When 
the form is completed, CRO Safety personnel will be notified electronically and will retrieve the 
form. If the event meets serious criteria and it is not possible to access the EDC system, send an 
email to CRO Safety at medpace-safetynotification@medpace.com or call the CRO SAE hotline 
(phone number listed below), and fax/email the completed paper SAE form to CRO (fax number 
listed below) within 24 hours of awareness. When the EDC system becomes available, the SAE 
information must be entered within 24 hours of the system becoming available.  
Safety Contact Information: Clinical Safety 
 
SAE hotline – USA: 
Telephone: +1-800-730-5779, dial 3 or +1-513-579-9911, dial 3 
Fax: +1-866-336-5320 or +1-513-579-5196 
Email: medpace-safetynotification@medpace.com 
 
SAE hotline – Europe: 
Telephone: +49 89 89 55 718 44 
Fax: +49 89 89 55 718 104 
Email: medpace-safetynotification@medpace.com 


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Follow-Up Reports 
The Investigator must continue to follow the subject until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the subject 
dies. 
Within 24 hours of receipt of follow-up information, the Investigator must update the SAE form 
electronically in the EDC system for the study and submit any supporting documentation (e.g., 
subject discharge summary or autopsy reports) to Clinical Safety via fax or e-mail. If it is not 
possible to access the EDC system, refer to the procedures outlined above for initial reporting of 
SAEs.  
8.6 
Pregnancy Reporting 
If a study subject becomes pregnant during the study or within 28 days of discontinuing study 
drug, the Investigator should report the pregnancy to Clinical Safety within 24 hours of being 
notified. Clinical Safety will then forward the Exposure in Utero form to the Investigator for 
completion.  
A subject becoming pregnant while on study drug will immediately be withdrawn from the study 
and early termination study procedures will be performed. 
The subject should be followed by the Investigator until completion of the pregnancy. If the 
pregnancy ends for any reason before the anticipated date, the Investigator should notify Clinical 
Safety. At the completion of the pregnancy, the Investigator will document the outcome of the 
pregnancy. If the outcome of the pregnancy meets the criteria for immediate classification as an 
SAE (i.e., postpartum complication, spontaneous abortion, stillbirth, neonatal death, or congenital 
anomaly), the Investigator should follow the procedures for reporting an SAE. 
8.7 
Expedited Reporting 
The Sponsor, or CRO (on behalf of the Sponsor), will report all relevant information about initial 
suspected unexpected serious adverse reactions (SUSAR) that are fatal or life-threatening as soon 
as possible to the FDA, applicable competent authorities in all the Member States concerned, and 
to the Central Ethics Committees, and in any case no later than 7 days after knowledge by the 
Sponsor or CRO of such a case, and relevant follow-up information will subsequently be 
communicated within an additional 8 days.  
All other SUSARs will be reported to the FDA, applicable competent authorities concerned and to 
the Central Ethics Committees concerned as soon as possible but within a maximum of 15 days of 
first knowledge by the Sponsor or CRO.  
The Sponsor and the CRO (on behalf of the Sponsor) will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, IRB/EC and investigators if 
country requirements are different than the above. 
The Sponsor will also inform all investigators as required.  
Expedited reporting of suspected unexpected serious adverse reactions related to non-
investigational medical products (NIMPs) will not be necessary. Listings of cases related to NIMPs 
will be included in the Development Safety Update Report. 


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8.8 
Follow-up Phone Calls 
For subjects who decide to discontinue assessments prior to Day 28, a study exit safety follow-up 
phone call will be conducted on Day 28 (+7 days) to assess survival, Clinical Cure, and adverse 
events.  
For subjects deemed clinically cured and discharged from the hospital, subjects are encouraged to 
return to the clinic to receive study procedures for the remaining key visit days until Day 28. If not 
able to visit the clinic on key visit days, a follow-up phone call will be conducted on key visit days 
(Day 4, 7, 14, 21 and 28) until Day 28. 
8.9 
Clinical Safety Laboratory Evaluations 
8.9.1 
Standard safety laboratory tests 
Laboratory results obtained in the course of standard medical care should be used to provide the 
information required below whenever available. All these tests are required at 
screening/baseline, Day 4, 7, 14, 21 and 28, except pregnancy testing (screening/baseline only) 
All the following tests will be performed by the local laboratory. 
- 
Chemistry:  
- 
Miscellaneous: glucose, osmolality, bicarbonate, total protein, albumin 
- 
Electrolytes: sodium, potassium, chloride, calcium 
- 
Liver function: total bilirubin, alanine transaminase (ALT), aspartate 
transaminase (AST), lactate dehydrogenase (LDH), alkaline phosphatase  
- 
Miscellaneous enzymes: creatine kinase (CK), amylase, C-reactive protein 
(CRP) 
- 
Renal function: blood urea nitrogen, creatinine, serum eGFR, phosphorus 
- 
Hematology & coagulation 
- 
Red blood cell (RBC), hemoglobin, hematocrit 
- 
WBC, neutrophils, lymphocytes, basophils, eosinophils, and monocytes 
(absolute counts or %) 
- 
INR, fibrinogen, platelets 
- 
Urine: glucose, protein, RBC, WBC 
- 
Pregnancy test for women of childbearing potential (serum or urine, screening only) 
8.9.2 
Immunogenicity (ADA) 
- 
The corresponding sample will be collected, stored and shipped per instructions (see 
laboratory manual).  
- 
Samples will be obtained at screening/baseline and Day 28.  
- 
Assays will be performed by a central laboratory. 


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- 
A primary and a back-up sample of 1.5 mL each of serum will be collected and stored 
at -20º C. 
8.9.3 
Future biomarker samples will be collected, where applicable. 
- 
The corresponding sample will be collected, stored and shipped per instructions (see 
laboratory manual).  
- 
Samples will be obtained at Day 4, 7, 14, 21, and 28. 
- 
Assays will be performed at a central laboratory. 
8.10 
Vital Signs 
Vital signs include heart rate, arterial blood pressure, respiratory rate, and temperature. 
Maximum daily temperature (defined as the maximum temperature reported on a single calendar 
day) will be recorded. Body temperature may be taken per the site’s preferred method but limited 
to oral, tympanic, rectal or core measurements and will be recorded in the appropriate eCRF. The 
same method of measuring a patient’s body temperature should be used throughout the study. 
8.10.1 
Baseline, Treatment, and Daily in-ICU 
Vital signs will be recorded at baseline prior to treatment (time 0), and then at 1, 2, 4, 12 and 24 
hours post treatment. Vital signs will also be recorded daily thereafter. 
8.11 
Electrocardiograms 
A standard 12-lead ECG will be obtained at baseline for reference. Abnormal ECG finding that 
would be observed during the course of the study will be duly documented and if appropriate, 
reported as adverse events. 
8.12 
Physical Examinations 
A standard physical exam by body systems (General Appearance, Head and Neck, Lymph Nodes, 
Cardiac, Pulmonary, Abdominal, Genitourinary, Osteoarticular, Extremities, Cutaneous, 
Neurological) will be performed at baseline, then at Day 4, 7, 14, 21, and 28 or in case of early 
termination. Changes from baseline will be assessed and if appropriate, reported as adverse events. 
 
8.13 
Chest X-rays 
Minimum of one Chest X-rays or a sequence of at least 2 Chest X-rays showing the presence of 
new or progressive infiltrate(s) suggestive of bacterial pneumonia to diagnose a pneumonia needs 
to be taken during screening. Chest X-rays may be taken at any time during the course of the study 
if medically necessary. All clinically relevant Chest X-rays may be uploaded to SureClinical. 
8.14 
Airway specimen 
Airway specimens will be collected by only acceptable methods such as BAL, mini-BAL, or 
protected endotracheal tube aspiration or by sputum after extubation as outlined in the 


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microbiology laboratory manual. Additionally, please refer to the manual for detailed handling, 
storing and shipping procedures. 
 


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9 
STATISTICS 
9.1 
Analytical Populations 
9.1.1 
Safety Population (Safety) 
All subjects who have received the investigational therapy. 
9.1.2 
Modified Intent-to Treat Population (mITT) 
All subjects who have been randomized and treated with any amount of study drug, regardless of 
microbiological documentation. 
9.1.3 
Microbiological Intent-to-Treat Population (micro-ITT) 
All mITT subjects for whom microbiological documentation of pneumonia due to P. aeruginosa 
at screening / baseline has been obtained. The micro-ITT population will be used for efficacy 
analyses. 
9.1.4 
Per-protocol Population (PP)  
All micro-ITT subjects who completed the study without any major protocol deviation. 
9.2 
Sample Size and Statement of Power 
It is assumed that the proportion of subjects with Clinical Cure will be 65% in the placebo group, 
and 85% in the 20 mg/kg dose group. With 69 subjects per group, there will be > 90% power for 
a statistically significant difference at a two-sided 0.05 level of significance. Sample size 
calculation was performed based on Fisher’s Exact test using binomial enumerations (PASS 
version 14). Assuming a 10% drop-out rate, 154 subjects (77 per group) will be randomized. 
9.3 
Statistical Methods 
Continuous data will be summarized by means, standard deviations, median, min, and max. 
Categorical data will be summarized by frequency and percentages.  
The primary endpoint of Clinical Cure rate at Day 21 will be analyzed using a stratified Cochran-
Mantel-Haenszel (CMH) test. The CMH test will be stratified by baseline randomization strata. 
Time to Clinical Cure will be analyzed using a stratified log rank test. Other continuous endpoints 
will be analyzed using an Analysis of Covariance (ANCOVA), with treatment as a main effect, 
site, and baseline strata as covariates. Treatment by site interaction will be evaluated separately. 
Secondary endpoints will be analyzed using a sequential procedure in predefined order. 
Categorical variables will be analyzed using a stratified CMH test. 
The primary comparisons for all endpoints will be between the 20 mg/kg dose group and placebo 
and will be done at 0.05 level of significance. The details of the planned analyses will be provided 
in the Statistical Analysis Plan. 


