A Phase I, Randomized, Double-blind, Placebo-controlled, Multi-centre, Ascending-dose Trial to Evaluate the Safety, Tolerability and Immunogenicity of Vaccine FP-02.2 in HBeAg-negative Hepatitis B Patients as an add-on Treatment to Entecavir or Tenofovir.
Phase: PHASE1
Conditions: Hepatitis B
Sponsor: Altimmune, Inc.

Phase I safety and immunogenicity of FP-02.2 in chronic hepatitis B 
    
   EudraCT number: 2015-000880-15 
 
Protocol Version 6; 11 August 2016                                          
Page 1 of 67 
Clinical Study Protocol 
 
LONG TITLE OF THE TRIAL 
A phase I, randomised, double-blind, placebo-controlled, multi-centre, 
ascending-dose trial to evaluate the safety, tolerability and immunogenicity of 
Vaccine FP-02.2 in HBeAg-negative hepatitis B patients as an add-on treatment 
to entecavir or tenofovir. 
 
SHORT STUDY TITLE  
Phase I safety and immunogenicity of FP-02.2 in chronic hepatitis B 
 
PROTOCOL VERSION NUMBER AND DATE 
Version 6 – 11 August 2016 
 
TRIAL REGISTRY NUMBER 
EudraCT number: 2015-000880-15 
 
OTHER RESEARCH REFERENCE NUMBERS  
FP02.2_CS_01 
 
SPONSOR / CO-SPONSORS / JOINT-SPONSORS 
Altimmune UK Ltd / Altimmune Inc 
 
 
 
 
 
 
 

Phase I safety and immunogenicity of FP-02.2 in chronic hepatitis B 
    
   EudraCT number: 2015-000880-15 
 
Protocol Version 6; 11 August 2016                                          
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SIGNATURE PAGE 
The undersigned confirm that the following protocol has been agreed and accepted and that the Chief 
Investigator agrees to conduct the trial in compliance with the approved protocol and will adhere to the 
principles of Good Clinical Practice, the principles of the Declaration of Helsinki, applicable local 
regulations, the Sponsor’s SOPs, and other regulatory requirements as amended. 
I agree to ensure that the confidential information contained in this document will not be used for any 
purpose other than the evaluation or conduct of the clinical investigation without the prior written 
consent of the Sponsor. 
I also confirm that I will make the findings of the study publically available through publication or other 
dissemination tools without any unnecessary delay and that an honest, accurate and transparent 
account of the study will be given; and that any discrepancies from the study as planned in this 
protocol will be explained. 
 
 

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Phase I safety and immunogenicity of FP-02.2 in chronic hepatitis B 
    
   EudraCT number: 2015-000880-15 
 
Protocol Version 6; 11 August 2016                                          
Page 4 of 67 
Signature of the Site Principal Investigator: 
I agree to the terms of this Protocol and all amendments.  I will conduct the study according to the 
procedures specified herein, and according to the principles of Good Clinical Practice (GCP) and local 
regulations.   
Site No.: ....................................................................................... 
Signature:  
...................................................................................................... 
 
Date: 
....../....../...... 
Name, Title (please print): 
...................................................................................................... 
 
 
Address: 
...................................................................................................... 
Telephone number 
...................................................................................................... 
 
 
 
 

Phase I safety and immunogenicity of FP-02.2 in chronic hepatitis B 
    
   EudraCT number: 2015-000880-15 
 
Protocol Version 6; 11 August 2016                                          
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KEY TRIAL CONTACTS 
 
Chief Investigator 
Prof. Mark Thursz, MB BS MD FRCP 
Department of Hepatology  
Imperial College London 
St Mary's Campus 
South Wharf Road 
London, W2 1NY, UK. 
Tel: +44(0)207 886 1903 
E-mail: m.thursz@imperial.ac.uk  
Sponsor 
Altimmune 
London Bioscience Innovation Centre 
2 Royal College Street 
London, NW1 0NH, UK 
Sponsor contacts 
Efe Egharevba; Bertrand Georges PhD 
Altimmune UK Ltd. 
Tel: +44(0)2076914908 
Fax: +44(0)2076819129 
E-mail: eegharevba@altimmune.com; 
bgeorges@altimmune.com 
 
Sybil Tasker, M.D. 
Altimmune, Inc. 
19 Firstfield Rd. Suite 200 
Gaithersurg, MD 20878 
Tel: +1-240-654-1450 ext 33 (office) 
 
+1-301-312-2426 (mobile) 
E-mail: stasker@altimmune.com 
Sponsor Medical Advisor  
Geoff Kitson, BMedSci, BMBS 
ProPharma Partners Limited 
The Courtyard, 30 Worthing Road, Horsham, West Sussex 
RH12 1SL, UK 
Tel: 
+44 (0)1372 451972 (out of hours) 
Tel: 
+44 (0)1403 793769 (working hours) 
Mob: +44 (0)7932 162918 
E-mail: gkitson@propharmapartners.uk.com 
Pharmacovigilance (serious adverse 
event reporting) 
PRA Health Sciences 
Safety and Risk Management  
Tel: +49 621 8782 154 
Fax: +44 1792 525 720 (EAPA) 
E-mail: MHGSafety@prahs.com 
Funder(s) 
Altimmune UK Ltd./ Altimmune Inc 
Sponsor contact for IMP 
Bertrand Georges PhD 
Tel: +44(0)2076914908 
Fax: +44(0)2076819129 
E-mail: bgeorges@altimmune.com 
 
 
 
 

Phase I safety and immunogenicity of FP-02.2 in chronic hepatitis B 
    
   EudraCT number: 2015-000880-15 
 
Protocol Version 6; 11 August 2016                                          
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TRIAL SUMMARY 
 
Trial Title 
A phase I, randomised, double-blind, placebo-controlled, multi-centre, ascending-
dose trial to evaluate the safety, tolerability and immunogenicity of Vaccine FP-02.2 
in HBeAg-negative hepatitis B patients as an add-on treatment to entecavir or 
tenofovir. 
Internal ref. no.  
FP-02.2_CS_01 
Clinical Phase  
Phase I 
Trial Design 
Randomised, double-blind, placebo-controlled, multi-centre, ascending-dose 
Trial 
Participants 
Hepatitis B-infected, HBeAg-negative patients, aged 18-65 years, receiving on-
going treatment with entecavir or tenofovir for at least 2 years 
Planned 
Sample Size 
Approximately 60 subjects equally randomised between 6 treatment arms with 10 
subjects per arm.  
Treatment 
duration 
Subjects will receive 2 months active treatment (3 injections administered 28 days 
apart, i.e. over a period of 56 days). Subjects will be followed up 6 months after the 
last injection. 
 
Objectives 
Outcome Measures 
Primary 
 
To assess the safety and tolerability of Vaccine 
FP-02.2 at Day 85 following vaccinations on 
Days 1, 29 and 57. 
Adverse events, clinical laboratory 
abnormalities, local tolerability, vital 
signs and electrocardiogram (ECG)  
 
Secondary 
 
To measure immunological response of 
Vaccine FP-02.2 at Day 85 following 
vaccinations on Days 1, 29 and 57.  
FP-02.2-specific T cell immunity  
 
Investigational 
Medicinal 
Product(s) 
Vaccine FP-02.2, a potential therapeutic Hepatitis B vaccine, is a freeze-dried 
product containing nine different synthetic peptides of 32-40 amino acids in length 
and covalently linked to a fluorocarbon delivery vector. Peptides have been 
selected from the natural sequence of Core (4 peptides), Polymerase (4 peptides) 
and Surface (1 peptide) antigens from the HBV proteome. 
Formulation, 
Dose, Route of 
Administration 
Subjects will receive one of the following formulations by an intramuscular injection 
of 1mL of: 
 
Low-dose FP-02.2 (150µg/peptide), 
 
High-dose FP-02.2 (500µg/peptide)  
 
Low-dose FP-02.2 (150µg/peptide) + IC31® (500/20nmol KLK/ODN1a) 
 
High-dose FP-02.2 (500µg/peptide) + IC31® (500/20nmol KLK/ODN1a) 
 
Placebo 
 
IC31 alone 
on three occasions, 28 days apart. 
Study schedule 
Screening  
Screening should be performed to confirm study eligibility 28 to 1 (±2) days before 
the first injection.  
 

Phase I safety and immunogenicity of FP-02.2 in chronic hepatitis B 
    
   EudraCT number: 2015-000880-15 
 
Protocol Version 6; 11 August 2016                                          
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Study period 
Up to 3 days prior to first injection eligible subjects will be randomised into one of 6 
treatment arms distributed across three cohorts as shown below: 
Study cohorts/treatment arms 
Cohort 
Treatment arm 
Approximate 
number of subjects 
1 
 
Placebo 
5 
FP-02.2 Low dose 
10 
2 
 
Placebo 
5 
IC31® adjuvant only 
5 
FP-02.2 Low dose + IC31® adjuvant 
10 
FP-02.2 High dose 
10 
3 
IC31® adjuvant only 
5 
FP-02.2 High dose + IC31® adjuvant 
10 
 
The subjects will receive 3 injections at intervals of 28 days (Day 1, Day 29, and 
Day 57). On the days of the injections the subjects will stay in the clinic for 4 hours 
post the first injection and 2 hours post injections 2 and 3, and be monitored closely 
including an assessment of local reactions at the injection site. Approximately 24 
hours after the first injection, the subjects will be asked to attend the clinic for safety 
assessments. For subsequent injections, subjects will receive a telephone call 
approximately 24 hours after each injection as a safety follow-up. The subjects will 
be asked to return to the clinic 7 days after each injection for further assessments 
as well as 28 days after the last injection (Day 85). A follow-up visit will be 
performed 6 months after the final injection. 
For each cohort, dosing will start with a sentinel group consisting of one subject 
receiving each active and control treatment (FP-02.2 (±IC31®), IC31® or placebo), 
e.g. for Cohort 1, the sentinel group will consist of 1 subject receiving placebo and 1 
subject receiving Low Dose Vaccine FP-02.2. After the assessments on Day 8, the 
Safety Review Committee (SRC) (defined as the country CIs, if applicable, and the 
study medical monitors) will review the safety data from the sentinel group and 
recommend whether or not the remaining subjects of a cohort should be dosed. 
Any PI with patients in the sentinel group will provide input to the SRC. The 
outcome of this review will be communicated to the sponsor. 
In order to progress to the next cohort, the SRC with input from the Investigators 
contributing patients to the dosing cohort will meet to review safety data up to Day 
36 from Cohort 1. Following this review subjects may be dosed in Cohort 2 
assuming the SRC review identifies no safety concerns. Similarly, subjects may be 
dosed in Cohort 3 after review of safety data up to and including Day 36 from 
subjects in Cohort 2.  
Criteria for 
evaluation 
Safety and Tolerability 
The safety evaluation will include adverse events (AEs), clinical laboratory safety 

Phase I safety and immunogenicity of FP-02.2 in chronic hepatitis B 
    
   EudraCT number: 2015-000880-15 
 
Protocol Version 6; 11 August 2016                                          
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tests (serum biochemistry and haematology), physical examinations (for diagnoses 
only), vital signs (blood pressure, pulse rate and body temperature), 12-lead ECG 
parameters and local injection site reactions. 
Immunogenicity 
IFNγ ELISpot assay (ex vivo and cultured) specific for Vaccine FP-02.2 peptides 
using cryopreserved peripheral blood mononuclear cells (PBMC). 
Exploratory: Other immunological assays such as T cell proliferation assays, 
intracellular cytokine assays, ELISA-based assays to measure Vaccine FP-02.2-
specific antibodies, or other suitable assays to measure the Vaccine FP-02.2-
specific immune response from PBMC or serum. The frequency of regulatory cells, 
expression of co-stimulatory and inhibitory markers measured by flow cytometry. In 
consenting subjects, gene expression may be studied, which has the potential for 
identifying genetic markers that predict vaccine immunogenicity, or successful 
clinical responses, as well as elucidating biological mechanisms of vaccine efficacy. 
Virological 
HBsAg (quantitative), HBsAb 
Sample size 
estimation 
No formal sample size calculation has been performed. A convenience sample of 
10 subjects will be enrolled into each of the six study arms (approximately 60 
subjects overall) which is considered an appropriate study size at this phase of 
development of Vaccine FP-02.2. 
Statistical 
considerations 
There are six treatment arms dosed in 3 cohorts: 
1. Low-dose FP-02.2 (Cohort 1) 
2. High-dose FP-02.2 (Cohort 2) 
3. Low-dose FP-02.2 + adjuvant (IC31®) (Cohort 2) 
4. High-dose FP-02.2 + adjuvant (IC31®) (Cohort 3) 
5. Placebo (pooled Placebo subjects from Cohorts 1 and 2) 
6. IC31® only (pooled IC31® subjects from Cohorts 2 and 3) 
The standard summary statistics for continuous baseline and outcome variables 
are: number of subjects (n), mean, standard deviation, co-efficient of variation (CV), 
median, quartiles, minimum and maximum. The standard summary statistics for 
categorical baseline and outcome variables are: count and proportion (expressed 
as percentage). 
Adverse events shall be coded according to the current version of the Medical 
Dictionary for Regulatory Activities. The subject incidence, severity, duration, 
relatedness and outcome of all treatment emergent AEs will be tabulated by 
treatment arm, system organ class and preferred term. Injection site tolerability will 
be tabulated by treatment arm, time point, reaction, and grade of severity. 
Safety data in general will be listed and summarised by treatment arm and time 
point using the standard summary statistics over the safety analysis set. 

Phase I safety and immunogenicity of FP-02.2 in chronic hepatitis B 
    
   EudraCT number: 2015-000880-15 
 
Protocol Version 6; 11 August 2016                                          
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Shift tables will be presented for safety laboratory results and vital signs. Listings of 
safety laboratory results and vital signs will have assessments below and above the 
reference range highlighted, together with an indicator for clinical significance. 
Immunological outcome variables will be summarised by treatment arm and by time 
point tabulated using the standard summary statistics. A detailed description of the 
planned analysis of each immunogenicity and virological endpoint will be presented 
in a separate statistical analytical plan. 
 
 
 

Phase I safety and immunogenicity of FP-02.2 in chronic hepatitis B 
    
   EudraCT number: 2015-000880-15 
 
Protocol Version 6; 11 August 2016                                          
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FUNDING AND SUPPORT IN KIND 
FUNDER(S) 
(Names and contact details of ALL organisations 
providing funding and/or support in kind for this 
trial) 
FINANCIAL AND NON FINANCIAL SUPPORT 
GIVEN 
Altimmune  
100% financial support 
 
 
 
 

Phase I safety and immunogenicity of FP-02.2 in chronic hepatitis B 
    
   EudraCT number: 2015-000880-15 
 
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ROLE OF STUDY SPONSOR AND FUNDER 
Altimmune (formerly known as Vaxin) is the Sponsor of the study. 
The Sponsor will be responsible for the IMP supply management, the design and overall performance 
of the study, data analysis, clinical study report, archiving of the Trial Master File (TMF) after the end 
of the study and the publication of the results.  
The Sponsor may transfer all or parts of the responsibilities in regard to the performance of the study 
and data analysis, interpretation and publication to a Contract Research Organisation (CRO). The 
Sponsor will control the final decision in any of these aspects.  
 
