A Phase 1b/2, Multi-Centered, Randomized, Double-Blind, Placebo-Controlled Trial of the Safety and Microbiological Activity of a Single Dose of Bacteriophage Therapy in Cystic Fibrosis Subjects Colonized With Pseudomonas Aeruginosa
Phase: PHASE1
Conditions: Bacterial Disease Carrier, Cystic Fibrosis
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

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A Phase 1b/2, Multi-Centered, Randomized, Double-Blind, 
Placebo-Controlled Trial of the Safety and Microbiological Activity 
of a Single Dose of Bacteriophage Therapy in Cystic Fibrosis 
Subjects Colonized with Pseudomonas aeruginosa 
DMID Protocol Number: 20-0001 
DMID Funding Mechanism: 2UM1AI104681-08  
Pharmaceutical Support: Walter Reed Army Institute of Research (WRAIR) and Adaptive 
Phage Therapeutics (APT) 
IND Sponsor: National Institutes of Health (NIH)/National Institute of Allergy and Infectious 
Diseases (NIAID)/Division of Microbiology and Infectious Diseases (DMID) 
Lead Principal Investigators: Robert Schooley, MD & Pranita Tamma, MD, MHS 
DMID Clinical Project Manager: Erica Raterman, PhD 
Version Number: 7.0  
Day Month Year 
19 July 2024 
 
 
 

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STATEMENT OF ASSURANCE 
Each Institution will hold a current Federal Wide Assurance (FWA) issued by the Office of 
Human Research Protections (OHRP) for federally-funded human subjects research. Each FWA 
will designate at least one Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) registered with OHRP, for which the research will be reviewed and approved by the 
IRB/IEC and will be subject to continuing review [United States Code of Federal Regulations 
(CFR), 45 CFR 46.103(b)]. The IRB/IEC designated under an FWA may include an institution’s 
IRB/IEC, an independent IRB/IEC, or an IRB/IEC of another institution after establishing a 
written agreement with that other institution. 
 

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STATEMENT OF COMPLIANCE 
The study trial will be carried out in accordance with the Protocol, Good Clinical Practice 
(GCP), and as required by the following: 
• 
United States 45 CFR Part 46: Protection of Human Subjects 
• 
Food and Drug Administration (FDA) Regulations, as applicable: 21 CFR Part 50 (Protection 
of Human Subjects), 21 CFR Part 54 (Financial Disclosure by Clinical Investigators), 21 
CFR Part 56 (Institutional Review Boards), 21 CFR Part 11, and 21 CFR Part 312 
[Investigational New Drug (IND) Application]. 
• 
International Council for Harmonisation (ICH): Good Clinical Practice (ICH E6); 62 Federal 
Register 25691 (1997); and future revisions 
• 
Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of 
Research, Report of the National Commission for the Protection of Human Subjects of 
Biomedical and Behavioral Research 
• 
National Institutes of Health (NIH) Office of Extramural Research (OER), Research 
Involving Human Subjects, as applicable 
• 
National Institute of Allergy and Infectious Diseases (NIAID) Clinical Terms of Award, as 
applicable 
• 
Applicable Federal, State, and Local Regulations and Guidance 
• 
Applicable DMID Policies, Guidelines, and Plans to include but not limited to: Clinical 
Quality Management Policy, DMID Guidelines for Clinical Study Product Management, 
Guidelines for Writing Notes to the Study File, Study Product Management Plan (SPMP), 
Clinical Quality Management Plan (CQMP), etc. 

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SIGNATURE PAGE 
The signature below provides the necessary assurance that this trial will be conducted according 
to all stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable US federal regulations and 
ICH E6 Good Clinical Practice (GCP) guidelines. 
 
I agree to conduct the study in compliance with GCP and applicable regulatory requirements. 
I agree to conduct the study in accordance with the current protocol and will not make changes to 
the protocol without obtaining the sponsor’s approval and IRB/IEC approval, except when 
necessary to protect the safety, rights, or welfare of subjects. 
 
Site Investigator Signature: 
 
Signed: 
 
Date: 
 
 
Name 
Title 
 
 
 
 

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TABLE OF CONTENTS 
STATEMENT OF ASSURANCE ...................................................................................................2 
STATEMENT OF COMPLIANCE .................................................................................................3 
SIGNATURE PAGE .......................................................................................................................4 
TABLE OF CONTENTS .................................................................................................................5 
LIST OF TABLES .........................................................................................................................10 
LIST OF FIGURES .......................................................................................................................11 
LIST OF ABBREVIATIONS ........................................................................................................12 
PROTOCOL SUMMARY .............................................................................................................14 
STUDY SCHEMA.........................................................................................................................16 
 
KEY ROLES.........................................................................................................................17 
 
BACKGROUND AND SCIENTIFIC RATIONALE ..........................................................18 
 
Background .................................................................................................................18 
 
Scientific Rationale .....................................................................................................19 
2.2.1 Purpose of Study ............................................................................................19 
2.2.2 Study Population ............................................................................................19 
 
Potential Risks and Benefits .......................................................................................20 
2.3.1 Potential Risks ...............................................................................................20 
2.3.2 Potential Benefits ...........................................................................................26 
 
STUDY DESIGN, OBJECTIVES AND ENDPOINTS OR OUTCOME MEASURES .....27 
 
Study Design Description ...........................................................................................27 
 
Study Objectives .........................................................................................................28 
3.2.1 Primary ...........................................................................................................28 
3.2.2 Secondary .......................................................................................................28 
3.2.3 Exploratory ....................................................................................................28 
 
Study Endpoints or Outcome Measures .....................................................................28 
3.3.1 Primary ...........................................................................................................28 
3.3.2 Secondary .......................................................................................................29 
3.3.3 Exploratory ....................................................................................................29 

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STUDY INTERVENTION/INVESTIGATIONAL PRODUCT..........................................30 
 
Study Product Description ..........................................................................................30 
4.1.1 Formulation, Packaging, and Labeling ..........................................................30 
4.1.2 Product Storage and Stability .........................................................................31 
 
Acquisition/Distribution .............................................................................................31 
 
Protocol-Specified Medications/Treatments Other Than Study Products ..................31 
 
Dosage/Regimen, Preparation, Dispensing and Administration of Study 
Intervention/Investigational Product .........................................................................32 
4.4.1 Rationale for Dose Selection .........................................................................32 
 
Pre-determined Modification of Study Intervention/Investigational Product for an 
Individual Subject .....................................................................................................32 
 
Accountability Procedures for the Study Intervention/Investigational Product(s) .....32 
 
SELECTION OF SUBJECTS AND STUDY ENROLLMENT AND WITHDRAWAL ....34 
 
Eligibility Criteria .......................................................................................................34 
5.1.1 Subject Inclusion Criteria ..............................................................................34 
5.1.2 Subject Exclusion Criteria .............................................................................34 
 
Withdrawal from the Study, Discontinuation of Study Product, or Study Termination
 ..................................................................................................................................36 
5.2.1 Withdrawal from the Study or Discontinuation of the Study Product ...........36 
5.2.2 Subject Replacement ......................................................................................36 
5.2.3 Study Termination .........................................................................................37 
 
STUDY PROCEDURES ......................................................................................................38 
 
Screening ....................................................................................................................38 
 
Baseline/Dosing (Day 1) .............................................................................................39 
 
Planned Follow-up Visits ...........................................................................................40 
6.3.1 Follow-up Visits, Days 2 - 12 (Day 2, Day 5 ± 2, Day 8 + 3, Day 12 + 7 
[Stage 1 only]) ................................................................................................40 
6.3.2 Final Study Visit ............................................................................................41 
6.3.3 Early Termination Visit .................................................................................42 
 
Virtual Study Visits ....................................................................................................43 
 
Unscheduled Study Visits ...........................................................................................44 

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Protocol Deviations ....................................................................................................44 
 
DESCRIPTION OF CLINICAL AND LABORATORY EVALUATIONS .......................46 
 
Clinical Evaluations ....................................................................................................46 
7.1.1 Research Procedures ......................................................................................46 
7.1.2 Assessment of Concomitant Medications/Treatments Other Than Study 
Product ...........................................................................................................47 
7.1.3 Assessment of Subject Compliance with Study Intervention/Investigational 
Product ...........................................................................................................47 
 
Laboratory Evaluations ...............................................................................................47 
7.2.1 Clinical Laboratory Evaluations ....................................................................47 
7.2.2 Research Assays .............................................................................................48 
7.2.3 Secondary Analysis of Stored Specimens and Data ......................................49 
 
ASSESSMENT OF SAFETY ...............................................................................................50 
 
Assessing and Recording Safety Parameters ..............................................................50 
8.1.1 Adverse Events (AEs) ....................................................................................50 
8.1.2 Serious Adverse Events (SAEs) .....................................................................51 
 
Specification of Safety Parameters .............................................................................52 
8.2.1 Unsolicited Events .........................................................................................52 
8.2.2 Events of Special Interest ...............................................................................52 
8.2.3 Dose Escalation Criteria ................................................................................53 
 
Reporting Procedures ..................................................................................................53 
8.3.1 Reporting Serious Adverse Events ................................................................53 
8.3.2 Regulatory Reporting for Studies Conducted Under DMID Sponsored IND
 ........................................................................................................................54 
8.3.3 Reporting of Pregnancy .................................................................................54 
 
Type and Duration of Follow-up of Subjects After Adverse Events ..........................55 
 
Procedures to be Followed in the Event of Abnormal Laboratory Test Values .........55 
 
Halting Rules ..............................................................................................................55 
8.6.1 Study Halting Criteria ....................................................................................55 
8.6.2 Individual Infusion Halting Criteria ...............................................................56 
 
Safety Oversight .........................................................................................................56 

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8.7.1 Data and Safety Monitoring Board (DSMB) .................................................56 
8.7.2 PHAGE Advisory Group ...............................................................................57 
 
HUMAN SUBJECTS PROTECTION .................................................................................58 
 
Institutional Review Board/Independent Ethics Committee ......................................58 
 
Informed Consent Process ..........................................................................................58 
9.2.1 Other Informed Consent Procedures ..............................................................60 
 
Consent for Secondary Use of Stored Specimens and Data .......................................60 
 
Exclusion of Women, Minorities, and Children (Special Populations) ......................61 
 
Subject Confidentiality ...............................................................................................61 
 
Certificate of Confidentiality ......................................................................................61 
 
Costs, Subject Compensation, and Research Related Injuries ...................................62 
 
STATISTICAL CONSIDERATIONS .................................................................................63 
 Study Hypotheses .......................................................................................................63 
 Sample Size Considerations .......................................................................................63 
 Treatment Assignment Procedures .............................................................................63 
10.3.1 Randomization Procedures ............................................................................63 
10.3.2 Masking Procedures .......................................................................................63 
 Planned Interim Analyses ...........................................................................................64 
10.4.1 Interim Safety Review ...................................................................................64 
10.4.2 Interim Microbiological Activity Review ......................................................64 
 Final Analysis Plan .....................................................................................................65 
10.5.1 General Considerations ..................................................................................65 
10.5.2 Analysis Sets ..................................................................................................66 
10.5.3 Subject Disposition ........................................................................................66 
10.5.4 Demographics and Other Baseline Characteristics ........................................67 
10.5.5 Analysis of Primary Endpoints ......................................................................67 
10.5.6 Subgroup and Adjusted Analyses for Primary Endpoints .............................69 
10.5.7 Analysis of Exploratory Endpoints ................................................................69 
10.5.8 Missing Data ..................................................................................................70 
10.5.9 Safety Data .....................................................................................................70 

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10.5.10 
Clinical Laboratory Parameters and Vital Signs ...............................70 
 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ..............71 
 
QUALITY CONTROL AND QUALITY ASSURANCE ...................................................72 
 
DATA HANDLING AND RECORD KEEPING ................................................................73 
 Data Management Responsibilities ............................................................................73 
 Statistical and Data Coordinating Center/Biostatistician Responsibilities .................73 
 Data Capture Methods ................................................................................................73 
 Types of Data ..............................................................................................................73 
 Study Records Retention ............................................................................................73 
 
CLINICAL MONITORING .................................................................................................75 
 
PUBLICATION POLICY ....................................................................................................76 
 
LITERATURE REFERENCES ............................................................................................77 
 
APPENDICES ......................................................................................................................79 
 
Schedule of Events............................................................................79 
 
Cystic Fibrosis Questionnaire – Revised (CFQ-R) ...........................81 
 
Cystic Fibrosis Respiratory Symptom Diary (CFRSD) ....................81 
 
 

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LIST OF TABLES 
Table 1: Summary of Bacteriophage Safety Events Reported in the Peer-Reviewed 
Literature. ....................................................................................................................21 
Table 2: Components of WRAIR-PAM-CF1 ................................................................................30 
Table 3: Summary of Analysis of Primary Endpoints ...................................................................68 
 
 

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LIST OF FIGURES 
Figure 1: Treatment Arms ..............................................................................................................16 
Figure 2: Study Flow Diagram Illustrating Study and Subject Progression ..................................16 
 
 

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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
APT 
Adaptive Phage Therapeutics 
ALT 
Alanine Aminotransferase  
ARLG 
 The Antibacterial Resistance Leadership Group 
AST 
 Aspartate Aminotransferase 
AUC 
 Area Under Curve 
Bp 
 Base pairs 
BPM 
 Beats per Minute 
CF 
 Cystic Fibrosis  
CFQ-R 
 Cystic Fibrosis Questionnaire-Revised 
CFR 
Code of Federal Regulations 
CFRSD 
Cystic Fibrosis Respiratory Symptom Diary 
CFTR 
Cystic Fibrosis Transmembrane Conductance Regulator  
CFU 
Colony Forming Units 
cGMP 
Current Good Manufacturing Practice 
CMS 
Clinical Material Services 
CQMP 
Clinical Quality Management Plan 
CRF 
Case Report Form 
CROMS 
Clinical Research Operations and Management Support 
DAIDS 
Division of AIDS  
DHHS 
Department of Health and Human Services 
DMID 
Division of Microbiology and Infectious Diseases, NIAID, 
NIH, DHHS 
DOOR 
Desirability of Outcome Ranking 
DSMB 
Data and Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
eIND 
Emergency Investigational New Drug Application 
ESI 
Event of Special Interest 
FDA 
Food and Drug Administration 
FEV1 
 Forced Expiratory Volume in 1 second 
FWA 
 Federal Wide Assurance 
GCP 
Good Clinical Practice 
HLT 
High Level Term 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent or Institutional Ethics Committee 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 

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IV 
Intravenous  
LFT 
Liver Function Tests 
LLN 
Lower Limit of Normal 
MDR 
Multidrug-Resistant 
MedDRA 
Medical Dictionary for Regulatory Activities 
MM 
Medical Monitor 
mmHG 
Millimeters of Mercury 
MO 
Medical Officer 
MOP 
Manual of Procedures 
NDA 
New Drug Application 
NIAID 
National Institute of Allergy and Infectious Diseases, NIH, 
DHHS 
NIH 
National Institutes of Health 
OHRP 
Office for Human Research Protections 
OER 
Office of Extramural Research 
PI 
Principal Investigator 
PID 
Patient Identification  
PFU 
Plaque Forming Unit  
PK 
Pharmacokinetics 
PVG 
Pharmacovigilance Group 
QA 
Quality Assurance 
QC 
Quality Control 
QOL 
Quality of Life 
RBC 
Red Blood Cell 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SDCC 
Statistical and Data Coordinating Center 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SPMP 
Study Product Management Plan 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
US 
United States 
WRAIR 
Walter Reed Army Institute of Research 
WBC 
White Blood Cell 
YO 
Year old 
 

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PROTOCOL SUMMARY 
Title: 
A Phase 1b/2, Multi-Centered, Randomized, Double-Blind, Placebo-
Controlled Trial of the Safety and Microbiological Activity of a Single 
Dose of Bacteriophage Therapy in Cystic Fibrosis Subjects Colonized 
with Pseudomonas aeruginosa 
Design of the 
Study: 
Randomized, Double-Blind, Placebo-Controlled Trial 
Study Phase: 
1b/2 
Study 
Population: 
Up to 72 male and female subjects 18 years of age and older with Cystic 
Fibrosis (CF) and residing in the United States (US)  
Number of 
Sites: 
Up to 20 clinical sites in the US 
Description 
of Study 
Product or 
Intervention: 
A total of 4 x 107 to 4 x 109 plaque forming units (PFU) of a 4-component 
bacteriophage mixture administered intravenously  
Study 
Objectives: 
 
Primary: 
• 
Describe the safety of a single dose of intravenous (IV) bacteriophage 
therapy in clinically stable CF subjects with P. aeruginosa in 
expectorated sputum. 
• 
Describe the microbiological activity of a single dose of IV 
bacteriophage therapy in clinically stable CF subjects with P. 
aeruginosa in expectorated sputum. 
• 
Describe the benefit to risk profile of a single dose of IV bacteriophage 
therapy in clinically stable CF subjects with P. aeruginosa in 
expectorated sputum. 
 