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9.3.1 
Demographics, Baseline Characteristics, and Disposition 
Demographics and baseline characteristics will be summarized by treatment group and overall. 
Disposition will be summarized by treatment group, and various outcomes (completed or 
discontinued the study, and reasons for discontinuations, etc.).  
9.3.2 
Safety analysis 
Safety evaluations will include treatment emergent adverse events, vital signs, physical exam, and 
laboratory values. Safety will be summarized by treatment group. All treatment emergent adverse 
events, and serious adverse events, will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). Relationship to treatment, as well as severity will also be summarized. 
Changes in vital signs and physical exam will be summarized by group. Changes in laboratory 
values, as well as shifts (normal-> abnormal) will be summarized by treatment group. 
9.3.3 
Pharmacokinetic analyses 
Two types of pharmacokinetic analyses will be performed to assess the PK hypothesis that the PK 
profile of Aerucin in the target patient population is similar to the profile observed in healthy 
human volunteers (HV). The first pharmacokinetic analysis will consist of a population PK 
(compartmental modeling) approach using the combined concentration data collected in the PK 
sub-study and the sparse concentration data, pooled with the available PK data from healthy 
volunteers (Study ARC-11-01). A compartmental population PK model will be developed and the 
effects of select intrinsic and extrinsic factors, including but not limited to patient status (e.g., HV 
versus patient with pneumonia), high or low bacterial load, and cause of admission [trauma or non-
trauma]) on the PK of Aerucin will be evaluated via covariate analysis. The population PK model 
will be described by the estimation of mean structural model parameters, the magnitude of IIV in 
these parameters, and the magnitude of RV.  
The second pharmacokinetic analysis to be performed will be a non-compartmental analysis of the 
extensively sampled concentration-time data collected in the PK sub-study. The pharmacokinetic 
parameters to be derived from the individual concentration-time profiles will include: the 
maximum observed plasma concentration (Cmax), the time of occurrence of Cmax (tmax), the area 
under the plasma concentration-time curve from time 0 to Day 28 (AUC0-28), the terminal 
elimination rate constant (λz), and, if data permits, the terminal half-life (t1/2). Parameter estimates 
will be summarized and tabulated by individual and overall. Graphs of plasma concentration 
versus time profiles will be generated for each subject and graphs of mean ± SD profiles will be 
generated to compare patient and HV data. 
9.3.4 
Interim Analysis 
No interim analysis is planned. 
9.3.5 
Missing data 
Assessing microbiological outcome at Day 7, 14, 21 (Primary Efficacy endpoint), and 28 will be 
done using the nearest microbiological data available prior to that day (last observation carried 
forward, LOCF). 


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Missing data for secondary efficacy endpoints will be analyzed using the LOCF approach. 
For the purpose of sensitivity analysis, missing data will be imputed using baseline observation 
carried forward (BOCF) and observed case.  
9.4 
Data Monitoring Committee (DMC) 
An independent DMC will be reviewing on a regular basis the safety information collected to-date. 
The corresponding procedures will be defined in a charter. DMC meetings will include a blinded 
session, when personnel in charge of the study will provide background information to facilitate 
review, and an open session, closed to all but DMC members, during which access to unblinded 
reports and/or subject-specific data will be allowed.  
In addition, all SAEs deemed related will be communicated to the DMC, as defined in the charter, 
for immediate review. 
The Medical Monitor will call for a meeting of the DMC whenever safety concerns of immediate 
significance may arise, such as abnormal frequency of non-serious events or unrelated events. 
9.5 
Adjudication Committee 
An Independent Adjudication Committee will assess clinical outcomes post hoc, microbiological 
outcome, adequacy of antibiotic therapy at baseline for use in statistical analyses. Clinical outcome 
will be adjudicated consistent with the newly defined criteria (Table 7-1). 


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10 
DATA MANAGEMENT AND RECORD KEEPING 
10.1 
Data Management 
10.1.1 
Data Handling 
Data will be recorded at the site on electronic case report forms (eCRF) and reviewed by the 
clinical research associate (CRA) during monitoring visits. The CRAs will verify data recorded in 
the EDC system with source documents. All corrections or changes made to any study data must 
be appropriately tracked in an audit trail in the EDC system. An eCRF will be considered complete 
when all missing, incorrect, and/or inconsistent data has been accounted for. 
10.1.2 
Computer Systems 
Data will be processed using a validated computer system conforming to regulatory requirements. 
10.1.3 
Data Entry 
Data must be recorded using the EDC system as the study is in progress in a timely manner, 
keeping in mind that the EDC system is programmed to assist study personnel in complying with 
protocol requirements on a daily basis. This concerns both screening (pre-baseline) and post-
randomization study data. 
All site personnel must log into the system using their secure user name and password to enter, 
review, or correct study data. These procedures must comply with Title 21 of the Code of Federal 
Regulations (21 CFR Part 11) and other appropriate international regulations. All passwords will 
be strictly confidential. 
10.1.4 
Medical Information Coding 
For medical information, the following thesauri will be used: 
• MedDRA for medical history and adverse events, and 
• World Health Organization Drug Dictionary for prior and concomitant medications. 
10.1.5 
Data Validation 
Validation checks programmed within the EDC system, as well as supplemental validation 
performed via review of the downloaded data, will be applied to the data in order to ensure 
accurate, consistent, and reliable data. Data identified as erroneous, or data that are missing, will 
be referred to the investigative site for resolution through data queries. 
The eCRFs must be reviewed and electronically signed by the Investigator prior to locking and 
unblinding the database for analysis. 


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10.2 
Record Keeping 
Records of subjects, source documents, monitoring visit logs, eCRFs, inventory of study product, 
regulatory documents, and other Sponsor correspondence pertaining to the study must be kept in 
the appropriate study files at the site. Source data is defined as all information in original records 
and certified copies of original records of clinical findings, observations, or other activities in a 
clinical study necessary for the evaluation and reconstruction of the clinical study. Source data are 
contained in source documents (original records or certified copies). These records will be retained 
in a secure file for the period as set forth in the Clinical Study Agreement. Prior to transfer or 
destruction of these records, the Sponsor must be notified in writing and be given the opportunity 
to further store such records.  


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11 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL  
11.1 
Ethical Conduct of the Study 
Good Clinical Practice (GCP) is an international ethical and scientific quality standard for 
designing, conducting, recording, and reporting studies that involve human subjects. Compliance 
with this standard provides public assurance that the rights, safety, and wellbeing of study subjects 
are protected, consistent with the principles that have their origin in the Declaration of Helsinki, 
and that the clinical study data are credible. 
Prospective, planned deviations or waivers to the protocol are not allowed and must not be used 
e.g. it is not acceptable to enroll a subject if they do not meet the eligibility criteria or restrictions 
specified in the trial protocol. Investigators must comply with all applicable IRB/IEC and local 
requirements in the reporting of protocol deviations. 
11.2 
Institutional Review Board/Independent Ethics Committee 
11.2.1 
United States of America 
The Institutional Review Board (IRB) will review all appropriate study documentation in order to 
safeguard the rights, safety, and well-being of subjects. The study will only be conducted at sites 
where IRB approval has been obtained. The protocol, Investigator’s Brochure, Informed Consent 
Form (ICF), advertisements (if applicable), written information given to the subjects, safety 
updates, annual progress reports, and any revisions to these documents will be provided to the IRB 
by the Investigator. 
Federal regulations and ICH require that approval be obtained from an IRB prior to participation 
of subjects in research studies. Prior to study onset, the protocol, any protocol amendments, ICFs, 
advertisements to be used for subject recruitment, and any other written information regarding this 
study to be provided to a subject or subject’s legal guardian must be approved by the IRB. 
No drug will be released to the site for dosing until written IRB authorization has been received 
by the Sponsor. 
11.2.2 
Europe and other non-US countries 
It is the responsibility of the Sponsor or its designee (i.e., CRO) to obtain the approval of the 
responsible ethics committees according to the national regulations.  
The study will only start in the respective sites once the respective committee’s written approval 
has been given. 
11.3 
Informed Consent 
The ICF and any changes to the ICF made during the course of the study must be agreed to by the 
Sponsor or designee and the IRB/EC prior to its use and must be in compliance with all ICH GCP, 
local regulatory requirements, and legal requirements. 
The Investigator must ensure that each study subject is fully informed about the nature and 
objectives of the study and possible risks associated with participation and must ensure that the 
subject has been informed of his/her rights to privacy. The Investigator will obtain written 
informed consent from each subject or the subjects legal representative (if applicable) before any 


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study-specific activity is performed and should document in the source documentation that consent 
was obtained prior to enrollment in the study. The original signed copy of the ICF must be 
maintained by the Investigator and is subject to inspection by a representative of the Sponsor, their 
representatives, auditors, the IRB and/or regulatory agencies. A copy of the signed ICF will be 
given to the subject. 
11.3.1 
Russia 
For subjects who are unable to read and sign either version of the informed consent (i.e., shortened 
or complete version), decisions regarding the subject’s enrollment will be made by the CIP. 
11.4 
Subject Card 
On enrollment in the study, the subject will receive a subject card to be carried at all times. The 
subject card will state that the subject is participating in a clinical research study, type of treatment, 
number of treatment packs received, and contact details in case of an SAE. 
11.5 
Study Monitoring Requirements 
In the USA: It is the responsibility of the Investigator to ensure that the study is conducted in 
accordance with the protocol, Declaration of Helsinki, ICH GCP, and applicable regulatory 
requirements, and that valid data are entered into the eCRFs. 
In the European Union: It is the responsibility of the Investigator to ensure that the study is 
conducted in accordance with the protocol, ICH GCP, Directive 2001/20/EC, applicable regulatory 
requirements, and the Declaration of Helsinki (Seoul 2008) and that valid data are entered into the 
eCRFs. 
All study sites: To achieve this objective, the monitor’s duties are to aid the Investigator and, at 
the same time, the Sponsor in the maintenance of complete, legible, well organized and easily 
retrievable data. Before the enrollment of any subject in this study, the Sponsor or their designee 
will review with the Investigator and site personnel the following documents: protocol, 
Investigator’s Brochure, eCRFs and procedures for their completion, informed consent process, 
and the procedure for reporting SAEs. 
The Investigator will permit the Sponsor or their designee to monitor the study as frequently as 
deemed necessary to determine that data recording and protocol adherence are satisfactory. During 
the monitoring visits, information recorded on the eCRFs will be verified against source 
documents and requests for clarification or correction may be made. After the eCRF data is entered 
by the site, the CRA will review the data for safety information, completeness, accuracy, and 
logical consistency. Computer programs that identify data inconsistencies may be used to help 
monitor the clinical study. If necessary, requests for clarification or correction will be sent to 
investigators. The Investigator and his/her staff will be expected to cooperate with the monitor and 
provide any missing information, whenever possible. 
All monitoring activities will be reported and archived. In addition, monitoring visits will be 
documented at the investigational site by signature and date on the study-specific monitoring log. 
11.6 
Disclosure of Data 
Data generated by this study must be available for inspection by the FDA, the Sponsor or their 
designee, applicable foreign health authorities, and the IRB as appropriate. Subjects or their legal 