 
 
 

Phase I safety and immunogenicity of FP-02.2 in chronic hepatitis B 
    
   EudraCT number: 2015-000880-15 
 
Protocol Version 6; 11 August 2016                                          
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LIST OF CONTENTS 
 
SIGNATURE PAGE .............................................................................................................................. 2 
KEY TRIAL CONTACTS ....................................................................................................................... 5 
TRIAL SUMMARY ................................................................................................................................ 6 
FUNDING AND SUPPORT IN KIND ................................................................................................... 10 
ROLE OF STUDY SPONSOR AND FUNDER .................................................................................... 11 
LIST OF CONTENTS ......................................................................................................................... 12 
LIST OF ABBREVIATIONS ................................................................................................................ 16 
TRIAL FLOW CHART ......................................................................................................................... 18 
1 
BACKGROUND ...................................................................................................................... 21 
2 
RATIONALE............................................................................................................................ 23 
2.1 Assessment and management of risk...................................................................................... 24 
2.1.1 
Potential benefits ........................................................................................................... 24 
2.1.2 
Potential Risks ............................................................................................................... 24 
2.1.3 
Subject selection ........................................................................................................... 26 
2.1.4 
Study site ...................................................................................................................... 26 
2.1.5 
Dose selection ............................................................................................................... 27 
2.1.6 
Dose escalation ............................................................................................................. 28 
3 
OBJECTIVES AND OUTCOME MEASURES/ENDPOINTS .................................................... 29 
3.1 Primary objective..................................................................................................................... 29 
3.2 Secondary objectives .............................................................................................................. 29 
3.3 Outcome measures/endpoints................................................................................................. 29 
3.3.1 
Primary endpoints/outcomes ......................................................................................... 29 
3.3.2 
Secondary endpoints/outcomes..................................................................................... 30 
3.4 Exploratory endpoints/outcomes ............................................................................................. 30 
4 
TRIAL DESIGN ....................................................................................................................... 30 
5 
STUDY SETTING ................................................................................................................... 32 
6 
ELIGIBILITY CRITERIA .......................................................................................................... 32 
6.1 Inclusion criteria ...................................................................................................................... 32 
6.2 Exclusion criteria ..................................................................................................................... 33 
7 
TRIAL PROCEDURES ............................................................................................................ 34 
7.1 Recruitment............................................................................................................................. 34 
7.1.1 
Patient identification ...................................................................................................... 34 

Phase I safety and immunogenicity of FP-02.2 in chronic hepatitis B 
    
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7.2 Consent .................................................................................................................................. 34 
7.2.1 
Screening ...................................................................................................................... 34 
7.3 The randomisation scheme ..................................................................................................... 35 
7.3.1 
Method of implementing the allocation sequence .......................................................... 35 
7.4 Blinding ................................................................................................................................... 35 
7.5 Unblinding ............................................................................................................................... 36 
7.6 Trial assessments ................................................................................................................... 36 
7.6.1 
Safety assessments ...................................................................................................... 36 
7.6.2 
Immunological and virological assessments .................................................................. 38 
7.6.3 
Assessment schedule .................................................................................................... 39 
7.7 Follow-up assessments ........................................................................................................... 41 
7.8 Qualitative assessments – Nested studies .............................................................................. 42 
7.9 Allowed visit intervals .............................................................................................................. 42 
7.10 Withdrawal criteria................................................................................................................... 42 
7.10.1 
Possible reasons for discontinuing subjects from continued study treatment ................. 42 
7.10.2 
Site discontinuation ....................................................................................................... 44 
7.10.3 
Study termination .......................................................................................................... 44 
7.10.4 
Replacement of subjects ............................................................................................... 44 
7.11 Storage and analysis of samples ............................................................................................. 44 
7.11.1 
Safety laboratory ........................................................................................................... 44 
7.11.2 
Immunology ................................................................................................................... 46 
7.11.3 
Virology ......................................................................................................................... 46 
7.11.4 
Sampling handling and storage ..................................................................................... 46 
7.11.5 
Blood volume................................................................................................................. 46 
7.12 End of trial ............................................................................................................................... 47 
8 
TRIAL MEDICATION .............................................................................................................. 48 
8.1 Name and description of investigational medicinal product(s) ................................................. 48 
8.2 Legal status of the drug ........................................................................................................... 48 
8.3 Summary of Product Characteristics (SmPC) .......................................................................... 49 
8.4 Drug storage and supply ......................................................................................................... 49 
8.5 Dosage schedules................................................................................................................... 50 
8.6 Preparation and labelling of Investigational Medicinal Product ................................................ 50 
8.7 Dosage modifications .............................................................................................................. 50 
8.8 Known drug reactions and interaction with other therapies ...................................................... 50 

Phase I safety and immunogenicity of FP-02.2 in chronic hepatitis B 
    
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8.9 Concomitant medication .......................................................................................................... 50 
8.10 Trial restrictions ....................................................................................................................... 50 
8.11 Assessment of compliance ...................................................................................................... 51 
8.12 Name and description of each Non-Investigational Medicinal Product (NIMP) ........................ 51 
9 
PHARMACOVIGILANCE ........................................................................................................ 52 
9.1 Definitions ............................................................................................................................... 52 
9.2 Operational definitions for (S)AEs ........................................................................................... 53 
9.2.1 
Assessment of seriousness ........................................................................................... 53 
9.2.2 
Categorisation of adverse events .................................................................................. 53 
9.2.3 
Assessment of causality ................................................................................................ 54 
9.3 Recording and reporting of SAEs and SUSARs ...................................................................... 54 
9.4 Responsibilities ....................................................................................................................... 55 
9.5 Notification of deaths ............................................................................................................... 56 
9.6 Pregnancy reporting ................................................................................................................ 56 
9.7 Overdose ................................................................................................................................ 56 
9.8 Reporting urgent safety measures .......................................................................................... 56 
9.9 The type and duration of the follow-up of subjects after adverse events .................................. 56 
9.10 Development safety update reports ......................................................................................... 57 
10 
STATISTICS AND DATA ANALYSIS ...................................................................................... 57 
10.1 Treatment Arms ...................................................................................................................... 57 
10.2 Sample size calculation ........................................................................................................... 57 
10.3 Statistical analysis plan ........................................................................................................... 57 
10.4 Analysis Sets .......................................................................................................................... 58 
10.4.1 
Safety Analysis Set........................................................................................................ 58 
10.4.2 
Full Analysis Set (FAS) .................................................................................................. 58 
10.4.3 
Immunogenicity Analysis Set ......................................................................................... 58 
10.5 Baseline data .......................................................................................................................... 58 
10.6 Procedure(s) to account for missing or spurious data .............................................................. 58 
10.7 Subject Disposition and flow of patients .................................................................................. 59 
10.8 Study Conduct ........................................................................................................................ 59 
10.8.1 
IMP and NUC exposure ................................................................................................. 59 
10.8.2 
Protocol Violations ......................................................................................................... 59 
10.9 Safety analysis ........................................................................................................................ 59 
10.9.1 
Liver function ................................................................................................................. 59 

Phase I safety and immunogenicity of FP-02.2 in chronic hepatitis B 
    
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10.9.2 
Adverse Events ............................................................................................................. 59 
10.9.3 
Local tolerability ............................................................................................................. 60 
10.9.4 
Vital signs ...................................................................................................................... 60 
10.9.5 
ECG .............................................................................................................................. 60 
10.9.6 
Safety laboratory assessments ...................................................................................... 60 
10.9.7 
Other safety assessments ............................................................................................. 60 
10.10 
Immunogenicity analysis ................................................................................................... 60 
10.11 
Timing of analysis ............................................................................................................. 60 
11 
DATA HANDLING ................................................................................................................... 61 
11.1 Data collection tools and source document identification......................................................... 61 
11.2 Data handling and record keeping ........................................................................................... 61 
11.3 Access to Data ........................................................................................................................ 61 
11.4 Archiving ................................................................................................................................. 61 
11.5 Clinical study report ................................................................................................................. 62 
12 
MONITORING, AUDIT & INSPECTION .................................................................................. 62 
13 
ETHICAL AND REGULATORY CONSIDERATIONS .............................................................. 62 
13.1 Ethics Committee (EC) review & reports ................................................................................. 62 
13.2 Peer review ............................................................................................................................. 62 
13.3 Public and Patient Involvement ............................................................................................... 62 
13.4 Regulatory Compliance ........................................................................................................... 63 
13.5 Protocol compliance ................................................................................................................ 63 
13.6 Notification of Serious Breaches to GCP and/or the protocol .................................................. 63 
13.7 Data protection and patient confidentiality ............................................................................... 63 
13.8 Financial and other competing interests for the CI, PIs at each site and committee members for 
the overall trial management ........................................................................................................... 64 
13.9 Indemnity ................................................................................................................................ 64 
13.10 
Amendments ..................................................................................................................... 64 
13.11 
Post-trial care .................................................................................................................... 65 
13.12 
Access to the final trial dataset .......................................................................................... 65 
13.13 
Authorship eligibility guidelines and any intended use of professional writers.................... 65 
13.14 
Ethical conduct of the study .............................................................................................. 65 
14 
REFERENCES ....................................................................................................................... 66 
 
 
 
 

Phase I safety and immunogenicity of FP-02.2 in chronic hepatitis B 
    
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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
AESI 
AE of special interest 
ALT 
Alanine aminotransferase 
AR 
Adverse Reaction 
AST 
Aspartate transaminase 
CA 
Competent Authority 
CHB 
Chronic hepatitis B 
CI 
Chief Investigator 
CMI 
Cell-mediated immunity 
CRO 
Contract Research Organisation 
CTA 
Clinical Trial Authorisation 
DNA 
Deoxyribonucleic acid 
DSUR 
Development Safety Update Report 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ELISA 
Enzyme-linked immunosorbent assay 
ELISpot Assay 
Enzyme-Linked Immuno Spot Assay 
FAS 
Full analysis set 
GCP 
Good Clinical Practice 
GLP 
Good laboratory practice 
HBeAg 
Hepatitis B e antigen 
HBsAb 
Antibody to hepatitis B surface antigen 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HDV 
Hepatitis D virus 
HIV 
Human Immunodeficiency Virus 
HLA 
Human Leukocyte Antigen 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation of technical requirements for 
registration of pharmaceuticals for human use. 
IFN-γ 
Interferon gamma 
IM 
Intramuscular 

Phase I safety and immunogenicity of FP-02.2 in chronic hepatitis B 
    
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Protocol Version 6; 11 August 2016                                          
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IMP 
Investigational Medicinal Product 
INR 
International normalised ratio  
IRT 
Interactive Response Technology 
IUD 
Intrauterine device  
IUS 
Intrauterine hormone-releasing system  
MedDRA 
Medical Dictionary for Regulatory Activities 
NA 
Nucleoside analogue 
NUC 
nucleos(t)ide HBV polymerase inhibitor 
OECD 
Organisation for Economic Co-operation and Development 
PBMC 
Peripheral blood mononuclear cells 
PI 
Principal Investigator 
PT 
Prothrombin time 
SAE 
Serious Adverse Event 
SAP 
Statistical Analytical Plan 
SAR 
Serious Adverse Reaction 
SD 
Standard deviation 
SmPC 
Summary of Product Characteristics 
SRC 
Safety Review Committee 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
ULN 
Upper limit of normal 
 

Phase I safety and immunogenicity of FP-02.2 in chronic hepatitis B 
 
   EudraCT number: 2015-000880-15 
 
Protocol Version 6; 11 August 2016                                          
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TRIAL FLOW CHART 
Table 1 Flow chart 
 
Screening 
1st 
 
 
2nd 
 
 
3rd 
 
 
 
Follow- up 
Visit Number 
-6  
(SV) 
16  
(SV) 
26 
(SV) 
36 
(SV) 
46 
(SV) 
- 
(TC) 
56  
(SV) 
6 
(SV) 
- 
(TC) 
76 
(SV) 
86 
(SV) 
96, 9 
(SV) 
Study Day 
-28 to -1  
1 
2 
8  
29 
30 
36  
57  
58 
64 
85  
225 
Visit Windows  
±2 days 
 
 
±1 
day of 
Day 8 
28 (±7 
days) 
days 
after 
Visit 1 
 
7 (±1 
day) 
days 
after 
Visit 4 
28 (±7 
days) 
days 
after 
Visit 4 
 
7 (±1 
day) 
after 
Visit 6 
28 (±1 
day) 
after 
Visit 6 
24 (±4 
weeks) 
weeks after 
Visit 6 
Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Review eligibility  
X 
X 
 
 
X 
 
 
X 
 
 
 
 
Randomisation 
X 
 
 
 
 
 
 
 
 
 
 
 
Vaccination 
 
X 
 
 
X 
 
 
X 
 
 
 
 
Phone call 
 
 
 
 
 
X 
 
 
X 
 
 
X5 
HBsAg, HBsAb 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
HBV DNA 
X 
 
 
 
 
 
 
 
 
 
 
X 
Vital signs 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Dispense Diary 
 
X2 
 
 
X2 
 
 
X2 
 
 
 
 
Injection Site Tolerability  
 
X1 
X 
X 
X1 
X 
X 
X1 
X 
X 
 
 
Pregnancy test4 
X 
X3 
 
 
X3 
 
 
X3 
 
 
X 
 
Safety lab tests 
X 
 
 
X 
X3 
 
X 
X3 
 
X 
X 
X 
Physical examination5  
X 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
Fibroscan 
X 
 
 
 
 
 
 
 
 
 
 
 
Alcohol, drugs of abuse, 
HIV, HDV and HCV 
serology 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
 
Blood for PBMC7 
X 
X3 
 
X 
X3 
 
X 
X3 
 
X 
X 
X 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
X 
Documentation of  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X8 

Phase I safety and immunogenicity of FP-02.2 in chronic hepatitis B 
 
   EudraCT number: 2015-000880-15 
 
Protocol Version 6; 11 August 2016                                          
Page 19 of 67 
 
Screening 
1st 
 
 
2nd 
 
 
3rd 
 
 
 
Follow- up 
Visit Number 
-6  
(SV) 
16  
(SV) 
26 
(SV) 
36 
(SV) 
46 
(SV) 
- 
(TC) 
56  
(SV) 
6 
(SV) 
- 
(TC) 
76 
(SV) 
86 
(SV) 
96, 9 
(SV) 
Study Day 
-28 to -1  
1 
2 
8  
29 
30 
36  
57  
58 
64 
85  
225 
Visit Windows  
±2 days 
 
 
±1 
day of 
Day 8 
28 (±7 
days) 
days 
after 
Visit 1 
 
7 (±1 
day) 
days 
after 
Visit 4 
28 (±7 
days) 
days 
after 
Visit 4 
 
7 (±1 
day) 
after 
Visit 6 
28 (±1 
day) 
after 
Visit 6 
24 (±4 
weeks) 
weeks after 
Visit 6 
AEs  
 
AE: adverse event; CMI: cell-mediated immunity; DNA: deoxyribonucleic acid; ECG: electrocardiogram HBsAg/Ab: Hepatitis B surface 
Antigen/Antibody; HBV: Hepatitis B virus; HCV: Hepatitis C virus; HDV: Hepatitis D virus; HIV: Human Immunodeficiency Virus; SV: Site 
Visit; TC: Telephone Call 
 
1 On the days of the vaccination, injection site tolerability will be assessed by the Investigator up to a minimum of 4 hours after the first 
injection and approximately 24 hours and 7 days after the first injection. For subsequent injections, injection site tolerability will be assessed 
by the Investigator up to 2 hours on the day of injection by the study site. Further assessment of injection site tolerability will be recorded 
using diary cards from 2 hours to 7 days after injection. Data from the diary cards will be transcribed into the appropriate eCRF.  
2. The injection site diary is given to patients after the 1st, 4th and 6th visit, but can only be reviewed post drug, i.e. at the next sequential visit. 
3 Prior to injection of IMP. 
4 Women of childbearing potential only. Serum pregnancy test will be performed at screening; a urine pregnancy test will be performed at 
other scheduled time points. 
5 A full physical examination will be conducted at screening and a brief physical examination will be performed at other time points indicated 
and will include examination of general appearance, injection site, respiratory and cardiovascular systems and the abdomen, particularly the 
upper right quadrant. 
6 Visit intervals are as follows: 
 
screening and randomisation: subjects must be screened -1 to 28 days (±2 days) and can be randomised to treatment up to 3 days 
prior to the first injection.  
 
first dose: Visits 1 and 2 must be done on Days 1 and 2, respectively; Visit 3 may be done within ± 1 day of Day 8.  
 
second dose: Visit 4 may be done 28 days (± 7 days) after Visit 1; subjects must be contacted the day after Visit 4; Visits 5 should be 
done 7 (± 1 day) days after Visit 4. 
 
third dose: Visit 6 may be done 28 days (± 7 days) after Visit 4; subjects must be contacted the day after Visit 6; Visits 7 and 8 may 
be done 7 (± 1 day) and 28 (±1 day) days after Visit 6.  
 
follow-up: Visit 9 must be done at 24 (± 28 days) weeks after the last dose (Visit 6).  