Secondary: 
• 
N/A 
 

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Exploratory: 
• 
Characterize the serum and sputum pharmacokinetic (PK) profiles of a 
single dose of IV bacteriophage therapy in clinically stable CF subjects 
with P. aeruginosa in expectorated sputum. 
• 
Describe changes in lung function from the administration of a single 
dose of IV bacteriophage therapy through Day 30 ± 7. 
• 
Characterize geographically diverse P. aeruginosa isolates 
susceptibility to bacteriophages. 
• 
Describe subjects’ quality of life (QOL) before and after receiving 
bacteriophage therapy. 
Duration of 
Individual 
Subject 
Participation: 
 
Up to 44 days 
Estimated 
Time to Last 
Subject/Last 
Study Day: 
 
Approximately 48 months  
 
 

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STUDY SCHEMA 
Figure 1: Treatment Arms 
Stage 1 
Sentinel Stage 
(unblinded, dose-
escalation) 
 
Stage 2 
Double Blind Comparison 
Dose 
# of 
Subjects 
 
                    Stage 2a 
                        # of  
 Dose            Subjects 
 
Dose 
 Stage 2b 
# of 
Subjects 
Total # of subjects 
at the final 
selected dose 
(Combination of 
Stages 2a + 2b) 
 
 
 
 
 
 
 
 
 
 
 
4 x 107  
PFU 
2 
 
 
4 x 107 
PFU 
8 
 
 
 
 
 
 
↓ 
 
 
 
 
 
 
 
 
 
 
4 x 108 
PFU 
2 
 
4 x 108 
PFU 
8 
 
 Interim 
 
Optimal 
Stage 
2a dose  
~12-17 
~20-25 
↓ 
 
 
 
 
 
Analysis  
 
 
 
4 x 109 
PFU 
2 
 
4 x 109 
PFU 
8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Placebo 
 
8 
 
 
 
Placebo 
~12-17 
~20-25 
 
Figure 2: Study Flow Diagram Illustrating Study and Subject Progression  
 
 

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 KEY ROLES 
Lead PIs:                               
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DMID Clinical Project 
Manager: 
Robert Schooley, MD 
Professor of Medicine 
University of California, San Diego 
9500 Gilman Drive 
215 University Center, Mail Stop 0030 
San Diego, California 92093 
rschooley@ucsd.edu        
Telephone: (858) 246-2693 
Fax: (858) 534-5567 
 
Pranita Tamma, M.D., M.H.S. 
Associate Professor of Pediatrics  
John Hopkins University School of Medicine 
200 North Wolfe Street, Room 3149 
Baltimore, Maryland 21287 
Email: ptamma1@jhmi.edu 
Telephone: (410) 614-1492 
Fax: (410) 614-1491 
 
Erica Raterman, Ph.D. 
Division of Microbiology and Infectious Diseases (DMID) 
 
Statistical and Data 
Coordinating Center 
(SDCC): 
 
 
The Emmes Company 
401 N. Washington St. Suite 700 
Rockville, MD 20850 
Email: arlg_studies@emmes.com 
Phone: (301) 251-1161 

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 BACKGROUND AND SCIENTIFIC RATIONALE 
 Background  
Multidrug-resistant (MDR) bacterial infections remain a pressing global concern. The CF 
population is particularly prone to MDR infections. These manifest as frequent lower respiratory 
tract infections that are increasingly challenging to treat as resident bacteria routinely acquire 
additional mechanisms of drug resistance and develop an increasingly mucoid phenotype, 
rendering most antibiotics ineffective over time.1 P. aeruginosa remains the most common 
pathogen responsible for CF exacerbations.2 Few novel antibiotic agents recently approved by 
the FDA have substantial activity against highly drug-resistant P. aeruginosa.3 Because of the 
limited number of antibiotics available to treat respiratory infections in CF patients, particularly 
as they enter more advanced phases of disease, novel treatment approaches are desperately 
needed. 
Bacteriophages are viruses that target and kill bacteria.4 Since the 1940s, with the advent of 
modern antibiotics, their use in antimicrobial therapeutics in the western world has been largely 
abandoned. Although bacteriophage products have recently been approved in food safety 
applications (e.g., bacteriophages targeting Listeria monocytogenes),5 their use in human 
medicine remains experimental. In recent years, bacteriophage administration as adjunct therapy 
to systemic antibiotics for the treatment of complex infections under compassionate use 
conditions has increased as is evident by a growing number of case reports in the literature. 
Organisms that have been targeted with bacteriophage therapy include P. aeruginosa, 6-8 
Acinetobacter baumannii complex, 9,10 Staphylococcus aureus, 11-13 and Mycobacterium 
abscessus.14 Bacteriophage therapy has been used to treat a variety of infectious processes 
including bacterial pancreatitis, pneumonia in lung transplant recipients 7 and in patients with 
CF,6,14 left ventricular assist device infections,12 staphylococcal sepsis,15 burns,16 chronic 
sinusitis,13 and hardware-associated bone and joint infections.10,17 The role of bacteriophages in 
decolonizing patients harboring MDR pathogens in the intestinal tract has also been explored.18 
These clinical experiences have noted very few safety concerns, as described in Section 2.3.1. 
Serious adverse events (SAEs) attributable to bacteriophages have not been reported in the 
published literature. 
Unique features that make bacteriophages attractive for clinical use include: bactericidal activity, 
high specificity for target pathogens including MDR pathogens, biofilm penetration, avoidance 
of host tissue damage, preservation of the human microbiome, and potential synergy with 
antibiotics. However, much work remains before bacteriophage therapy can be routinely used in 
clinical practice. Major gaps in knowledge include: the optimal frequency, dosage, and duration 
of administration, availability of clinical laboratory testing technologies that reliably predict 
activity of bacteriophages for specific clinical applications, understanding factors affecting the 
kinetics of bacteriophage resistance during clinical use, optimal use of bacteriophages in 
combination with antibiotics and in combination with other bacteriophage regimens, and 
optimization of bacteriophage stability in pharmaceutical preparations.  

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Rigorous scientific studies are required to address these critical gaps in knowledge related to 
bacteriophage therapeutics. The overarching goal of the proposed clinical trial is to enhance the 
understanding of the safety and microbiological activity of bacteriophage therapy. 
 Scientific Rationale 
2.2.1 Purpose of Study 
This clinical trial is designed to describe the safety and microbiological activity of 
bacteriophages directed at P. aeruginosa in clinically stable CF subjects with P. aeruginosa 
respiratory colonization. This is a dose-ranging study of intravenous (IV) anti-pseudomonal 
bacteriophage therapy. Sentinel subjects will be enrolled first and receive a single IV dose of a 4-
component anti-pseudomonal bacteriophage (see Section 4.1 for details); all subjects will be 
monitored for the subsequent 96 hours (Stage 1) before enrollment in Stage 2 can begin. Stage 1 
subjects will continue to be monitored for 30 ± 7 days. After Stage 1 enrollment and the 96-hour 
monitoring period are complete, eligible subjects will be enrolled into Stage 2 and receive a 
single IV dose of a 4-component anti-pseudomonal bacteriophage or placebo and then will be 
monitored for 30 ± 7 days (Stage 2). Stage 2a will randomize subjects to placebo or one of three 
different doses of bacteriophage. After the last Stage 2a subject has been enrolled, study 
enrollment will be held for an Interim Analysis (Section 10.4) to determine the dose that will be 
used in Stage 2b. This trial will limit the route of administration of bacteriophages to the IV 
route. As the safest, yet still microbiologically active dosage of bacteriophages has yet to be 
defined, this will be a dose-ranging study evaluating 1 x 107 PFU, 1 x 108 PFU, and 1 x 109 PFU 
of each bacteriophage (equaling a total of 4 x 107 PFU, 4 x 108 PFU, and 4 x 109 PFU of 
bacteriophages in the 4-component bacteriophage mixture). It is expected that a single dose of 
bacteriophage will be safe and lead to at least a one-log10 decrease in P. aeruginosa colony 
forming units (CFU)/mL in sputum, compared to baseline.  
2.2.2 Study Population 
This is a Phase 1b/2 clinical trial that will enroll up to 72 CF subjects. Clinically stable 
volunteers will be recruited from up to 20 CF outpatient clinics in the US. All study visits will 
occur in the ambulatory setting. There will be no enrollment from international sites. A detailed 
review of the study will be discussed with potential subjects and consent will be obtained. 
Inclusion will be limited to subjects 18 years of age or older (at the time of the screening) who 
are capable of providing informed consent. Furthermore, subjects should be capable and willing 
to complete all study visits and perform all procedures required by this protocol. Individuals who 
are pregnant, planning to become pregnant at any time during the study period, or breastfeeding 
will not be included as the impact of bacteriophage therapy on pregnancy, fetuses, and neonates 
is unknown. Cystic fibrosis (CF) primarily affects persons of European backgrounds and 
generally has an unequal distribution across races and ethnicities. It is expected that the racial 
and ethnic distribution of enrolled subjects will reflect those of the local CF communities from 
where subjects are recruited but may not reflect the US population as a whole. Prisoners and 
other potentially vulnerable populations will not be enrolled.  

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 Potential Risks and Benefits 
2.3.1 Potential Risks 
The scientific literature regarding the use of bacteriophage therapy for clinical use has not 
indicated any clear safety risks. As subjects will be receiving bacteriophage IV, there may be 
risks associated with this route of administration. Placement of a peripheral venous catheter can 
cause discomfort, minor bleeding, and infections from skin flora.  
There have been several case reports and case series, as well as limited clinical trials 
investigating the safety of bacteriophage therapy. Although significant variability exists across 
published studies, there have not been SAEs related to bacteriophage therapy in the published 
literature. Table 1 describes published studies on bacteriophage use in humans and includes 
reported adverse events (AEs). There are no consistent mild or moderate AEs across studies that 
have been associated with bacteriophage therapy.  
From a theoretical point of view, the immediate lysis of bacteria following bacteriophage 
administration may result in skin flushing, hemodynamic changes in pulse and blood pressure, 
and respiratory difficulties. 
From prior experiences with bacteriophage the following may occur, allergic reactions, 
temporary increases in liver enzymes, temporary shortness of breath or wheezing, temporary 
decrease in blood pressure, temporary feeling of being flushed or sweaty, development of fever, 
and temporary increase in heart rate.  
A theoretical risk with bacteriophage therapy is the risk of transduction. This means the 
bacteriophage may serve as a vector to transfer DNA from one bacterium to another. The 
transferred DNA may include antibiotic resistance genes, as well as other clinically relevant 
genes. The likelihood of this occurring is unknown; however, experimental data from the current 
trial indicate this risk is very low. More specifically, whole genome sequencing analyses of 
paired P. aeruginosa isolates obtained from the sputum samples of 19 subjects pre and post 
bacteriophage or placebo treatment from Stage 2a were performed to assess whether there was 
any evidence of transduction by bacteriophage among subjects enrolled in the trial. The results 
indicate that there is no evidence of transduction by the bacteriophage within enrolled subjects. 
The Investigator’s Brochure (IB) provided by National Institutes of Health (NIH)/National 
Institute of Allergy and Infectious Diseases (NIAID)/Division of Microbiology and Infectious 
Diseases (DMID) with pharmaceutical support from Walter Reed Army Institute of Research 
(WRAIR) and Adaptive Phage Therapeutics (APT), Inc., describes experiences with providing 
bacteriophages under FDA emergency IND (eIND) and Compassionate Use. No AEs have been 
reported on the cardiovascular system, renal system, endocrine system, skin, central nervous 
system, or on lipase/amylase values. There was one case in which a patient developed fever, 
wheezing, and shortness of breath two hours following 2 consecutive doses of IV bacteriophage 
administration dosed at 1 x 1011 PFU. The symptoms resolved with acetaminophen, solumedrol, 
albuterol, and diphenhydramine. The same bacteriophage mixture was subsequently tolerated by 
the patient without further incident when the bacteriophage dosage was reduced to 1 x 1010 PFU. 

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Some patients receiving bacteriophage mixtures were noted to have asymptomatic isolated 
elevations in liver function tests (LFTs) including either aspartate aminotransferase (AST) or 
alanine aminotransferase (ALT), which normalized following cessation of bacteriophage 
therapy. For some of the patients with elevated AST/ALT, resolution could not be determined. 
No cases of phage-related drug-induced liver injury have been reported. Refer to the IB for 
additional details. 
Table 1: Summary of Bacteriophage Safety Events Reported in the Peer-Reviewed 
Literature.   
Publication 
Source of 
Bacteriophages 
Brief Description 
Bacteriophage 
Dosing 
(highest dose 
given, PFU) 
Adverse Events 
(AEs) 
Aslam 
202019 
 
PMID: 
33005701 
Naval Medical 
Research 
Center, APT, 
Armata 
Pharmaceuticals, 
Roach 
Laboratory, 
Baylor College 
of Medicine, 
Walter Reed 
Army Institute 
of Research. 
Describes 10 
patients treated 
with intravenous 
bacteriophages for 
a variety of 
infections and 
caused by a variety 
of organisms.  
Highest dose 
administered 
for a treatment 
course: 5 x 109 
IV q6h for 14 
days.  
 
Two infusions 
up to 1 x 1011 
were 
administered to 
one patient, but 
with adverse 
events.  
In one case, an 82-
year-old (YO) 
male developed 
fever, wheezing, 
and shortness of 
breath after 2 
infusions of 1 × 
1011 PFU/mL 
concentration. 
Symptoms 
resolved with 
acetaminophen, 
solumedrol, 
albuterol 
nebulization, and 
diphenhydramine, 
and the patient 
continued phage 
therapy at a lower 
dose without 
further incident. 
No AEs reported 
in other 9 patients. 
Aslam,  
201912 
 
PMID: 
30661974 
AmpliPhi 
Biosciences 
 
3 bacteriophages 
65 YO male with 
LVAD infection 
with MSSA and 
open chest wound 
3 x 109 IV q12h 
for 28 days  
 
 
None reported 

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LaVergne, 
201820 
 
PMID: 
29687015 
Naval Medical 
Research Center 
provided phages  
 
1 bacteriophage 
77 YO male with 
traumatic brain 
injury with 
craniotomy site 
infection with 
MDR A. baumannii 
2.14 × 107 IV 
q2h for 8 days  
 
 
Two hours after 
first dose became 
briefly 
hypotensive (no 
pressors)  
Duplessis, 
201921 
 
PMID: N/A 
US Navy and 
APT  
 
Personalized 
phage cocktails 
ranging from 1 
to 3 phages 
13 case studies of 
eIND bacteriophage 
use  
 
Two pediatric uses: 
10 YO female and 
2 YO males 
Eleven adult uses 
ranging from 18 – 
77 YO, including 
males and females 
 
Duration of phage 
therapy ranged 
from 2 days to 19 
weeks 
Varied per 
case; highest 
reported case 
dose 1.0 x 1010 
PFU/mL IV 
No identified 
adverse effects 
attributed to phage 
therapy  
Cano, 202022 
 
PMID: 
32699879 
APT 
 
1 bacteriophage 
62 YO male with a 
relatively 
susceptible K. 
pneumoniae 
prosthetic knee 
infection 
6.3 x 1010 IV 
q24h for 40 
days  
 
 
None reported 
Tkhilaishvili, 
20208 
 
PMID: 
31527029 
George Eliava 
Institute of 
Bacteriophages 
 
1 bacteriophage 
80 YO female with 
a MDR P. 
aeruginosa 
prosthetic knee 
infection & 
osteomyelitis 
1 x 108 q8h 
through each 
drain for local 
delivery for 5 
days 
 
 
None reported  
Aslam, 
20197 
 
 
PMID: 
31207123 
 
AmpliPhi 
Biosciences, 
Naval Medical 
Research 
Center, and APT 
provided 
bacteriophages 
Patient 1: 67 YO 
male lung 
transplant recipient 
(hypersensitivity 
pneumonitis) with 2 
MDR P. 
aeruginosa 
Patient 1: 5 x 
109 IV q2-4h 
and nebulized 
q6-12h for 29 
days and 
separated 56 
days 
None reported 

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Patient 1: varied 
between 3-5 
bacteriophages 
 
Patient 2: 4 
bacteriophage 
cocktail  
 
Patient 3: 1 
bacteriophage 
pneumonia 
hospitalizations 
 
Patient 2: 52 YO 
female non-CF lung 
transplant recipient 
with MDR P. 
aeruginosa 
pneumonia 
 
Patient 3: 28 YO 
male CF lung 
transplant recipient 
with Burkholderia 
species pneumonia 
 
 
 
Patient 2: 4 x 
109 IV q12h for 
4 weeks 
 
 
 
 
Patient 3: 3.5 x 
107 IV q12-24h 
for 12 weeks 
Dedrick,  
201914 
 
PMID: 
31068712 
SEA-PHAGES 
program and U 
of Pittsburgh 
 
3 bacteriophage 
cocktail 
15 YO female CF 
lung transplant 
recipient with M. 
abscessus sternal 
wound infection 
with infected skin 
nodules 
1 x 109 IV q12h 
for ~4 months  
 
 
 
During first 2 days 
patient felt sweaty 
and flushed but 
no other changes  
Schooley, 
20179 
 
PMID: 
28807909 
AmpliPhi 
Biosciences, 
Naval Medical 
Research 
Center, and 
Texas A&M 
 
9 bacteriophage 
custom cocktail 
(not all 
administered at 
same time) 
68 YO male with 
MDR A. baumannii 
necrotizing 
pancreatitis with 
infected pancreatic 
pseudocysts 
5 x 109 IV for 2 
weeks (varying 
intervals but 
mostly q6-8h; 
intra-cavitary 
q6h for ~12 
weeks 
 
 
None reported 
Nir-Paz, 
201910 
 
PMID: 
30869755 
Naval Medical 
Research Center 
and APT 
 
2 bacteriophage 
cocktail 
42 YO male with 
MDR A. baumannii 
and K. pneumoniae 
osteomyelitis 
5 x 107 IV q8h 
for 11 days 
 
  
None reported  
Law, 20196 
 
AmpliPhi 
Biosciences 
26 YO female with 
severe CF 
4 x 109 IV q6h 
for 8 weeks  
None reported 

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PMID: 
31102236 
 
4 bacteriophage 
cocktail 
exacerbation with 
MDR P. 
aeruginosa 
 
 
Ferry, 201823 
 
PMID: 
30060002 
Pherecydes 
Pharma 
 
4 bacteriophage 
cocktail 
60 YO male with 
non-small lung 
cancer with MDR 
P. aeruginosa 
osteomyelitis near 
sacroiliac joint 
1.2 to 9.7 x 108 
instilled into 
infected bone 
for 4h at a time 
q3days over 12 
days 
None reported 
Jault, 201916 
 
PMID: 
30292481 
Pherecydes 
Pharma 
 
12 
bacteriophage 
cocktail. 
25 patients with 
burn wounds 
infected with P. 
aeruginosa 
randomized to 
topical 
bacteriophage 
cocktail vs. 
standard of care 
(silver sulfadiazine) 
1 x 106 
topically qday 
for 7 days 
 
 
1 death in each 
study arm 
determined to be 
unrelated to 
assigned treatment 
 
Mild AEs 
unrelated to the 
study drug: 
 
In 3 of 13 patients 
in bacteriophage 
group: 
hyperthermia (1), 
bacteremia (1), ear 
infection (1), 
pseudomonal 
sepsis (1), 
superinfection (1), 
urinary tract 
infection (1), 
decreased oxygen 
saturation (1), 
hematuria (1), 
hemorrhagic 
urinary tract (1), 
hypoxia (1) 
 
In 7 of 13 patients 
in standard 
group: 
pancytopenia (1), 
hyperthermia (1), 

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impaired hearing 
(1), bacteremia 
(1), bronchitis (1), 
fascial infection 
(1), pneumonia 
(1), pseudomonas 
infection (1), 
septic shock (3), 
skin graft (2), 
post-procedural 
hemorrhage (1), 
lung disorder (1), 
urticarial (1), 
hemorrhagic shock 
(1) 
Corballino, 
201918 
 
PMID: 
31414123 
George Eliava 
Institute 
of 
Bacteriophages 
 
1 custom 
bacteriophage 
57 YO male with 
Crohn’s disease 
colonized with 
MDR K. 
pneumoniae 
 
 
1 x 106 oral and 
intra-rectal 
bacteriophages 
q12h for 3 
weeks 
 
 
None reported 
Ooi, 201913 
 
PMID: 
31219531 
AmpliPhi 
Biosciences 
 
1 custom 
bacteriophage 
Open-label study of 
9 adults with 
chronic S. aureus 
sinusitis  
3 patients 
received 3 x 108 
nasal irrigations 
q12h for 7 
days; 3 patients 
received 3 x 108 
q12h for 14 
days, and 3 
patients 
received 3 x 109 
q12h for 14 
days   
6 mild AEs in 6 
subjects (diarrhea, 
epistaxis, 
oropharyngeal 
pain, cough, nose 
pain, deceased 
bicarbonate level) 
Fabjian, 
202024 
 
PMID: 
32139910 
AmpliPhi 
Biosciences 
 
3 bacteriophage 
cocktail 
Open-label study of 
13 patients with 
severe S. aureus 
infections  
1 x 109 IV q12h 
for ~14 days 
 
 
None reported  
 

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2.3.2 Potential Benefits 
There is no expected clinical benefit to subjects who enroll into this trial. The data from this trial 
will further the science of bacteriophage therapy for future patients with infectious processes, 
including potentially the CF population. The findings will determine if future clinical trials using 
bacteriophage therapy would potentially benefit patients with infections and inform the optimal 
dosage, safety concerns, and expected microbiological activity associated with bacteriophage 
therapy for such a trial.   