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representatives may request their medical information be given to their personal physician or other 
appropriate medical personnel responsible for their welfare. 
Subject medical information obtained during the study is confidential and disclosure to third 
parties other than those noted above is prohibited. 
11.7 
Retention of Records 
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator 
will keep records, including the identity of all participating subjects (sufficient information to link 
records, e.g., eCRFs and hospital records), all original signed ICFs, copies of all eCRFs, SAE 
forms, source documents, and detailed records of treatment disposition. The records should be 
retained by the Investigator according to specifications in the ICH guidelines, local regulations, or 
as specified in the Clinical Study Agreement, whichever is longer. The Investigator must obtain 
written permission from the Sponsor before disposing of any records, even if retention 
requirements have been met. 
If the Investigator relocates, retires, or for any reason withdraws from the study, the Sponsor should 
be prospectively notified. The study records must be transferred to an acceptable designee, such 
as another Investigator, another institution, or to the Sponsor. 
11.8 
Publication Policy 
Following completion of the study, the data may be considered for publication in a scientific 
journal or for reporting at a scientific meeting. Each Investigator is obligated to keep data 
pertaining to the study confidential. The Investigator must consult with the Sponsor before any 
study data are submitted for publication.  
This is a multicenter study. Therefore, the primary publication will be made under the oversight 
of the Steering Committee, or when designated, the Publication Committee. Individual study sites 
or groups of study sites will not be allowed to publish their individual results prior to the core 
publication being made. It is intended to publish the core result of this study within 12 months of 
the database being locked and unblinded. The Sponsor reserves the right to deny publication rights 
until mutual agreement on the content, format, interpretation of data in the manuscript, and journal 
selected for publication are achieved. 
11.9 
Financial Disclosure 
Investigators are required to provide financial disclosure information to the Sponsor to permit the 
Sponsor to fulfill its obligations under 21 CFR Part 54. In addition, investigators must commit to 
promptly updating this information if any relevant changes occur during the study and for a period 
of 1 year after the completion of the study. 
11.10 
Insurance and Indemnity 
In accordance with the relevant national regulations, the Sponsor has taken out subject liability 
insurance for all subjects who have given their consent to the clinical study. This cover is designed 
for the event that a fatality, physical injury, or damage to health occurs during the clinical study’s 
execution. 


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11.11 
Legal Aspects 
The clinical study is submitted to the relevant national competent authorities in all participating 
countries to achieve a clinical trial authorization (CTA). 
The study will commence (i.e., initiation of study centers) when the CTA and favorable Ethics 
opinion have been received.  


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12 
STUDY ADMINISTRATIVE INFORMATION 
12.1 
Protocol Amendments 
Any amendments to the study protocol will be communicated to the investigators by the CRO or 
the Sponsor. All protocol amendments will undergo the same review and approval process as the 
original protocol. A protocol amendment may be implemented after it has been approved by the 
IRB/EC and, where appropriate, Competent Regulatory Authority approval prior to 
implementation, unless immediate implementation of the change is necessary for subject safety. 
In this case, the situation must be documented and reported to the IRB within 5 working days and 
in the countries outside of the United States according to the national regulation. 
12.2 
Study Termination 
The study can be terminated at any time for any reason by the Sponsor. 
In addition, the study may be terminated for safety reasons upon recommendation by the DMC 
and review by the Steering Committee. Per its charter, the DMC will, at the conclusion of each of 
its meeting, make any of the following recommendations: 
– Continue the study without modification 
– Continue the study with modifications 
– Continue the study pending additional information 
– Suspend the study pending additional information; or 
– Stop the study due to safety concerns 
12.3 
Address List 
12.3.1 
Sponsor 
Aridis Pharmaceuticals, Inc. 
5941 Optical Court 
San Jose, CA 95138 
Phone: 408-385-1742  
Fax: 408-960-3822 
12.3.2 
Contract Research Organization 
Medpace, Inc.  
5375 Medpace Way 
Cincinnati, OH 45227 
Telephone: 513-579-9911 
Fax: 513-579-0444 
12.3.3 
Drug Safety 
Medpace Clinical Safety 
5375 Medpace Way 
Cincinnati, OH 45227 
Telephone: +1-800-730-5779, ext. 2999 or +1-513-579-9911, ext. 2999 
Fax: +1-866-336-5320 or +1-513-579-0444 


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Email: Medpace-safetynotification@medpace.com 
12.3.4 
Biological Specimens 
Clinical Laboratory 
Medpace Reference Labs 
5365 Medpace Way 
Cincinnati, OH 45227 
Telephone: +1-800-749-1737 or +1-513-366-3270 
Fax: +1-800-705-2177 or +1-513-366-3273 
Microbiological Laboratory 
International Health Management Associates, Inc. (IHMA) 
2122 Palmer Drive  
Schaumburg, IL 60173-3817 
Tel: +1-847-303-5003  
Fax: +1-312-637-3121 
Website: www.ihmainc.com 
 
 
 
 


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13 
APPENDIX A:  CLINICAL LABORATORY ANALYTICS 
Safety laboratory tests are described in Section 8.9. All safety laboratory tests will be performed 
by the site’s local laboratory. 
Required special laboratory tests include PK and ADA. Additional laboratory tests may be 
performed during the study or thereafter using bio banked samples. All special laboratory tests will 
be performed by a central laboratory. 
Sampling methods, including those related to special laboratory evaluation, PK and 
immunogenicity (ADA) samples is provided in the Laboratory Manual. 


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14 
APPENDIX B:  OTHER TRIAL SPECIFIC PROCEDURES 
14.1 
APACHE II Score 
The score computed by the study site according to standard practice will be entered in the EDC 
system. The corresponding worksheet, including all the data that were used to compute the 
recorded score, will be stored as source data in the site study files. 
14.2 
SOFA Score 
The score computed by the study site according to standard practice will be entered in the EDC 
system. The corresponding worksheet, including all the data that were used to compute the 
recorded score, will be stored as source data in the site study files.  
14.3 
Microbiological basis for randomization and treatment 
Any patients with pneumonia who are intubated (or have a tracheostomy) in whom evidence that 
P. aeruginosa is the infective pathogen can be randomized and treated. Such evidence can be 
provided by several means, either based on available cultures or on rapid testing methods. 
Patients with culture results of more than one pathogen can be included, if P. aeruginosa is 
regarded a key pneumonia causing pathogen. 
14.3.1 
Culture 
Acceptable sampling methods are BAL, mini-BAL and ETA (ETA sample with < 10 squamous 
epithelial cells and > 25 polymorphonuclear cells per low power field). Acceptable airway 
specimens must have been obtained less than 72 hours prior to randomization. 
Any method of identification of P. aeruginosa is acceptable, including standard microbial culture 
(quantitative, semi-quantitative), mass spectrometry or PCR. 
If randomization and treatment is based on such evidence, a new sample must be obtained prior to 
treatment for standard microbial culture by the local microbiology laboratories. The culture at the 
local microbiology lab should include identification of genus and species, quantitative, 
semi-quantitative culture and susceptibility testing. 
14.3.2 
Rapid testing 
Rapid testing is accepted as acceptable evidence of infection by P. aeruginosa whenever no other 
acceptable evidence is available. In such cases, a fresh airway specimen must be obtained by BAL, 
mini-BAL or ETA. The same specimen must be used for standard microbial cultures (quantitative, 
semi-quantitative)by the local and central laboratories. Rapid diagnostic testing will not be used 
for other purpose than screening and randomization in this study. In particular, they will not be 
used to assess microbiological outcomes. 
Acceptable rapid diagnostic testing discussed hereunder are IUO / RUO. Other methods available 
at the site may be used (e.g., mass spectrometry, PCR, etc.). 


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14.3.2.1 
Rapid testing using the IUO FilmArray LRTI Paneli 
The BioFire Diagnostics, LLC (a BioMérieux company)’s IUO FilmArray lower respirometry 
tract infection (LRTI) panel can be used to determine whether P. aeruginosa is present in the 
sample obtained at baseline for the purpose of screening and randomizing patients who meet 
eligibility criteria. The corresponding methods are provided in the Laboratory Manual. 
Briefly, the IUO FilmArray (FA) LRTI panel allows for identifying the etiological agent(s) of LRT 
infections. This is a multiplexed device, allowing the simultaneous detection of multiple bacteria, 
including P. aeruginosa, viruses and fungi. Semi-quantitative results can be obtained for bacteria 
(reported positive if detected at levels of 10e3.5 copies/mL or above). Although any relevant 
sample can be used, including sputum, only BAL, mini-BAL and ETA samples are allowed at 
baseline and prior to extubation to ensure the quality of standard microbial cultures and to avoid 
any ambiguity that would preclude determining the etiological agent or assessing bacterial load 
with confidence.  
The procedure entails injecting an adequate airway specimen and rehydration medium to the IUO 
LRTI pouch, and then inserting the pouch in the FilmArray instrument. Time to results is about 1 
hour. 
14.3.2.2 
Rapid testing using the GeneXpert RUO PA Cartridgeii 
The CE marked Cepheid GeneXpert PA Assay, performed on the GeneXpert® Instrument Systems, 
is a qualitative in vitro test designed for the detection of Pseudomonas aeruginosa Gram negative 
bacteria. 
The GeneXpert (GX) Instrument Systems automate and integrate sample preparation, nucleic acid 
purification and amplification, and detection of the target sequences in simple or complex samples 
using real-time PCR assays. The systems consist of an instrument, personal computer, and 
preloaded software for performing tests and viewing the results. The systems require the use of 
single-use disposable cartridges that hold the PCR reagents and host the PCR process. Because the 
cartridges are self-contained, cross- contamination between samples is minimized. For a full 
description of the system, see the GeneXpert Dx System Operator Manual or the GeneXpert 
Infinity System Operator Manual. 
The primers and probes in the GeneXpert PA Assay detect proprietary sequences for the detection 
of Pseudomonas aeruginosa.  
Endotracheal aspirates (ETA) may be used with the GeneXpert PA assay kit. For ETA samples, a 
swab is dipped into the sample, then material on the swab is eluted by breaking the swab into the 
Sample Reagent vial, followed by vortexing. The disposable transfer pipette provided in the 
GeneXpert PA kit is used to transfer the eluate to the Sample Chamber of the cartridge (Figure 2). 
All reagents required for sample preparation and real time PCR analysis are preloaded in the 
cartridge. Bacterial cells in the eluate are mixed with the sample preparation control and treatment 
                                                 
i FilmArray is a registered trademark of BioFire Diagnostics, LLC (a BioMérieux company). 
ii GeneXpert is a registered trademark of Cepheid. 


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reagents, cells are captured on a filter and lysed by sonication. The released DNA is eluted, mixed 
with dry PCR reagents, and the solution is transferred to the reaction tube for real- time PCR and 
detection. Time to result is approximately 50 minutes. 
14.4 
Quantitative/semi-quantitative microbiology 
Quantitative airway specimen cultures will be performed at baseline and follow up by the local 
microbiological laboratory as outlined in the microbiology laboratory manual. The necessary 
materials will be provided. Whenever possible the local microbiology laboratory is to report 
quantitative microbiology outcomes when available. Semi-quantitative methods for BAL, 
mini-BAL, ETA specimens will be acceptable if they represent the methodologies typically 
performed at the local reference laboratory centers and quantitative methods are not available. 