Phase I safety and immunogenicity of FP-02.2 in chronic hepatitis B 
 
   EudraCT number: 2015-000880-15 
 
Protocol Version 6; 11 August 2016                                          
Page 20 of 67 
The scheduled assessments may shift in instances where a visit window is used; subsequent visit dates should be recalculated from the date 
of the new visit. If a second dose visit is missed, the dose can be given 6 weeks after the first dose and noted as out of window. If the dose is 
later than 6 weeks, the second dose visit can be skipped and given at Visit 3 at 8 weeks as per schedule to avoid a delay in the schedule.  
7 PBMC samples for CMI; in consenting subjects HLA typing and other genomic analyses may also be performed. 
8 Only SAEs and AESIs need to be documented during Follow-up (Visit 9). 
9 Subjects will be contacted at approximately 4 week intervals during the follow-up phase. 
 

Phase I safety and immunogenicity of FP-02.2 in chronic hepatitis B 
   EudraCT number: 2015-000880-15    
 
Protocol Version 6; 11 August 2016                                         
 Page 21 of 67 
1 
BACKGROUND 
Hepatitis B virus (HBV) has infected >2 billion people worldwide, of whom more than 360 million 
people (5% of the world’s population) remain chronically infected. HBV is the tenth leading cause of 
death worldwide with over 600,000 HBV-related deaths per year. Life threatening liver disease 
(cirrhosis, liver failure and hepatocellular carcinoma) occurs in as many as 40% of patients with 
chronic hepatitis B (CHB). Even though prophylactic vaccination programmes have led to declines in 
de novo HBV infections in many countries, the burden of disease in adult patients remains high. The 
treatment of CHB has improved dramatically in the last 10 years, owing to the development of new 
antiviral compounds including polymerase inhibitors or pegylated alpha-interferon. Despite significant 
retardation in HBV-related disease progression and reduction in mortality, those treatments rarely 
achieve clinical cure 13, manifested by surface antigen (HBsAg) loss, notably due to their inability to 
promote an effective anti-HBV immunologic control. Treatment guidelines recommend antiviral therapy 
with nucleos(t)ide HBV polymerase inhibitors (NUCs) for all patients with biochemical or histological 
disease. Antiviral treatment can rarely be stopped and lifelong therapies are usually required, as 
NUCs only suppress HBV replication without inducing a clearance of infected liver cells. Long term 
safety of NUC therapy is uncertain, while long term cost implications are unsustainable. Therapies are 
urgently needed to enable timely cessation of NUC treatment and deliver efficient and effective 
healthcare. Therapeutic vaccination is a promising approach to induce immune control over the 
disease. CD4+ and CD8+ T cell responses have been shown to be critical for clearance of acute HBV 
infection and immune control can be linked to the strength and quality of HBV-specific T cell 
responses. CHB patients are known to have profound defects in anti-HBV-specific T cell immune 
responses, thereby compromising critical protective and disease control mechanisms. So far, two 
large trials evaluating therapeutic vaccines (with or without approved treatments) as a means to 
potentially promote an anti-HBV immunity in CHB patients have reported disappointing results with no 
evidence of HBsAg clearance (or increased rate of hepatitis B e antigen [HBeAg] seroconversion) 8, 15. 
A limitation of these two trials was the use of HBsAg, which was primarily designed to preferentially 
boost antibody-mediated immune responses as opposed to induction of CD4+ and CD8+ T cell 
responses, as observed in individuals with spontaneously resolved infections 6. Altimmune’s novel 
therapeutic vaccine, FP-02.2, is designed to restore effective T cell immunity with potential for disease 
modification and potentially serological cure. 
This study evaluating the safety and immunogenicity of FP-02.2 is a double blind, randomised and 
placebo controlled clinical trial in HBeAg-negative CHB patients receiving entecavir or tenofovir. The 
study will assess two doses of the vaccine given as single intramuscular (IM) injections on three 
occasions four weeks apart. While it is anticipated that FP-02.2 will be immunogenic in the absence of 
an adjuvant as demonstrated with a similar vaccine relying on the same vaccine platform 4, a co-
formulation with an adjuvant (IC31®) will be also tested to potentially achieve a higher level of immune 
response and/or counteract immune tolerance mechanisms. Seventy-two evaluable patients will be 
randomised into six treatment arms 1. Low-dose FP-02.2, 2. High-dose FP-02.2, 3. Low-dose FP-02.2 
+ adjuvant (IC31®), 4. High-dose FP-02.2 + adjuvant (IC31®), 5. Placebo, 6. IC31® only, distributed 
over three cohorts according to the scheme set out in Error! Reference source not found.. This 
group size is not powered to measure efficacy but is of standard size to assess differences in vaccine 
treatments. The CHB patient population to be recruited in the study are HBeAg-negative, representing 
the majority of cases in many areas. The vaccine will be tested as an add-on to entecavir or tenofovir, 
two antiviral drugs known to be highly effective in their ability to inhibit HBV replication but also to 
promote a partial restoration of HBV-specific T cell functionality 2. The study intends to recruit male 

Phase I safety and immunogenicity of FP-02.2 in chronic hepatitis B   
 EudraCT number: 2015-000880-15    
  
Protocol Version 6; 11 August 2016                                          
Page 22 of 67 
and female subjects, aged 18-65 years who have received nucleotide/nucleoside treatment for at least 
2 years.  
FP-02.2 is a freeze-dried vaccine containing 9 synthetic peptides (each 32 to 40 amino-acid residues) 
and mannitol. Each of the 9 peptides is modified by a fluorocarbon moiety providing immune 
enhancing properties 5. FP-02.2 peptides are derived from three HBV antigens with four peptides 
derived from HBV polymerase, four from HBV core protein and one from HBV surface protein 
representing collectively 18.7% of the HBV proteome. These peptides are derived from the most 
conserved portions of the HBV proteome, presumably bearing higher viral fitness costs and resulting 
in a high level of T cell cross-reactivity irrespective of the HBV genotype. The peptides, derived 
immunodominant antigen regions, have the ability to promote dual CD4+ and CD8+ T cell responses 
and support broad coverage across ethnically diverse populations. The manufacturing of the peptides 
relies on a well-established solid phase synthesis using Fmoc chemistry and conventional Reversed-
Phase High-Performance Liquid Chromatography purification systems for the production of a fully 
characterisable active pharmaceutical ingredient with low cost of goods. Vaccine FP-02.2/IC31® is an 
adjuvanted formulation of FP-02.2, in which FP-02.2 is combined with the clinically-tested vaccine 
adjuvant IC31®. IC31® is composed of synthetic TLR9 agonist (ODN1a) complexed with a cationic 
peptide (KLK). The positively-charged KLK peptide provides a delivery system and stabilising function 
for ODN1a, which cannot activate the immune system by itself, likely due to its short half-life. KLK also 
contributes to the depot effect of IC31®, prolonging antigen exposure to professional antigen 
presenting cells at the site of injection. IC31® has been assessed extensively in pre-clinical and 
clinical studies demonstrating an acceptable safety profile and excellent adjuvanticity in combination 
with various vaccines 9, 14, 10, 12. 
The sequence of each of the 9 peptides contained within FP-02.2 has been identified from within the 
HBV proteome using a bioinformatics platform so that each peptide contains a high density cluster of 
human major histocompatibility complex class I and class II binding epitopes that can be recognised 
by a broad population irrespective of their genetic background. In addition these peptides have been 
selected to direct the immune system to target conserved regions of the virus thereby being able to 
induce immune responses against the prevalent HBV genotypes, A, B, C and D. These peptides were 
demonstrated to promote poly-functional CD4+ and CD8+ T cell responses in peripheral blood 
mononuclear cells (PBMC) isolated from CHB donors, irrespective of infecting HBV genotypes or 
patient ethnicities. In mice, FP-02.2 induces a strong T cell response that is significantly enhanced in 
the presence of IC31®. FP-02.2 promotes a robust T cell response either in the spleen or in the liver 
either in naïve mice or mice infected with an AAV-HBV replicon. Two good laboratory practice (GLP)-
compliant toxicology studies have been completed with Vaccine FP-02.2 ± IC31®, one evaluating 
repeated doses toxicology in mice and the other evaluating local injection site tolerability in rabbits. In 
the repeat-dose toxicity study performed in mice, IM immunisation of FP-02.2 ± IC31® on four 
occasions over 6 weeks was well tolerated, with no treatment related deaths, minor changes in clinical 
pathology and several histopathological changes observed at injection sites. Observed changes were 
consistent with expected local and systemic responses to a potent immunostimulatory vaccine 
product. In the local tolerability study performed in rabbits, IM immunisation of FP-02.2 ± IC31® was 
well tolerated with no evidence of systemic toxicity or local dermal intolerance. Changes to muscle 
tissue observed with histopathological examination on Day 5 were considered almost totally reversible 
following a second assessment on Day 22. 
There is no available clinical research data to date on the investigational product. 

Phase I safety and immunogenicity of FP-02.2 in chronic hepatitis B   
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Protocol Version 6; 11 August 2016                                          
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2 
RATIONALE  
Limited treatment options are available for CHB, the leading cause of end-stage liver disease and 
hepatocellular carcinoma worldwide. Only interferon-alpha has been able to induce HBsAg loss, which 
is considered to be a clinical “cure”, in a relatively low proportion of patients (<10%) and therefore 
establishing a clinical precedent for predicting efficacy. Interferons have a high cost, a poor tolerability 
(particularly in combination with ribavirin) and some HBV genotypes remain poorly responsive to 
treatment. Consequently, NUCs remain the main treatment strategies with five NUCs being approved 
in Europe to treat CHB. The most potent and preferred drugs, entecavir (brand name Baraclude®, 
Bristol-Myers Squibb) or tenofovir disoproxil furamate (tenofovir, brand name Viread®; Gilead), have a 
favourable side-effect profile and are able to induce HBV deoxyribonucleic acid (DNA) suppression in 
almost all patients and have a high barrier to resistance. However, these treatments suppress but do 
not eradicate HBV and rarely achieve clinical “cure‟ through HBsAg loss or seroconversion. Therefore, 
patients will require long durations if not life-long treatment to maintain virus suppression and to derive 
continued clinical benefit. Furthermore, the long-term safety of NUC therapy is currently unknown and 
costs for entecavir and tenofovir treatment are frequently reimbursed for only 2-3 years in many 
countries. Therefore, novel therapies that enable a timely stopping of NUC therapy are urgently 
needed. 
Therapeutic vaccination is a very promising intervention for hepatitis B as a way to induce immune 
control over the disease. T cell responses have been shown to be critical for clearance of acute HBV 
infection. Cellular immune responses differ between the different phases of CHB and immune control 
of HBV can clearly be linked to the strength and quality of HBV-specific T cell responses 3, 2. 
Therapeutic HBV vaccines based exclusively on HBsAg have failed to show benefit due to pre-existing 
immune tolerance from high levels of circulating HBsAg, even under effective concomitant antiviral 
treatment. Novel vaccine strategies based on combinations of HBsAg with other HBV antigens have 
emerged1 but have not yet shown efficacy in a clinical study. The limited clinical investigations to date 
have been completed to address T cell correlates of protection with limitations related to the genetic 
variability of the virus. 
The design of FP-02.2 takes advantage of a vaccine platform developed by Altimmune (formerly 
Vaxin, formerly Immune Targeting Systems) that is dedicated to the development of synthetic peptide-
based vaccines aimed at promoting T cell responses against mutating viruses. This platform 
comprises two complementary arms i) a bioinformatics methodology to select broadly immunogenic 
long peptide sequences against viral regions conserved across genotypes and ii) a novel vaccine 
formulation using multiple fluorocarbon-linked peptides to produce a depot following IM administration 
that prolongs vaccine half-life and enhances immunogenicity in situ.  
The nine peptides included in FP-02.2 have been selected based on an extensive screening process 
relying on bioinformatics, preclinical screening and key manufacturing aspects. FP-02.2 has been 
designed to deliver the most conserved domains of HBV surface, core and polymerase antigens 
(corresponding cumulatively to 18.7% of the HBV proteome) to achieve multi-epitopic CD4+ and CD8+ 
T cell responses, irrespective of ethnicity, human leukocyte antigen (HLA) background or infecting 
HBV genotype. This approach is required to optimise antiviral activity by exerting broad immune 
pressure on the virus and consequently minimising viral escape mechanisms. This approach has a 
significant advantage over other vaccine approaches in development, such as DNA or viral vaccines, 
by allowing for multi-use booster capability.  

Phase I safety and immunogenicity of FP-02.2 in chronic hepatitis B   
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Protocol Version 6; 11 August 2016                                          
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In two study arms, FP-02.2 will be used in conjunction with the vaccine adjuvant IC31® to potentially 
increase immune responses to the vaccine and overcome immune tolerance and the suppression 
mechanism observed in CHB. A fixed dose of IC31® will be used (500nmol KLK/ 20nmol ODN1a) that 
has been previously tested in 8 Phase I/IIa clinical trials in combination with TB or seasonal influenza 
vaccines. 
This study will be the first in man study for Vaccine FP-02.2 and will assess the safety and tolerability 
of three IM injections of a therapeutic hepatitis B fluoropeptide vaccine in HBeAg-negative hepatitis B 
patients as an add-on treatment to entecavir or tenofovir. Immunogenicity analysis of the specific T 
cell responses induced by Vaccine FP-02.2 or Vaccine FP-02.2/IC31® will be undertaken to aid 
selection of the optimal dose to be used for future studies.  
Clinical evaluation of Vaccine FP-02.2 will seek to address these key issues: 
1. 
At estimated effective dose(s), and in the presence or absence of an estimated effective dose of a 
compatible adjuvant, is the vaccine safe and tolerated in nucleoside analogue (NA)-treated HBV 
patients with stable disease? 
2. 
Is there evidence of induction of an immune response to the vaccine and what impact does an 
adjuvant (IC31®) have on the immune response – i.e. magnitude and anti-viral phenotype of T cell 
response.  
3. 
To what extent is the immune response robust and durable? 
4. 
Is there evidence of a pharmaco-dynamic effect of the vaccine indicative of potential efficacy i.e. 
reduction in serum HBsAg and/or increase in serum antibody to HBsAg; if so is the response dose 
dependent and is the response modified by inclusion of IC31®? 
 