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 STUDY DESIGN, OBJECTIVES AND ENDPOINTS OR 
OUTCOME MEASURES 
 Study Design Description 
This is a Phase 1b/2, multi-center, randomized, placebo-controlled, double-blind study of a 
single dose of IV bacteriophage in approximately 72 clinically stable adult CF subjects colonized 
with P. aeruginosa in expectorated sputum. The primary study outcomes include safety and 
microbiological activity of IV bacteriophage therapy.  
As part of screening, an expectorated sputum sample will be obtained from each subject and 
tested for the presence of P. aeruginosa. If P. aeruginosa is isolated from the sputum and all 
eligibility criteria are met, the subject will be eligible for the study. If P. aeruginosa is not 
isolated, the subject will be considered a screen failure. Screening for susceptibility of P. 
aeruginosa to the 4-component bacteriophage mixture will not occur prior to administration of 
study treatment.   
Stage 1 (Unblinded Safety Assessment/Dose-Escalation in Sentinel Subjects): Following 
screening, eligible subjects will be assigned into one of the three IV bacteriophage dosing 
regimens (arms). A total of 6 sentinel subjects will be enrolled in Stage 1 of the study. The arms 
will be sequentially enrolled with dose escalation by one log10 starting at 4 x 107 PFU. In each 
dosing arm, two subjects will be enrolled to serve as sentinels. Each sentinel subject will receive 
a single dose of IV bacteriophage therapy, followed by a 30 ± 7 days observation period. Refer 
to Section 8.2.3.1 for details regarding dosing in sentinel subjects.  
Stage 2 (Double Blind Comparison): If no SAEs (related to the study product) are identified 
during the 96 hours after bacteriophage administration for all Sentinel Subjects in Stage 1, the 
study will proceed to Stage 2. In Stage 2a, 32 subjects will be randomly assigned to one of four 
arms: one of three IV bacteriophage doses or placebo in a 1:1:1:1 allocation. The subjects and 
the protocol team will be blinded to active versus placebo preparations. An interim analysis will 
be performed to determine the bacteriophage dosing with the most favorable safety and 
microbiological activity profile (Section 10.4). This will occur after 8 subjects per arm have been 
randomized and completed their Day 8 + 3 days Follow-up Visit. The interim analysis will use 
data from Stage 2a to identify the bacteriophage dose and the sample size that will be used for 
Stage 2b (Section 10.4). During Stage 2b, subjects will be randomized into the bacteriophage 
(dose selected based on Interim Analysis following Stage 2a) or placebo arm. The final sample 
size is expected to be up to 72 subjects total with up to 25 subjects in the placebo arm and up to 
25 subjects in the bacteriophage arm.  

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 Study Objectives 
3.2.1 Primary  
• 
Describe the safety of a single dose of IV bacteriophage therapy in clinically stable CF 
subjects with P. aeruginosa in expectorated sputum.  
• 
Describe the microbiological activity of a single dose of IV bacteriophage therapy in 
clinically stable CF subjects with P. aeruginosa in expectorated sputum. 
• 
Describe the benefit to risk profile of a single dose of IV bacteriophage therapy in clinically 
stable CF subjects with P. aeruginosa in expectorated sputum. 
3.2.2 Secondary 
• 
N/A 
3.2.3 Exploratory  
• 
Characterize the serum and sputum PK profiles of a single dose of IV bacteriophage therapy 
in clinically stable CF subjects with P. aeruginosa in expectorated sputum. 
• 
Describe changes in lung function from the administration of a single dose of IV 
bacteriophage therapy through Day 30 ± 7. 
• 
Characterize geographically diverse P. aeruginosa isolates susceptibility to bacteriophages. 
• 
Describe subjects’ quality of life (QOL) before and after receiving bacteriophage therapy. 
 Study Endpoints or Outcome Measures 
3.3.1 Primary  
• 
Number of grade 2 or higher treatment-emergent AEs through Day 30 ± 7.  
• 
Change from baseline to Day 30 ± 7 days in log10 P. aeruginosa total colony counts in 
quantitative sputum cultures after administration of IV bacteriophages/placebo. 
• 
Desirability of Outcome Ranking (DOOR) using the greatest reduction by Day 8 + 3 days 
Follow-up Visit. 
More desirable Rank 1 
No SAE (related to study product) and > 2 log10 reduction 
in P. aeruginosa CFU/mL 
↑ 
Rank 2 
No SAE (related to study product) and 1-2 log10 reduction 
in P. aeruginosa CFU/mL 
↓ 
Rank 3 
No SAE (related to study product) and < 1 log10 reduction 
in P. aeruginosa CFU/mL 
Less desirable 
Rank 4 
SAE (related to study product) 

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3.3.2 Secondary  
• 
N/A 
3.3.3 Exploratory  
• 
Population mean PK parameter estimates and the magnitude of the associated inter-
individual variability for IV bacteriophage therapy in serum and sputum. 
• 
Individual post hoc PK parameter estimates and calculated exposure measures in serum for 
IV bacteriophage therapy. 
• 
Individual post hoc PK parameter estimates and calculated exposure measures in sputum for 
IV bacteriophage therapy. 
• 
Changes in the forced expiratory volume in 1 second (FEV1) from the administration of IV 
bacteriophages through Day 30 ± 7 days. 
• 
Changes in log10 P. aeruginosa colony counts of each morphology in quantitative sputum 
cultures from administration of IV bacteriophages through Day 30 ± 7 days. 
• 
Proportion of P. aeruginosa isolates susceptible to individual bacteriophages and the 
bacteriophage cocktail. 
• 
Change from baseline through Day 30 ± 7 days Follow-up Visit of QOL as measured with 
the Cystic Fibrosis Questionnaire-Revised (CFQ-R) and the Cystic Fibrosis Respiratory 
Symptom Diary (CFRSD).  
 
 

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 STUDY INTERVENTION/INVESTIGATIONAL PRODUCT 
 Study Product Description 
Bacteriophage are viruses that infect bacteria and act by attaching to their bacterial host, 
releasing nucleic acid into the host, and replicating until host lysis. The product used in this study 
is designated WRAIR-PAM-CF1. WRAIR-PAM-CF1 is a cocktail of four bacteriophages: 
PaWRA01Phi11, PaWRA01Phi39, PaWRA02Phi83, and PaWRA02Phi87 (see Table 2) which 
are lytic against P. aeruginosa, naturally occurring, demonstrated to be pure, and free of known 
deleterious genes, including lysogeny (so theoretically should not incorporate into the 
chromosome of the bacterial host), antibiotic resistance genes, and toxin genes. Each 
bacteriophage lot is manufactured at APT in accordance with current Good Manufacturing 
Practices (cGMPs). Bacteriophage product is diluted with Plasma-Lyte A, pH 7.4. Glycerol is 
added as a cryoprotective agent to a final concentration of 20% (v/v). Residual purification agent 
(< 100 µg/mL), host cell protein (< 100 µg/mL), and endotoxin (< 250 EU/mL) may be present 
per product specification. All aforementioned residuals are present in levels that are considered 
acceptable per FDA recommendations. Refer to the IB for further details.  
4.1.1 Formulation, Packaging, and Labeling 
Bacteriophage 
The bacteriophage will be packaged in two milliliter (2 mL) vials. Each vial will contain 1 mL of 
a single bacteriophage at a concentration of 1 x 109 to 1 x 1011 PFU/mL suspended in Plasma-
Lyte A and 20% (v/v) of glycerol. Bacteriophage is a clear to slightly turbid suspension, 
essentially free of foreign particulates. The bacteriophage will be labeled according to 
manufacturer specifications and regulatory requirements and include the statement “Caution: 
New Drug – Limited by Federal Law to Investigational Use.” Additional label contents are 
detailed in the protocol-specific Manual of Procedures (MOP).  
The 4-component bacteriophage mixture will include a 1:1:1:1 combination of four individual 
bacteriophage (see Table 2) and will contain a total of 4 x 107 PFU, 4 x 108 PFU, or 4 x 109 
PFU, depending on the target dose. The final phage combination to be administered to each 
subject will be diluted to the target dose with normal saline. Dosing will be based on the actual 
product potency, according to instructions that will be provided in the MOP, which will be 
updated as necessary, based on the most recent potency results. 
Table 2: Components of WRAIR-PAM-CF1 
Bacteriophage  
Genome size, bp 
Family 
Genus 
 PaWRA01Phi11 
66,800 
Myoviridae 
Pbunavirus 
 PaWRA01Phi39 
66,708 
Myoviridae 
Pbunavirus 
 PaWRA02Phi83 
45,439 
Podoviridae 
Bruynoghevirus 
 PaWRA02Phi87 
44,893 
Podoviridae 
Bruynoghevirus 

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Placebo (Normal Saline, 0.9% Sodium Chloride, USP) 
0.9% Sodium Chloride Injection, USP, is a sterile, nonpyrogenic, isotonic solution of sodium 
chloride and water for injection. Each mL contains sodium chloride 9 mg and contains no 
preservatives, antimicrobial agents, or added buffer. The solution is clear in appearance with a 
pH range of 4.5 to 7.0. Normal saline used for the placebo will be supplied in pre-filled infusion 
bags. Each infusion bag should only be used for one dosing preparation.   
The placebo will be labeled according to manufacturer specifications and regulatory 
requirements and include the statement “Caution: New Drug – Limited by Federal Law to 
Investigational Use.” Additional label contents are detailed in the protocol-specific MOP. 
4.1.2 Product Storage and Stability 
Bacteriophage 
Bacteriophage must be stored and shipped at -80°C, with allowable fluctuation of ± 10°C, and 
remain frozen until dosing preparation. Prior to use, vials should be thawed at room temperature 
(20–25°C; 68–77°F; vials thaw within 30 minutes) and the bacteriophage preparation should be 
administered within 3 hours of thawing. Each vial should only be used for one dosing 
preparation and should not be frozen for multi-use. Any remaining bacteriophage following 
dilution should be discarded as biohazardous waste.     
Placebo (Normal Saline, 0.9% Sodium Chloride, USP) 
Store at 20ºC to 25ºC [See USP Controlled Room Temperature; excursions between 15°C and 
30°C are permitted]. Protect from freezing. 
 Acquisition/Distribution  
Bacteriophage 
Bacteriophage will be provided by APT and distributed through the DMID Clinical Material 
Services, Fisher BioServices. Normal saline (0.9% Sodium Chloride for Injection, USP) for 
dilution, will also be distributed through the DMID Clinical Material Services, Fisher 
BioServices.  
Placebo 
Normal saline (0.9% Sodium Chloride for Injection, USP) used as the placebo, will be provided 
by DMID Clinical Materials Services (CMS, Fisher BioServices). 
Refer to the protocol-specific MOP for shipping instructions.   
 Protocol-Specified Medications/Treatments Other Than Study Products 
N/A 

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 Dosage/Regimen, Preparation, Dispensing and Administration of Study 
Intervention/Investigational Product 
Bacteriophage 
Bacteriophage should be thawed at room temperature and diluted in normal saline to a final 
administration volume of 25 mL. The final dilution will be administered as a 30-minute IV 
infusion, with a range of 15-35 minutes.   
Placebo 
Placebo will be normal saline at a final volume of 25 mL and administered as a 30-minute IV 
infusion, with a range of 15-35 minutes. 
All bacteriophage and placebo preparation should occur in an investigational pharmacy by an 
unblinded pharmacist and aliquoted appropriately for equal volume administrations in order to 
maintain the double-blind design. All bacteriophage preparation will occur in a Class II 
Biological Safety Cabinet. Refer to the protocol-specific MOP for information on the 
preparation, labeling, and administration of the study product.   
4.4.1 Rationale for Dose Selection 
The minimum and maximum doses that are being investigated in this study were informed by 
previous case reports, case series, and clinical trials, which generally used IV doses ranging from 
approximately 107 PFU to 1010 PFU (see Table 1). A single dose is being administered to 
evaluate the safety of the 4-component bacteriophage product prior to moving to a multi-dose 
regimen.  
 Pre-determined Modification of Study Intervention/Investigational 
Product for an Individual Subject 
N/A 
 Accountability Procedures for the Study Intervention/Investigational 
Product(s) 
Bacteriophage and placebo will be stored and shipped from the DMID contract Clinical Material 
Services (CMS) to the Clinical Sites. Once received, bacteriophage and placebo will be stored in 
and dispensed by the Investigational Pharmacy.  
The FDA requires accounting for the disposition of all investigational products. The Investigator 
is responsible for ensuring that a current record of product disposition is maintained, and product 
is dispensed only at an official study site by authorized personnel as required by applicable 
regulations and guidelines. Records of product disposition, as required by federal law, consist of 
the date received, date administered, quantity administered, and the subject number to whom the 
drug was administered.  

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The Investigational Pharmacist will be responsible for maintaining accurate records of the 
shipment and dispensing of the investigational product. The pharmacy records must be available 
for inspection by the DMID monitoring contractors and are subject to inspection by a regulatory 
agency (e.g., FDA) at any time. An assigned Study Monitor will review the pharmacy records. 
Any unused solution left in the IV infusion bag or IV administration tubing after administration 
to the subject should be discarded as biohazardous waste. Unused, thawed (with or without 
dilution) investigational bacteriophage vials will be discarded as biohazardous waste. Upon 
completion of the study and after the final monitoring visit, any remaining unused study product 
will either be returned or destroyed appropriately at the clinical site as per sponsor requirements 
and instructions, or in accordance with disposition plans. Refer to the MOP for complete drug 
accountability and monitoring. 

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 SELECTION OF SUBJECTS AND STUDY ENROLLMENT 
AND WITHDRAWAL 
 Eligibility Criteria 
Subject Inclusion and Exclusion Criteria must be confirmed by a study clinician licensed to make 
medical diagnoses. No exemptions are granted on Subject Inclusion/Exclusion Criteria in DMID-
sponsored studies. Questions about eligibility will be directed toward the DMID Medical Officer 
(MO). If subjects are (1) in the process of receiving or (2) planning on receiving (in the next 30 
days) the COVID-19 vaccine, eligibility screening should be deferred to at least 2 weeks after the 
last COVID-19 vaccination 
5.1.1 Subject Inclusion Criteria 
Subjects must meet all the inclusion criteria to be eligible to participate in the study:  
1. Adult (≥ 18 years) at the time of screening. 
2. Confirmed CF diagnosis based on a compatible clinical syndrome confirmed by either an 
abnormal sweat chloride testing or CFTR gene variations.*  
*Can be obtained from documentation in medical records; actual test results not necessary. 
3. Likely able to produce at least 2 mL of sputum during a 30-minute sputum collection 
following a hypertonic saline treatment or other approach to increase sputum production.*  
*Determined by investigator or their designee judgement. Approaches for obtaining sputum 
may include, but are not limited to, inhaled hypertonic saline (e.g., 3%, 7%, or 10%), inhaled 
hypertonic bicarbonate, inhaled mannitol, or spontaneously expectorated sputum. The same 
approach is recommended, whenever possible, for all sputum collections for a given subject, 
refer to the MOP for further details.  
4. P. aeruginosa (regardless of CFU/mL) isolated from a sputum, throat culture, or other 
respiratory specimen in the past 12 months. 
5. Confirmed P. aeruginosa isolation from a sample of expectorated sputum at the Screening 
Visit.  
6. Capable of providing informed consent. 
7. Capable and willing to complete all study visits and perform all procedures required by this 
protocol. 
5.1.2 Subject Exclusion Criteria 
Subjects who meet any of the exclusion criteria will not be enrolled in the study:  
1. Body weight < 30 kg. 
2. FEV1 < 20% of predicted value at screening, using the Hankinson equations.25 

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3. Elevated LFTs obtained at screening.*  
*a. Alanine aminotransferase (ALT) > 5 x the upper limit of normal (ULN) or aspartate 
transaminase (AST) > 5 x ULN or total bilirubin > 3 x ULN, OR 
b. Total bilirubin > 1.5 x ULN combined with either ALT > 3 x ULN or AST > 3 x ULN. 
ULN reflect local laboratory ranges. 
4. Acute clinical illness requiring a new oral, parenteral, or inhaled antibiotic(s) ≤ 30 days prior 
to the Baseline Visit.*  
*Does not include chronic suppressive medications or cyclic dosing medications such as 
inhaled antibiotics. 
5. Women who are pregnant, planning to become pregnant during the study period, or 
breastfeeding.* 
*Women of childbearing potential must have a negative serum β-HCG test during screening 
and agree to use an effective method of contraception for the duration of the trial. A female is 
considered of childbearing potential unless postmenopausal, or surgically sterilized, and at 
least 3 months has passed since sterilization procedure. 
a.  Female surgical sterilization procedures include tubal ligation, bilateral 
salpingectomy, hysterectomy, or bilateral oophorectomy. 
b.  Female is considered postmenopausal if she is > 45 years old and has gone at least 
12 months without a spontaneous menstrual period without other known or suspected 
cause. 
c.  Effective methods of contraception include (a) abstinence, (b) partner vasectomy, (c) 
intrauterine devices, (d) hormonal implants (such as Implanon), or (e) other 
hormonal methods (birth control pills, injections, patches, vaginal rings). 
6. Active treatment of any mycobacterial or fungal organisms ≤ 30 days prior to baseline. 
Chronic treatment for suppression of fungal populations is allowable. 
7. Anticipated need to change chronic antibiotic regimens during the study period.* 
*Subjects on cyclic dosing medications such as inhaled antibiotics, must be able and express 
willingness to keep the therapies at the time of screening constant (either remain on the 
therapy or not remain on the therapy) for the duration of the follow-up period 
(approximately 30 days). Subjects on chronic suppressive antimicrobial therapy must be able 
and express willingness to stay on the therapies for the duration of their follow-up period. 
This includes chronic azithromycin therapy. 
8. Known allergy to any component of the study product. 
9. Any significant finding that, in the opinion of the investigator, would make it unsafe for the 
subject to participate in this study. 