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15 
APPENDIX C:  CONVERSION TABLE FOR FIO2 
The conversion table [9] below applies to determining FiO2 when supplemental oxygen is 
administered, and the subject is not mechanically ventilated. Oxygen flow is for 100% oxygen. 
Oxygen flow (L/min) FiO2 (%) 
Nasal cannula 
1 
24 
2 
28 
3 
32 
4 
36 
5 
40 
6 
44 
Oxygen mask 
5-6 
40 
6-7 
50 
7.8 
60 
9 
90 
10 
99+ 
Mask with reservoir bag 
6 
60 
7 
70 
8 
80 
 


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16 
REFERENCES 
1. DiCocco JM, Croce MA. Ventilator-associated pneumonia: an overview. Expert Opin 
Pharmacother. 2009 Jun;10(9):1461-7. 
2. Guidelines For Preventing Health-Care-Associated Pneumonia, 2003, Recommendations of 
CDC and the Healthcare Infection Control Practices Advisory Committee. 
(Available Upon Request.) 
3. Eggimann P, Revelly JP. Should antibiotic combinations be used to treat ventilator-
associated pneumonia? Semin Respir Crit Care Med. 2006. 
4. Restrepo MI, Anzueto A, Arroliga AC, Afessa B, Atkinson MJ, Ho NJ, Schinner R, Bracken 
RL, Kollef MH. Economic burden of ventilator-associated pneumonia based on total 
resource utilization. Infect Control Hosp Epidemiol. 2010 May;31(5):509-15. 
5. Pedersen SS, Hoiby N, Espersen F and Koch C. Role of alginate in infection with mucoid 
Pseudomonas aeruginosa in cystic fibrosis. Thorax 1992;47:6-13. 
6. Pedersen SS, Kharazmi A, Espersen F and Hoiby N. Pseudomonas aeruginosa alginate in 
cystic fibrosis sputum and the inflammatory response. Infect Immun 1990a;58:3363-3368. 
7. Pedersen SS, Espersen F, Hoiby N and Jensen T. Immunoglobulin-A and Immunoglobulin-
G antibody responses to alginates from Pseudomonas aeruginosa in patients with cystic 
fibrosis. J Clin Microbiol 1990b;28:747-755. 
8. Pier, G.B., et al. Opsonophagocytic Killing Antibody to Pseudomonas aeruginosa Mucoid 
Exopolysaccharide in Older Noncolonized Patients with Cystic Fibrosis. N Engl J Med 
1987; 317:793-798. 
9. AARC Clinical Practice Guideline, In Vitro pH and Blood Gas Analysis and Hemoximetry, 
Respiratory Care, 38:505-510, 1993. 
 

SAP_001.pdf: 
 
 
Statistical Analysis Plan 
(SAP) 
 
 
Placebo-controlled, double-blind, randomized study of 
Aerucin® as adjunct therapy to antibiotics in the treatment 
of P. aeruginosa pneumonia 
 
 
 
 
Protocol Number: 
AR-105-002 
Development Phase: 
2/3 
Sponsor: 
Aridis Pharmaceuticals, Inc. 
 
5941 Optical Court 
San Jose, CA 95138 
Protocol Version Number: 
V3.0 
Protocol Date: 
09 November 2018 
 
 
 
 
SAP Version: 
V1.0  
SAP Date: 
13 August 2019 
 
 
 
 
Confidentiality Statement 
This document is confidential. It contains proprietary information belonging to Aridis Pharmaceuticals, 
Inc.. Any viewing or disclosure of such information that is not authorized in writing by Aridis 
Pharmaceuticals, Inc. is strictly prohibited. Such information may be used solely for the purpose of 
reviewing or performing this study. 




SAP AR-105-002 
Version 1.0, 13 August 2019 
Page 3 of 26 
TABLE OF CONTENTS 
 
SAP APPROVAL FORM..................................................................................................2 
TABLE OF CONTENTS ..................................................................................................3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................5 
1. 
INTRODUCTION ..........................................................................................7 
2. 
STUDY OBJECTIVES ..................................................................................7 
2.1. 
Primary Clinical Efficacy Objective .................................................................7 
2.2. 
Primary Clinical Safety Objective ....................................................................7 
2.3. 
Secondary Clinical Efficacy Objectives ...........................................................7 
2.4. 
Pharmacokinetics (PK) Objective .....................................................................7 
2.5. 
Secondary Safety Objectives ............................................................................7 
2.6. 
Microbiological Efficacy Objectives ................................................................8 
3. 
STUDY DESIGN ............................................................................................8 
3.1. 
General Study Design and Plan ........................................................................8 
3.2. 
Randomization and Blinding ..........................................................................10 
3.3. 
Breaking the Blind ..........................................................................................10 
3.4. 
Study Drug Administration.............................................................................10 
3.5. 
Study Assessments..........................................................................................10 
4. 
SAMPLE SIZE DETERMINATION .........................................................13 
5. 
STUDY ENDPOINTS ..................................................................................13 
5.1. 
Primary Clinical Efficacy Endpoint ................................................................13 
5.2. 
Secondary Clinical Efficacy Endpoints ..........................................................14 
5.3. 
Microbiological Endpoints .............................................................................14 
5.4. 
Pharmacokinetic Endpoints ............................................................................14 
5.5. 
Safety Endpoints .............................................................................................15 
6. 
STATISTICAL METHODOLOGY ...........................................................15 
6.1. 
General Considerations ...................................................................................15 
6.1.1. 
Definition of Baseline .....................................................................................15 
6.1.2. 
General Analysis Approach ............................................................................15 
6.1.3. 
Hypotheses ......................................................................................................15 
6.1.4. 
Multiplicity .....................................................................................................16 


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6.1.5. 
Handling of Dropouts and Missing Data ........................................................16 
6.2. 
Analysis Populations ......................................................................................16 
6.2.1. 
Safety Population ............................................................................................16 
6.2.2. 
Intent-to Treat Population (ITT) .....................................................................16 
6.2.3. 
Microbiological Intent-to-Treat Population (micro-ITT) ...............................16 
6.2.4. 
Per-protocol Population (PP) ..........................................................................17 
6.3. 
Subject Data and Study Conduct ....................................................................17 
6.3.1. 
Subject Disposition .........................................................................................17 
6.3.2. 
Protocol Deviations ........................................................................................17 
6.3.3. 
Demographic and Baseline Characteristics ....................................................17 
6.3.4. 
Medical History ..............................................................................................18 
6.3.5. 
Prior and Concomitant Medications ...............................................................18 
6.3.6. 
Compliance to Study Drug .............................................................................19 
6.4. 
Efficacy Analyses ...........................................................................................19 
6.4.1. 
Primary Clinical Efficacy Endpoint ................................................................19 
6.4.1.1. 
Primary Analysis ............................................................................................19 
6.4.1.2. 
Secondary Analyses ........................................................................................19 
6.4.2. 
Secondary Clinical Efficacy Endpoints ..........................................................20 
6.4.2.1. 
Clinical Cure ...................................................................................................20 
6.4.2.2. 
Mortality .........................................................................................................20 
6.4.2.3. 
Respiratory Functional Assessments and SOFA Scores ................................21 
6.4.2.4. 
Health Economics Assessments .....................................................................21 
6.4.3. 
Microbiological Endpoints .............................................................................22 
6.4.4. 
Subgroup Analysis ..........................................................................................22 
6.5. 
Pharmacokinetic Analyses ..............................................................................23 
6.6. 
Safety Analyses ..............................................................................................23 
6.6.1. 
Adverse Events ...............................................................................................24 
6.6.2. 
Clinical Safety Laboratory Evaluations ..........................................................24 
6.6.3. 
Vital Signs ......................................................................................................25 
6.6.4. 
Electrocardiograms (ECG) .............................................................................26 
6.6.5. 
Physical Examinations ....................................................................................26 
6.7. 
Interim Analyses .............................................................................................26 
7. 
PROGRAMMING SPECIFICATIONS .....................................................26 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ABG 
arterial blood gas 
ADA 
anti-drug antibody  
AE 
adverse event 
ALT 
alanine transaminase 
ANOVA 
analysis of variance 
APACHE II 
acute physiology and chronic health evaluation II 
AST 
aspartate transaminase 
ATC 
Anatomical therapeutic class 
BAL 
broncho-alveolar lavage 
BMI 
body mass index 
BUN 
blood urea nitrogen 
CK 
creatine kinase 
CRP 
c-reactive protein 
CMH 
Cochran-Mantel-Haenszel 
CSR 
clinical study report 
DMC 
Data Monitoring Committee 
ECG 
electrocardiography 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ETA 
endotracheal aspiration 
GFR 
glomerular filtration rate 
ICU 
intensive-care units 
INR 
international normalized ratio 
ITT 
Intent-to-Treat 
IWRS 
interactive web-based randomization system 
LDH 
lactate dehydrogenase 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
micro-ITT 
Microbiological Intent-to-Treat  
P. aeruginosa 
Pseudomonas aeruginosa 
PK 
Pharmacokinetic(s) 
PP 
Per-protocol Population 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SOC 
standard of cure 
SOFA 
sequential organ failure assessment 
TEAE 
treatment-emergent adverse event 


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Abbreviation 
Definition 
TESAE 
treatment-emergent serious adverse event 
VABP 
ventilator-associated bacterial pneumonia 
WBC 
white blood cell 
WHO 
World Health Organization 
 
 


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1. 
INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to provide a description of the statistical 
methods to be implemented for the analysis of data from the study with Protocol AR-105-002 
(Version 3.0, 09 November 2018). The SAP will be finalized prior to database lock. Any deviations 
from the SAP after database lock will be documented in the final Clinical Study Report (CSR). 
2. 
STUDY OBJECTIVES 
2.1. 
Primary Clinical Efficacy Objective 
To assess the efficacy of Aerucin, administered as a single dose in addition to standard of care 
(SOC) antibiotic regimen on Clinical Cure rates (resolution of pneumonia) between SOC alone 
and SOC with Aerucin at Day 21. 
2.2. 
Primary Clinical Safety Objective 
To assess the clinical safety and tolerability of Aerucin in the study population. 
2.3. 
Secondary Clinical Efficacy Objectives 
To assess the effect of Aerucin, administered as a single dose in combination with SOC antibiotic 
regimen as an adjunct therapy of P. aeruginosa pneumonia, as compared to standard antibiotic 
therapy alone, on the following parameters: 
1. 
Clinical Cure rates at Day 28, 14 and 7, using the same criteria as for the primary efficacy 
objective.  
2. 
Time to Clinical Cure. 
3. 
Mortality and Pneumonia-related mortality post-treatment. 
4. 
Respiratory functional assessment: Time on mechanical ventilation (including if 
tracheostomy is in place). Time on supplemental oxygenation. Measures of respiratory health 
such as changes in PaO2/FiO2, using arterial blood gases and/or pulse oximetry measurements. 
5. 
Overall clinical status: Changes in sequential organ failure assessment (SOFA) score. 
6. 
Health economics: antibiotic utilization, duration of stay in the intensive care unit (ICU), 
duration of hospitalization, duration of intubation with ventilation or duration of mechanical 
ventilation if tracheostomy in place. 
2.4. 
Pharmacokinetics (PK) Objective 
To assess the PK Profile of Aerucin. 
2.5. 
Secondary Safety Objectives 
To assess the immunogenicity of Aerucin. 