2.1 
Assessment and management of risk 
2.1.1 Potential benefits 
It is anticipated that the results of the Phase I study with Vaccine FP-02.2 will establish the safety 
profile and potential immunogenicity profile of the vaccine in patients with stable HBV infections. The 
incorporation of various immunogenicity readouts in the study protocol will provide information on the 
immune response to the vaccine over a range of dosages and formulations, so as to enable selection 
of a suitable dosage and formulation for use in larger scale clinical trials, including a Phase II study 
powered to establish significance for efficacy readouts. Volunteers taking part in the study may obtain 
some benefit, in terms of attaining an immune response that may be therapeutic to current HBV 
infection but this should not be expected.  
2.1.2 Potential Risks 
The potential risks associated with Vaccine FP-02.2 administration are anticipated to be: 
Unintended Immune Stimulation 
FP-02.2 is a vaccine formulation that is intended to induce a specific cellular immune response 
towards targeted HBV epitopes. Primary pharmacodynamic studies in animals, and data generated 
utilising human PBMC indicate that the fluorocarbon conjugation of the peptides in the Vaccine FP-
02.2 formulation enhances the specific cellular immune response. Clinical trials conducted with 
another peptide-based vaccine product 11 found no increase in the incidence of auto-antibodies 
amongst treated subjects, compared to those receiving placebo. Moreover, clinical trials conducted 

Phase I safety and immunogenicity of FP-02.2 in chronic hepatitis B   
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Protocol Version 6; 11 August 2016                                          
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with a similar peptide based vaccine product targeting influenza A 4 found no immune stimulation 
issues in adults (young and old). 
The risk for Vaccine FP-02.2 to induce an unintended or autoimmune response in humans is 
considered to be low as evidenced by: 
 
The presence of pre-existing immunity to Vaccine FP-02.2 antigens in HBV patients chronically 
exposed to HBV 
 
The absence of significant sequence homology with human proteins 
The vaccine was designed to recover HBV specific T cells and bring their frequencies to protective 
levels. We have demonstrated in an in vitro PBMC assay, low frequency CD4+ and CD8+ T cells 
specific for the nine FP-02.2 peptides can be expanded in many, if not all, HBV patients. This indicates 
that during infection, similar viral peptides are presented during the course of the infection to the 
immune system.  
In clinical studies conducted in patients with other therapeutic HBV vaccines, no notable adverse 
effects or acute flares of hepatitis were detected. For example, in an open-label, controlled, 
randomised study, 195 patients with HBeAg-positive CHB received 12 doses of HBsAg with AS02B 
adjuvant candidate vaccine plus lamivudine daily for 52 weeks or lamivudine daily alone15. The 
combined administration of vaccine and lamivudine was safe and well tolerated in the context of a 
vigorous HBsAg-specific lymphoproliferative response, cytokine production and anti-HBs antibodies. 
Also a phase III clinical study conducted in patients with chronic HBV evaluating Nasvac, a therapeutic 
HBV vaccine administered on 5 occasions, 7 reported no notable adverse events (AEs) or acute flares 
of hepatitis. Nevertheless, the theoretical risk of Vaccine FP-02.2 inducing an immune response, 
resulting in the death of hepatocytes infected with HBV, which could result in fulminant hepatic failure, 
remains and will be monitored for by regularly assessing liver function tests. 
In conclusion, this information indicates that the nine long peptides selected for inclusion into a novel 
HBV vaccine are at low risk of inducing cross-reactive immunity that may lead to auto-reactive T cell 
responses. In addition, the risk of generalised, non-specific immune stimulation following Vaccine FP-
02.2 administration is considered to be low. 
Local and Systemic Reactions 
In a repeat-dose toxicity study performed in mice, intramuscular immunisation of FP-02.2 ± IC31® on 
four occasions over 6 weeks was well tolerated, with no treatment-related deaths, minor changes in 
clinical pathology and several histopathological changes observed at injection sites. Observed 
changes were consistent with expected local and systemic responses to a potent immunostimulatory 
vaccine product. A local tolerability study performed in rabbits, intramuscular immunisation of FP-02.2 
± IC31® was well tolerated with no evidence of systemic toxicity or local dermal intolerance. Changes 
to muscle tissue observed with histopathological examination on Day 5 were considered almost totally 
reversible following a second assessment on Day 22.  
Local injection site and systemic reactions to vaccinations are common with all vaccinations and pain, 
erythema and induration of mild intensity can be expected at the injection site and fever, malaise or 
body aches may occur. 

Phase I safety and immunogenicity of FP-02.2 in chronic hepatitis B   
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Protocol Version 6; 11 August 2016                                          
Page 26 of 67 
Reproductive Effects 
No reproductive toxicity studies have been performed. There is no evidence from examination of the 
reproductive tract tissues in the repeated dose toxicity study in mice, of an effect of Vaccine FP-02.2 
on the female or male reproductive organs. A number of contraceptive requirements are included in 
the protocol. The risk of adverse effects on reproduction is considered to be very low. 
Other Risk Factors and Precautions 
There may be other effects or risk factors that are currently unknown.  
To assess unknown risks clinical studies will include assessment of a full panel of haematology, 
clinical chemistry and liver function parameters, physical examination, electrocardiogram (ECG), vital 
signs, as well as local tolerability. 
Until reproductive toxicity data are available it is important that women participating in trials and female 
partners of male subjects do not become pregnant. Contraceptive requirements will be mandated for 
each trial, and described in the Investigator’s Brochure (IB). 
Other Toxicity 
No other toxicity is anticipated for Vaccine FP-02.2 to that discussed in the previous sections. 
 
2.1.3 Subject selection 
The study is designed as a first in man study in patients with stable HBeAg-negative CHB who are 
otherwise healthy with no compromise in their liver function. The rationale for moving directly into 
patients with CHB, and not administering Vaccine FP-02.2 to healthy volunteers first, was based on 
the following points: 
 
Evaluating the safety of Vaccine FP-02.2, in the absence of HBV exposure i.e. in healthy 
volunteers will not adequately assess safety of the immune response generated to FP-02.2 in the 
context of existing HBV infection. 
 
Patients with CHB have, unlike 90% of the population, failed to clear the initial infection and the 
chronic exposure to HBV has a significant impact on the immune responsiveness to HBV antigens, 
compared to healthy non-infected subjects; therefore, the immune response to Vaccine FP-02.2 in 
patients is likely to be very different to the immune response to Vaccine FP-02.2 in healthy 
volunteers. 
From these considerations, it was determined that assessing safety and immunogenicity of Vaccine 
FP-02.2 in healthy volunteers would be of limited value with the results likely to show a greater 
immune response generated to Vaccine FP-02.2 and not being able to assess the key safety variable 
i.e. the acute immune-toxicity in the presence of HBV infected liver cells. Therefore, it was determined 
that it is most appropriate to conduct this first in man study in stable patients chronically infected with 
HBV.  
 
2.1.4 Study site 
Having made the decision to initiate the first in man study in patients chronically infected with HBV, 
consideration was given to where the study should be conducted. The safety aspects of the study 

Phase I safety and immunogenicity of FP-02.2 in chronic hepatitis B   
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Protocol Version 6; 11 August 2016                                          
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were the most important consideration. Sites need to be able to manage both acute systemic 
reactions (immediately after injection) and the longer term safety of patients, have access to a facility 
which is able to manage an acute flare and has expertise, experience and ability to care for patients 
with CHB. An effective immunotherapeutic product will induce an immune response against the HBV, 
which will result in the death of hepatocytes infected with HBV; if sufficient hepatocytes are killed in 
this process, an acute flare with hepatic decompensation could theoretically occur.  
To mitigate the risks identified above the following procedures will be undertaken: 
 
A sentinel group will be dosed prior to the dosing of each of the study cohorts. 
 
All subjects will be kept in clinic for 4 hours after the first injection and 2 hours post dose following 
injection 2 and 3, for observation and assessment for any acute reaction. It is not possible to 
measure pharmacokinetic parameters for a vaccine and, therefore, no serial blood samples will be 
taken. The observation period will only assess acute safety. Following the four-hour review after 
the first dose, or the two-hour review period following the second and third doses, it is considered 
unlikely that any acute reactions will develop and it is appropriate for the subject to return home.  
 
After discharge, the patient should call the Investigator at their site on the contact number 
provided, for any non-urgent medical advice. If the patient becomes very unwell, they should seek 
emergency care and the evaluating physician should call the Investigator for advice and 
information. 
 
Subjects will return to the clinic for a safety check 24±2 hours after the first administration of 
investigational medicinal product (IMP). The assessment will include a general assessment, vital 
signs, discussion regarding AEs and assessment of the injection site. 
 
Bloods for assessing liver function will be taken at 7 days after each injection and prior to the 
subsequent injection. These results will be reviewed by the Principal Investigator (PI) for each site. 
Any subject experiencing an increase in alanine aminotransferase (ALT) to 10 times the upper limit 
of normal (ULN), a prothrombin time, reported as the international normalised ratio (INR) of more 
than 1.3 or a total bilirubin greater than 3 times the ULN, will be called back to study site for 
assessment and will not receive any more doses of Vaccine FP-02.2. Subjects with an ALT above 
5 times the ULN will be closely monitored and dosed at the discretion of the Investigator. 
 
Any subject experiencing a flare with decreased liver function will be managed by the PI for the 
site, as per local clinical protocols.  
 
A safety review committee (SRC) (defined as the country CIs, if applicable, and the study medical 
monitors) will review and assess all safety data for Cohorts 1 and 2 after at least 15 or 30 subjects, 
respectively, have completed Day 36 assessments.  
Communication between the sites to discuss subject safety is of critical importance and, in addition to 
the SRC. Sites are encouraged to contact the Sponsor’s medical monitor or regional CIs for any 
questions or concerns about the study, especially if related to patient safety. 
 
2.1.5 Dose selection 
Dosages for early human studies with vaccines are often based on optimal immunogenic doses in 
animal models (based on amount of antigen, without correction for bodyweight or body surface area), 
and demonstration that this optimal immunogenic dose (in terms of µg of antigen) does not cause 
overt toxicity when injected into a suitable pre-clinical toxicity species, such as mice, rats or rabbits. 
Injection of the optimal immunogenic dose into the toxicity study species will provide a safety margin 

Phase I safety and immunogenicity of FP-02.2 in chronic hepatitis B   
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Protocol Version 6; 11 August 2016                                          
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(of at least 10-fold, and often greater) when compared to the same dose injected into humans, when 
the dosage is corrected for bodyweight differences between species. Pre-clinical results in mice 
demonstrate that the highest immunogenicity was observed using a dose of 100µg/peptide. Safety 
and immunogenicity of the vaccine platform (using multiple fluoropeptides) have previously been 
evaluated across three phase I clinical studies in the context of a universal influenza A vaccine. The 
first study (NCT01265914) was a dose escalation study in healthy young adults, where the 6 
fluoropeptide ‘flu vaccine was given at days 1, 29 and 99 and tested at doses of 50, 150 and 
500µg/peptide 4. The second study (NCT01677676) was a dose optimisation study testing doses of 
150 and 250µg/peptide administered at days 1 and 29, with and without an adjuvant (Advax - a novel 
polysaccharide adjuvant), in healthy young adults. The third study (NCT02071329) assessed the flu 
vaccine at 250µg/peptide with or without Advax and/or concomitant TIV in healthy older adults (65-74 
years) administered on days 1 and 29. Across all studies, a robust T Cell immune response to the 
vaccine was measured in subjects receiving doses between 150 and 500µg/peptide and after two 
injections. 
Taking this previous clinical experience with the vaccine platform together with immunogenicity in 
mice, it was reasonable to propose 150µg/peptide as the starting dose for the first-in-man study for 
FP-02.2. Moreover, this dosage was within in the range of effective dosages that have been studied in 
clinical trials of similar peptide vaccine approaches such as lipopeptide-based vaccines that reported 
acceptable safety profiles. For example, a dosage range of 50-500µg/peptide (250µg – 2500µg total 
peptide) was examined in a healthy volunteer trial of a human immunodeficiency virus (HIV) 
lipopeptide vaccine, with good tolerability and immunogenicity 11. 
The range of human dosages in the planned phase I study will be 150µg and 500µg per peptide (i.e. 
up to ~10µg/kg per peptide for a 50kg subject). In the repeat dose toxicity study, the dosage 
administered to mice (0.05mL of human formulation, containing 25µg per peptide = 1000µg/kg per 
peptide for a 25 g mouse) provides a 100-fold safety margin over the planned maximum human 
dosage, which equates to an 8-fold margin allowing for allometric scaling. For a 70 kg subject the 
safety margin will be approximately 11. For IC31®, the human dosage in the planned phase I study 
will be 500 nmol/20 nmol KLK/ODN1a, in a volume of 1mL for human administration (i.e. up to 10 
nmol/0.4 nmol/kg for a 50 kg subject). The dosage administered to mice (0.05mL of human 
formulation, containing 25 nmol/1 nmol = 1000 nmol/40 nmol/kg for a 25 g mouse), therefore provides 
a 100-fold safety margin over the planned maximum human dosage, which equates to an 8-fold safety 
margin allowing for allometric scaling. 
2.1.6 Dose escalation 
For reasons of participants’ safety, the clinical trial design will be performed in a stepwise fashion 
introducing each component based on the determined risk attributed to that cohort’s treatment. Table 
2 outlines the dosing regimen. 

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Table 2 Dosing regimen. 
Cohort 
Treatment arm 
Approximate 
number of subjects 
1 
 
Placebo 
5 
FP-02.2 Low-dose 
10 
2 
 
Placebo 
5 
IC31® adjuvant only 
5 
FP-02.2 Low-dose + IC31® adjuvant 
10 
FP-02.2 High-dose 
10 
3 
IC31® adjuvant only 
5 
FP-02.2 High-dose + IC31® adjuvant 
10 
 
For each cohort, the first subject from each treatment arm will form a sentinel group, e.g. for Cohort 1, 
the sentinel group will consist of 1 subject receiving placebo and 1 subject receiving Low-dose 
Vaccine FP-02.2. The CI and any PI(s) involved in dosing sentinel subjects will review safety data 
collected up to and including Day 8 visit as detailed in Section 4 before recommending whether or not 
the remaining subjects of a cohort should be dosed. 
In order to escalate between doses, the SRC will review safety and tolerability data up to and including 
the Day 36 visit from subjects in Cohort 1 and verify no safety concerns have been detected before 
enrolling subjects into Cohort 2. Similarly, subjects may be enrolled into Cohort 3 after review of safety 
and tolerability data up to and including Day 36 from subjects from Cohort 2. If safety and tolerability 
data are not acceptable the SRC may recommend lowering the dose of FP-02.2 or omitting the use of 
IC31®. 
All data used to support dose escalation will be quality checked. Dose decisions between cohorts will 
be documented. 
 
3 
OBJECTIVES AND OUTCOME MEASURES/ENDPOINTS 
3.1 
Primary objective 
To assess the safety and tolerability of Vaccine FP-02.2 at Day 85 following vaccinations on Days 1, 
29 and 57. 
 
3.2 
Secondary objectives 
To measure immunological response of Vaccine FP-02.2 at Day 85 following vaccinations on Days 1, 
29 and 57. 
 
3.3 
Outcome measures/endpoints 
3.3.1 Primary endpoints/outcomes 
 
Solicited AEs related to injection site tolerability during the week following each vaccine 
administration 
 
Unsolicited AEs through day 85 

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 
Serious adverse events (SAEs) and AEs of special interest (AESIs) through 6 months after last 
vaccine dose  
 
Vital signs 
 
ECG 
 
Safety Laboratory including laboratory assessment of liver inflammation and function 
 
3.3.2 Secondary endpoints/outcomes 
Immunological parameters: 
The immunogenicity of Vaccine FP-02.2 will be determined using an IFNγ ELISPOT assay. The output 
for the ELISPOT assay will be number of cells producing interferon gamma (IFN-) in response to 
exposure to native peptides derived from FP-02.2 using an ex vivo and cultured assay. Negative 
assay controls will contain no peptide and positive controls will use a T cell mitogen.  
Additional exploratory immunological assays such as T Cell proliferation assays, intracellular cytokine 
staining assays, ELISA-based assays to measure FP-02.2-specific antibodies or other suitable assays 
may be used to further characterise the immune responses to Vaccine FP-02.2. The frequency of 
regulatory cells, expression of co-stimulatory and inhibitory markers may be measured by flow 
cytometry. 
Immunological data from samples collected within the follow-up phase will be regarded as exploratory, 
including IFNγ ELISPOT data.  
Virological parameters: 
The following will be measured by means of ELISA-based assays:  
 
Quantitative HBsAg  
 
Anti HBsAg antibody  
 
A validated HBV DNA TaqMan assay will be used to quantitatively measure HBV DNA. 
 