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10. Enrolled in a clinical trial within ≤ 30 days of the Baseline/Dosing Visit, or participating in a 
clinical trial while enrolled in this clinical trial (inclusive of vaccine trials). 
11. Currently or previously enrolled in this trial. 
 Withdrawal from the Study, Discontinuation of Study Product, or Study 
Termination  
5.2.1 Withdrawal from the Study or Discontinuation of the Study Product  
Subjects may voluntarily withdraw their consent for study participation at any time without 
penalty or loss of benefits to which they are otherwise entitled. An investigator may also 
withdraw a subject from receiving the study product for any reason. Follow-up safety evaluations 
will be conducted, if the subject agrees. If a subject withdraws or is withdrawn prior to 
completion of the study, the reason for this decision must be recorded in the case report forms 
(CRFs).  
The reasons, might include, but are not limited to the following: 
• 
Subject no longer meets eligibility criteria 
• 
Subject meets individual halting criteria (reference to Section 8.6.2) 
• 
Subject becomes noncompliant 
• 
Subject has a medical disease or condition, or new clinical finding(s) for which continued 
participation, in the opinion of the investigator, might compromise the safety of the subject, 
interfere with the subject’s successful completion of this study, or interfere with the 
evaluation of responses 
• 
Subject lost to follow-up 
• 
Subject determined by a physician’s discretion to require additional therapy not indicated in 
the protocol to ensure subject’s health and well-being (or treatment failure, if applicable) 
The investigator should be explicit regarding study follow-up (e.g., safety follow-up) that might 
be carried out even though the subject will not receive further study product. If the subject 
consents, all AEs will be followed through the study defined follow-up period and all SAEs 
through resolution. The procedures that collect safety data for the purposes of research must be 
inclusive in the original informed consent or the investigator may seek subsequent informed 
consent using an IRB/IEC-approved consent form with the revised procedures. 
The investigator will inform the subject that already collected data will be retained and analyzed 
even if the subject withdraws from this study.  
5.2.2 Subject Replacement 
Subjects who withdraw, are withdrawn from this study, or are lost to follow-up after signing the 
Informed Consent Form (ICF) and after administration of the study product will not be replaced. 

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Subjects who withdraw, are withdrawn from this study, or are lost to follow-up after signing the 
ICF, but prior to administration of study product, may be replaced.  
5.2.3 Study Termination  
If the study is prematurely terminated by the sponsor, any regulatory authority, or the 
investigator for any reason, the investigator will promptly inform the study subjects and assure 
appropriate therapy or follow-up for the subjects, as necessary. The investigator will provide a 
detailed written explanation of the termination to the IRB/IEC. 

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 STUDY PROCEDURES 
The following sections describe the study procedures and data that will be collected. For each 
procedure, subjects are to be assessed by the investigator or delegated site personnel. A Schedule 
of Events is located in Appendix A.  
If a subject is prescribed antibiotic therapy with activity against P. aeruginosa after receipt of the 
study product, the subject will continue in the study and be included in an intent to treat analysis. 
Receipt of antibiotic therapy with activity against P. aeruginosa will be documented as a 
concomitant medication and the underlying condition for which the antibiotics were taken will 
be reported as an AE. 
 Screening  
Screening, Visit 1 (Up to Day -7): 
Informed consent must be obtained prior to the subject entering the study, and before any 
protocol specific procedures are performed. Subjects will be screened in accordance with pre-
defined inclusion and exclusion criteria as described in Section 5.1. Subjects will be provided 
with a description of the study through the ICF (purpose and study procedures) and asked to read 
and sign the ICF. After the subject has provided informed consent to participate in the study, 
screening will include: 
• 
Review eligibility criteria with the subject  
• 
Serum HCG pregnancy test on all females of childbearing potential  
• 
Complete medical history. The medical history will also include a full account of the 
subject’s routine respiratory physiotherapy regimen.  
• 
Complete medication history. Medication history will include medications taken within the 
past 30 days and those that remain active. 
• 
Demographic information (age, gender, race, ethnicity) 
• 
Height and weight measurement 
• 
Review of systems 
• 
Physical examination* 
• 
Vital signs* 
• 
Spirometry  
• 
Sputum collection, to be collected following spirometry, as determined necessary by the local 
investigator to increase sputum production 
• 
Liver function tests (see Section 7.2.1 for complete list of tests) 
 

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*Standard of care results obtained for clinical care purposes within 72 hours of screening are 
acceptable for screening. 
 Baseline/Dosing (Day 1) 
Baseline, Visit 2 (Day 1): 
• 
Confirm eligibility criteria, as needed 
• 
Urine pregnancy test on all female subjects of childbearing potential prior to administration 
of study product/placebo 
• 
Review of systems 
• 
Treatment assignment (Stage 1 only) or randomization (Stage 2 only) 
• 
CFQ-R, prior to administration of study product/placebo and preferably before the collection 
of study data (Stage 2 only). If subject is ready to produce sputum, prioritize sputum 
collection over administration of the CFQ-R. 
• 
Administration of study product (bacteriophage or placebo) 
• 
Vital signs (before administration of study product or placebo AND within 30-60 minutes 
after administration of study product or placebo is completed) 
• 
Review and record concomitant medications  
• 
Symptom directed physical examination (before administration of study product or placebo 
AND 30-60 minutes after administration of study product or placebo is completed) 
• 
Spirometry (before administration of study product or placebo) 
• 
Sputum collection (to be collected following spirometry, as determined necessary by the 
local investigator to increase sputum production) both pre- and post-infusion for 
microbiological and PK assessment. See Section 7.2.1 and 7.2.2 for timing of sample 
collection. 
• 
Serum collection both pre- and post-infusion for PK assessment. See Section 7.2.2 for timing 
of sample collection. 
• 
Hematology (see Section 7.2.1 for complete list of tests)* 
• 
Clinical chemistry (see Section 7.2.1 for complete list of tests)* 
• 
Liver function tests (see Section 7.2.1 for complete list of tests)* 
• 
CFRSD, prior to administration of study product/placebo and preferably before the collection 
of study data (Stage 2 only). If subject is ready to produce sputum, prioritize sputum 
collection before administration of the CFRSD.  
• 
Clinical assessment of AEs 
• 
Events of Special Interest [ESIs] (i.e., pulmonary exacerbations), See Section 8.2.2 

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* Labs obtained at the Screening Visit do not have to be repeated at the Baseline Visit, if 
collected within 7 days from the Baseline Visit.  
 Planned Follow-up Visits 
6.3.1 Follow-up Visits, Days 2 - 12 (Day 2, Day 5 ± 2, Day 8 + 3, Day 12 + 7 [Stage 1 only]) 
Follow-up, Visit 3 (Day 2): 
• 
Review of systems 
• 
Review concomitant medications  
• 
Symptom directed physical examination 
• 
Spirometry  
• 
Vital signs 
• 
Sputum collection (to be completed after spirometry, as determined necessary by the local 
investigator to increase sputum production) for microbiological and PK assessments 
• 
Serum collection for PK assessments 
• 
Hematology (see Section 7.2.1 for complete list of tests) 
• 
Clinical chemistry (see Section 7.2.1 for complete list of tests) 
• 
Liver function tests (see Section 7.2.1 for complete list of tests) 
• 
CFRSD, preferably before the collection of study data (Stage 2 only). If subject is ready to 
produce sputum, prioritize sputum collection before administration of the CFRSD. 
• 
Clinical assessment of AEs 
• 
Events of Special Interest [ESIs] (i.e., pulmonary exacerbations), see Section 8.2.2 
Follow-up, Visit 4 (Day 5 ± 2 days): 
• 
Review of systems 
• 
Review concomitant medications  
• 
Symptom directed physical examination 
• 
Spirometry  
• 
Vital signs 
• 
Sputum collection (to be completed after spirometry, as determined necessary by the local 
investigator to increase sputum production) for microbiological and PK assessments 
• 
Hematology (see Section 7.2.1 for complete list of tests) 
• 
Clinical chemistry (see Section 7.2.1 for complete list of tests) 
• 
Liver function tests (see Section 7.2.1 for complete list of tests) 

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• 
CFRSD, preferably before the collection of study data (Stage 2 only). If subject is ready to 
produce sputum, prioritize sputum collection over administration of the CFRSD. 
• 
Clinical assessment of AEs 
• 
Events of Special Interest [ESIs] (i.e. pulmonary exacerbations), see Section 8.2.2 
Follow-up, Visit 5 (Day 8 + 3 days): 
In Stage 2, this is a virtual visit, see Section 6.4.  
• 
Review of Systems 
• 
Review concomitant medications  
• 
Sputum collection for microbiological and PK assessments 
• 
CFRSD, preferably before the collection of study data (Stage 2 only). If subject is ready to 
produce sputum, prioritize sputum collection over administration of the CFRSD. 
• 
Clinical assessment of AEs 
• 
Events of Special Interest [ESIs] (i.e., pulmonary exacerbations), see Section 8.2.2 
If the subject does not have the necessary equipment or internet access for a virtual visit, this 
visit may be conducted in-person, with the same procedures as the virtual visit, and this will not 
be considered a protocol deviation. 
Follow-up, Visit 6 (Day 12 + 7 days): 
Note: This visit is only applicable for Stage 1. 
• 
Review of systems 
• 
Review concomitant medications  
• 
Symptom directed physical examination 
• 
Spirometry 
• 
Vital signs 
• 
Sputum collection (to be completed after spirometry, as determined necessary by the local 
investigator to increase sputum production) for microbiological and PK assessments 
• 
Hematology (see Section 7.2.1 for complete list of tests) 
• 
Clinical chemistry (see Section 7.2.1 for complete list of tests) 
• 
Liver function tests (see Section 7.2.1 for complete list of tests) 
• 
Clinical assessment of AEs 
6.3.2 Final Study Visit 
The Final Study Visit is the Follow-up, Visit 7 that occurs on Day 30 ± 7 days and includes the 
following: 

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• 
Review of systems 
• 
Review concomitant medications 
• 
Symptom directed physical examination 
• 
Spirometry 
• 
Vital signs 
• 
Sputum collection (to be completed after spirometry, as determined necessary by the local 
investigator to increase sputum production) for microbiological and PK assessments 
• 
Hematology (see Section 7.2.1 for complete list of tests) 
• 
Clinical chemistry (see Section 7.2.1 for complete list of tests) 
• 
Liver function tests (see Section 7.2.1 for complete list of tests) 
• 
CFRSD, preferably before the collection of study data (Stage 2 only). If subject is ready to 
produce sputum, prioritize sputum collection over administration of the CFRSD. 
• 
CFQ-R, preferably before the collection of study data (Stage 2 only). If subject is ready to 
produce sputum, prioritize sputum collection over administration of the CFQ-R. 
• 
Clinical assessment of AEs 
6.3.3 Early Termination Visit  
If a subject terminates or is withdrawn from the study prior to the final Follow-up Visit, all 
attempts will be made to collect the following as part of an Early Termination Visit: 
• 
Review of systems 
• 
Review concomitant medications 
• 
Symptom directed physical examination 
• 
Spirometry* 
• 
Vital signs 
• 
Sputum collection (to be completed after spirometry, as determined necessary by the local 
investigator to increase sputum production) for microbiological and PK assessments   
• 
Hematology (see Section 7.2.1 for complete list of tests)* 
• 
Clinical chemistry (see Section 7.2.1 for complete list of tests)* 
• 
Liver function tests (see Section 7.2.1 for complete list of tests)* 
• 
CFRSD, preferably before the collection of study data (Stage 2 only). If subject is ready to 
produce sputum, prioritize sputum collection over administration of the CFRSD. 
• 
Clinical assessment of AEs 

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• 
Events of special interest [ESIs] (i.e., pulmonary exacerbations), if this visit occurs prior to 
Visit 5, Day 8 + 3 days (see Section 8.2.2) 
*If the visit occurs > 7 days after a scheduled visit. If the visit occurs ≤ 7 days after a scheduled 
visit, laboratory tests may be collected and spirometry may be performed at the discretion of the 
local investigator. 
If a subject is considered by the local investigator to be too ill to attend an in-person or virtual 
Early Termination Visit, this visit may be conducted by telephone call. 
 Virtual Study Visits 
Virtual study visits will be allowable as substitutes for in-person study visits for circumstances 
precluding in-person visits (e.g., subject has a COVID-19 diagnosis, subject fractures a bone 
preventing ambulation). Prior to conducting a virtual study visit, the reason for the requested 
virtual visit should be reviewed and approved by the protocol PI. If a virtual study visit is 
conducted without prior approval from the protocol PI, it will be considered a protocol deviation.  
Note: Visit 5 (Day 8 + 3 days) will always be conducted virtually in Stage 2 without the need for 
prior approval by the protocol PI. 
Virtual study visits will only be allowed for follow-up visits (Day 2, Day 5 ± 2 days, Day 12 + 7 
days), the Final Study Visit (Day 30 ± 7 days), or an Early Termination Visit. Virtual study visits 
will not be allowed for the Screening or Baseline/Dosing Visit. Virtual visits will not be allowed 
in cases of Unscheduled Visits for safety follow-up for AEs and SAEs related to the study 
product.   
The following will be collected during the virtual study visits: 
• 
Review of systems 
• 
Review of concomitant medications 
• 
Sputum collection for microbiological and PK assessments 
• 
CFRSD (Stage 2 only). If subject is ready to produce sputum, prioritize sputum collection 
over administration of the CFRSD. 
• 
CFQ-R (Stage 2, Visit 7 [Day 30 ± 7] only). If subject is ready to produce sputum, prioritize 
sputum collection over administration of the CFQ-R. 
• 
Clinical assessment of AEs 
• 
Events of special interest [ESIs] (i.e., pulmonary exacerbations), if this visit occurs prior to 
Visit 5, Day 8 + 3 days (see Section 8.2.2) 
 
A pre-labeled sputum collection kit with instructions and shipping documents will be provided to 
the subject prior to the visit. Refer to the MOP for further details.  
 

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Study procedures that cannot be performed virtually (e.g., vitals, physical examination) will not 
be considered protocol deviations. 
 Unscheduled Study Visits  
Unscheduled Study Visits may occur at the investigator’s discretion. If an Unscheduled Study 
Visit occurs, every attempt will be made to collect the following, but it will not be considered a 
protocol deviation if not collected:  
• 
Review of systems 
• 
Review concomitant medications 
• 
Symptom directed physical examination 
• 
Spirometry* 
• 
Vital signs 
• 
Sputum collection (to be completed after spirometry, as determined necessary by the local 
investigator to increase sputum production) for microbiological and PK assessments  
• 
Hematology (see Section 7.2.1 for complete list of tests)* 
• 
Clinical chemistry (see Section 7.2.1 for complete list of tests)* 
• 
Liver function tests (see Section 7.2.1 for complete list of tests)* 
• 
CFRSD, preferably before the collection of study data (Stage 2 only). If subject is ready to 
produce sputum, prioritize sputum collection over administration of the CFRSD. 
• 
Clinical assessment of AEs 
• 
Events of special interest [ESIs] (i.e., pulmonary exacerbations), if this visit occurs prior to 
Visit 5, Day 8 + 3 days (see Section 8.2.2) 
*If the visit occurs > 7 days after a scheduled visit. If the visit occurs ≤ 7 days after a scheduled 
visit, laboratory tests may be collected and spirometry may be performed at the discretion of the 
local investigator. 
 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or protocol-
specific MOP requirements. Any missing CFQ-R or CFRSD assessments will not be considered 
a protocol deviation. The noncompliance may be either on the part of the subject, the 
investigator, or the study site staff. As a result of deviations, corrective actions should be 
developed by the site and implemented promptly. It is the responsibility of the site PI and other 
study personnel to use continuous vigilance to identify and report protocol deviations. All 
individual protocol deviations will be addressed in subject study records. All protocol deviations 
will be collected and stored in a sponsor-determined location. Protocol deviations must be sent to 
the reviewing IRB/IEC per its guidelines. The site PI and other study personnel are responsible 
for knowing and adhering to their IRB/IEC requirements. 

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If an Unscheduled Study Visit occurs, per Section 6.5, any assessments/procedures that do not 
occur will not be considered protocol deviations. 