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2.6. 
Microbiological Efficacy Objectives 
To assess the effect of Aerucin, administered as a single dose in combination with SOC antibiotic 
regimen as an adjunct therapy of P. aeruginosa pneumonia, as compared to standard antibiotic 
therapy alone, on the following parameters: 
1. Eradication of index P. aeruginosa at Day 21 and 28 post-treatment, 
2. Re-infection/new infection defined as a reoccurrence of pneumonia due to P. aeruginosa 
within the 28-day follow-up period, 
3. Reduction in bacterial load related to the index P. aeruginosa 
3. 
STUDY DESIGN 
3.1. 
General Study Design and Plan 
This study is an international, multicenter, prospective, double blind, randomized, 
placebo-controlled, parallel design protocol. It will be performed at multiple ICUs. 
Patients with a documented diagnosis of pneumonia, due to P. aeruginosa, and require ICU care, 
who are intubated (or have a tracheostomy tube in place) and are mechanically ventilated, are 
eligible for screening.  
Patients meeting all other eligibility requirements will be assessed for P. aeruginosa pulmonary 
infection on the basis of culture results (known from recent quantitative/semi-quantitative cultures) 
or on the basis of rapid diagnostic testing of a fresh airway specimen using methods available at 
the site (e.g. mass spectrometry, Polymerase Chain Reaction, etc.), or using devices such as CE 
marked Cepheid’s GeneXpert® with “Investigational / Research Use Only” (IUO / RUO) PA 
Cartridge, or BioFire Diagnostics, LLC (a BioMerieux company)’s IUO FilmArray® LRTI Panel.  
Acceptable airway samples are broncho-alveolar lavage (BAL), mini-BAL, or endotracheal 
aspiration (ETA) (ETA sample with <10 squamous epithelial cells and >25 polymorphonuclear 
cells per low power field). It is expected that some subjects will have a positive rapid diagnostic 
test result that will not be confirmed by standard microbial culture (quantitative, or semi-
quantitative). These subjects will be followed according to all the procedures described in this 
protocol but will not accrue toward the target microbiologically evaluable intent to treat population 
(micro-ITT). Subjects with a positive diagnosis of P. aeruginosa pulmonary infection will be 
randomized to receive either investigational product or matching placebo (more than one pathogen 
allowed, if P. aeruginosa is regarded a key pneumonia causing pathogen). In total, approximately 
154 microbiologically evaluable subjects will be randomized 1-1 to be treated with placebo plus 
SOC or Aerucin (20 mg/kg) plus SOC in this Phase 2/3 study.  
The randomization procedure will account for the fact that many study sites will enroll only a few 
patients. Randomization will account for existence of sub-populations regarding oxygen status at 
baseline (PaO2/FiO2 200 or >200). 
Study subjects will receive a single treatment dose (at Day 0) in addition to SOC antibiotic 
treatment, and then enter a safety, efficacy and PK follow-up study period for a total study duration 
of 28 days. The selection of SOC antibiotics is made in accordance with local best practices at the 
discretion of the investigator and should not exceed a duration of 14 days. 


SAP AR-105-002 
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The clinical course of pneumonia will be assessed daily by the investigator. Once Clinical Cure 
has been determined, the clinical status of the subject will be monitored to confirm continuation 
of Clinical Cure, re-infection (pneumonia due to P. aeruginosa), or new infection (pneumonia due 
to an unknown pathogen or a pathogen other than P. aeruginosa). “Clinical Cure” can be declared 
at any time during the study by the PI provided, that the required criteria are met either based on 
documented improvements in signs and symptoms, +/- changes documented by chest X-ray (if 
performed as part of SOC), as interpreted by the investigator.  
The assessment of Clinical Cure (resolution of pneumonia) by the site investigator will be used for 
the primary analysis. An adjudication committee will apply newly defined Clinical Cure criteria 
post hoc in a secondary analysis. “Clinical Cure” will be assessed for analytical purposes on Day 
7, 14, 21 (primary efficacy endpoint) and 28.  
Clinical safety assessments will be performed on an ongoing basis while predefined laboratory 
assessments will be performed at baseline, and thereafter at Day 4, 7, 14, 21, and 28. Test results 
obtained for medical reasons between these mandatory time points will be assessed for adverse 
events and documented accordingly.  
Secondary efficacy endpoints will be assessed in a similar manner during the 28-day period, when 
appropriate, daily when possible (e.g., time on mechanical ventilation including if tracheostomy is 
in place, time on supplemental oxygenation, measures of respiratory health such as changes in 
PaO2/FiO2 using arterial blood gases and/or pulse oximetry measurements), or upon occurrence 
(e.g., antibiotic utilization, duration of stay in the ICU, duration of hospitalization, duration of 
intubation with ventilation, or duration of mechanical ventilation if tracheostomy in place). 
Microbiological endpoints of eradication and re-infection/new infection will be determined based 
on quantitative/semi quantitative cultures performed by the local laboratory and testing of isolates 
performed by a central microbiology laboratory.  
Two PK analyses will be performed to assess the PK profile of Aerucin in the target patient 
population. The pharmacokinetics of Aerucin will be assessed using a population PK 
(compartmental modeling) approach as well as a non-compartmental analysis approach. A PK sub-
study (“Full PK”) will be included, wherein more extensive sampling will be performed in a small 
number of patients (from select sites) who provide consent (i.e., 16 patients to obtain 8 patients on 
active treatment). In the remaining patients, a sparse sampling strategy will be implemented with 
only a few samples obtained from each patient at varying time points (“Sparse PK”). A 
compartmental population PK model will be developed using the PK data collected from the sub-
study and the sparse samples. PK parameters will be estimated as well as between-subject or inter-
individual variability and residual variability. The effects of select factors describing the 
characteristics of sub-populations of interest (e.g. high or low bacterial load, cause of admission 
[trauma or non-trauma], and type of pneumonia) on the PK of Aerucin will be assessed via 
covariate analysis. In addition to the population PK evaluation, non-compartmental analysis of the 
PK sub-study data will be performed.  
The investigational therapy will be studied as an adjunct to antibiotic therapy as prescribed by the 
study investigator according to the SOC in his/her institution. The duration and nature of the initial 
and any subsequent antibiotic therapy related to the baseline pneumonia event and other infections 
will be recorded. Duration of antibiotic treatment for the index pneumonia should not exceed 14 
days. 


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3.2. 
Randomization and Blinding  
This is a double-bind, placebo-controlled study. Study subjects will be first stratified as follows: 
- 
Stratum 1: ventilator-associated bacterial pneumonia (VABP) or non-VABP 
- 
Stratum 2: PaO2/FiO2 ≤200 or >200 
- 
Stratum 3: Americas, Eastern EU, Western EU and Asia 
Randomization will proceed in a 1:1 ratio, in blocks of 4, for the study overall.  
A computer-generated randomization schedule will be used to allocate study treatment according 
to the above randomization scheme. Upon confirmation of eligibility, the study personnel will be 
prompted to randomize the study subject using the electronic data capture (EDC) / interactive web-
based randomization system (IWRS) system. 
3.3. 
Breaking the Blind  
The Investigator will be allowed to break the blind if, in his/her opinion, this is necessary to provide 
proper medical care to his/her patient. In general, study drug unblinding should not impact any 
necessary treatment decisions by the investigator. Prior to breaking the blind, the Investigator will 
confer with the Medical Monitor to confirm the necessity of such action. 
In the absence of the Investigator, the Medical Monitor may break the blind for a specific study 
subject under such urgent circumstances and after assessing the necessity of such action with a 
sub-investigator. 
Members of the Data Monitoring Committee (DMC) will be allowed to break the blind if it is 
deemed necessary to assess specific adverse events. 
The circumstances leading to breaking the blind will be fully documented in detail in a memo to 
file and as required, in the EDC system. 
3.4. 
Study Drug Administration 
Upon randomization, the number of vials of study drug based on subject’s weight required for 
treatment will be displayed by the EDC / IWRS system, and access will be given to the inventory 
corresponding to the treatment allocation of the subject. Study personnel will then select the 
specific vials required, up to a maximum of 20 vials from the inventory available on site. Subjects 
weighing over 120 kg will receive the amount of Aerucin or placebo corresponding to 120 kg, 
i.e. 20 vials. 
The entire content of the bag must then be administered intravenously at room temperature in 
approximately 2 hours. The study drug will be administered once, intravenously, in a strictly 
monitored setting. 
3.5. 
Study Assessments 
Table 1 presents the schedule of assessments of the study. 
 