3.4 
Exploratory endpoints/outcomes  
 
HBV genotype characterisation (limited to genotype A, B C or D) by means of ELISA to understand 
if there is a relationship between immunological responses and infecting HBV genotype will be 
performed on Day 1. 
 
In consenting subjects, gene expression may be studied which has the potential for identifying 
genetic markers that predict vaccine immunogenicity, or successful clinical responses, as well as 
elucidating biological mechanisms of vaccine efficacy. HLA genotyping will be performed to 
understand if the vaccine specific immune responses are independent of the subject’s HLA 
background.  
 
4 
TRIAL DESIGN 
This is a double-blind, randomised, placebo-controlled, dose-ascending study to evaluate the safety, 
tolerability and immunogenicity of Vaccine FP-02.2 in HBeAg-negative hepatitis B patients as an add-
on treatment to entecavir or tenofovir. 

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Actively treated subjects will receive either a Low or High dose of Vaccine FP-02.2 with or without 
IC31®. 
A placebo arm is included in the study. Safety and immunogenicity data generated from the placebo 
arm will allow comparison to data generated from the Vaccine FP-02.2 High and Low dose study 
arms. The placebo group is also necessary to understand the rate of natural HBsAg seroconversion in 
an untreated study arm. An IC31® alone arm is included in the study which will additionally allow 
comparison of safety and immunogenicity data with data generated from the Vaccine FP-02.2 High 
and Low dose/IC31® study arms. 
Approximately of 60 subjects (excluding replacements for subjects deemed ineligible after dosing) will 
complete this trial and will be assigned equally to 6 study arms (approximately 10/study arm). 
Screening will occur up to 28 days prior to the first injection.  
Up to 3 days before the first injection, eligible subjects will be randomised to treatment arm as shown 
in Table 2, depending on the cohort.  
Subjects will receive 3 injections at intervals of 28 days (Day 1, Day 29, and Day 57). On the days of 
the injections the subjects will stay in the clinic for at least 4 hours after the first injection and 2 hours 
after the second and third injections and be monitored closely including an assessment of local 
reactions at the injection site. Approximately 24 hours after the first injection, the subjects will be 
asked to attend the clinic for safety assessments. For subsequent injections, subjects will receive a 
telephone call approximately 24 hours after each injection for safety follow-up. The subjects will be 
asked to return to the clinic 7 days after each injection for further assessments as well as 28 days after 
the last injection (Day 85). A follow-up visit will be performed 6 months after the end of the treatment 
period (i.e. 6 months after the last dose). 
The first cohort starts with a low dose of Vaccine FP-02.2, 150µg/peptide (1350µg total peptide or 
placebo). The next cohort receives a higher dose of Vaccine FP-02.2, 500µg/peptide (4500µg total 
peptide) or a low dose of Vaccine FP-02.2, 150µg/peptide, in conjunction with 500nmol/20nmol 
KLK/ODN1a IC31® or placebo or 500nmol/20nmol KLK/ODN1a IC31® alone. The final cohort will test 
the high dose of Vaccine FP-02.2, in conjunction with 500 nmol/20 nmol KLK/ODN1a IC31® or 
500nmol/20nmol KLK/ODN1a IC31® alone. See Table 2. 
For each cohort, dosing will start with a sentinel group consisting of one subject from each treatment 
arm, receiving active or control (FP-02.2 (IC31®), IC31® or placebo), e.g. for Cohort 1, the sentinel 
group will consist of 1 subject receiving placebo and 1 subject receiving Low-dose Vaccine FP-02.2. 
After the assessments on Day 8, the SRC will meet and review the safety data from the sentinel group 
and recommend whether or not the remaining subjects of a cohort should be dosed. Any PI with 
patients in the sentinel group will provide input to the SRC meeting. 
In order to progress to the next cohort, the SRC with input from the Investigators contributing patients 
will meet to review safety data up to Day 36 from Cohort 1. Following this review subjects may be 
dosed in Cohort 2 assuming the SRC has identified no safety concerns. Similarly, subjects may be 
dosed in Cohort 3 after review of safety data up to and including Day 36 from subjects in Cohort 2.  
 

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5 
STUDY SETTING 
This is a multi-national, multi-centre clinical trial and each site is responsible for recruitment, treatment, 
follow-up and continuing care for subjects enrolled in each site. 
The study sites were selected based on their large cohorts of patients with HBeAg-negative chronic 
HBV infection and appropriate experience in clinical trials. 
 
6 
ELIGIBILITY CRITERIA 
6.1 
Inclusion criteria 
1. Male and female subjects aged 18-65 years. 
2. Diagnosed with CHB defined as HBsAg positive for at least 24 months. 
3. Subject has received entecavir or tenofovir for at least 2 years with a stable dose for at least 6 
months prior to screening. 
4. HBeAg negative for at least 2 years prior to inclusion in the study. 
5. HBV DNA <50 IU/mL for ≥ 12 months 
6. ALT or AST ≤ 1.5 x the ULN via the local laboratory at the Screening Visit 
7. Able to give written informed consent to participate 
8. Females should fulfil one of the following criteria: 
a. At least one year menopausal 
b. Surgically sterile 
c. Same-sex relationship  
d. Women of childbearing potential not surgically sterilised or with laboratory confirmed 
menopausal status are required to use a highly effective contraceptive measure with low 
used dependency such as:  
 
o Combined (oestrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation 
o Progestogen-only hormonal contraception implants associated with inhibition of 
ovulation 
o Intrauterine device (IUD) 
o Intrauterine hormone-releasing system (IUS) 
o Bilateral tubal occlusion 
o Vasectomised partner – must have had medical assessment of successful surgery. 
From screening until one menstrual cycle after the last dose of IMP (Day 57).  
Subjects who practice true abstinence or who exclusively have same sex partners need not 
use contraception, provided it is in line with their preferred and usual lifestyle. Periodic 
abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception. Should any such subject stop 
practicing true abstinence, they must use contraception as described above. 

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Males should fulfil one of the following criteria: 
o Surgically sterile 
o Willing to abstain from sexual intercourse or use a reliable form of contraception (e.g. 
condom with spermicide), if having sex with a pregnant or non-pregnant woman of 
childbearing potential, from screening until 3 months after the final dose of IMP. 
o Surgically sterilised or post-menopausal female partner or same-sex relationship 
 
6.2 
Exclusion criteria 
1. Liver disease other than CHB (a diagnosis of steatosis is permitted providing inclusion criterion 6 is 
met). 
2. Evidence of Liver cirrhosis on Fibroscan at screening (Liver cirrhosis is defined as a Fibroscan 
measurement of >11.5 KPa), or previous history or evidence of cirrhosis on radiological imaging, 
Fibroscan or liver biopsy.  
3. Positive serology for HIV-1 or HIV-2 or HCV or HDV antibodies. 
4. Immunodeficient or autoimmune conditions due to disease or medication e.g. systemic steroids 
within previous 12 weeks. (Topical or inhaled steroids are permissible). 
5. Clinically relevant co-morbidity, e.g. autoimmune disease. 
6. Clinically relevant anaemia or leukopenia in the opinion of the investigator. 
7. Cancer or treatment for cancer within 3 years prior to screening excluding basal cell carcinoma of 
the skin, which is allowed. 
8. Known or suspected intolerance or hypersensitivity to the IMP or closely related compounds or any 
of the stated ingredients. 
9. Receipt of any IMP within 90 days prior to screening or currently receiving IMP or intent to receive 
IMP. 
10. Current substance or alcohol abuse that in the opinion of the Investigator would interfere with 
compliance or with interpretation of study results. 
11. Any condition that in the opinion of the Investigator might interfere with study objectives. 
12. Pregnant or breastfeeding. 
13. Subjects should not have received, during the 6 month period prior to screening, any medications 
or other treatments that may adversely affect the immune system such as allergy injections, 
immunoglobulins, interferons, cytotoxic drugs or other drugs known to be frequently associated 
with significant major organ toxicity, or systemic corticosteroids (oral or injectable). 
Immunosuppressive treatment such as azathioprine or mercaptopurine is not permitted in the 
6 months prior to screening. 
14. Administration of live vaccines (such as live influenza vaccinations or live travel vaccinations) from 
10 days prior to the screening visit until Day 85. 
 
 
 

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7 
TRIAL PROCEDURES  
7.1 
Recruitment 
7.1.1 Patient identification 
Patients who may be eligible for the study will be identified by the Investigator from the site’s records 
of patients with CHB. If a network of hospitals/clinics exists, other hospitals/clinics may identify 
suitable patients and refer them to the investigator’s site.  
 
7.2 
Consent  
Written informed consent will be obtained from all subjects at the screening visit, prior to entry into the 
study. The Investigator will explain to each subject orally and in writing the nature, significance, risks 
and implications of the trial before inclusion. In particular, the subjects will be informed about the 
following: 
 
the possibility of withdrawing from the clinical trial at any time by revoking the consent and without 
any resulting disadvantage. 
 
how personal and health-related data will be collected and used during the study. 
All subjects will receive a copy of the subject information sheet and a copy of their signed and dated 
informed consent form (ICF).  
 
7.2.1 Screening 
The following screening assessments will be conducted between days -28 and -1: 
 
Sign informed consent 
 
Obtain medical history and demographic data 
 
Review of eligibility criteria 
 
Laboratory studies: 
o HBsAg monitoring 
o HBsAb monitoring 
o HBV DNA monitoring 
 
Vital signs 
 
Physical examination including measurement of weight and height 
 
Fibroscan 
 
Serum pregnancy test in women of childbearing potential 
 
Safety laboratory tests 
 
Urine dipstick test for drug abuse and alcohol screen 
 
Test for HIV, HDV and HCV 
 
Documentations of AEs 
 
Blood for cell-mediated immunity (CMI) 
 
12-lead ECG 
Patients who pass screening but are not dosed within 28 days may be re-screened once.  
 

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Subjects who have given their written informed consent will be allocated unique subject identification 
numbers in sequential order according to their admission to the study within each site by Interactive 
Response Technology (IRT). This number will be used for identification throughout the study and will 
not be used for any other participant. 
 
7.3 
The randomisation scheme 
Subjects will be randomly assigned to 1 of 6 blinded treatment groups by the IRT into 3 cohorts as 
described in Table 2. 
Following completion of the Screening activities, subjects who meet the all the inclusion and none of 
the exclusion criteria will be registered by the IRT. 
The first subjects in each treatment arm of a cohort (i.e. active alone, active +IC31®, placebo and 
IC31® alone, as applicable) will form the sentinel group and, where possible, all sentinel subjects per 
treatment will be dosed at the same clinical site. Subsequently subjects in each cohort will be 
randomised to the applicable active or control treatment, to meet the required number of subjects to 
be dosed in each arm. 
The randomisation list will be drawn up by an independent statistician.  
 
7.3.1 Method of implementing the allocation sequence 
After successfully completing the screening visit, subjects will be assigned a unique randomisation 
number in the order in which they are randomised. Randomisation numbers are provided in Table 3, 
these numbers are different to the subject identification numbers allocated at admission to the study. 
Table 3 Randomisation Numbers  
Cohort 
Randomisation numbers 
Sentinel randomisation numbers 
1 
1001–1018 
1001–1002 
2 
2001–2036 
2001–2004 
3 
3001–3018 
3001–3002 
 
7.4 
Blinding 
The Pharmacy staff will be unblinded for the purpose of final drug preparation. The pharmacist will 
consult the IRT for dose allocation and the Pharmacy staff will prepare each dose in compliance with 
the randomisation list. 
Blinding of treatment assignment is critical to the integrity of this clinical study. Methods used to 
ensure blinding are described in the following paragraphs. 
Due to the fact that formulations cannot be made to look identical, a double-observer technique will be 
used to maintain blind at the clinical site. Study staff either preparing the syringes and/or vaccinating 
the participants will be independent and will not take part in any other activity of the study (e.g. clinical 
assessments).  
Injection materials and their labels should not be shown to subjects and subjects should be instructed 
to look away during the vaccination. 

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Knowledge of the randomisation list will be limited to the persons responsible for creation of the 
randomisation list, pharmacy staff who prepare the study treatments, and any unblinded study 
monitors or auditors, until all data has been entered in the electronic Case Report Form (eCRF), 
quality control and verification of the eCRF and assignment of subjects to the analysis populations has 
been completed, the database has been locked and the study formally unblinded. 
Data provided to the SRC will be blinded. 
 
7.5 
Unblinding 
If unblinding is required in the interest of the safety of a subject, an Investigator will discuss the matter 
with the Sponsor before using the IRT to unblind. In a medical emergency, the Investigator or delegate 
may unblind via the IRT for that subject without prior consultation with the Sponsor. In that event, the 
Investigator or delegate will notify the Sponsor as soon as possible that the randomisation code has 
been broken for the subject. If the blind is broken, the date, time, and reason must be recorded. For 
new patients, the method of unblinding for emergency purposes will be via the IRT. 
 
7.6 
Trial assessments 
7.6.1 Safety assessments 
7.6.1.1 Medical history 
A complete medical history will be obtained at the screening visit and relevant medical history will be 
recorded in the eCRF. Enquiries will be made regarding all body systems including allergies/drug 
sensitivities, past surgeries, substance abuse and any other diseases or disorders. 
7.6.1.2 Safety laboratory tests 
Safety laboratory tests will be performed at the times indicated in the flow chart Error! Reference 
source not found.Error! Reference source not found.Error! Reference source not found.Error! 
Reference source not found.(see Error! Reference source not found.Table 1 Flow chart. At the 
screening visit the subjects will be screened for alcohol and drugs of abuse and infection with HIV, 
HDV and HCV. Further details are provided in Section 7.11.1. 
The Investigator must review the laboratory report and document this review by signing the laboratory 
report form. Any clinically relevant values or changes in laboratory test values, as assessed against 
the normal reference ranges, must be recorded in the AE section of the subject’s eCRF. 
7.6.1.3 Vital signs 
Vital signs will be measured at the times indicated in the flow chart (see Table 1 Flow chart). Vital 
signs include sitting blood pressure, pulse rate (after at least 5 min rest), and body temperature.  
7.6.1.4 Electrocardiogram 
A 12-lead ECG will be performed by the local site at the times indicated in the flow chart (see Error! 
Reference source not found.). 
7.6.1.5 Physical examination 
A physical examination will be performed by a physician at the times indicated in the flow chart (see 
Error! Reference source not found.). A full physical examination will be conducted at screening 

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including examination of weight and height, general appearance, eyes, ears, nose, throat, 
chest/respiratory system, heart/cardiovascular system, gastrointestinal system/liver, musculoskeletal 
system/extremities, dermatological system/skin, thyroid/neck, lymph nodes, and neurological 
system/psychiatric system. 
A brief physical examination will be conducted at all other times including examination of general 
appearance, respiratory and cardiovascular systems and the abdomen, particularly the upper right 
quadrant. Any clinically relevant change in physical examination should be recorded as an AE. 
7.6.1.6 Documentation of adverse events 
See Section 9. 
7.6.1.7 Documentation of local tolerability 
Injection site tolerability will be assessed by the Investigator up to a minimum of 4 hours after the first 
injection and approximately 24 hours and 7 days after the first injection. For subsequent injections, 
injection site tolerability will be assessed by the Investigator up to 2 hours on the day of injection, 24 
hours by means of a phone call and 7 days post injection.  
Additionally, a diary card will be provided to the subjects to record injection site reactions from 4 hours 
(first injection) or 2 hours (subsequent injections) post injection to 7 days post injection. Data from the 
diary card will be transcribed into the appropriate eCRF. 
The following solicited local injection site reactions will be assessed: 
 
Erythema/redness 
 
Swelling 
 
Induration/hardening 
 
Pain/tenderness (pain on pressure) 
 
Pain (spontaneous; pain without pressure) 
 
Pruritus/itching or burning sensation 
 
Wheal(s) 
The symptoms will be graded as described in Table 4 Grading of solicited local injection site reactions. 