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 DESCRIPTION OF CLINICAL AND LABORATORY 
EVALUATIONS 
 Clinical Evaluations 
7.1.1 Research Procedures  
• 
Demographics: Demographics will be obtained by subject interview including age, 
race/ethnicity, and gender.  
• 
Height and weight measurement: The subject’s height (centimeters) and weight 
(kilograms) will be measured.  
• 
Medical history: The detailed medical history will include completion of a standard template 
by the study team through a combination of medical record review and subject interview. 
Medical history will be obtained regarding significant medical disorders of the head, eyes, 
ears, nose, throat, mouth, cardiovascular system, lungs, gastrointestinal tract, liver, pancreas, 
kidney, urologic system, nervous system, blood, lymph nodes, endocrine system, 
musculoskeletal system, skin, and genital/reproductive tract. Medical history will also 
include a full account of the subject’s routine respiratory physiotherapy regimen.  
• 
Medication history: A complete medication history will be obtained to include prescription 
medications, over-the-counter drugs, herbals, vitamins, and supplements the subject has 
taken. Information regarding any prophylactic systemic or inhaled anti-infective regimens 
will also be collected. Medication history will be collected both by a review of the medical 
records as well as by subject interview.  
• 
Review of systems: A subject interview will be performed by a study clinician who is 
licensed to make medical diagnoses. The review of systems will include specific issues with 
various systems including: general well-being, headaches, vision, hearing, balance, mental 
health, dizziness, breathing issues, palpitations, nausea, vomiting, diarrhea, abdominal pain, 
leg swelling, joint swelling, rashes, and urinary symptoms. Refer to the MOP for further 
details. 
• 
Vital signs: The following vital signs will be obtained: systolic and diastolic blood pressures 
in millimeters of mercury (mmHg), heart rate [beats per minute (BPM)], respiratory rate, and 
body temperature in degrees Celsius (oral measurement).  
• 
Physical examination: Complete physical examination (except for a breast, rectal, and 
genitourinary examination).  
• 
Symptom directed physical examination: A symptom directed physical examination will 
include the general appearance, lung auscultation (including evaluating for symmetric chest 
rise, increased work of breathing, and listening for rhonchi or wheezing), and examination of 
any other body site as indicated by subject symptomatology.   

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• 
Spirometry: Spirometry will occur prior to required sputum collections, as considered 
necessary by the local investigator to increase sputum production. Spirometry will be 
performed according to the standard American Thoracic Society protocol.   
• 
Cystic Fibrosis Questionnaire-Revised (CFQ-R): The CFQ-R is a quality of life (QOL) 
questionnaire designed to measure the impact that CF has on overall health, daily life, and 
perceived well-being and symptoms.26 The CFQ-R (Appendix B), contains 50 items and will 
be administered during study visits for Stage 2 subjects26. For additional details on data 
collection, refer to the MOP.  
• 
Cystic Fibrosis Respiratory Symptom Diary (CFRSD): The CFRSD is a QOL 
questionnaire, which evaluates the effect of treatment on respiratory infection symptom 
severity in patients with CF and chronic respiratory infection.27 The CFRSD (Appendix C) 
will be collected during study visits for Stage 2 subjects. For additional details on data 
collection, refer to the MOP. 
• 
Clinical assessment of AEs and ESIs (see Section 8) 
7.1.2 Assessment of Concomitant Medications/Treatments Other Than Study Product 
Active medications will be reviewed by subject interview and a review of subject medical 
records. Use of a new medication should prompt evaluation for the presence of a new AE or 
diagnosis of a new medical condition. Chronic medications, rescue medications, and over-the 
counter medications are allowed. 
7.1.3 Assessment of Subject Compliance with Study Intervention/Investigational Product  
Subjects will be directly observed while receiving a single dose of study product or placebo by a 
member of the study team who is licensed to administer the study product or placebo. 
Administration data will be recorded in the source and entered into the electronic case report 
form (eCRF). 
 Laboratory Evaluations 
7.2.1 Clinical Laboratory Evaluations 
Each site will maintain a list of the normal ranges and units of measurement for the laboratory 
parameters to be determined during this study, and the data and certification number of the 
laboratory. If the normal ranges change during the course of the study, the site investigator must 
update this list with the new ranges and effective dates. The normal laboratory reference ranges 
will also be retained in the regulatory binder at each site. 
• 
Serum HCG pregnancy test: A serum HCG pregnancy test will be performed by the local 
laboratory for all women of childbearing potential at the Screening Visit and the results must 
be negative prior to treatment assignment/randomization.  
• 
Urine HCG pregnancy test: A urine HCG pregnancy test will be performed by the local 
laboratory for all women of childbearing potential on the day of the Baseline Visit and the 
results must be negative prior to treatment assignment/randomization. 

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• 
Sputum collection for microbiological assessments (minimum of 2 mL sample per time 
point) will be obtained per standard clinical practice, following spirometry, as considered 
necessary by the local investigator to increase sputum production. Hypertonic saline 
treatment or other approaches to increase sputum production may be used, as needed, for 
sputum collection. Approaches for obtaining sputum may include, but are not limited to, 
inhaled hypertonic saline (e.g., 3%, 7% or 10%), inhaled hypertonic bicarbonate, inhaled 
mannitol, or spontaneously expectorated sputum. The same approach is recommended, 
whenever possible, for all sputum collections for a given subject; refer to the MOP for further 
details. At the Baseline/Dosing Visit, sputum collection will occur prior to administering 
investigational product/placebo and at 2 hours post completion of administering study 
product/placebo and flushing the IV line (± 1 hour). Samples will be collected by the local 
laboratory and will be sent to a central laboratory for analysis. Refer to the MOP for details.  
• 
Clinical chemistries will be measured at the local laboratory and include serum creatinine, 
blood urea nitrogen, glucose, sodium, potassium, chloride, bicarbonate, and calcium. 
• 
Hematology will be measured at the local laboratory and include complete blood count with 
red blood cell (RBC) count, hemoglobin, hematocrit, total white blood cell (WBC) count 
with differential counts, and platelet count. 
• 
Liver function tests will be measured at the local laboratory and include AST, ALT, alkaline 
phosphatase, total bilirubin, lactate dehydrogenase, albumin, and total protein. Only AST, 
ALT, and total bilirubin are necessary at Screening.  
7.2.2 Research Assays  
• 
Serum PK studies (~3 mL sample of whole blood per time point) will be conducted per the 
directions in the MOP. At the Baseline/Dosing Visit, blood will be collected at any time (on 
the same calendar day) prior to the start of investigational product/placebo administration, 
and at 30 min, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, and 3.5 hours post completion 
of administering study product and flushing the IV line (all time points are ± 10 min). At 
Follow-up Visit 3 (Day 2), the PK serum sample will be collected once at any time, the time 
must be recorded, during the in-person visit. Samples will be collected by the local laboratory 
and sent to a central laboratory for analysis.  
• 
Sputum PK studies (minimum of 2 mL sample per time point) will be obtained per standard 
clinical practice, following spirometry, as considered necessary by the local investigator to 
increase sputum production. Hypertonic saline treatment or other approaches to increase 
sputum production may be used, as needed, for sputum collection. Approaches for obtaining 
sputum may include, but are not limited to, inhaled hypertonic saline (e.g., 3%, 7% or 10%), 
inhaled hypertonic bicarbonate, inhaled mannitol, or spontaneously expectorated sputum. 
The same approach is recommended, whenever possible, for all sputum collections for a 
given subject, refer to the MOP for further details. At the Baseline/Dosing Visit, sputum 
collection will occur prior to administering investigational product/placebo, and at 2 hours 
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Samples will be collected by the local laboratory and will be sent to a central laboratory for 
analysis. Refer to the MOP for details.  
• 
P. aeruginosa colony counts will be performed by the central lab using quantitative bacterial 
cultures on sputum specimens collected from the time of bacteriophage administration 
through Day 30 ± 7 days. Quantities of sputum (10 mg) will be measured precisely and 
added to 1 mL Sputolysin mucolytic agent to liquefy the sample. The liquefied sample will 
be diluted sequentially and plated onto MacConkey agar and Sheep’s Blood Agar Plates 
using a 1 µL loop for each replicate. Colonies will be counted on the highest dilution in 
which individual colonies can be enumerated and colony counts adjusted appropriately based 
on the dilution factor and the mass of the sample to determine the true concentration of P. 
aeruginosa. Colonies representing different morphotypes will be definitively identified using 
MALDI-TOF to ensure that each enumerated colony type represents P. aeruginosa. Refer to 
the MOP for additional details. 
• 
P. aeruginosa susceptibility to bacteriophages may be performed by the central lab on P. 
aeruginosa isolates in sputum cultures, depending on sample availability. 
7.2.2.1 Laboratory Specimen Preparation, Handling, and Storage 
Specific instructions are included in the MOP.   
7.2.2.2 Laboratory Specimen Shipping 
Specific instructions are included in the MOP. 
7.2.3 Secondary Analysis of Stored Specimens and Data 
The information and samples/specimens collected for this study may be used for future, currently 
unknown, research. The secondary research may include, but is not limited to additional work on 
bacteriophage treatment; cystic fibrosis; and infections of the blood, lung, skin, or other parts of 
the body. The research may include, but is not limited to further investigating bacteriophage 
susceptibility testing, serum neutralizing antibodies, whole genome sequencing the P. 
aeruginosa isolates, and changes to the respiratory microbiome. No human genetic testing or 
sequencing of human DNA will be performed using the samples/specimens collected. 
 

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 ASSESSMENT OF SAFETY 
 Assessing and Recording Safety Parameters 
This study will assist in enhancing the understanding of the safety and microbiological activity of 
IV bacteriophage therapy in clinically stable CF subjects with P. aeruginosa in expectorated 
sputum. Safety will be assessed by the frequency and severity of AEs. 
8.1.1 Adverse Events (AEs) 
International Council for Harmonisation (ICH) E6 defines an AE as any untoward medical 
occurrence in a patient or clinical investigation subject administered a pharmaceutical product 
regardless of its causal relationship to the study treatment. The FDA defines an AE as any 
untoward medical occurrence associated with the use of a drug in humans, whether or not 
considered drug related. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of medicinal (investigational) 
product. The occurrence of an AE may come to the attention of study personnel during study 
visits and interviews of a study recipient presenting for medical care, or upon review by a study 
monitor.  
All AEs of grade 2 or higher including lab abnormalities, abnormal clinical finding, and 
including local (infusion site) and systemic (subjective and quantitative) reactions, will be 
captured on the appropriate data collection form and eCRF regardless of causality or clinical 
significance. 
Grade 1 AEs including lab abnormalities, abnormal clinical finding, and including local (infusion 
site) and systemic (subjective and quantitative) reactions, will be captured on the appropriate 
data collection form and eCRF only if assessed by the treating clinician as related to the study 
product. 
Information to be collected for AEs includes event description, date of onset, assessment of 
severity, relationship to study product, potential alternate etiologies (assessed only by those with 
the training and authority to make a diagnosis and listed on the Form FDA 1572 as an 
investigator), date of resolution, seriousness, and outcome. AEs occurring during the trial 
collection and reporting period will be documented appropriately regardless of relationship.  
Any medical condition that is present at the time that the subject is screened will be considered 
as baseline and not be reported as an AE. However, if the frequency and/or severity of any pre-
existing medical condition increases, it should be recorded as an AE. 
8.1.1.1 Adverse Events Grading 
AEs, including laboratory and clinical symptoms, will be graded for severity according to the 
Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0, November 2017 
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assessed for relationship to study product. AEs characterized as intermittent require 
documentation of onset and duration of each episode. The start and stop date of each reported 
AE will be recorded on the appropriate data collection form and eCRF.  
Relationship to Study Product: The assessment of the AE’s relationship to study product will 
be performed by a delegated, licensed study clinician listed on the Form FDA 1572. The 
assessment will be part of the documentation process. Whether the AE is related to the study 
product or not, is not a factor in determining what is or is not reported in this trial. If there is any 
doubt as to whether a clinical observation is an AE, the event should be reported.   
In a clinical trial, the study product must always be suspect. The AEs will be assessed for 
relationship to the study product using the terms “related” or “not related”: 
• 
Related – There is a reasonable possibility that the study product caused the AE. Reasonable 
possibility means that there is evidence to suggest a causal relationship between the study 
product and the AE.  
• 
Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event. 
• 
Note: Pulmonary exacerbations are known to occur in individuals with CF with some 
frequency and will be considered unrelated to the study drug if they occur after Visit 5, Day 
8 + 3 days. If a pulmonary exacerbation occurs during the ESI collection period 
(Baseline/Dosing through Visit 5), it may be considered related, at the discretion of the local 
investigator. 
8.1.2 Serious Adverse Events (SAEs) 
An AE or suspected AE is considered an SAE if, in the view of either the site PI or sponsor, it 
results in any of the following outcomes:  
• 
Death, 
• 
A life-threatening AE,  
• 
Inpatient hospitalization or prolongation of existing hospitalization,  
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, or  
• 
A congenital anomaly/birth defect.   
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalizations may be considered serious 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 in this definition. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
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An SAE is classified as a Suspected Unexpected Serious Adverse Reaction (SUSAR) if the event 
is related to study drug and not identified as an expected reaction to the drug per the IB.   
SAEs will be: 
• 
Assessed for severity and relationship to study product and alternate etiology (if not related 
to study product) by a delegated, licensed study clinician listed on the Form FDA 1572. 
• 
Recorded on the appropriate SAE data collection form and appropriate eCRF. 
• 
Followed through resolution by a licensed study clinician (for IND studies, a physician listed 
on the Form FDA 1572 as the site PI or Sub-Investigator).  
• 
Reviewed and evaluated by DMID, the Data and Safety Monitoring Board (DSMB) (during a 
periodic review unless related), and the IRB/IEC (per reporting requirements). 
 Specification of Safety Parameters 
Safety will be assessed by the frequency and severity of AEs from the administration of the study 
product through the follow-up period.    
8.2.1 Unsolicited Events 
Unsolicited events are AEs that occur following administration of study product.  Subjects will 
be queried at each follow-up visit and during any follow-up telephone calls to evaluate 
occurrence of any AEs. Medical records should be reviewed at each visit for AEs. 
8.2.2 Events of Special Interest  
The following ESIs will be collected from the time of first administration of study product until 
Visit 5, Day 8 + 3 days: 
Pulmonary exacerbations, defined as:  
1) Initiation of oral or IV antibiotics by the treating clinicians for respiratory symptoms, 
OR  
2) Four or more of the following signs/symptoms28: 
• Increase in sputum quantity or a change in quality; 
• 
New or increased hemoptysis; 
• 
Worsening cough; 
• 
Increased shortness of breath; 
• 
New onset malaise/fatigue/lethargy; 
• 
Temperature > 38°C; 
• 
Change in physical examination of the chest; 
• 
Decrease in FEV1 > 10% from Baseline; and/or 

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• 
Radiographic changes consistent with a pulmonary exacerbation. 
Any ESI that meets the criteria of an SAE (Section 8.1.2) will be recorded and reported as an 
SAE instead of an ESI. 
8.2.3 Dose Escalation Criteria 
Dose escalation will occur in the sentinel subjects in Stage 1 of this trial (see Section 8.2.3.1). 
Individual subjects will not undergo dose escalation.  
8.2.3.1 Sentinel Subjects 
Following subject screening for Stage 1, eligible subjects will be assigned into one of the three 
IV bacteriophage dosing regimens. The arms will be sequentially enrolled with dose escalation 
by one log10 starting at 4 x 107 PFU. In each dosing arm, two subjects will be enrolled to serve as 
sentinels. Each sentinel subject will receive a single dose of IV bacteriophage, followed by a 96-
hour observation period. Enrollment will be held between each of the three dose levels; if no 
SAE (related to study product) occurs and no halting criteria are met (Section 8.6) during the 96-
hour observation period for both subjects on the given dose level, the next two Stage 1 sentinel 
subjects will be enrolled. If an SAE (related to study product) occurs during the 96-hour 
observation period, the study will be temporarily suspended and discussed with the DMID 
Medical Officer, DMID Medical Monitor (MM), and the DSMB on how to proceed. Sentinel 
subjects will be followed for approximately 30 ± 7 days according to Appendix A. 
 Reporting Procedures 
8.3.1 Reporting Serious Adverse Events 
All AE/ESI/SAEs will be collected in the eCRF. 
SAEs will be followed until resolution even if this extends beyond the study-reporting period. 
Resolution of an AE is defined as the return to pretreatment status or stabilization of the 
condition with the expectation that it will remain chronic.  
Any AE that meets a protocol-defined criterion as an SAE that is assessed to be related to 
the study product must be submitted within 24 hours of site awareness on an SAE form to 
the DMID Pharmacovigilance Group, at the following address:  
DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support (CROMS) 
6500 Rock Spring Dr. Suite 650 
Bethesda, MD 20817, USA 
SAE Hot Line: 1-800-537-9979 (US) or 1-301-897-1709 (outside US) 
SAE FAX Number: 1-800-275-7619 (US) or 1-301-897-1710 (outside US) 
SAE Email Address: PVG@dmidcroms.com 

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In addition to the SAE form, select SAE data fields must also be entered into the Statistical and 
Data Coordinating Center (SDCC) system. Please see the protocol-specific MOP for details 
regarding this procedure.  
Other supporting documentation of the event may be requested by the DMID pharmacovigilance 
group (PVG) and should be provided as soon as possible.  
The DMID MM and DMID Clinical Project Manager will be notified of study product-related 
SAE by the DMID PVG. The DMID MM will review and assess the SAE for regulatory 
reporting and potential impact on study subject safety and protocol conduct. 
SAEs assessed as not related to the study product will be captured on the appropriate AE eCRF 
but do not require separate reporting to the DMID Pharmacovigilance Group. Both related and 
not related SAEs will be captured in the database.   
8.3.2 Regulatory Reporting for Studies Conducted Under DMID Sponsored IND 
Following notification from the site PI or appropriate sub-investigator, DMID, as the IND 
sponsor, will report any suspected, unexpected SAE, or SUSAR, to the regulatory authorities.  
The DMID will report an AE as a suspected, unexpected AE only if there is evidence to suggest 
a causal relationship between the study intervention and the AE. The DMID will submit an IND 
safety report to the FDA and will notify all participating site PIs (i.e., all PIs to whom the 
sponsor is providing drug under its IND(s) or under any PI’s IND(s)) of potential serious risks 
from clinical studies or any other source, as soon as possible. The DMID will report SUSARs to 
the FDA per regulations and after the sponsor determines that the information qualifies for 
reporting as specified in 21 CFR Part 312.32. Relevant follow up information to an IND safety 
report will be submitted as soon as the information is available. Upon request from FDA, DMID 
will submit to the FDA any additional data or information that the agency deems necessary, as 
soon as possible, but in no case later than 15 calendar days after receiving the request.   
All SAEs designated as “not related” to study product(s), will be reported to the FDA at least 
annually in a summary format. 
8.3.3 Reporting of Pregnancy 
Female subjects of childbearing age who become pregnant during the study after the 
administration of study drug will continue in the study as this is a single-dose study. Pregnancy 
occurring during a clinical investigation, although not considered an SAE, must be reported 
within the same timelines as an SAE. The positive pregnancy test will be recorded in the 
database within 5 days of site awareness, on the Pregnancy Report form. The report will include 
pregnancy outcome (e.g., any premature terminations, elective or therapeutic, any spontaneous 
abortions or stillbirths), as well as the health status of the mother and child, including date of 
delivery and infant’s sex and weight. Any subject with a positive pregnancy test, who has 
received study product(s), will be followed through eight (8) weeks post live delivery or elective 
or natural termination of the pregnancy, whichever occurs first. If the database is locked at the 
time of pregnancy, a supplemental report will be generated and completed after birth, which will 

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be appended to the database. Any occurring AEs or SAEs that occur to the mother or fetus will 
be recorded in the eCRF in the database and on the SAE Report form. 
 Type and Duration of Follow-up of Subjects After Adverse Events 
AEs will be assessed and followed from initial recognition of the AE through end of the protocol 
defined follow-up period for each stage.  
SAEs will be followed through resolution even if the duration of follow-up goes beyond the 
protocol-defined follow-up period. 
Resolution of an AE is defined as the return to pre-treatment status or stabilization of the 
condition with the expectation that it will remain chronic. 
 Procedures to be Followed in the Event of Abnormal Laboratory Test 
Values  
Any Grade 2 or higher abnormal laboratory value will be reported as an AE, regardless of the 
relationship to the study product or clinical significance. Grade 1 laboratory abnormalities will 
be reported as AEs if assessed by the investigator as related to the study product. Laboratory 
abnormalities reported as AEs will be followed until the abnormality stabilizes, normalizes or 
returns to a baseline level, whichever comes first, at the discretion of the investigator.  
 