 
 


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Table 1. 
Schedule of Assessments 
Visit 
Screening, 
Baseline, and 
Randomization 
Treatment 
Follow-up 
(Daily until 
index 
pneumonia is 
considered 
resolved)
Follow-up 
Any 
setting 
End of Study14 or 
Early Termination17 
Day 
-1 
0 
1 to 28 
Daily 
4, 7, 14, 
21 
28 or 
Day of Termination 
Informed Consent
X
Eligibility
X
Demographics
X
Type of Pneumonia10 
X
Medical history
X
Surgical History
X
Case history
X
Concomitant medications
X
X
X
X
X
Physical exam
X
X
X
Vital signs11
X
X
X
X
X
12-lead ECG
X
Safety laboratory tests 
X 
 
X1 
X 
X 
Sampling: ADA
X3
X
Sampling: Future Biomarkers 
(where applicable)  
 
 
 
X 
X 
Sampling: PK
X4
X5,6
X5,6
X5,6
X5,6
Microbiology: rapid testing
X
Microbiology: classic
X
X1
X1
X1
Sampling: microbiology
X
X1
X1
X1
Respiratory data
X
X2
X1
X
X
Arterial 
gases 
or 
pulse 
oximetry16
X 
X 
 
X 
X 
PaO2/FiO2 ratio
X
X
X
X
X
APACHE II
X
SOFA
X
X
X2
Randomization
X7
Treatment
X
Assessment of Clinical Cure
X8
X
X
Adverse events
X
X
X
X
Chest X-Rays
X12
Pregnancy Test  
(Urine or Serum)
X13 
 
 
 
 
Discharge data
X9
Study Follow-Up Phone Call
X15
X15


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Visit 
Screening, 
Baseline, and 
Randomization 
Treatment 
Follow-up 
(Daily until 
index 
pneumonia is 
considered 
resolved)
Follow-up 
Any 
setting 
End of Study14 or 
Early Termination17 
Day 
-1 
0 
1 to 28 
Daily 
4, 7, 14, 
21 
28 or 
Day of Termination 
1. 
To be performed if medically necessary. Follow-up airway specimens to be obtained as medically necessary and 
prior to extubation and at Day 28 (if not extubated prior to then) for quantitative or semi-quantitative culture.  
2. 
SOFA and respiratory data to be collected on Day 0, 12 hours after treatment initiation and on Day 4, 7, 14, 21, 28 
while intubated and mechanically ventilated. Parameters for SOFA score calculation should not be older than 72 
hours. 
3. 
ADA only at screening / baseline and Day 28, or at early termination. 
4. 
Pre-dose PK sample to be obtained prior to treatment initiation. 
5. 
PK samples to be obtained for the FULL PK sub-study at the following times after initiation of treatment: 2 hours 
(end of infusion), 4h, 12h, and 24 hours and 1 sample at each of the following visits: Day 4, 7, 14, 21, and 28.  
6. 
PK samples for the SPARSE PK sub-study at the following times after initiation of treatment: 1 sample at 2 hours 
(end of infusion), 1 sample at either 4h, 12h, or 24 hours post-treatment initiation (inclusive) and 1 sample at any of 
the following visits: Day 4, 7, 14, 21, or 28.  
7. 
Eligible subjects are randomized on Day -1, Treatment day is Day 0 for the purpose of monitoring and collecting 
the required samples over the first 24 hours. 
8. 
Clinical Cure will be assessed at Day 7, 14, 21, 28 for the analytical purposes.  
9. 
Discharge data to be obtained when discharge occurs or Day 28, whichever occurs first. 
10. Patients with pneumonia who are intubated are eligible for screening regardless of the type of pneumonia, which 
will be recorded at the time of screening for all study subjects. 
11. Vital signs will be recorded at baseline prior to treatment (time 0) and then at 1, 2, 4, 12, and 24 hours post treatment. 
Vital signs will also be recorded daily thereafter. 
12. In addition to the screening timepoint, chest x-ray(s) are to be taken at any time as medically indicated. 
13. Women of child bearing potential must take a urine or serum pregnancy test at the time of Screening. 
14. For subjects with early discharge, effort must be made to perform all protocol defined procedures outlined for End 
of Study/Early Termination. 
15. Subjects who decide to discontinue study assessments prior to Day 28 will receive a study exit safety follow-up 
phone call on key days (Day 4, 7, 14, 21, 28) until Day 28 (+7 days) to assess Clinical Cure, survival and the status 
of any adverse events. 
16. Changes in PaO2/FiO2 ratio (e.g. by arterial blood gases), if available and whenever possible OR changes in non-
invasive measures of oxygenation (e.g. by pulse oximetry) 
17. A few days before or after the specified date is acceptable (2 days)
 
 
 
 
 


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4. 
SAMPLE SIZE DETERMINATION 
The primary efficacy endpoint is the proportion of subjects with Clinical Cure at Day 21. 
It is assumed that the proportion of subjects with Clinical Cure will be 65% in the placebo 
group, and 85% in the 20 mg/kg dose group. With 69 subjects per group, there will be >90% 
power for a statistically significant difference at a two-sided 0.05 level of significance. Sample 
size calculation was performed based on Fisher’s Exact test using binomial enumerations 
(PASS version 14). Assuming a 10% drop-out rate, approximately 154 subjects (77 per group) 
will be randomized. 
5. 
STUDY ENDPOINTS 
5.1. 
Primary Clinical Efficacy Endpoint 
The primary efficacy endpoint is the proportion of patients with Clinical Cure at Day 21 in 
patients treated with Aerucin versus the placebo group as assessed by the investigator. The 
investigators’ assessment will be the primary analysis of the primary endpoint. 
Additionally, newly defined Clinical Cure criteria (Table 2) will be applied post-hoc by an 
independent adjudication committee. 
Table 2 
 
Criteria for Clinical Cure 
1. The subject must be alive through the index day visit  
2. The patient must have improved respiratory function evaluated at the index day, 
because:  
 The patient is now off the ventilator and extubated  
or 
3. if the patient entered the study with mechanical ventilation due to reasons other than 
pneumonia and was assessed “likely ventilated beyond day 28” at screening, criteria #1 
(survival) and #4 (no signs and symptoms of pneumonia) are sufficient to establish 
Clinical Cure (presumed not ventilated) 
4. The subject must show no clinical signs and symptoms of bacterial pneumonia at the 
index day, which is determined by  
 Not receiving any antibiotic therapy active against the initial P. aeruginosa strain 
or against persisting pulmonary bacterial infection for 48 hours (antibiotic therapy 
for documented extra-pulmonary infection permitted) 
and 
 Resolution of signs and symptoms of bacterial pneumonia, as determined by the 
PI based on their clinical assessment. Parameters to be considered may include:  
o Absence of lung abscess or empyema 
o Fever > 38°C or hypothermia (< 35°C) attributable to the primary 
bacterial pneumonia 
o Tachypnea or shortness of breath (> 22 respirations/min) if off the 
ventilator and/or back to baseline respiratory rate


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o Tachycardia (> 100 bpm) or bradycardia (< 60 bpm) and/or back to 
baseline heart rate 
o Improvement of hypoxemia (ABG or PaO2/FiO2 > 200 or pulse 
oximetry > 90%) 
o If patient still produces sputum - negative P. aeruginosa culture from 
sputum, blood or pleural fluid 
5.2. 
Secondary Clinical Efficacy Endpoints 
The secondary clinical efficacy endpoints are the following: 
1. 
Proportion of patients with Clinical Cure at Day 28 
2. 
Proportion of patients with Clinical Cure at Day 14 
3. 
Proportion of subjects who died (All-cause mortality) at  Day 28 
4. 
Proportion of subjects who died due to pneumonia (Pneumonia-related mortality) at Day 
28 
5. 
Proportion of patients with Clinical Cure at Day 7 
6. 
Change from baseline in respiratory functional assessment: Time on mechanical 
ventilation (including if tracheostomy is in place). Time on supplemental oxygenation. 
Measures of respiratory health such as changes in PaO2/FiO2, using arterial blood gases 
and/or pulse oximetry measurements. 
7. 
Mean change from baseline in overall clinical status measured by SOFA scores. 
8. 
Health economics: antibiotic utilization, duration of stay in the ICU, duration of 
hospitalization, duration of intubation with ventilation or duration of mechanical 
ventilation if tracheostomy is in place.  
5.3. 
Microbiological Endpoints 
The microbiological endpoints have the following: 
1. Microbiological outcome as measured by the proportion of subjects with the index P. 
aeruginosa pneumonia based on the data provided by the local microbiology laboratory 
and central microbiology laboratory. 
2. Proportion of subjects achieving the eradication of P. aeruginosa at Day 21 and 28. 
Eradication is considered as obtained when a specimen of respiratory secretions is 
obtained between the visit day and Day 28 and is negative. When no specimen is obtained 
within this time frame, microbiological outcome will be assessed as “Eradicated” only if 
the study subject is not receiving any antibiotic active against the initial strain after the 
study drug administration visit day and displays no signs and symptoms of pneumonia. 
3. 
Change in bacterial load related to the index P. aeruginosa on the basis of quantitative or 
semi-quantitative cultures by the local microbiological laboratory. 
5.4. 
Pharmacokinetic Endpoints 
The pharmacokinetic endpoints are the following: 


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 Assessment of the PK parameters during full PK sub-study. 
 Assessment of the PK parameters during sparse PK sub-study. 
5.5. 
Safety Endpoints 
The safety endpoints are the following: 
1. Assessment of clinical adverse events 
2. Assessment of clinical laboratory safety tests  
3. Assessment of immunogenicity to Aerucin 
6. 
STATISTICAL METHODOLOGY 
6.1. 
General Considerations 
6.1.1. 
Definition of Baseline 
For all efficacy and safety endpoints, baseline is defined as the last measurement or assessment 
prior to the administration of the study drug. 
6.1.2. 
General Analysis Approach 
Categorical data will generally be summarized with counts and percentages of subjects.  The 
denominator used for the percentage calculation will be clearly defined.  Continuous data will 
generally be summarized with descriptive statistics including n (number of non-missing 
values), mean, median, standard deviation, minimum, and maximum. 
The comparisons for the endpoints will be between the 20 mg/kg dose group and the placebo 
and will be performed at a two-sided 0.05 level of significance. 
6.1.3. 
Hypotheses  
1. Treatment of P. aeruginosa pneumonia with Aerucin improves the rate of Clinical Cure 
of the index pneumonia. 
2. Treatment of P. aeruginosa pneumonia with Aerucin results in an increase in survival 
rate in the target population 
3. Treatment of P. aeruginosa pneumonia with Aerucin improves microbiological, 
functional and health economic outcomes overall. 
4. Aerucin at the proposed dose level is safe based on clinical observation, standard 
laboratory tests, and frequency and nature of related adverse events. 
5. Aerucin does not trigger an adverse immunogenic response (i.e., anti-Aerucin 
immunogenicity). 


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6.1.4. 
Multiplicity 
The study has one primary efficacy endpoint. The secondary efficacy endpoints will be tested 
sequentially at the 0.05 level to control the overall Type I error rate. Each key secondary 
endpoint will be tested in pre-specified order. 
6.1.5. 
Handling of Dropouts and Missing Data 
Missing data will be handled as follows: 
 For clinical outcome at Day 7, 14, 21, and 28, missing data will be handled using the 
nearest clinical data available prior to that day, i.e. last observation carried forward 
(LOCF) approach. 
 For microbiological outcome at Day 7, 14, 21, and 28, missing data will be handled 
using the nearest microbiological data available prior to that day, i.e. LOCF approach. 
 In cases of missing or incomplete dates [e.g. adverse event (AE) and concomitant 
medications], the missing component(s) will be assumed as the most conservative value 
possible. For example, AEs with missing start dates, but with stop dates either 
overlapping into the treatment period or missing, will be counted as treatment-
emergent, taking the worst-case approach. When partial dates are present in the data, 
both a partial start date and/or a partial stop date will be evaluated to determine whether 
it can be conclusively established that the AE started prior to the start of study drug or 
ended prior to the start of study drug. If the above cannot be conclusively established 
based on the partial and/or present dates, then the AE will be considered as treatment-
emergent. Actual data values will be presented in the data listings. 
 A conservative approach will be taken to assess the relationship of an AE to study drug: 
if the relationship of an event is missing, it will be considered treatment-related. 
Missing severity for an AE will not be imputed. 
 Missing values for other variables will not be imputed and only observed values will 
be used in data analyses and summaries. 
6.2. 
Analysis Populations 
6.2.1. 
Safety Population 
The Safety Population is defined as all subjects who have received the study drug. All safety 
data will be analyzed using the Safety Population.  In the event that a subject took the wrong 
study drug (i.e., did not take the randomized study drug), the actual treatment received will be 
used for analysis. 
6.2.2. 
Intent-to Treat Population (ITT) 
The ITT Population is defined as all subjects who have been randomized and treated with any 
amount of study drug, regardless of microbiological documentation. Subjects will be analyzed 
by randomized treatment group. 
6.2.3. 
Microbiological Intent-to-Treat Population (micro-ITT)  
The micro-ITT Population is defined as all ITT subjects for whom microbiological 
documentation of pneumonia due to P. aeruginosa at screening/baseline has been obtained. 