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Table 4 Grading of solicited local injection site reactions 
 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Erythema/redness 
0-2.4 cm 
2.5-5 cm 
5.1-10 cm 
>10 cm 
Necrosis or 
exfoliative 
dermatitis 
Swelling 
0-2.4 cm 
2.5-5 cm and 
does not 
interfere with 
activity 
5.1-10 cm or 
interferes with 
activity 
>10 cm or 
prevents daily 
activity 
Necrosis 
Induration/hardening 
0-2.4 cm 
2.5-5 cm and 
does not 
interfere with 
activity 
5.1-10 cm or 
interferes with 
activity 
>10 cm or 
prevents daily 
activity 
Necrosis 
Pain/tenderness (pain 
on pressure) 
Absent 
Mild discomfort 
to touch 
Discomfort 
with 
movement 
Significant 
discomfort at 
rest 
Emergency room 
visit or 
hospitalisation 
Pain (spontaneous; 
pain without pressure) 
Absent 
Does not 
interfere with 
activity 
Repeated use 
of non-opioid 
pain reliever 
> 24 hours or 
interferes with 
activity 
Any use of 
opioid pain 
reliever or 
prevents daily 
activity 
Emergency room 
visit or 
hospitalisation 
Pruritus/itching 
Absent 
Mild 
Moderate 
Severe  
Not applicable 
Wheal(s) 
0-2.4 cm 
2.5-5 cm 
5.1-10 cm 
>10 cm 
Not applicable 
Burning sensation 
Absent 
Mild 
Moderate 
Severe  
Not applicable 
Erythema, swelling, induration, tenderness, and pain are graded according to the FDA Guidance for Industry: 
Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical 
Trials (2007). 
7.6.1.8 Additional safety examinations 
If there are any unclear symptoms or observations the responsible physician in charge may perform 
further medical examinations, other than outlined in this protocol, including further clinical laboratory 
tests, in order to clarify the relevance or to diagnose symptoms. 
 
7.6.2 Immunological and virological assessments 
7.6.2.1 Determination of immunological parameters 
Blood samples will be collected at the times indicated in the flow chart to evaluate CMI responses. 
 
IFN-γ ELISpot assay (ex vivo and cultured assay): to determine Vaccine FP-02.2-specific 
IFN-γ production from cryopreserved PBMC 

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 
Other immunological assays may be performed such as T cell proliferation assays, intracellular 
cytokine assays, ELISA-based assays to measure Vaccine FP-02.2-specific antibodies, or 
other suitable assays to measure the immune response from PBMC or serum. 
 
The frequency of regulatory cells, expression of co-stimulatory and inhibitory markers may be 
measured by flow cytometry from cryopreserved PBMC. 
 
HLA genotyping will be performed on cryopreserved PBMC samples from consenting subjects 
to build an understanding of how the immune response to Vaccine FP-02.2 may or may not be 
independent of HLA genotype. Further genotyping may be performed from consenting subjects 
to assess the relationship between immune responses to the vaccine or HBV and associated 
gene profiles.  
7.6.2.2 Determination of virological parameters 
 
Quantitative HBV DNA levels (PCR) 
 
Quantitative HBsAg levels (ELISA) 
 
Quantitative HBsAb levels (ELISA) 
Immunological (IFNγ ELISpot assay) and virological assessments will follow the OECD Principles of 
GLP. 
 
7.6.3 Assessment schedule 
Screening Visit  
The screening assessment is described in Section7.2.1. 
Randomisation will be performed by IRT up to 3 days prior to first injection to allow data from 
screening to be available for confirmation of eligibility criteria and for the central pharmacy to supply 
medication to site. 
Visit 1:  
The following assessments and procedures will be performed on Day 1: 
Pre-vaccination 
 
Review of eligibility criteria 
 
Urine pregnancy test in women of childbearing potential 
 
Blood for CMI 
 
HBsAg and HBsAb monitoring 
 
Vital signs 
 
Physical examination  
 
Documentation of concomitant medication 
 
Documentation of AEs  
 
Vaccination 
 
Contact IRT for drug supply 
 
Dispense diary card 
Post-vaccination 
 
Injection site tolerability 

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 
Documentation of concomitant medication 
 
Documentation of AEs  
 
The subject will be asked to stay in the clinic for at least 4 hours following the first injection. 
 
Visit 2  
The following assessments and procedures will be performed on Day 2: 
 
Vital signs 
 
Physical examination  
 
Injection site tolerability 
 
Documentation of AEs and concomitant medications 
 
Review diary card for local tolerability 
 
Visit 3  
The following assessments will be performed on Day 8: 
 
Vital signs 
 
Physical examination  
 
Injection site tolerability 
 
Safety laboratory tests 
 
Documentation of concomitant medication 
 
Blood for CMI 
 
Documentation of AEs  
 
Review diary card for local tolerability 
 
Dispense new diary cards 
Visits 4 and 6 (administration of booster vaccinations)  
The following assessments will be performed on Days 29 and 57: 
Pre-vaccination 
 
Urine pregnancy test in women of childbearing potential (pre-vaccination) 
 
Safety laboratory tests (pre-vaccination) 
 
Vaccination 
 
Vital signs 
 
HBsAg and HBsAb monitoring 
 
Physical examination  
 
Documentation of concomitant medication 
 
Documentation of AEs  
 
Blood for CMI  
 

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Post-vaccination 
 
Injection site tolerability (post-vaccination) 
 
Documentation of concomitant medication 
 
Documentation of AEs 
 
Dispense diary card  
The subject will be asked to stay in the clinic for 2 hours after each booster vaccination. 
 
Telephone Contact 24 hours after booster vaccinations  
Telephone contact enquiring about AEs and injection site tolerability (assessed by subject) on days 30 
and 58. 
 
Visits 5 and 7  
The following assessments will be performed on Days 36 and 64: 
 
Vital signs 
 
Physical examination  
 
Injection site tolerability 
 
Safety laboratory tests 
 
Documentation of concomitant medication 
 
Blood for CMI 
 
Documentation of AEs 
 
Review diary card for local tolerability 
 
Visit 8:  
The following assessments will be performed on Day 85: 
 
HBsAg and HBsAb monitoring 
 
Vital signs 
 
Physical examination 
 
Urine pregnancy test in women of childbearing potential 
 
Safety laboratory tests 
 
Documentation of concomitant medication 
 
Blood for CMI  
 
Documentation of AEs 
 
7.7 
Follow-up assessments 
Subjects will be contacted (telephone call) by clinic staff at approximately 4-weekly intervals between 
Day 85 and Day 225 to check subject health.  
Visit 9: 
A follow-up visit will be performed at Day 225. The following assessments will be performed: 

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 
HBsAg and HBsAb monitoring 
 
HBV DNA monitoring 
 
Vital signs 
 
Physical examination 
 
Safety laboratory tests 
 
Documentation of concomitant medication 
 
Blood for CMI 
 
12-lead ECG 
 
Documentation of SAEs and AESIs (autoimmune disease and liver flares) 
7.8 
Qualitative assessments – Nested studies 
Not applicable. 
 
7.9 
Allowed visit intervals 
Allowed visit intervals are as follows: 
 
screening and randomisation: subjects must be screened 7 to 28 days (±2 days) and can be 
randomised to treatment up to 3 days prior to the first injection. 
 
first dose: Visits 1 and 2 must be done on Days 1 and 2, respectively; Visit 3 may be done 
within ± 1 day of Day 8  
 
second dose: Visit 4 may be done within 28 days (± 7 days) of Visit 1; subjects must be 
phoned the day after Visit 4; Visit 5 should be done 7 (± 1 day) days after Visit 4 
 
third dose: Visit 6 may be done 28 days (± 7 days) after Visit 4; subjects must be phoned the 
day after Visit 6; Visits 7 and 8 should be done 7 (± 1 day) and 28 days (±1 day) respectively 
after Visit 6 
 
follow-up: Visit 9 must be done 24 (± 4 weeks) weeks after the last dose (Visit 6) 
The scheduled assessments may shift in instances where a visit window is used; subsequent visit 
dates should be recalculated from the date of the new visit. If a second dose visit is missed, the dose 
can be given 6 weeks after the first dose and noted as out of window. If the dose is later than 6 weeks, 
the second dose visit can be skipped and given at Visit 3 at 8 weeks as per schedule to avoid a delay 
in the schedule. 
 
7.10 Withdrawal criteria  
Participation in the study is strictly voluntary. A subject has the right to withdraw from the study at any 
time and for any reason. If he/she chooses to withdraw, the Investigator must be informed 
immediately. The Investigator has the right to terminate participation of any subject at any time if the 
Investigator deems it in the subject's best interest. The reason and circumstances for premature 
discontinuation will be documented in the subject's eCRF. 
In general, all subjects should be encouraged to continue follow up until the end of the study even if 
they are withdrawn from continued study treatment, to allow collection of late safety data as well as 
immunogenicity and virology data. 
 
7.10.1 Possible reasons for discontinuing subjects from continued study treatment 
Examples of possible reasons for premature withdrawal of subjects: 

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 
Major protocol violations; 
 
Pregnancy; 
 
Serious intercurrent illness; 
 
AEs which, in the judgement of the PI or Co-Investigator and subject to discussion with the 
Sponsor’s medical advisor, justifies discontinuation; 
 
Non-compliance with study requirements; 
 
Withdrawal of consent by the subject; 
 
Subjects experiencing clinically significant injection site reactions or clinically significant 
changes in haematology and serum biochemistry results, considered possibly related to 
administration of the IMP, after a dose may not receive the subsequent dose of medication, at 
the discretion of the PI, in discussion with the Chief Investigator (CI) or the Sponsor’s medical 
advisor. However, safety, virology and immunogenicity data will continue to be collected until 
the end of the study unless the subject withdraws his/her consent. 
If a subject is withdrawn from study treatment, relevant study procedures e.g. physical examination, 
clinical laboratory analyses for safety and immunogenicity will be performed wherever possible. The 
reason(s) for discontinuation will be recorded in the appropriate section of the eCRF. Any subject who 
prematurely terminates participation and who has received at least one injection of the study treatment 
will undergo relevant post-study procedures for reasons of medical prudence, including a final 
examination and safety laboratory studies, unless the subject has withdrawn his/her consent and 
refuses to be examined and/or have blood drawn. 
If a subject terminates participation due to an AE possibly related to the study medication or study 
procedures, the subject should be followed up by additional examinations according to the medical 
judgment of the Investigator until the abnormal condition is resolved or the Investigator deems further 
observations or examinations to be no longer medically indicated. If the subject refuses to be followed 
up the Investigator should explain the importance of the follow-up and encourage the subject to allow 
follow up. Subjects who elect to discontinue dosing should be encouraged to continue with other study 
procedures until the end of study if they are willing. 
Study stopping rules 
Individual subjects 
An individual subject will have treatment discontinued if he/she experiences any one or more of the 
following events: 
 
ALT ≥ 10 times the ULN 
 
INR > 1.3  
 
Total bilirubin >3 times the ULN  
Study as a whole 
Dosing will be stopped for all subjects and enrolment discontinued if 20% or more of subjects 
experience one or more of the following events  
 
ALT ≥ 10 times the ULN 
 
INR > 1.3  
 
Total bilirubin >3 times the ULN  
 
Serious adverse events considered related to investigational products  

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 
Severe systemic reactions. 
 
7.10.2 Site discontinuation 
A site may be closed for the following reasons: 
 
The site is unlikely to be able to recruit sufficient patients within the agreed time frame 
 
The site does not respond to study management requests 
 
Repeated protocol violations 
7.10.3 Study termination 
The Sponsor reserves the right to modify or terminate the study at any time. All subjects recruited to 
the study prior to termination, including those who have been withdrawn, will be followed until 
225 days after their last injection. 
 Possible reasons for termination are: 
 
Safety reasons –the incidence of AEs in this or any other study using the same IMP indicates a 
potential health risk for the subjects. 
 
New scientific knowledge becomes known that makes the objectives of the study no longer 
feasible/valid 
 
Unsatisfactory enrolment of patients 
7.10.4 Replacement of subjects  
Eligible subjects who are randomised and withdrawn before their second dose of IMP will be replaced. 
Subjects who have received two doses of IMP who are subsequently withdrawn from the study will not 
be replaced. 
 
7.11 Storage and analysis of samples 
It is the responsibility of the trial site to ensure that samples are appropriately labelled in accordance 
with the trial procedures to comply with local legislation. Biological samples collected from participants 
as part of this trial will be transported, stored, accessed and processed in accordance with local 
legislation relating to the use and storage of human tissue for research purposes. Information for 
specific handling and storage conditions can be found in the laboratory manual.  
 
7.11.1 Safety laboratory 
Blood and urine samples will be collected for safety laboratory tests and screening for alcohol, drugs 
of abuse and HIV, HDV and HCV infection at the times indicated in the flow chart (see Table 1 Flow 
chart). The analytes listed in Table 5 will be determined. 
Clinical laboratory tests (see Table 5) will be performed at local site hospital laboratories. Procedures 
for sample collection, processing, and storage will be described in a separate laboratory manual. 
Additional and repeat testing may be performed at the discretion of the Investigator. 
 

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Table 5 Clinical laboratory safety test analytes 
Panel 
Parameters 
Haematology 
 
White blood cells (leukocytes) 
Red blood cells (erythrocytes) 
Haemoglobin  
Haematocrit  
Mean corpuscular volume 
Mean corpuscular haemoglobin 
Mean corpuscular haemoglobin 
concentration 
Neutrophils [a] 
Lymphocytes [a] 
Monocytes [a] 
Eosinophils [a] 
Basophils [a] 
Platelets 
 
Serum biochemistry  
 
Sodium 
Potassium 
Urea 
Creatinine 
Albumin  
Calcium  
Phosphate 
Glucose 
Total protein 
C-reactive protein 
Aspartate transaminase (AST) 
Alkaline phosphatase (ALP) [b] 
Alanine aminotransferase (ALT) 
Creatine kinase [c] 
Gamma-glutamyl transferase (gamma 
glutamyl transpeptidase) (GGT) 
Lactate dehydrogenase 
Total and direct bilirubin 
Coagulation 
International normalized ratio of prothrombin time (INR) 
Urinalysis 
 
Protein 
Bilirubin 
Urobilinogen 
Ketones 
Glucose 
Leukocyte esterase  
Red blood cells 
pH 
Nitrites 
Specific gravity 
Urine microscopy [d] 
Microscopy to be performed if clinically indicated (as per local procedures) 
Viral serology [d] 
 
Human immunodeficiency virus (HIV 
I and II) 
Hepatitis C virus (HCV) antibodies 
Hepatitis D virus (HDV) antibodies 
Drugs of abuse and 
alcohol screen [d] 
 
Amphetamine/ecstasy 
Ethanol 
Cannabinoids 
Cocaine 
Urine creatinine 
Opiates 
Benzodiazepines  
Methadone metabolites 
Barbiturates 
 
Serum/urine pregnancy 
test [e] 
Beta human chorionic gonadotropin 
 
[a] Given as both absolute count and as a percentage of total leukocyte count. 
[b] Alkaline phosphatase iso-enzymes (liver-specific and bile duct specific) will be measured if original alkaline 
phosphatase test result is above the upper limit of normal. 
[c] Creatine kinase MB or Troponin T will be measured where clinically indicated. 
 [d] At Screening Visit only. 
[e] A serum pregnancy test will be performed in all women of childbearing potential at the Screening Visit. Serum 
HCG concentrations above 5 mIU/mL. Urine pregnancy tests will be performed during the remainder of the 
study at the times indicated in the flow chart. 
 