In the approach to grading laboratory values, if the Lower Limit of Normal (LLN) entered at the 
site falls within CTCAE defined graded values, the CTCAE ranges will be used to grade an AE, 
rather than using local laboratory ranges for determining normal and abnormal laboratory values.  
 
Intermittent abnormal laboratory values such as electrolyte abnormalities or blood glucose levels 
that are part of the same clinical diagnosis (e.g., uncontrolled diabetes) can be recorded once 
with the highest grade for each fluctuating AE (Grade 2 or higher for this trial), including the 
start and stop dates of the intermittent syndrome. If the event has a clear resolution for a duration 
of at least 48 hours and then recurs, it should be treated as a separate AE. An AE resolution is 
defined as return to pre-treatment status or baseline for duration of more than 48 hours. 
 Halting Rules 
8.6.1 Study Halting Criteria 
If any of the following events occur, enrollment and dosing for all subjects will be suspended 
until the event is assessed by the DSMB: 
• 
Any subject develops an SAE related to the study product through the last study visit. 
• 
Two (2) or more subjects in the study (cumulative among all dose levels) experience a Grade 
3 (severe) AE (including clinical, vital signs, and laboratory AEs identified from blood tests) 
that is related to study product and is of the same type [High Level Term (HLT)] through the 
last study visit. 

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• 
Any subject develops anaphylaxis within 24 hours after receiving the study product. 
• 
Any subject reports two or more pulmonary exacerbations during the ESI collection period, 
from the time of study product administration through Visit 5, Day 8 + 3 days. 
8.6.2 Individual Infusion Halting Criteria 
An individual infusion will be stopped if a drug-related hypersensitivity is suspected, including 
anaphylaxis during the infusion. Symptoms of anaphylaxis may begin within seconds or minutes 
of infusion initiation. Infusion of the investigational product will be halted and will not be 
restarted if any of the following occur:  
• 
Skin or mucous membrane manifestations: hives; Grade 2 or higher pruritus; flushing; 
swollen joints; swollen lips, tongue, or uvula 
• 
Respiratory compromise: dyspnea, wheezing, or stridor 
• 
A decrease in systolic blood pressure to < 90 mmHg or a > 30% reduction in the systolic 
blood pressure 
• 
Development of a ventricular dysrhythmia; or bradycardia < 45 BPM that is associated with 
complaints of dizziness, nausea, or feeling faint 
• 
Syncope 
• 
Confusion and/or slurred speech 
• 
Any other condition that the site PI judges to unduly increase the risk to the subject 
 Safety Oversight  
8.7.1 Data and Safety Monitoring Board (DSMB) 
Safety oversight will be conducted by a DSMB that is an independent group with expertise to 
interpret data from this clinical trial and will monitor subject safety and advise DMID. The 
DSMB members will be separate and independent of study personnel participating in this study 
and will not have scientific, financial, or other conflict of interest related to this study. The 
DSMB must consist of at least three voting members, including a biostatistician experienced in 
statistical methods for clinical trials and clinicians with relevant expertise in CF and bacterial 
infections. 
The DSMB will operate under the rules of a DMID-approved charter that defines the data 
elements to be assessed and the procedures for data reviews and will be written at the 
organizational meeting of the DSMB. Procedures for DSMB reviews/meetings will be defined in 
the charter. Reports may include enrollment and demographic information, medical history, 
concomitant medications, physical assessments, clinical laboratory values, dosing compliance, 
ESIs, and unsolicited AE/SAEs. The DSMB will review SAEs on a regular basis and ad hoc 
during this trial. The DMID MM and MO will be responsible for reviewing SAEs in real time.  

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As defined in the charter, the DSMB will review data at pre-specified intervals during the course 
of the study for subject and overall study progress and will conduct ad hoc reviews as 
appropriate when a halting rule is met or for immediate concerns regarding observations during 
this study. 
Additional data may be requested by the DSMB, and interim statistical reports may be generated 
as deemed necessary and appropriate by DMID. The DSMB will receive data in aggregate and 
presented by treatment arm. The DSMB will review grouped and unblinded data in the closed 
session only. As an outcome of each review/meeting, the DSMB will make a recommendation as 
to the advisability of proceeding with study, and to continue, modify, or terminate this trial. 
8.7.2 PHAGE Advisory Group 
The PHAGE Advisory group will consist of a small group of investigators and clinicians 
affiliated with this clinical trial and/or the ARLG and at least one DMID representative who will 
review the unblinded data provided by the SDCC during the interim analysis between Stage 2a 
and Stage 2b and make a recommendation to DMID on the sample size and the optimal 
bacteriophage dose to be considered for Stage 2b. After completion of Day 8 + 3 days Follow-up 
Visit for all subjects in Stage 2a, the PHAGE Advisory Group will review safety and 
microbiological data, unblinded to treatment arm, comparing the benefit to risk profile of each of 
the treatment groups, taking into consideration AEs and log reductions in P. aeruginosa 
CFU/mL through Day 8. Then, the PHAGE Advisory Group will recommend to DMID the most 
appropriate sample size (See Section 10.2) and the most effective and safest dose to administer in 
Stage 2b. Refer to Section 10.4 for more details on the Interim Analysis. 
 

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 HUMAN SUBJECTS PROTECTION 
The investigator will ensure that this study is conducted in compliance with 21 CFR part 50 and 
in full conformity with the principles set forth in The Belmont Report: Ethical Principles and 
Guidelines for the Protection of Human Subjects of Research of the US National Commission for 
the Protection of Human Subjects of Biomedical and Behavioral Research (April 18, 1979) and 
codified in 45 CFR Part 46 and/or the ICH E6 (R2).  
 Institutional Review Board/Independent Ethics Committee 
Each site PI will obtain IRB approval for this protocol to be conducted at his/her research site(s), 
and send supporting documentation to the DMID (through a Coordinating Center such as the 
ARLG) before initiating recruitment of subjects. The investigator will submit applicable 
information to the IRB/IEC on which it relies for the review, to conduct the review in accordance 
with 45 CFR 46, ICH E6 GCP, and as applicable, 21 CFR 56 (Institutional Review Boards) and 
21 CFR 50 (Protection of Human Subjects), other federal, state, and local regulations. The 
IRB/IEC must be registered with OHRP as applicable to the research. The DMID/ARLG must 
receive the documentation that verifies IRB/IEC approval for this protocol, associated informed 
consent documents, and - upon request - any recruitment material and handouts or surveys 
intended for the subjects, prior to the recruitment and enrollment of subjects at the site. 
Any amendments to the protocol or consent materials must be approved by the IRB/IEC before 
implementation. The IRB/IEC review and approval will occur at least annually throughout the 
enrollment and follow-up of subjects, and may cease if annual review is no longer required by 
applicable regulations and the IRB/IEC. The investigator will notify the IRB/IEC of deviations 
from the protocol and reportable SAEs, as applicable to the IRB/IEC policy. 
Each institution engaged in this research will hold a current FWA issued by the OHRP for 
federally funded research. 
A single IRB of record will be accountable for compliance with regulatory requirements for this 
multi-center study, at participating sites. A formal Reliance Agreement will be required between 
the single IRB and participating sites. The formal Reliance Agreement will set forth the specific 
responsibilities of the IRB and each participating site. Participating sites will then rely on the 
IRB of record to satisfy the regulatory requirements relevant to the IRB review. Participating 
sites will maintain essential required documentation of IRB reviews, approvals, and 
correspondence, and must provide copies of any agreements and essential documentation to the 
DMID/Coordinating Center (such as the ARLG) or regulatory authorities upon request.  
 Informed Consent Process 
Informed consent is a process that is initiated prior to an individual agreeing to participate in a 
trial and continuing throughout the individual’s trial participation. Before any study procedures 
are performed, informed consent will be obtained and documented. Subjects will sign one of two 
consents depending on the study stage (Stage 1 or Stage 2) that is open for enrollment at the time 
of informed consent. Subjects will receive a concise and focused presentation of key information 

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about the clinical trial, verbally and with a written consent form. The explanation will be 
organized, and presented in lay terminology and language that facilitates understanding why one 
might or might not want to participate. 
An investigator or designee will describe the protocol to potential subjects. The key information 
about the purpose of the study; the procedures and experimental aspects of the study, risks, and 
discomforts; any expected benefits to the subject; and alternative treatment will be presented first 
to the subject.   
Subjects will also receive an explanation that the trial involves research, and a detailed summary 
of the proposed study procedures and study interventions/products. The explanation will include 
aspects of the trial that are experimental, the probability for random assignment to treatment 
groups, any expected benefits, all possible risks (including a statement that the particular 
treatment or procedure may involve risks to the subject or to the embryo or fetus, if the subject is 
or may become pregnant, and other risks that are currently unforeseeable), the expected duration 
of the subject’s participation in the trial, alternative procedures that may be available, and the 
important potential benefits and risks of available alternative procedures.  
Subjects will be informed that they will be notified in a timely manner if information becomes 
available that may be relevant to their willingness to continue participation in the trial. Subjects 
will receive an explanation as to whether any compensation and any medical treatments are 
available if injury occurs, and, if so, what they consist of, or where further information may be 
obtained. Subjects will be informed of the anticipated financial expenses, if any, to the subject 
for participating in the trial, as well as any anticipated prorated payments, if any, to the subject 
for participating in the trial. They will be informed of whom to contact for answers to any 
questions relating to the research.  
Information will also include the foreseeable circumstances and/or reasons under which the 
subject’s participation in the trial may be terminated. The subjects will be informed that 
participation is voluntary and that they are free to withdraw from the study for any reason and at 
any time without penalty or loss of benefits to which the participant is otherwise entitled.   
The extent of the confidentiality of the subjects’ records will be defined, and subjects will be 
informed that applicable data protection legislation will be followed. Subjects will be informed 
that the monitor(s), auditors(s), IRB, NIAID, and regulatory authority (ies) will be granted direct 
access to the subject’s original medical records for verification of clinical trial procedures and/or 
data without violating the confidentiality of the subject, to the extent permitted by the applicable 
laws and regulations, and that, by signing a written informed consent form, the subject is 
authorizing such access.  
Subjects will be informed that records identifying the subject will be kept confidential, and, to 
the extent permitted by the applicable laws and/or regulations, will not be made publicly 
available and, if the results of the trial are published, the subject’s identity will remain 
confidential. Subjects will be informed whether private information collected from this research 
and/or specimens will be used for additional research, even if identifiers are removed.   

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Subjects will be allowed sufficient time to consider participation in this research trial, and have 
the opportunity to discuss this trial with their family and/or friends prior to agreeing to 
participate. 
Informed consent forms (ICFs) will be IRB-approved and subjects will be asked to read and 
review the consent form. Subjects must sign the ICF prior to starting any study procedures 
performed specifically for this trial. 
Once signed, a copy of the ICF will be given to subjects for their records. Subjects may 
withdraw consent at any time throughout the course of the trial. The rights and welfare of 
subjects will be protected by emphasizing to them that the quality of their medical care will not 
be adversely affected if they decline to participate in this study. 
Study personnel may employ recruitment efforts prior to obtaining study consent if a patient-
specific screening consent is on record or if the IRB has agreed that chart review is allowed 
without a fully executed screening consent. In cases where there is not a patient-specific 
screening consent on record, site clinical staff may pre-screen via chart review and refer potential 
subjects to the Research staff. Research staff will obtain written consent per the standard 
informed consent process before conducting protocol-specific screening activities. 
New information will be communicated by the site PI to subjects who consent to participate in 
this trial in accordance with IRB requirements. The informed consent document will be updated 
and subjects will be re-consented per IRB requirements, if necessary. Subjects will be given a 
copy of all ICFs that they sign. 
9.2.1 Other Informed Consent Procedures  
Illiterate Subjects  
If illiterate, subjects will be consented according to the procedures approved by the reviewing 
IRB.   
 Consent for Secondary Use of Stored Specimens and Data 
Residual samples/specimens are those that are left over after protocol-specified testing and this 
study has been completed. As part of the main consent form, subjects enrolled in this study will 
consent to remaining (residual) blood and sputum specimens being kept for possible use in 
secondary research studies. Residual specimens will be stored coded in the ARLG Biorepository, 
until released for secondary research. The researchers using the samples/specimens will not be 
able to link the samples back to subjects or directly identify subjects. No human genetic testing 
will be performed on these residual samples/specimens. The recipients of specimens will be 
informed that these specimens have an NIH certificate of confidentiality. Use of the specimens 
for secondary research unrelated to this study will require review by an IRB.   

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 Exclusion of Women, Minorities, and Children (Special Populations) 
Children will be excluded from this trial as the study entry criteria only allows enrollment of 
adults. Non-English speakers, illiterate individuals, and non-writing individuals will be allowed 
to participate in the study, provided the reviewing IRB approves methods and materials given to 
subjects, to include but not limited to the written informed consent written in the language 
understandable to the subject. Women and minorities will not be excluded from participation 
provided all study entry criteria are met. Investigational sites should follow the direction of the 
reviewing IRB prior to enrollment of subjects considered to be “vulnerable”. 
 Subject Confidentiality 
Subject confidentiality is strictly held in trust by the participating investigators, their staff, and 
the sponsor(s) and their agents. This confidentiality includes documentation, investigation data, 
subject’s clinical information, and all other information generated during participation in the 
study. No information concerning the study or the data generated from the study will be released 
to any unauthorized third party without prior written approval of the sponsor. Subject 
confidentiality will be maintained when study results are published or discussed in conferences.   
All information provided by the sponsor and all data and information generated by the 
participating sites as part of this trial (other than a subject’s medical records) will be kept 
confidential by the site PI and other study personnel to the extent permitted by law. This 
information and data will not be used by the site PI or other study personnel for any purpose 
other than conducting this trial. These restrictions do not apply to: (1) information which 
becomes publicly available through no fault of the site PI or other study personnel, (2) 
information which is necessary to disclose in confidence to an IRB solely for the evaluation of 
this trial, (3) information which is necessary to disclose in order to provide appropriate medical 
care to a study subject, or (4) study results which may be published as described in Section 15 
Publication Policy.  
The study monitor or other authorized representatives of the sponsor or governmental regulatory 
agencies may inspect all documents and records required to be maintained by the investigator, 
including but not limited to, medical records (office, clinic, or hospital) and pharmacy records 
for the subjects in this study. The clinical study sites will permit access to such records. 
All records will be kept locked and all computer entry and networking programs will be carried 
out with coded numbers only and with password protected systems. All non-clinical specimens, 
evaluation forms, reports, and other records that leave the site will be identified only by a coded 
number. 
 Certificate of Confidentiality 
To protect privacy, the NIH provides a Certificate of Confidentiality. With this Certificate, the 
researchers cannot be forced to release information that may identify the research subject, even 
by a court subpoena, in any federal, state, or local civil, criminal, administrative, legislative, or 
other proceedings. The researchers will use the Certificate to resist any demands for information 

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that would identify the subject, except as explained below. 
The Certificate cannot be used to resist a demand for information from personnel of the US 
Government that is used for auditing or evaluation of federally funded projects, like this study, or 
for information that must be released in order to meet the requirements of the FDA. 
A Certificate of Confidentiality does not prevent the subject from voluntarily releasing 
information about themselves or their involvement in this research. If any person or agency 
obtains a written consent to receive research information, then the researchers may not use the 
Certificate to withhold that information.   
The Certificate of Confidentiality does not prevent the researchers from reporting without the 
participant’s consent, information that would identify the participant as a participant in the 
research project regarding matters that must be legally reported including: child and elder abuse, 
sexual abuse, or wanting to harm themselves or others.   
The release of individual private information or specimens for other research will only occur if 
consent was obtained from the individual to whom the information, document, or biospecimen 
pertains, for the purposes of other research that is compliant with applicable Federal regulations 
governing the protection of human subjects in research.  
 Costs, Subject Compensation, and Research Related Injuries 
There is no cost to subjects for the research tests, procedures, and study product while taking part 
in this trial. Procedures and treatment for clinical care may be billed to the subject, subject’s 
insurance, or third party.   
If it is determined by the site PI that an injury occurred to a subject as a direct result of the tests 
or treatments that are done for this trial, then referrals to appropriate health care facilities will be 
provided to the subject. Study personnel will try to reduce, control, and treat any complications 
from this trial. Immediate medical treatment may be provided by the participating site. No 
financial compensation will be provided to the subject by the ARLG, NIAID, NIH, by the 
participating sites, or other sponsors for any injury suffered due to participation in this trial. 
 