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The micro-ITT population will be used for efficacy analyses. Subjects will be analyzed by 
randomized treatment group. 
6.2.4. 
Per-protocol Population (PP)  
The PP Population is defined as all micro-ITT subjects who completed the study without any 
major protocol deviation. Major protocol deviations may include but are not limited to: 
 Have major inclusion or exclusion violations 
 Take the wrong study drug (i.e., did not take the randomized study drug) 
 Do not have Day 21 assessment unless deemed a treatment failure at an earlier time 
point 
 Receive non-study potentially-effective concomitant antibiotic therapy against                
P. aeruginosa except in case of treatment failure 
Based on the above criteria, the validity listings will be provided to identify which subjects to 
be excluded from the Per-protocol Population (PP). After the study team’s review in a blinded 
manner, the decision to exclude a subject from the PP Population will be finalized and a list of 
subjects with major protocol deviations leading to exclusion from the PP Population will be 
finalized and documented prior to unblinding the randomized treatment assignments.. 
6.3. 
Subject Data and Study Conduct 
6.3.1. 
Subject Disposition 
Subject disposition will be summarized by treatment group and in total for all randomized 
subjects. The following subject disposition categories will be included in the summary: 
 Subjects who were randomized, 
 Subjects who received study drug, 
 Subjects who did not receive study drug, 
 Subjects who completed the study, and 
 Subjects who did not complete the study. 
For subjects who did not complete the study, a summary will be provided by reason for 
discontinuation. Counts and percentages of subjects in each defined analysis population will 
be tabulated by treatment group and in total based on all randomized subjects. 
6.3.2. 
Protocol Deviations  
The number of subjects with reportable protocol deviations in each category will be 
summarized by treatment group and in total for the ITT Population.  
All protocol deviations will be listed by subject. 
6.3.3. 
Demographic and Baseline Characteristics  
The following demographic and baseline characteristics will be summarized: 


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 Age (years) and age categories (<65 years or ≥65 years); 
 Sex; 
 Race; 
 Ethnicity; 
 Height (cm); 
 Weight (kg); 
 Body mass index (BMI) (kg/m2) ; 
 Randomization stratum 1: VABP or non-VABP; 
 Randomization stratum 2: PaO2/FiO2 ≤200 or >200; 
 Randomization stratum 3: Americas, Eastern EU, Western EU or Asia; 
 Baseline APACHE score: ≥20 and <20; 
 Baseline pathogen status: Monopathogen (P. aeruginosa only) or Multiple pathogens 
in baseline culture; 
 Baseline pathogen susceptibility for P. aeruginosa: Multi Drug Resistant (MDR) or 
Susceptible for P. aeruginosa; 
 Reason for admission to ICU at baseline (Trauma or Non-trauma); 
 Randomization confirmed method: Rapid test only or Culture confirmed 
randomization; and 
 Time from Pneumonia Diagnosis (days). 
Demographic and baseline characteristics will be summarized with descriptive statistics or 
counts and percentages of subjects as appropriate by treatment group and in total for the ITT,  
micro-ITT, and PP Populations. 
6.3.4. 
Medical History  
Medical history will be coded to system organ class and preferred term using the Medical 
Dictionary for Regulatory Activities (MedDRA, Version 19.1).  Counts and percentages of 
subjects with medical history by system organ class and preferred term will be summarized by 
treatment group and in total based on the ITT Population. 
6.3.5. 
Prior and Concomitant Medications  
Prior and concomitant medications will be coded to anatomical therapeutic chemical (ATC) 
class and preferred term using the World Health Organization Drug Dictionary (WHO DDE 
B2 September 1, 2016). 
Prior medications are medications used before the administration of the study drug. 
Concomitant medications are medications that were taken on or after the administration of the 
study drug. 
The counts and percentages of subjects taking prior and concomitant medications by ATC class 
and preferred term will be summarized by treatment group and in total based on the micro-ITT 
Population. In addition, the number and percentage of subjects taking prior antibiotics within 
48 hours of study treatment will be summarized by ATC class and preferred term for each 
treatment group. 
All prior and concomitant medications and procedures will be listed by subject.  


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6.3.6. 
Compliance to Study Drug  
Compliance with study drug will be summarized and will be defined as the actual dose of study 
drug taken divided by intended dose multiplied by 100. Percent compliance as a continuous 
variable and the proportion of patients with <90% and ≥90% compliance will be summarized 
by treatment group for the Safety and micro-ITT Populations. 
6.4. 
Efficacy Analyses 
6.4.1. 
Primary Clinical Efficacy Endpoint 
6.4.1.1. 
Primary Analysis 
The primary efficacy endpoint is the proportion of patients with clinical cure at Day 21 in 
patients treated with Aerucin versus the placebo group as assessed by the investigator. The 
investigators’ assessment will be the primary analysis of the primary endpoint.  
The proportion of patients with clinical cure rate at Day 21 will be summarized by randomized 
treatment based on the micro-ITT Population and will be analyzed using a stratified Cochran-
Mantel-Haenszel (CMH) test based on baseline randomization strata (stratum 1: VABP or non-
VABP, stratum 2: PaO2/FiO2 ≤200 or >200, and stratum 3: Americas, Eastern EU, Western 
EU and Asia). The P-value from the stratified CMH test will be presented.  Prior to the 
unblinding, the assessment of each strata and strata combinations with respect to the sample 
size and the corresponding number of endpoints if any or some strata need to be combined to 
be able to process with the analysis or an alternative method is called for (e.g. Fisher’s Exact 
test).   
For the primary analysis, subjects who dropped out or had missing outcome data will be 
included in the denominator. Missing data will be imputed using the nearest clinical data 
available prior to that day, i.e. LOCF approach.  
Sensitivity Analyses  
Sensitivity analyses of the primary efficacy endpoint will be conducted as follows: 
 The proportion of patients with clinical cure at Day 21 will be analyzed based on the 
PP Population.  
 The proportion of patients with clinical cure at Day 21 will be analyzed with missing 
data imputed as the following. If the last observation of clinical outcome assessment 
prior to Day 21 is a failure, failure will be carried forward to Day 21. Otherwise, 
missing outcome at Day 21 will be imputed as ‘Indeterminate’. 
 The proportion of patients with clinical cure at Day 21 will be analyzed based on 
observed case. 
6.4.1.2. 
Secondary Analyses  
The clinical cure at Day 21 assessed by an independent adjudication committee based on newly 
defined clinical cure criteria post hoc will be the secondary analysis. The secondary analysis 
will be performed based on the micro-ITT and PP Populations in the same manner as the 
primary analysis. 


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6.4.2. 
Secondary Clinical Efficacy Endpoints 
Secondary endpoints will be analyzed using a hierarchical sequential testing procedure in the 
following predefined order. 
1. Proportion of patients with Clinical Cure at Day 28 
2. Proportion of patients with Clinical Cure at Day 14 
3. All-cause mortality at Day 28 
4. Pneumonia-related mortality at Day 28 
5. Proportion of patients with Clinical Cure at Day 7 
6. Change from baseline in respiratory functional assessment: Time on mechanical 
ventilation (including if tracheostomy is in place). Time on supplemental oxygenation. 
Measures of respiratory health such as changes in PaO2/FiO2, using arterial blood gases 
and/or pulse oximetry measurements. 
7. Mean change from baseline in overall clinical status measured by SOFA scores. 
8. Health economics: antibiotic utilization, duration of stay in the ICU, duration of 
hospitalization, duration of intubation with ventilation or duration of mechanical 
ventilation if tracheostomy is in place.   
6.4.2.1. 
Clinical Cure  
The proportion of subjects with clinical cure at Day 7, Day 14, and Day 28 will be analyzed 
using stratified CMH test. The P-value will be presented. The number and percentages of 
subjects with the clinical cure at the different timepoints will be summarized by treatment 
group for the micro-ITT Population.  
Time to clinical cure is defined as the number of days from the administration of the study 
drug to the date of the first clinical cure assessed by the investigator plus 1.  
Time to clinical cure will be evaluated by the Kaplan-Meier method and compared using the 
stratified log-rank test based on the stratification factors at randomization. The stratified log -
rank P-value will be presented. In addition, the Kaplan-Meier estimate of Q1, Q3, and the 
median time to the event and the associated 95% confidence interval will be presented for each 
treatment group. Subjects without clinical cure will be censored to the last assessment date. 
The number and percentage of subjects with clinical cure and subjects censored will be 
tabulated by treatment group for the micro-ITT Population. 
6.4.2.2. 
Mortality  
All-cause mortality and pneumonia-related mortality rate by Day 7, 14, 21, and 28 will be 
tabulated by treatment group for the micro-ITT Population and analyzed using a stratified 
CMH test based on the stratification factors at randomization. The P-value from the stratified 
CMH test will be presented. In addition, plots of the Kaplan-Meier estimate of the survival 
distribution function over time will be presented by treatment group. 