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7.11.2 Immunology 
Blood samples will be processed to isolate, cryopreserve and store PBMC. This may be conducted at 
a central laboratory at Altimmune or at Investigator sites. Further details can be found in the laboratory 
manual.  
Subsequent primary immunological analysis (IFNγ ELISpot) will be conducted at Altimmune. Any 
cryopreserved PBMC prepared and stored at Investigator sites will be transferred to Altimmune prior 
to analysis. 
Other specialist laboratories may be used for exploratory immunological analyses and for HLA 
genotyping. A PBMC sample from either the screening visit or Visit 1 will used for HLA genotyping in 
consenting subjects. PBMC samples isolated at other time points may be used for other genotyping as 
required. 
 
7.11.3 Virology 
Blood samples will be collected for the assessment of virological parameters (HBsAg, HBsAb, HBV 
DNA) at the times indicated in the flow chart (see Table 1 Flow chart). Isolation of serum or plasma will 
be performed at the clinical site following methods detailed in the laboratory manual. Serum and 
plasma will be stored at the clinical site under appropriate conditions (further details are provided in 
the laboratory manual) until shipment to Altimmune laboratories. Batched samples will be sent from 
Altimmune laboratories to King’s Liver Labs for virological analysis as detailed in the laboratory 
manual. 
 
7.11.4 Sampling handling and storage 
The handling of the samples will be described in a separate laboratory manual.  
Samples will be retained for a period up to 10 years and will only be used for purposes described in 
this protocol. 
 
7.11.5 Blood volume 
The estimated blood volumes collected from each subject during the study for safety, immunology and 
virology tests as described in Sections 7.11.1, 7.11.2, and 7.11.3, respectively, are presented in Table 
6 Approximate Blood volumes [a]. 

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Table 6 Approximate Blood volumes [a]. 
 
Sample 
Volume 
Number of 
Samples 
Total Volume 
(mL) 
Safety 
 
 
 
 
Serum biochemistry [b] 
5.0 
8 
40.0 
 
Haematology [b] 
2.0 
8 
16.0 
 
Coagulation [b] 
2.0 
8 
16.0 
 
Serum pregnancy test [b,c] 
3.5 
1 
3.5 
 
Serology (HCV/HIV I and II, HDV) [b] 
3.5 
1 
3.5 
Immunoanalysis 
 
 
 
 
Cellular immunoanalysis (PBMC) [d] 
40 
9 
360.0 
Virology 
 
 
 
 
HBsAg, HBsAb, HBV DNA quantitative [e] 
4.0/8.0 [f] 
6 
32.0 
Total [a] 
 
 
 
 
Male subjects 
 
 
467.5 
 
Female subjects 
 
 
471.0 
HBsAg = hepatitis B surface antigen; HBsAb = antibody to hepatitis B surface antigen; HCV = hepatitis C virus; HDV = 
hepatitis D virus; HIV = human immunodeficiency virus; PBMC = peripheral blood mononuclear cells. 
[a] Sample volumes are based on direct venipuncture; where a cannula is used an extra 1mL will be drawn and discarded. 
Specific volumes for safety analysis may vary from site to site. 
[b] Analysis to be performed by site-specific Hospital Laboratories.  
[c] All women of childbearing potential; serum pregnancy test will be conducted at the Screening Visit. 
[d] Isolation of PBMC may be performed at a central laboratory, at Altimmune, or at the Investigator site.  
[e] Analysis to be performed by King’s Liver Labs which is a Clinical Pathology Accreditation UK Ltd. (CPA UK Ltd.) enrolled 
Laboratory.  
[f] 4.0 mL of blood will be collected for virology except at screening and visit 9 when 8.0mL of blood will be collected. 
 
The planned blood volume is not greater than 150mL each month. However, the number of samples 
collected and the volume required for each analysis may change during the study (i.e. if additional 
samples are collected for repeated assessments). Extra blood samples for safety assessments will be 
taken only as and when needed. No more than an extra 50mL blood will be taken each month for 
immunology and virology assessments.  
 
7.12 End of trial 
The end of the active study period is defined as the last Day 85 visit of the last subject participating in 
the trial. The end of the trial includes the late safety follow up period and is defined as the last Day 225 
visit for the last subject participating in the trial. If the trial is terminated early, the trial ends when the 
Sponsor notifies the Investigator in writing that the trial has finished, or when the last subject attends 
the Day 255 visit, whichever is later. The Sponsor will notify the relevant competent authorities (CAs) 
and main Ethics Committees (ECs) of the end of a clinical trial within 90 days of its completion or 15 
days if the trial is terminated early. A supplementary follow-up notification will be submitted to the 
relevant CAs and ECs after the last Day 225 visit. 
 

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8 
TRIAL MEDICATION 
8.1 
Name and description of investigational medicinal product(s) 
Vaccine FP-02.2 
Vaccine FP-02.2 is a lyophilised product containing 0.6mg of nine different synthetic peptides 
(designated P877, P151, P113, P856(K), P753(K), P376, P797(K), P277(K) and P1266(K)), each 
covalently linked to a single fluorocarbon moiety on the N-terminus under a controlled process and 
30mg Mannitol (EP grade). The nine peptides are 32 to 40 amino acids in length and correspond to 
conserved regions of Hepatitis B viral proteins. The fluorocarbon conjugated peptides, called 
fluoropeptides (the active Drug Substances), are designed to enhance the delivery of the antigens to 
the human immune system and induce therapeutic T cell responses against infection. 
Vaccine FP-02.2 is a white to off-white powder presented in a 2mL clear glass vial sealed with a metal 
crimp. The vaccine is intended to be reconstituted with 600μl of 28mM L-histidine (EP grade) and 
600μl sterile NaCl 0.9% in a total 1200μl to achieve a sterile, isotonic, neutral pH, clear to slightly 
translucent solution with no visible particles which will be injected intramuscularly. 1mL of the 
reconstituted Vaccine FP-02.2 will administer a 500μg/peptide dose. The reconstituted Vaccine FP-
02.2 can be diluted with placebo component (see below) in order to administer 150μg/peptide dose in 
1mL. Where applicable, Vaccine FP-02.2 can be prepared with IC31® to produce either a 
500µg/peptide or 150µg/peptide dose both containing IC31® at a strength of 500nmol/mL KLK and 
20nmol/mL ODN1a. Full preparation instructions and details of shelf life will be described in a separate 
pharmacy manual.  
Placebo 
The Placebo is comprised of placebo component (50mg/mL mannitol (EP grade) in 28mM L-histidine 
(EP grade)) diluted 1:1 in sterile NaCl 0.9%.  
Placebo component is stored in 2mL glass vials containing 1.225mL of placebo component which, 
after thawing, is diluted 1:1 with sterile NaCl 0.9% to achieve an isotonic, neutral pH, clear and 
colourless solution, free from particulate matter which will be injected intramuscularly. Full preparation 
instructions and details of shelf life will be detailed in a separate pharmacy manual. 
IC31® 
IC31® is a two-component adjuvant composed of the synthetic peptide KLK and the synthetic 
oligodeoxynucleotide ODN1a. IC31® is packaged in 2mL clear glass vials and contains 1mL of a 
sterile turbid suspension, neutral pH at a strength of 1000nmol/mL KLK and 40nmol/mL ODN1a in 
5mM phosphate and sterile NaCl 0.9%. IC31® is prepared by diluting 1:1 with placebo component. 
Full preparation instructions and details of shelf life will be detailed in a separate pharmacy manual. 
 
8.2 
Legal status of the drug  
The trial is being carried out under a Clinical Trial Authorisation (CTA). Vaccine FP-02.2 and IC31® 
are therefore only to be used by the named Investigators, for the patients specified in this protocol, 
and within the trial. 
 

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8.3 
Summary of Product Characteristics (SmPC) 
Vaccine FP-02.2 and IC31® are not approved and there is no SmPC for the IMPs. Details of Vaccine 
FP-02.2 and IC31® can be found in the latest version of the IB. 
 
8.4 
Drug storage and supply  
The Sponsor will supply Vaccine FP-02.2, placebo component, 28mM L-histidine and IC31® to the 
central Pharmacy site or the local hospital pharmacy with the relevant documentation including 
certificate of analysis. Further details will be provided in the pharmacy manual. Transport of lyophilised 
Vaccine FP-02.2, 28mM L-histidine, placebo component and IC-31® from the central pharmacy to 
sites will be via an approved courier and at monitored temperatures appropriate for each substance. 
When the Pharmacist receives the materials for use in the study, he/she will check the conditions and 
contents of the package. The pharmacy staff will acknowledge receipt of the trial materials and report 
any anomalies in the inventory to both the Sponsor and GMP storage facility. The supplies will then be 
logged in to the pharmacy and the records will be updated in accordance with the pharmacy SOPs. 
Lyophilised Vaccine FP-02.2 and frozen placebo component will be stored at minus 20°C (-20°C) 
(±5°C). Liquid IC31® adjuvant and 28mM L-histidine will be stored refrigerated, at 2-8°C. Liquid sterile 
NaCl 0.9% must be stored at room temperature. It is anticipated that temporary changes in 
temperature will occur when the refrigerator or freezer door is open for the removal of IMP as detailed 
in the pharmacy manual.  
Records of the temperatures that Vaccine FP-02.2, IC31®, 28mM L-histidine or placebo component 
are stored will be maintained throughout the study. If deviations occur from the recommended storage 
conditions, these will be notified to the Sponsor’s contact. The clinical material affected will not be 
used until the Sponsor has assessed the impact of the deviation and has determined whether the 
material can be used. 
The central or hospital Pharmacy will prepare injections for all clinical sites upon receipt of a suitably 
signed trial-specific prescription or similar. All study drugs will be handled according to Pharmacy 
standard operating procedures (SOPs) and pharmacy manual. An unblinded pharmacy monitor will be 
permitted to check the supplies, storage and dispensing procedures. During the preparation, the 
Pharmacist will ensure that records are kept in sufficient detail for the sequence of operations to be 
determined. Sufficient reconciliation will take place in order to ensure that the correct quantity of 
treatment has been accounted for at each stage of the process. 
Once reconstituted the IMP will be stored in the refrigerator at 2-8°C until transport to clinical sites as 
detailed in the pharmacy manual.  
The receipt, dispensing and return of any trial material to and from pharmacy will be logged on the 
appropriate forms in the pharmacy. 
At a time convenient to both the Sponsor and the Pharmacy all unused drugs will be returned to the 
Sponsor together with an account of the quantities supplied and used during the study. If required by 
the Sponsor, the Pharmacist will arrange for the recorded destruction of unused study drugs. 
 

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8.5 
Dosage schedules 
Each dose of Vaccine FP-02.2, Vaccine FP-02.2/IC31®, Placebo or IC31® will be administered as an 
IM injection (1.0mL) in the deltoid muscle, where possible, of the non-dominant arm by appropriately 
trained clinical staff members. The first dose will be administered on Day 1, the second dose 
approximately 4 weeks later on Day 29 and the third dose approximately 4 weeks after the second 
dose on Day 57. Subjects will stay in the unit for at least 4 hours following administration of the first 
dose and at least 2 hours following administration of the second and third doses.  
 
8.6 
Preparation and labelling of Investigational Medicinal Product 
Detailed reconstitution instructions will be provided to the Pharmacies by the Sponsor. In brief: 
The bulk drug product will be reconstituted at the Pharmacy as described in separate pharmacy 
handling instructions provided by the Sponsor. Individual subject treatments will be dispensed by the 
pharmacist and labelled in accordance with local Good Manufacturing Practice legislation. 
Reconstitution instructions will be detailed in the Pharmacy manual. 
 
8.7 
Dosage modifications  
No dosage modifications for individual subjects are allowed. The SRC may recommend reducing the 
dose in any treatment arm after the first dose in sentinel subjects; or the dose(s) in the next treatment 
arm after review of safety data at Day 36 from the previous treatment arm, as described in Section 4. 
In either case, the Sponsor will decide whether the study is stopped or whether to continue with a 
lower dose. If the dose(s) is reduced after the first dose in the sentinel subjects, those subjects will be 
withdrawn; if the Sponsor decides to continue, the remaining subjects in the treatment arm will be 
given the reduced dose(s). 
 
8.8 
Known drug reactions and interaction with other therapies 
Please refer to Section 2.1.2 and the IB for an overview of the risks associated with the IMP including 
information about potential drug reactions. No interactions with other therapies are known so far. 
  
8.9 
Concomitant medication 
In the interests of subject safety and acceptable standards of medical care the Investigator will be 
permitted to prescribe additional treatment(s) at his/her discretion in addition to treatment with 
entecavir or tenofovir. 
All treatments, including vaccinations, must be recorded in the subjects’ eCRFs (medication, dose, 
treatment duration and indication).  
 
8.10 Trial restrictions  
Women of childbearing potential must use a highly effective contraceptive method within the time 
frames mentioned below.  
Women of childbearing potential are defined as: 

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 
Not surgically sterile 
 
Not post-menopausal (post-menopausal is defined as at least one year amenorrhea in woman 
over 50 years. Women younger than 50 years should have laboratory confirmation of 
menopausal status) 
Women of childbearing potential not surgically sterilised or with laboratory confirmed menopausal 
status are required to use a highly effective contraceptive measure with low used dependency such 
as:  
 
Combined (oestrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation 
 
Progestogen-only hormonal contraception implants associated with inhibition of ovulation 
 
Intrauterine device (IUD) 
 
Intrauterine hormone-releasing system (IUS) 
 
Bilateral tubal occlusion 
 
Vasectomised partner – must have had medical assessment of successful surgery. 
From screening until one menstrual cycle after the last dose of IMP (Day 57). 
Males should fulfil one of the following criteria: 
 
Surgically sterile 
 
Willing to abstain from sexual intercourse or use a reliable form of contraception (e.g. condom), 
if having sex with a pregnant or non-pregnant woman of childbearing potential, from screening 
until 3 months after the final injection of IMP/Placebo. 
 
Surgically sterile female partner 
8.11 Assessment of compliance 
The injections will be administered by study personnel and therefore IMP compliance is not a concern. 
The study personnel will be appropriately trained on IMP administration procedures and 
documentation requirements prior to study start. 
Non-compliance with study procedures will be reported to the Sponsor who will decide if persistent 
non-compliant subjects should be withdrawn from continued study treatment.  
 
8.12 Name and description of each Non-Investigational Medicinal Product (NIMP) 
As part of the study inclusion criteria, trial participants will currently receive either entecavir (brand 
name Baraclude®, Bristol-Myers Squibb) or tenofovir disoproxil furamate (brand name Viread®, 
Gilead) as standard of care medicine. 
Additional information on these products can be found in the respective, regulated local specific 
documents. 
Tenofovir 
Tenofovir is recommended as an option for the treatment of adults with chronic HBeAg-positive or 
HBeAg-negative hepatitis B with compensated liver disease, with evidence of active viral replication, 
persistently elevated serum ALT levels and histological evidence of active inflammation and/or 
fibrosis. Tenofovir is a NA which works by blocking the enzyme reverse transcriptase, which is 

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responsible for hepatitis B virus (HBV) replication. Full details of uses, side effects and 
contraindications are presented in regulated local specific documents.  
Entecavir  
Entecavir is recommended as an option for the treatment of adults with chronic HBeAg-positive or 
HBeAg-negative hepatitis B with compensated liver disease, with evidence of active viral replication, 
persistently elevated ALT levels and histological evidence of active inflammation and/or fibrosis. 
Entecavir is a NA which works by inhibiting the viral DNA polymerase responsible for HBV replication, 
which is responsible for hepatitis B virus (HBV) replication. Full details of uses, side effects and 
contraindications are presented in regulated local specific documents. 
9 
PHARMACOVIGILANCE 
9.1 
Definitions 
The definitions of an adverse event (AE), adverse reaction (AR), serious adverse event (SAE), serious 
adverse reaction (SAR), and suspected unexpected serious adverse reaction (SUSAR) are provided 
in Table 7 Pharmacovigilance definitions. 
 