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 STATISTICAL CONSIDERATIONS 
 Study Hypotheses 
The study does not include formal hypothesis testing for the three primary endpoints.  
 Sample Size Considerations 
The sample size for Stage 2 (Stage 2a/2b) was determined using the DOOR outcome measure. 
The sample size was calculated to provide desired precision of the estimate of the DOOR 
probability in order to describe the benefit to risk profile of a single dose of IV bacteriophage in 
clinically stable CF subjects with P. aeruginosa in expectorated sputum. If the true DOOR 
probability comparing IV bacteriophage and placebo is 70%, when the total sample size in each 
arm is 20 (combining subjects from Stages 2a and 2b), the two-sided normal approximate 95% 
confidence interval for DOOR probability is calculated at 51% and 89%, respectively, with the 
lower limit larger than 50% (see Section 10.5.5).  
An interim analysis will be performed when the 8 subjects per arm in Stage 2a (40% = 8/20) 
have completed their Day 8 + 3 days Follow-up Visit (Section 10.4.2). Based on the observed 
data, two of the doses of IV bacteriophage therapy will be dropped from the study at the interim 
analysis, and the planned sample size will be re-evaluated as to whether it provides the desired 
precision of estimates of the DOOR probability for a selected dose and placebo. If necessary, 
after completion of Stage 2a and per details in Section 10.4.2, the sample size will be increased 
up to 17 subjects for each of the two arms in Stage 2b (a total of up to 25 for the placebo arm and 
up to 25 for the selected bacteriophage dose in Stage 2). 
 Treatment Assignment Procedures 
10.3.1 Randomization Procedures 
According to a computer generated, randomized allocation list using permuted block design, in 
Stage 2a, subjects will be randomly assigned to one of four arms: one of three IV bacteriophage 
doses or placebo in a 1:1:1:1 allocation. In Stage 2b, subjects will be randomly assigned to one 
of two arms: the selected IV bacteriophage dose after interim analysis or placebo in a 1:1 ratio.  
The list of randomized allocations will be generated by statisticians at the SDCC (The Emmes 
Company). The SDCC will assign each subject a randomization code and assignment from the 
list. The randomization code will be released at the Baseline Visit according to Appendix A. 
Instructions for use of the enrollment module are included in the EDC System User’s Guide.  
10.3.2 Masking Procedures 
A double-blind/masking technique will be used in Stage 2 of the study. The three IV 
bacteriophage doses and placebo will be packaged identically for administration so that treatment 
blind/masking is maintained. The subject and the investigator or delegate(s) who are involved in 
the treatment or clinical evaluation of the subjects will be unaware of the treatment group 

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assignments. The study investigational pharmacist will remain unblinded throughout the study 
and will be informed of the appropriate dose for subjects according to procedures detailed in the 
MOP. 
To maintain the overall quality and legitimacy of the clinical trial, randomization code breaks 
should occur only in exceptional circumstances when knowledge of the actual treatment is 
absolutely essential for further management of the subject. Investigators are encouraged to 
discuss with the study team if he/she believes that unblinding is necessary. 
The investigator is encouraged to maintain the blind as much as possible. The actual allocation 
must NOT be disclosed to the subject and/or other study personnel including other site 
personnel, monitors, corporate sponsors or project office staff. There should not be any written 
or verbal disclosure of the code in any of the corresponding subject documents. 
The investigator must report all code breaks (with reason) as they occur on the corresponding 
CRF page. 
Unblinding will not be in and of itself a reason for termination from the study. 
 Planned Interim Analyses 
There will be one planned interim analysis of the primary endpoints after all subjects in Stage 2a 
have completed their Day 8 + 3 days Follow-up Visit, or sooner if early withdrawal. Enrollment 
will be held until the dose for Stage 2b is determined from the planned interim analysis. The 
statistical methods for the interim analysis will be fully specified in advance in a statistical 
analysis plan (SAP). 
10.4.1 Interim Safety Review  
The DSMB will evaluate safety at pre-specified intervals. Ongoing review and summary of 
subjects’ safety will occur to allow for early detection of a safety signal that may result from an 
AE. The DSMB will advise the trial sponsor on whether to continue, modify, or terminate the 
trial based on risk assessment. 
10.4.2 Interim Microbiological Activity Review 
An interim analysis will be performed to select the IV bacteriophage dose with the most 
favorable benefit to risk profile compared to placebo for further evaluation in Stage 2b, and to 
exclude proceeding with bacteriophage doses that do not reduce pseudomonal colony counts or 
are associated with safety issues, when all subjects in Stage 2a have completed their Day 8 + 3 
days Follow-up Visit or last study visit if early withdrawal.  
Continuous variables will be summarized by number of subjects, mean, standard deviation (SD), 
median, quartiles (1st and 3rd quartiles), minimum, and maximum values. Categorical variables 
will be summarized by number and percentage of subjects. The interim analysis will consist of a 
quantitative evaluation of potential effect sizes and associated precision using a predicted 
intervals and predicted interval plots approach.29 Briefly, predicted intervals for DOOR 
probability will be calculated under a range of assumptions including: (1) the trends in outcomes 

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observed at interim analysis will continue to end of study, (2) both DOOR distributions are 
identical, and (3) best and worst case scenarios for remaining outcomes. By relying on prediction 
intervals, no statistical hypothesis testing is required and no power is lost at interim analysis. In 
addition, as supplementary information, (predictive) conditional power will be calculated to 
quantify the probability of rejecting the null hypothesis, i.e., DOOR probability ≤ 50%, at the 
final analysis under a range of assumptions.   
Similar to DOOR, changes in log10 P. aeruginosa CFU/mL (total and each morphology) in 
sputum cultures from administration of IV bacteriophages through Day 8 + 3 days, will be 
evaluated, using predicted interval plots to assess the precision for measuring differences in log10 
CFU/mL count. 
The planned sample size (20 subjects per Stage 2b arm) will be reevaluated after completion of 
Stage 2a. If necessary, the sample size will be increased up to 25 subjects for the two arms in 
Stage 2b (up to 25 subjects for the placebo arm and up to 25 subjects for the selected 
bacteriophage dose) to provide the desired precision of estimates. 
An unblinded statistician at the SDCC will report to the PHAGE Advisory Group. The PHAGE 
Advisory Group will make a recommendation to the DMID on the sample size (see Section 10.2) 
and the optimal dose to be considered for Stage 2b. This will only be a recommendation. 
Ultimately, DMID will review the recommendation and make the final decision on how to 
proceed regarding Stage 2b. Blinding to treatment assignment will be maintained at all 
investigational sites, and the results of the interim analysis will not be shared with the site 
investigators prior to the completion of the trial. The DMID will receive recommendations 
throughout the trial from the DSMB. DMID is responsible for deciding actions based upon the 
recommendations of the DSMB. 
The blinded statistician at the SDCC will be involved in SAP revisions before and after the 
interim analysis and before the final analysis as part of the study team. This blinded statistician 
will be involved in discussions regarding modifications to the protocol, statistical methods, 
identification of protocol violations, or data validation efforts that occur after the interim 
analysis. A separate unblinded statistician at the SDCC who reports to the PHAGE Advisory 
Group will perform the interim analyses and generate the interim report but will not be involved 
in discussions about modifications to the protocol, statistical methods, identification of protocol 
violations, or data validation efforts. 
 Final Analysis Plan 
10.5.1 General Considerations 
The SAP, which includes more technical and detailed elaboration of the principal features stated 
in the protocol, will be prepared separately and finalized before the interim analysis. 
Safety will be assessed by estimating the occurrence of Grade 2 or higher treatment-emergent 
AEs in the IV bacteriophage therapies compared to placebo through Day 30 ± 7 days.  

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Microbiological activity will be assessed by estimating changes in log10 P. aeruginosa CFU/mL 
(total and each morphology) in sputum cultures from baseline through Day 30 ± 7 days. 
The benefit to risk profile will be assessed by comparing the DOOR of IV bacteriophage arms 
and placebo arm through Day 8 + 3 days. The DOOR will be analyzed by estimating the DOOR 
probability (Section 10.5.5), (i.e., the probability of a randomly selected subject having a better 
DOOR if assigned to receive an IV bacteriophage therapy compared to placebo).  
All statistical calculations will be performed using up-to-date versions of SAS version 9.4 or 
higher (SAS Institute Inc., Cary, NC, USA) or language and environment for statistical 
computing 3.6.1 or higher (R Foundation for Statistical Computing, Vienna, Austria), unless 
otherwise specified. All PK analyses will be performed using NONMEM version 7.3 or higher 
(ICON Development Solutions, Ellicott City, MD). For continuous variables, summary statistics 
will include sample size, mean, SD, median, quartiles, minimum, and maximum values. 
Frequencies and percentages will be calculated for categorical variables. All reported confidence 
intervals will be two-sided 95%. Graphical displays will be produced. 
10.5.2 Analysis Sets 
Four analysis sets will be considered in the statistical analysis of the study: 
1. Screened Set: The screened set will consist of all subjects who undergo the Screening 
Visit and receive a patient identification (PID) number. 
2. Intent-to-treat/Randomized Set: The intent-to-treat (ITT) set will consist of all 
randomized subjects regardless of whether or not they received study product or placebo. 
3. Safety Set: The safety set will consist of all randomized subjects who received at least one 
dose of study product or placebo. Subjects will be analyzed based on the treatment 
received. 
4. Pharmacokinetics Set: The PK set will consist of all randomized subjects who 
contributed at least two of each a sputum and a blood sample.   
On the basis of the ITT principle, all of the primary endpoints will be analyzed on the ITT set.  
10.5.3 Subject Disposition 
The number of subjects in two of the study sets (ITT and Safety) will be summarized by groups; 
the screened set will only be summarized by study center.  
Screen failures (i.e., subjects screened but not randomized) and the associated reasons for failure 
will be tabulated overall. The number and percentage of subjects who complete the treatment 
period (including Day 30 ± 7 days) and of subjects who prematurely discontinue during the same 
period will be presented for each group and pooled across groups for the ITT set. The reasons for 
premature discontinuation as recorded on the termination pages of the eCRF will be summarized 
(number and percentage) by treatment groups for ITT set. 

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10.5.4 Demographics and Other Baseline Characteristics  
Demographic variables and other baseline characteristics will be summarized by treatment arm 
for the Safety and ITT sets.  
Prior medication is defined as any medication taken before the date of study product or placebo. 
Concomitant medication is defined as any medication started on or after the date of study 
product or placebo dose.  
Concomitant medication use will be summarized by the number and proportion of subjects in 
each arm receiving each medication within each therapeutic class for the safety set. If a subject 
took a specific medication multiple times or took multiple medications within a specific 
therapeutic class, that subject would be counted only once for the coded drug name or 
therapeutic class. 
10.5.5 Analysis of Primary Endpoints 
Grade 2 or higher treatment-emergent AEs will be summarized descriptively. The type of AE, 
number of events (n) and number (%) of subjects with events in each arm will be tabulated. The 
type of AE, number of AEs and the number (%) of subjects with events will be presented by 
system organ class (SOC), HLT, and preferred term. Subjects are counted once in each SOC, 
HLT, and preferred term. The difference in proportion of the number (%) of subjects with events 
between IV bacteriophage and placebo arms will be calculated with the corresponding exact 95% 
confidence interval.  
Changes in log10 P. aeruginosa CFU/mL (total and each morphology) in quantitative sputum 
cultures from administration of IV bacteriophages through Day 30 (± 7 days), Visit 7, will be 
summarized descriptively. Descriptive statistics will be presented by arms. The difference in 
mean change between IV bacteriophage and placebo arms will be estimated with the 
corresponding 95% confidence interval (log10-transformed and original scales). Area Under 
Curve (AUC) calculated using the trapezoidal rule will be used to summarize log10 P. aeruginosa 
CFU/mL the over the time. The difference in AUC between IV bacteriophage and placebo arms 
will be calculated with the corresponding 95% confidence interval. 
The DOOR will be summarized by estimating the DOOR probability, using the equation 
DOOR probability= Pr[DOOR IV > DOOR P] +
1
2 Pr[DOOR IV = DOOR P], 
where DOOR IV and DOOR P are the DOOR for bacteriophage and placebo arms, respectively, 
and PrൣDOOR IV > DOOR p൧ is the proportion of a DOOR from IV bacteriophage dose exceeding 
a DOOR from placebo and Pr[DOOR IV = DOOR P] is the proportion of two DOOR outcomes 
being same. The corresponding 95% confidence interval will be calculated.  
In addition, the DOOR will be analyzed as follows: DOOR distribution by arms, cumulative 
difference (point estimate and confidence band) in DOOR categories for bacteriophage vs. 
placebo, point estimate and confidence interval of difference in mean partial credit vs. placebo, 
and DOOR distribution for bacteriophage vs. placebo arm. 

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Each of the components of the DOOR will be compared between the IV bacteriophage and 
placebo arms: presence/absence of SAE and reduction in P. aeruginosa CFU/mL (> 2 log10, 1-2 
log10 reduction, < 1 log10 reduction). 
All analyses are summarized in the Table 3 below. 
Table 3: Summary of Analysis of Primary Endpoints 
Outcome/Variable 
Summary Measures 
Analysis of Methods 
Analysis Set 
1) Grade 2 or higher 
treatment-emergent 
AEs  
• 
The number of 
events 
• 
The number of 
subjects with 
events 
• 
Evaluated until 
Day 30 
• 
Descriptive statistics 
(frequency and 
percentage) in each arm 
• 
Difference in 
bacteriophage vs. placebo 
arm and the corresponding 
95% confidence interval 
ITT 
2) Log10 P. aeruginosa 
CFU/mL  
• 
Mean change 
from baseline 
• 
Evaluated until 
Day 30 
• 
Descriptive statistics (the 
number of subjects, mean, 
SD, quartiles, minimum, 
median, and maximum) 
• 
Confidence interval for 
mean change from 
baseline in each arm 
• 
Difference in mean change 
from bacteriophage vs. 
placebo arm and its 
corresponding 95% 
confidence interval (log10-
transformed and original 
scales) 
• 
Plot median (Q1,Q3) over 
time by arm 
ITT 
 
 
• 
AUC over times 
• 
Difference in AUC of 
bacteriophage vs. placebo 
and its corresponding 95% 
confidence interval.  
 
3) DOOR  
• 
DOOR 
Probability 
 
• 
95% confidence interval 
for DOOR Probability of 
bacteriophage vs. placebo 
ITT 

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Outcome/Variable 
Summary Measures 
Analysis of Methods 
Analysis Set 
 
• 
DOOR 
Categories 
distribution 
• 
Evaluated until 
Day 8 
• 
Descriptive statistics 
(frequency and 
percentage) in each arm 
• 
Cumulative difference in 
DOOR categories for 
bacteriophage vs. placebo 
(point estimate and 
confidence band) 
• 
Point estimate and 
confidence interval of 
difference in mean partial 
credit of bacteriophage vs. 
placebo arm 
• 
DOOR distribution of 
bacteriophage vs. placebo 
arm 
 
 
10.5.6 Subgroup and Adjusted Analyses for Primary Endpoints 
As an explanatory analysis, subgroup analyses of the primary outcomes may be conducted to 
explore whether estimated treatment effects vary significantly between subcategories of trial 
subjects, including, but not limited to, bacteriophage susceptibility and presence of co-infection 
with other organisms recovered on sputum cultures collected during the study period. In 
addition, the primary endpoints will adjust for pre-randomization variables, which might 
reasonably be expected to be predictive of favorable outcomes. 
 
10.5.7 Analysis of Exploratory Endpoints 
Exploratory endpoints will be summarized by appropriate statistics. Continuous variables will be 
summarized by number of subjects, mean, SD, median, quartiles, minimum, and maximum 
values. Categorical variables will be summarized by number and percentage of subjects. Blood 
and sputum samples collected from the sentinel subjects in Part 1 will be used for exploratory 
analysis purposes. Phage PK will be analyzed using compartmental population PK models to 
obtain population mean estimates of clearances and volumes as well as estimates of inter-
individual variability. Individual estimates of clearances and volumes will be obtained from post 
hoc estimates and used to estimate exposure in the central compartment and a peripheral 
compartment representing the sputum. Additional details regarding exploratory analysis will be 
included in the SAP. 

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10.5.8 Missing Data 
The endpoints could be missing for subjects who withdraw from the trial or for other reasons. 
The reasons for withdrawal will be reported and compared qualitatively by arm. The effect that 
any missing data might have on results will be assessed via sensitivity analysis. If the pattern of 
missing data is different to that envisaged at the design stage, further sensitivity analyses will be 
provided that are tailored to the missing data pattern observed. The amount of missing data will 
be compared between randomized arms. The baseline characteristics of subjects with missing 
data will be compared to subjects without missing data. 
10.5.9 Safety Data 
An event that occurs during the treatment period will be considered a treatment-emergent AE if 
it was not present before the first dose of investigational product or was present before the first 
dose of investigational product and increased in severity during the treatment period. Adverse 
events (AEs) will be coded by primary system organ class and preferred term using the Medical 
Dictionary for Regulatory Activities (MedDRA). 
The type of AE, number of events (n) and number (%) of subjects with events in each group will 
be tabulated. The type of AE, number of AEs and the number (%) of subjects with AEs will be 
presented by SOC, HLT, and preferred term. Subjects are counted once in each SOC, HLT, and 
preferred term. In addition, summaries of AEs by grouped causal relationship to treatment (all-
cause/treatment-related) and grade will be provided by system organ class and preferred term. 
The incidence of treatment-emergent AEs, on-therapy SAEs, and AEs leading to premature 
discontinuation will be summarized by preferred term and treatment group and will be sorted by 
decreasing frequency for the investigational product. In addition, the incidence of fatal on-
therapy SAEs (i.e., events that caused death) will be summarized separately by treatment arm 
and preferred term. An SAE will be defined as an on-therapy SAE if it occurred during or after 
the infusion of investigational/placebo product. 
Listings will be presented for subjects with SAEs, subjects with AEs leading to discontinuation, 
subjects with ESIs, and subjects who die (if any). 
10.5.10 Clinical Laboratory Parameters and Vital Signs 
Descriptive statistics for clinical laboratory values and changes from the baseline values at each 
assessment time point will be presented by treatment arm for each clinical laboratory parameter. 
Descriptive statistics for vital signs and changes from baseline values at each visit and at end of 
study will be presented by arm. 
 

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 SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
Each participating site will maintain appropriate research records for this trial, in compliance 
with §21 CFR 312.62, ICH E6, Section 4.9, and regulatory and institutional requirements for the 
protection of confidentiality of subjects. Each site will permit authorized representatives of the 
DMID, its designees, and appropriate regulatory agencies to examine (and when required by 
applicable law, to copy) clinical records for the purposes of quality assurance (QA) reviews, 
audits, and evaluation of the study safety and progress. These representatives will be permitted 
access to all source data and source documents, which include, but are not limited to, hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects’ memory aid or 
evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies or transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and participant files and records 
kept at the pharmacy, at the laboratories, and medico-technical departments involved in the 
clinical trial. 