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6.4.2.3. 
Respiratory Functional Assessments and SOFA Scores  
The following respiratory functional assessment endpoints will be summarized by treatment 
group based on the micro-ITT Population: 
 Time on mechanical ventilation (including if tracheostomy is in place); 
 Time on supplemental oxygenation; and 
 Measures of respiratory health such as changes in PaO2/FiO2, using arterial blood gases 
and/or pulse oximetry measurements. 
Time on mechanical ventilation is defined as the total number of days on mechanical 
ventilation after the administration of the study drug.  
Time on supplemental oxygenation is defined as the total number of days on supplemental 
oxygenation after the administration of the study drug.  
Time on mechanical ventilation and time on supplemental oxygenation will be summarized by 
treatment group. 
PaO2/FiO2 ratio and SOFA score at baseline, post-baseline visits, and change from baseline 
will be summarized by treatment group based on the micro-ITT Population.  
Time on mechanical ventilation, time on supplemental oxygenation, change from baseline in 
PaO2/FiO2 ratio and SOFA scores will be analyzed using an Analysis of Variance (ANOVA) 
model, with treatment as a main effect, site and baseline randomization strata as factors. 
Treatment by site interaction will be evaluated separately. The least squares (LS) mean, 
standard errors, and the 2-tailed 95% confidence intervals of the change for each treatment 
group will be estimated. For the between-treatment group comparisons, the differences in LS 
means, corresponding standard errors, 95% confidence intervals, and p-values will be obtained 
from the ANOVA model and presented. 
6.4.2.4. 
Health Economics Assessments 
The following health economics endpoints will be summarized by treatment group for the 
micro-ITT Population: 
 Duration of antibiotic utilization; 
 Duration of stay in the ICU; and 
 Duration of hospitalization. 
Duration of antibiotic utilization is defined as the number of days that the subjects received 
antibiotic therapy after the administration of the study drug. 
Duration of stay in the ICU is defined as the total number of days of ICU stay after the 
administration of the study drug. 
Duration of hospitalization is defined as the total number of days of hospitalization after the 
administration of the study drug. 
Duration of antibiotic utilization, duration of stay in the ICU, and duration of hospitalization 
will be analyzed using an ANOVA model, with treatment as a main effect, site and baseline 


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randomization strata as factors. The treatment differences in LS means, corresponding standard 
errors, 95% confidence intervals, and p-values will be obtained from the ANOVA model and 
presented. 
6.4.3. 
Microbiological Endpoints 
Microbiological endpoints include the following: 
 Eradication of index P. aeruginosa at Day 21 and 28; 
 Re-infection/new infection defined as a reoccurrence of pneumonia due to P. 
aeruginosa within the 28-day follow-up period; and 
 Change in bacterial load related to the index P. aeruginosa on the basis of quantitative 
or semi-quantitative cultures by the local microbiological laboratory. 
Microbiological endpoints of eradication and re-infection/new infection will be determined 
based on quantitative/semi quantitative cultures performed by the local laboratory and testing 
of isolates performed by a central microbiology laboratory.  
For microbiological outcome of eradication of index P. aeruginosa, if no specimen of 
respiratory secretions is obtained at the specific time point, the nearest microbiological data 
available prior to that day (Day 7, 14, 21, or 28) will be used, i.e. using LOCF approach. When 
there is no specimen obtained prior to that day, microbiological outcome will be assessed as 
“Eradicated” only if the study subject is not receiving any antibiotic active against the initial 
strain after the study drug administration and prior to that day and displays no signs and 
symptoms of pneumonia. 
The eradication rate of index P. aeruginosa and reinfection rate of pneumonia due to P. 
aeruginosa will be summarized by treatment group based on the micro-ITT Population and 
analyzed using a stratified CMH test based on the stratification factors at randomization. The 
P-value from the stratified CMH test will be presented. 
Change in bacterial load (log10cfu/mL) related to the index P. aeruginosa based on the local 
microbiological laboratory will be presented by treatment group for the micro-ITT Population. 
6.4.4. 
Subgroup Analysis 
The following selected subgroups may be performed for subgroup analysis for the primary 
efficacy endpoint, i.e. the proportion of patients with clinical cure rate at Day 21 as assessed 
by the investigator based on the micro-ITT Population. 
 Randomization stratum: Geographic regions (Americas, Eastern EU, Western EU, 
versus Asia) 
 Randomization stratum: PaO2/FiO2 >200 versus ≤200 
 APACHE score ≥20 versus <20 at baseline 
 Monopathogen (P. aeruginosa only) versus multiple pathogens in baseline culture 
 Multi Drug Resistant (MDR) versus susceptible for P. aeruginosa at baseline 
 Reason for admission to ICU at baseline (Trauma versus Non-trauma) 
 Rapid test only versus culture confirmed randomization 
 Age (<65 years versus ≥65 years) 


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In addition, the above subgroup analysis will also be performed for the selective secondary 
efficacy endpoints, i.e. the proportion of patients with clinical cure rate at Day 7, Day 14, and 
Day 28 as assessed by the investigator based on the micro-ITT Population. 
6.5. 
Pharmacokinetic Analyses 
Pharmacokinetic endpoints include the assessment of the PK parameters during full PK sub-
study and during sparse PK sub-study. 
For full PK sub-study, for each patient participating in the FULL PK sub-study, a total of ten 
(10) PK samples will be obtained. Sampling times are as follows: 
 Prior to the beginning of infusion (pre-dose, time 0) 
 2 hours (end of infusion), 
 4 hours,  
 12 hours,  
 24 hours,  
 96 hours (Day 4 visit), 
 168 hours (Day 7 visit),  
 336 hours (Day 14 visit),  
 504 hours (Day 21 visit),  
 672 hours (Day 28 visit). 
A non-compartmental analysis will be performed to characterize the PK of Aerucin for the 
full PK sub-study. 
For sparse PK sub-study, for subjects participating in the SPARSE PK sub-study, four (4) PK 
samples will be obtained for each at the following times: 
 Prior to the beginning of infusion (pre-dose, time 0) 
 2 hours (end of infusion),  
 at any one of the following timepoints:  4h 12h, or 24h post-dose initiation (inclusive),  
 at any of the following visits:  Day 4, 7, 14, 21, or 28.  
A population PK (compartmental modeling) approach will be used to characterize the PK of 
Aerucin for the sparse PK population. 
All pharmacokinetic analyses will be performed by another vendor and described in a 
standalone PK analysis plan. 
6.6. 
Safety Analyses 
Safety data will be summarized by actual treatment received and in total based on the Safety 
Population. 


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6.6.1. 
Adverse Events 
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a pharmaceutical product, which does not necessarily have a causal relationship 
with this treatment. Adverse events, which include clinical laboratory test variables, will be 
monitored and documented from the time of randomization until 28 days after last dose. 
Adverse events will be coded using MedDRA (Version 19.1). Treatment-emergent adverse 
events (TEAEs) are defined as AEs that start on or after the administration of the study drug. 
An overview of AEs will be provided including counts and percentages of subjects with the 
following: 
 Any AEs 
 Any TEAEs (overall and by maximum severity) 
 Any drug-related TEAEs (overall and by maximum severity) 
 Any serious AEs (SAEs) (overall and by maximum severity) 
 Any drug-related serious AEs (overall and by maximum severity) 
  Any treatment-emergent serious AEs (TESAEs) 
 Any TEAEs leading to discontinuation of study drug 
 Any AEs leading to death 
The number and percentage of subjects with at least one TEAE will be presented by system 
organ class and preferred term. Drug-related TEAE, SAEs, Drug-related SAEs, and TESAEs 
will be summarized in the same manner. In the case of multiple occurrences of the same AE 
within the same subject, each subject will be counted only once for each SOC and preferred 
term. 
Summaries will be provided by maximum severity for the number and percentage of subjects 
with TEAEs by system organ class and preferred term. For this summary, subjects with 
multiple adverse events will be counted only once by the maximum severity with in an SOC 
and preferred term.  
Subject listings of SAEs, TEAEs leading to discontinuation of study drug, and AEs leading to 
death will be provided.  All adverse events will be listed.  
6.6.2. 
Clinical Safety Laboratory Evaluations 
Standard safety laboratory tests 
Standard safety laboratory tests are required at screening/baseline, Day 4, 7, 14, 21 and 28, 
except pregnancy testing (screening/baseline only). All the following tests will be performed 
by the local laboratory. 
- 
Chemistry:  
- 
Miscellaneous: glucose, osmolality, bicarbonate, total protein, albumin 
- 
Electrolytes: sodium, potassium, chloride, calcium 


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- 
Liver function: total bilirubin, alanine transaminase (ALT), aspartate 
transaminase (AST), lactate dehydrogenase (LDH), alkaline phosphatase  
- 
Miscellaneous enzymes: creatine kinase (CK), amylase, C-reactive protein 
(CRP) 
- 
Renal function: blood urea nitrogen (BUN), creatinine, serum glomerular 
filtration rate (eGFR), phosphorus 
- 
Hematology & coagulation 
- 
Red blood cell (RBC), hemoglobin, hematocrit 
- 
WBC, neutrophils, lymphocytes, basophils, eosinophils, and monocytes 
(absolute counts or %) 
- 
INR, fibrinogen, platelets 
- 
Urine: glucose, protein, RBC, WBC 
- 
Pregnancy test for women of childbearing potential (serum or urine, screening only) 
Laboratory test results (Chemistry, Hematology, and Coagulation) at each scheduled visit and 
change from baseline will be summarized by treatment group and in total.  
Shift tables, showing individual subject changes from baseline to each post baseline time point 
will be presented for each laboratory parameter, by treatment group, using the normal, 
abnormal categorization noted below. 
 Normal: result is within the local lab normal range 
 Abnormal: result is either higher or lower than the normal range 
All clinical laboratory data will be listed. Values outside the normal ranges will be flagged. 
Immunogenicity (ADA) 
Immunogenicity (ADA) samples will be obtained at screening/baseline and Day 28. Assays 
will be performed by a central laboratory. 
6.6.3. 
Vital Signs 
Vital signs include heart rate, arterial blood pressure, respiratory rate, and temperature. 
Maximum daily temperature (defined as the maximum temperature reported on a single 
calendar day) will be recorded. Body temperature may be taken per the site’s preferred method 
but limited to oral, tympanic, rectal or core measurements and will be recorded in the 
appropriate electronic case report form (eCRF). The same method of measuring a patient’s 
body temperature should be used throughout the study. 
Descriptive statistics will be used to summarize vital signs measurements and change from 
baseline by each scheduled key time point. 
All vital sign assessments will be listed by subject. 


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6.6.4. 
Electrocardiograms (ECG) 
A standard 12-lead ECG will be obtained at baseline for reference. Abnormal ECG finding 
that would be observed during the course of the study will be duly documented and if 
appropriate, reported as adverse events. 
All 12-lead ECG data will be listed by subject. 
6.6.5. 
Physical Examinations  
A standard physical exam by body systems (General Appearance, Head and Neck, Lymph 
Nodes, Cardiac, Pulmonary, Abdominal, Genitourinary, Osteoarticular, Extremities, 
Cutaneous, Neurological) will be performed at baseline, then at Day 4, 7, 14, 21, and 28 or in 
case of early termination. Changes from baseline will be assessed and if appropriate, reported 
as adverse events. 
Physical exam findings by body systems will be tabulated using counts and percentages at 
baseline and each scheduled post-baseline visit. 
6.7. 
Interim Analyses 
No interim analysis is planned. 
7. 
PROGRAMMING SPECIFICATIONS 
Analyses will be performed using SAS® version 9.3 or higher. All available data will be 
presented in subject data listings which will be sorted by subject as applicable. Detailed 
Programming Specifications will be provided in a separate document.