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 QUALITY CONTROL AND QUALITY ASSURANCE 
Following a written DMID-accepted site quality management plan, each participating site is 
responsible for conducting routine QA and quality control (QC) activities to internally monitor 
study progress and protocol compliance. The site PI will provide direct access to all study-related 
source data/data collection forms, reports, training documentation, and regulatory files for the 
purpose of monitoring and auditing by the sponsor, and inspection by local and regulatory 
authorities. The site PI will ensure all study personnel are appropriately trained and applicable 
documentations are maintained on site. 
The SDCC will implement QC procedures beginning with the data entry system and generate 
data QC checks that will be run on the database. Any missing data or data anomalies will be 
communicated to the participating site(s) for clarification and resolution. 
 

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 DATA HANDLING AND RECORD KEEPING 
 Data Management Responsibilities 
The investigator is responsible to ensure the accuracy, completeness, legibility, and timeliness of 
the data reported. All source documents should be completed in a neat, legible manner to ensure 
accurate interpretation of data. Black or blue permanent ink is required to ensure clarity of 
reproduced copies. When making changes or corrections, the original entry should be crossed out 
with a single line, and the change should be initialed and dated. DO NOT ERASE, 
OVERWRITE, OR USE CORRECTION FLUID OR TAPE ON THE ORIGINAL. 
Data reported in the eCRF derived from source data collection forms/source documents should 
be consistent or the discrepancies should be explained. 
 Statistical and Data Coordinating Center/Biostatistician Responsibilities 
Data collection is the responsibility of the study personnel at the participating clinical study site 
under the supervision of the site PI. During the study, the site PI must maintain complete and 
accurate documentation for the study. 
The Emmes Company will serve as the SDCC for this study and will be responsible for data 
management, quality review, analysis, and reporting of the study data. 
 Data Capture Methods 
Clinical (including, but not limited to, AE/SAEs/ESIs, concomitant medications, medical history, 
physical assessments, and clinical laboratory values) will be collected on data collection forms, 
as appropriate, by study personnel then entered into eCRFs via a 21 CFR Part 11-compliant 
internet data entry system provided by the SDCC. The data system includes password protection 
and internal quality checks, such as automatic range checks, to identify data that appear 
inconsistent, incomplete, or inaccurate.  
All data collection forms/source documents (including laboratory reports) must be reviewed by 
the clinical team and data entry staff, who will ensure that the data are accurate and complete. 
Responses to QOL questionnaires will be collected on paper and entered by designated study 
staff into the eCRF for scoring and analysis. For additional details on data entry and reporting, 
refer to the MOP.  
 Types of Data 
Data for this trial will include clinical, safety, QOL questionnaires, and outcome measures. 
 Study Records Retention 
Study records and reports including, but not limited to, eCRFs, source documents, ICFs, 
laboratory test results, and study product disposition records will be retained for 2 years after a 
marketing application is approved for the study product for the indication for which it is being 

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investigated; or, if no application is to be filed or if the application is not approved for the 
study:product, until 2 years after the investigation is discontinued and the FDA has been notified.  
These documents will be retained for a longer period; however, if required by local regulations. 
Informed consent forms (ICFs) for future use will be maintained as long as the sample/specimen 
exists. 
No records will be destroyed without the written consent of the sponsor. It is the responsibility of 
the sponsor to inform the site PI when these documents no longer need to be retained.  
 

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 CLINICAL MONITORING 
A separate clinical monitoring plan will describe the conduct of the monitoring, to include but 
not limited to the monitoring frequency and the level of detail of the monitoring.  
Site monitoring is conducted to ensure that the human subjects’ protections, study and laboratory 
procedures, study intervention administration, and data collection processes are of high quality 
and meet sponsor, ICH/GCP guidelines and applicable regulations, and that this trial is 
conducted in accordance with the protocol, protocol-specific MOP and applicable sponsor 
standard operating procedures (SOPs). The sponsoring agency, DMID, or its designee will 
conduct site-monitoring visits as detailed in the clinical monitoring plan. 
Site visits (in-person or remote, as appropriate) will be made at intervals defined by the clinical 
monitoring plan and may be made more frequently as directed by DMID. Monitoring visits will 
include, but are not limited to, review of regulatory files, accountability records, eCRFs, ICFs, 
medical and laboratory reports, and protocol and GCP compliance. Site monitors will have 
access to each participating site, study personnel, and all study documentation according to the 
DMID-approved site monitoring plan. Study monitors will meet with site PIs to discuss any 
problems and actions to be taken and will document site visit findings and discussions. 
 

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 PUBLICATION POLICY 
Results from primary and exploratory endpoint analyses may be distributed by the SDCC to key 
study team members (protocol PIs, protocol statisticians, and other necessary study team 
members) after database lock and prior to the generation of all the Clinical Study Report Tables, 
Listings, and Figures. These analyses may be used by the PIs for manuscript and abstract 
development while the Clinical Study Report is being finalized. 
Following completion of the study, the lead PI is expected to publish the results of this research 
in a scientific journal. All investigators funded by the NIH must submit or have submitted for 
them to the National Library of Medicine’s PubMed Central (http://www.ncbi.nlm.nih.gov/pmc/) 
an electronic version of their final, peer-reviewed manuscripts upon acceptance for publication, 
to be made publicly available no later than 12 months after the official date of publication. The 
NIH Public Access Policy ensures the public has access to the published results of NIH funded 
research. It requires investigators to submit final peer-reviewed journal manuscripts that arise 
from NIH funds to the digital archive PubMed Central upon acceptance for publication. Further, 
the policy stipulates that these papers must be accessible to the public on PubMed Central no 
later than 12 months after publication. 
Refer to: 
• 
NIH Public Access Policy, http://publicaccess.nih.gov/ 
• 
NIH Office of OER Grants and Funding, http://grants.nih.gov/grants/oer.htm 
As of January 2018, all clinical trials supported by the NIH must be registered on 
ClinicalTrials.gov, no later than 21 days after the enrollment of the first participant. Results of all 
clinical trials supported by the NIH, generally, need to be submitted no later than 12 months 
following the primary completion date. A delay of up to 2 years is available for trials that meet 
certain criteria and have applied for certification of delayed posting. 
As part of the result posting, a copy of this protocol (and its amendments) and a copy of the SAP 
will be posted on ClincialTrials.gov. 
For this trial the responsible party is DMID which will register the trial and post results.   
The responsible party does not plan to request certification of delayed posting. 
Refer to: 
• 
Public Law 110-85, Section 801, Clinical Trial Databases 
• 
42CFR11 
• 
NIH NOT-OD-16-149 

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 LITERATURE REFERENCES 
1. 
Lyczak JB, Cannon CL, Pier GB. Lung infections associated with cystic fibrosis. Clin 
Microbiol Rev 2002;15:194-222. 
2. 
Koch C. Early infection and progression of cystic fibrosis lung disease. Pediatr Pulmonol 
2002;34:232-6. 
3. 
Tamma PD, Hsu AJ. Defining the Role of Novel beta-Lactam Agents That Target 
Carbapenem-Resistant Gram-Negative Organisms. J Pediatric Infect Dis Soc 2019;8:251-60. 
4. 
Aslam S, Schooley RT. What's Old is New Again - Bacteriophage Therapy in the 21(st) 
century. Antimicrob Agents Chemother 2019. 
5. 
Moye ZD, Woolston J, Sulakvelidze A. Bacteriophage Applications for Food Production 
and Processing. Viruses 2018;10. 
6. 
Law N, Logan C, Yung G, et al. Successful adjunctive use of bacteriophage therapy for 
treatment of multidrug-resistant Pseudomonas aeruginosa infection in a cystic fibrosis patient. 
Infection 2019;47:665-8. 
7. 
Aslam S, Courtwright AM, Koval C, et al. Early clinical experience of bacteriophage 
therapy in 3 lung transplant recipients. Am J Transplant 2019;19:2631-9. 
8. 
Tkhilaishvili T, Winkler T, Müller M, Perka C, Trampuz A. Bacteriophages as Adjuvant 
to Antibiotics for the Treatment of Periprosthetic Joint Infection Caused by Multidrug-Resistant 
Pseudomonas aeruginosa. Antimicrob Agents Chemother 2019;64. 
9. 
Schooley RT, Biswas B, Gill JJ, et al. Development and Use of Personalized 
Bacteriophage-Based Therapeutic Cocktails To Treat a Patient with a Disseminated Resistant 
Acinetobacter baumannii Infection. Antimicrob Agents Chemother 2017;61. 
10. 
Nir-Paz R, Gelman D, Khouri A, et al. Successful Treatment of Antibiotic-resistant, 
Poly-microbial Bone Infection With Bacteriophages and Antibiotics Combination. Clin Infect 
Dis 2019;69:2015-8. 
11. 
Fabijan AP LR, Ho J, Maddocks S, Ben Zakour NL, Iredell JR. . Safety of Bacteriophage 
Therapy in Severe Staphylococcus aureus Infection, Nature Microbiology, in press. 
12. 
Aslam S, Pretorius V, Lehman SM, Morales S, Schooley RT. Novel bacteriophage 
therapy for treatment of left ventricular assist device infection. J Heart Lung Transplant 
2019;38:475-6. 
13. 
Ooi ML, Drilling AJ, Morales S, et al. Safety and Tolerability of Bacteriophage Therapy 
for Chronic Rhinosinusitis Due to Staphylococcus aureus. JAMA Otolaryngol Head Neck Surg 
2019. 
14. 
Dedrick RM, Guerrero-Bustamante CA, Garlena RA, et al. Engineered bacteriophages 
for treatment of a patient with a disseminated drug-resistant Mycobacterium abscessus. Nat Med 
2019;25:730-3. 
15. 
de Jong MD, Tran TT, Truong HK, et al. Oseltamivir resistance during treatment of 
influenza A (H5N1) infection. N Engl J Med 2005;353:2667-72. 
16. 
Jault P, Leclerc T, Jennes S, et al. Efficacy and tolerability of a cocktail of bacteriophages 
to treat burn wounds infected by Pseudomonas aeruginosa (PhagoBurn): a randomised, 
controlled, double-blind phase 1/2 trial. Lancet Infect Dis 2019;19:35-45. 

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17. 
Tkhilaishvili T, Winkler T, Muller M, Perka C, Trampuz A. Bacteriophages as adjuvant 
to antibiotics for the treatment of periprosthetic joint infection caused by multidrug-resistant 
Pseudomonas aeruginosa. Antimicrob Agents Chemother 2019. 
18. 
Corbellino M, Kieffer N, Kutateladze M, et al. Eradication of a multi-drug resistant, 
carbapenemase-producing Klebsiella pneumoniae isolate following oral and intra-rectal therapy 
with a custom-made, lytic bacteriophage preparation. Clin Infect Dis 2019. 
19. 
Aslam S, Lampley E, Wooten D, et al. Lessons Learned From the First 10 Consecutive 
Cases of Intravenous Bacteriophage Therapy to Treat Multidrug-Resistant Bacterial Infections at 
a Single Center in the United States. Open Forum Infect Dis 2020;7:ofaa389. 
20. 
LaVergne S, Hamilton T, Biswas B, Kumaraswamy M, Schooley RT, Wooten D. Phage 
Therapy for a Multidrug-Resistant Acinetobacter baumannii Craniectomy Site Infection. Open 
Forum Infect Dis 2018;5:ofy064. 
21. 
Duplessis C, Stockelman MG, Hamilton T, et al. A Case Series of Emergency 
Investigational New Drug Applications for Bacteriophages Treating Recalcitrant Multi-drug 
Resistant Bacterial Infections: Confirmed Safety and a Signal of Efficacy. 2019. 
22. 
Cano EJ, Caflisch KM, Bollyky PL, et al. Phage Therapy for Limb-threatening Prosthetic 
Knee Klebsiella pneumoniae Infection: Case Report and In Vitro Characterization of Anti-
biofilm Activity. Clinical Infectious Diseases 2020. 
23. 
Ferry T, Boucher F, Fevre C, et al. Innovations for the treatment of a complex bone and 
joint infection due to XDR Pseudomonas aeruginosa including local application of a selected 
cocktail of bacteriophages. J Antimicrob Chemother 2018;73:2901-3. 
24. 
Petrovic Fabijan A, Lin RCY, Ho J, Maddocks S, Ben Zakour NL, Iredell JR. Publisher 
Correction: Safety of bacteriophage therapy in severe Staphylococcus aureus infection. Nat 
Microbiol 2020;5:652. 
25. 
Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of 
the general U.S. population. Am J Respir Crit Care Med 1999;159:179-87. 
26. 
Cystic Fibrosis Questionnaire (CFQ); Cystic Fibrosis Questionnaire Revised (CFQ-R). 
American Thoracic Society, 2007. (Accessed August 10, 2020, at 
https://qol.thoracic.org/sections/instruments/ae/pages/cfq-cfq-r.html.) 
27. 
Goss CH, Edwards TC, Ramsey BW, Aitken ML, Patrick DL. Patient-reported 
respiratory symptoms in cystic fibrosis. Journal of Cystic Fibrosis 2009;8:245-52. 
28. 
Fuchs HJ, Borowitz DS, Christiansen DH, et al. Effect of aerosolized recombinant human 
DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with 
cystic fibrosis. The Pulmozyme Study Group. N Engl J Med 1994;331:637-42. 
29. 
Evans SR, Li L, Wei L. Data Monitoring in Clinical Trials Using Prediction. Drug 
Information Journal 2007;41:733-42. 

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  APPENDICES 
 
Schedule of Events 
Visit 
Screen 
Baseline/ 
Dosing 
Follow-up Visits 
Early Termination 
Visit1/Unscheduled 
Study Visit 
Visit Number 
1 
2 
3 
4 
518 
619 
7 
N/A 
Day (Window) 
Up to 
Day -7 
1 
2 
5 ± 2 
8 + 3 
12 + 7 
30 ± 7 
Variable 
Informed 
Consent 
X 
 
 
 
 
 
 
 
Eligibility 
Criteria 
X 
X 
 
 
 
 
 
 
Serum HCG 
Pregnancy Test 
X2 
 
 
 
 
 
 
 
Urine 
Pregnancy Test 
 
X2 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Height and 
Weight 
Measurement  
X 
 
 
 
 
 
 
 
Medical 
History3 
X 
 
 
 
 
 
 
 
Medication 
History4 
X 
 
 
 
 
 
 
 
Review of 
systems 
X 
X 
X 
X 
X 
X 
X 
X 
Treatment 
Assignment 
(Stage 1) 
/Randomizatio
n (Stage 2)  
 
X 
 
 
 
 
 
 
Administration 
of Study 
Product 
 
X 
 
 
 
 
 
 
Concomitant 
Medications 
 
X 
X 
X 
X 
X 
X 
X 
Physical 
Examination  
X5 
 
 
 
 
 
 
 
Symptom 
Directed 
Physical 
Examination  
 
X6 
X 
X 
 
X 
X 
X 
Vital Signs 
X5 
X6 
X 
X 
 
X 
X 
X 
Spirometry 
X 
X7 
X 
X 
 
X 
X 
X8 
Sputum 
Collection9 
X 
X10 
X 
X 
X 
X 
X 
X 

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Visit 
Screen 
Baseline/ 
Dosing 
Follow-up Visits 
Early Termination 
Visit1/Unscheduled 
Study Visit 
Visit Number 
1 
2 
3 
4 
518 
619 
7 
N/A 
Day (Window) 
Up to 
Day -7 
1 
2 
5 ± 2 
8 + 3 
12 + 7 
30 ± 7 
Variable 
Clinical 
Chemistry 
 
X11,15 
X 
X 
 
X 
X 
X12 
Liver Function 
Tests 
X13 
X11,15 
X 
X 
 
X 
X 
X12 
Hematology 
 
X11,15 
X 
X 
 
X 
X 
X12 
Serum for PK 
 
X14 
X 
 
 
 
 
 
CFQ-R (Stage 
2 only)17 
 
X15 
 
 
 
 
X 
 
CFRSD (Stage 
2 only)17 
 
X15 
X 
X 
X 
 
X 
X 
Safety 
Assessment  
 
X 
X 
X 
X 
X 
X 
X 
Events of 
Special Interest 
 
X 
X 
X 
X 
 
 
X16 
1May be conducted by telephone call if subject is too ill to attend in-person or virtual visit, per local investigator. 
2Pregnancy testing will be performed for all female subjects of childbearing potential and the results of both the 
HCG test at screening and urine test at baseline must be negative prior to treatment assignment/randomization. 
3Including full account of the subject’s routine respiratory physiotherapy regimen.  
4Medication history within the past 30 days and those that remain active. 
5Standard of care results obtained for clinical care purposes within 72 hours of screening are acceptable for 
screening. 
6Before administration of study product or placebo AND 30-60 minutes after completed administration of study 
product or placebo. 
7Spirometry to occur prior to study product/placebo administration. 
8If the visit occurs > 7 days after a scheduled visit. If the visit occurs ≤ 7 days after a scheduled visit, spirometry 
may be performed at the discretion of the local investigator. 
9At in-person visits to be completed after spirometry, as considered necessary by the local investigator to increase 
sputum production. 
10Sputum will be obtained pre-infusion and post-infusion for microbiological and PK assessments (see Sections 
7.2.1 and 7.2.2 for details). 
11Labs obtained at the Screening Visit do not have to be repeated at the Baseline Visit, if collected within 7 days 
from the Baseline Visit. 
12If the visit occurs > 7 days after a scheduled visit. If the visit occurs ≤ 7 days after a scheduled visit, laboratory 
tests may be collected at the discretion of the local investigator. 
13AST, ALT, and total bilirubin only. 
14Serum will be obtained pre-infusion and post-infusion for PK assessments (see Section 7.2.2 for details). 
15Prior to administration of Study Product/Placebo. 
16If the visit occurs prior to Visit 5, Day 8 + 3 days. 
17Preferably before the collection of study data. If the subject is ready to produce sputum, prioritize sputum 
collection over administration of the CFQ-R/CFRSD. 
18In Stage 2, this is a virtual visit. 
19This visit is only applicable for Stage 1.

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Cystic Fibrosis Questionnaire – Revised (CFQ-
R) 
 
Cystic Fibrosis Respiratory Symptom Diary 
(CFRSD)