Table 7 Pharmacovigilance definitions 
Term 
Definition 
Adverse Event (AE) 
Any untoward medical occurrence in a participant to whom a medicinal 
product has been administered, including occurrences which are not 
necessarily caused by or related to that product. 
Adverse Reaction 
(AR) 
 
An untoward and unintended response in a participant to an investigational 
medicinal product which is related to any dose administered to that 
participant. 
The phrase "response to an investigational medicinal product" means that a 
causal relationship between a trial medication and an AE is at least a 
reasonable possibility, i.e. the relationship cannot be ruled out. 
All cases judged by either the reporting medically qualified professional or 
the Sponsor as having a reasonable suspected causal relationship to the 
trial medication qualify as adverse reactions. 
Serious Adverse 
Event (SAE) 
A serious adverse event is any untoward medical occurrence that: 
 results in death 
 is life-threatening 
 requires inpatient hospitalisation or prolongation of existing 
hospitalisation 
 results in persistent or significant disability/incapacity 
 consists of a congenital anomaly or birth defect 
Other ‘important medical events’ may also be considered serious if they 
jeopardise the participant or require an intervention to prevent one of the 
above consequences. 
NOTE: The term "life-threatening" in the definition of "serious" refers to an 

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event in which the participant was at risk of death at the time of the event; it 
does not refer to an event which hypothetically might have caused death if it 
were more severe. 
Serious Adverse 
Reaction (SAR) 
An adverse event that is both serious and, in the opinion of the reporting 
Investigator, believed with reasonable probability to be due to one of the 
trial treatments, based on the information provided. 
Suspected 
Unexpected Serious 
Adverse Reaction 
(SUSAR) 
A serious adverse reaction, the nature and severity of which is not 
consistent with the information about the IMP set out in the Investigator’s 
Brochure (IB) relating to this trial. 
Adverse Event of 
Special Interest (AESI)  
AESI refers to adverse events of significant scientific, medical, and public 
interest among pandemic vaccines. For this study AESI are hepatic flares 
and autoimmune conditions 
 
9.2 
Operational definitions for (S)AEs  
The occurrence of AEs will be assessed by non-directive questioning of the subject at each visit. 
Additionally, AEs volunteered by the subject during or between visits or detected through observation, 
physical examination, laboratory test or other assessments will be documented. Subjects will be 
instructed that they must immediately report any AEs, subjective complaints or objective changes in 
their well-being to the Investigator or the clinic personnel, regardless of the perceived relationship 
between event and test product.  
All AEs must be fully recorded throughout the entire study period (from Screening Visit to Day 85) and 
will be entered into the subjects’ eCRF, whether or not they are considered to be drug-related. Each 
AE should be described in detail: onset time and date, offset time and date, description of event, 
severity, relationship, action taken and outcome. From Day 85 and Day 225 only SAEs and AESIs will 
be collected. 
Adverse events should be followed until recovery to the normal state has been achieved. In the event 
of a subject not returning to the clinical unit, every attempt will be made to contact the subject up to 
Day 85 after which the outcome of this event will be recorded as lost at follow-up.  
 
9.2.1 Assessment of seriousness 
The criteria for seriousness are provided in the definition of an SAE given in Table 7. 
 
9.2.2 Categorisation of adverse events 
The intensity of an AE will be categorised as follows: 
 
Mild: the event causes a minor discomfort, does not interfere with daily activity of the subject or 
does not lead to establishment of a correcting treatment; 
 
Moderate: the event perturbs the usual activity of the subject and is of a sufficient severity to make 
the subject uncomfortable; 

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 
Severe: the event prevents any usual routine activity of the subject and causes severe discomfort. 
The term "severe" is used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (such as severe headache). This is not the same as "serious," which is based 
on patient/event outcome or action criteria usually associated with events that pose a threat to a 
patient's life or functioning. 
 
9.2.3 Assessment of causality 
Causal relationship assessment to drug treatments is required for purposes of reporting AEs. To 
promote consistency, the following guidelines should be taken into consideration along with good 
clinical and scientific judgment when determining the relationship of Vaccine FP-02.2 to an AE: 
 
Reasonable Possibility: a causal relationship with the IMP cannot be excluded  
 
No Reasonable Possibility: there is no reasonable evidence to suggest a causal relationship 
between Vaccine FP-02.2 and the AE. 
 
No Possibility: there is no possibility for a causal relationship. This assessment will likely only be 
applied to AEs recorded prior to administration of IMP. 
9.2.3.1 Action Taken 
Action taken will be defined as: 
 
None; 
 
Clinical management of the AE; 
 
Dosing stopped. 
9.2.3.2 Outcome 
Outcome will be defined as: 
 
Resolved; 
 
Ongoing; 
 
Lost to follow up. 
 
9.3 
Recording and reporting of SAEs and SUSARs  
The expectedness of the SAEs in relation to the IMP will be determined using the IB. 
SAEs occurring on this study will be reported to the Sponsor Pharmacovigilance provider (PRA Health 
Sciences) and the Sponsor’s medical representative within 24 hours of discovery or notification of the 
event. For contact details refer to the Key trial contacts section in this protocol. The Investigator will be 
requested to complete a separate SAE reporting form in addition to the information on the eCRF. 
A SUSAR that is fatal or life-threatening must be reported to the CA and EC immediately (within 7 
days) after the Sponsor becomes aware of the event. Any additional information must be reported 
within 8 days of sending the first report.  

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A SUSAR which is not fatal or life-threatening must be reported to the CA and EC according to country 
specific requirements after the Sponsor becomes aware of the event. 
 
9.4 
Responsibilities 
Principal Investigator (PI):  
 
Checking for AEs when participants attend for treatment / follow-up and ensuring that all AEs are 
recorded. 
 
Using medical judgement in assigning seriousness and causality and providing an opinion on 
expectedness using the IB approved for the trial.  
 
Ensuring that all SAEs are recorded and reported to the Sponsor within 24 hours of becoming 
aware of the event and provide further follow-up information as soon as available. Ensuring that 
SAEs are followed up with Sponsor if a record of receipt is not received within 2 working days of 
initial reporting. 
Chief Investigator (CI) or delegate: 
 
Clinical oversight of the safety of patients participating in the trial, including an ongoing review of 
the risk / benefit. 
 
Using medical judgement in assigning seriousness and causality where it has not been possible to 
obtain local medical assessment. 
 
Immediate review of all SUSARs, if the study is unblinded.  
 
Review of specific SAEs in accordance with the trial risk assessment and protocol as detailed in 
the Trial Monitoring Plan. 
 
Assisting in assigning Medical Dictionary for Regulatory Activities (MedDRA) or Body System 
coding to all SAEs and SARs. 
Sponsor or delegate: 
 
Central data collection and verification of AEs, ARs, SAEs, SARs and SUSARs according to the 
trial protocol.  
 
Reporting safety information to the CI, delegate or independent clinical reviewer for the ongoing 
assessment of the risk / benefit according to the Pharmacovigilance Plan. 
 
Reporting safety information to the SRC according to the Trial Monitoring Plan. 
 
Expedited reporting of SUSARs to the CAs and ECs within required timelines. 
 
Assigning expectedness. 
 
Notifying Investigators of SUSARs that occur within the trial, if the study is unblinded. 
 
The unblinding of a participant for the purpose of expedited SUSAR reporting. 
 
Checking for (annually) and notifying PIs of updates to the IB for the trial. 
 
Preparing standard tables and other relevant information for the development safety update report 
(DSUR) in collaboration with the CI  
 
Assigning MedDRA or Body System coding to all SAEs in consultation with the CI or delegate. 
 

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Safety review committee (SRC) 
 
The SRC will review safety data from a sentinel group of each cohort before commencement to the 
remaining cohort. In addition, the SRC will review safety data after two injections in each cohort, 
prior to progression from Cohort 1 to Cohort 2, and prior to progression from Cohort 2 to 3. 
 
For review of data from the sentinel group, the SRC will consist of the PI(s) from the site(s) 
involved with sentinel dosing, the CI and the Sponsor’s medical advisor. 
 
For review of data to allow progression between cohorts the SRC will consist of the CI, all PIs and 
the Sponsor’s medical advisor. In addition, representative(s) from the Sponsor, or their delegate, 
may attend but without voting rights. 
 
9.5 
Notification of deaths 
Any untoward medical occurrence resulting in death fulfils the definition of an SAE and is subject to 
expedited reporting as described in Section9.3. 
 
9.6 
Pregnancy reporting  
All pregnancies within the trial (either the trial participant or the participant’s partner) should be 
reported to the Sponsor’s Pharmacovigilance provider (PRA Health Sciences) in the first instance 
using the relevant Pregnancy Reporting Form for follow up and the Clinical Lead and the Medical 
Monitor should also be notified.  
Pregnancy is not considered an AE unless a negative or consequential outcome is recorded for the 
mother or child/foetus. If the outcome meets the serious criteria, this would be considered an SAE. 
If a subject is confirmed to be pregnant, use of the IMP will be discontinued immediately, however, the 
subject may continue with study follow up at the discretion of the investigator and obstetrician. The 
Investigator must provide follow-up information about the course of the pregnancy and outcome. 
 
9.7 
Overdose  
An overdose is not expected, as the IMP is administered via IM injection. Should subjects allocated to 
the low dose of the IMP receive a higher dose than the allocated dose this should be reported in the 
eCRF and the Sponsor should be informed. Any deviations from the assigned dose will be handled as 
a protocol deviation. 
 
9.8 
Reporting urgent safety measures  
If any urgent safety measures are taken the CI/Sponsor shall immediately and in any event no later 
than 3 days from the date the measures are taken, give written notice to the CAs and the relevant ECs 
of the measures taken and the circumstances giving rise to those measures. 
 
9.9 
The type and duration of the follow-up of subjects after adverse events 
The Investigator will initiate appropriate treatment according to his/her medical judgment and will 
decide whether to discontinue dosing if an AE or a concurrent health condition occurs. 

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The subject may be followed up by additional examinations according to the medical judgment of the 
Investigator and the nature of the AE, until the abnormal condition is resolved or the Investigator 
deems further observations or examinations to be no longer medically indicated. 
Any SUSAR will need to be reported to the Sponsor irrespective of how long after IMP administration 
the reaction has occurred. 
 
9.10 Development safety update reports 
The Sponsor will submit DSURs once a year throughout the clinical trial, or on request to the CAs, 
ECs and Investigative sites. 
The report will be submitted within 60 days of the Developmental International Birth Date (DIBD; 
8 June 2015) of the trial each year until the trial is declared ended. 
 
10 STATISTICS AND DATA ANALYSIS 
10.1 Treatment Arms 
There are six treatment arms: 
1. Low-dose FP-02.2 (Cohort 1) 
2. High-dose FP-02.2 (Cohort 2) 
3. Low-dose FP-02.2 + adjuvant (IC31®) (Cohort 2) 
4. High-dose FP-02.2 + adjuvant (IC31®) (Cohort 3) 
5. Placebo (pooled Placebo subjects) 
6. IC31® only (pooled IC31® subjects) 
 
10.2 Sample size calculation 
No formal sample size calculation has been performed. It is planned to randomise approximately 10 
subjects into each of the six treatment arms, which is considered an appropriate study size at this 
phase of development of Vaccine FP-02.2.  
 
10.3 Statistical analysis plan 
The proposed statistical analyses for this study will be detailed in a separate statistical analysis plan 
(SAP), which will be finalised prior to database lock. Any changes to the statistical analysis described 
in this protocol do not require a protocol amendment but must be described as a ‘change to the 
protocol planned statistical analysis’ in the SAP and the clinical study report. 
The statistical analysis and report will conform to the relevant ICH requirements. 
Data listings and summary tables will be generated using the software SAS© Version 9.3 or later. All 
data recorded in the eCRFs will be included in data listings. The SAS datasets and programs will be 
made available to the Sponsor at study closure. 
Summary tables and data listings will be presented by treatment arm and time point. 

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The standard summary statistics for continuous variables will comprise number of valid observations, 
arithmetic mean, standard deviation, median, quartiles, minimum, and maximum. The geometric mean 
and coefficient of variation will also be presented for continuous variables which are positive and 
substantively positively skewed (such as liver enzyme levels, ELISpot counts and measures of viral 
load). The standard summary statistics for categorical data will comprise absolute and relative 
frequencies (proportions). 
If continuous variables are assessed both at and after baseline, change from baseline will be 
calculated and summarised. If categorical variables are assessed both at and after baseline, then 
cross-tabulations will be presented by category at baseline.  
 
10.4 Analysis Sets 
Membership of analysis sets will be determined at a blinded data review meeting convened by the 
Sponsor. 
 
10.4.1 Safety Analysis Set 
The safety analysis set will contain all subjects who were randomised and received at least 1 injection 
of Vaccine FP-02.2, Vaccine FP-02.2/IC31®, placebo or IC31®. 
 
10.4.2 Full Analysis Set (FAS) 
The FAS comprises of all members of the safety analysis set with at least one complete post-
vaccination immunogenicity result. 
 
10.4.3 Immunogenicity Analysis Set 
The immunogenicity analysis set comprises of all members of the FAS with immunogenicity 
assessments at screening followed by days 1, 8, 29, 36, 57, 64 and 85 and with no major protocol 
violations. Subjects with missing day 1 PBMC may be included if screening PBMC data are available 
to calculate a baseline. 
 
10.5  Baseline data  
Baseline data will be tabulated using the standard summary statistics over all randomised subjects.  
 
10.6 Procedure(s) to account for missing or spurious data  
There will be no imputation for missing data. Summaries will be over all valid cases at that time point 
in the applicable analysis set. 
The nature and extent of missing data or spurious data will be reviewed at a blinded data review 
meeting. 
 

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10.7 Subject Disposition and flow of patients 
Subject disposition tabulation will display number of patients screened and randomised, number of 
subjects in each analysis population, and having completed or withdrawn, as well as reasons for 
withdrawal/drop-out.  
A subject will be considered enrolled at the time of randomisation. Subjects will be considered to have 
completed the study if they have taken all of the scheduled doses of IMP and have completed all 
applicable safety assessments and other study-related procedures.  
The disposition table will be detailed enough to enable construction of a CONSORT-style flow 
diagram. 
 
10.8 Study Conduct 
10.8.1 IMP and NUC exposure 
IMP and NUC exposure will be tabulated using the standard summary statistics. 
 
10.8.2 Protocol Violations 
Protocol violations will be listed and tabulated using the standard summary statistics. Violations with 
the potential for compromising the integrity or interpretation of the study will be referred to as 'major', 
other violations will be referred to as 'minor'. Whether or not each protocol deviation is categorised as 
'major' will be determined at a blinded data review meeting convened by the Sponsor. 
 
10.9  Safety analysis 
Safety data in general will be listed and summarised by treatment arm and time point using the 
standard summary statistics over the safety analysis set. 
 
10.9.1 Liver function 
Liver function test results will be presented using the standard summary statistics and shift tables.  
 
10.9.2 Adverse Events 
Adverse events shall be coded according to the current version of MedDRA. 
The subject incidence, severity, duration, relatedness and outcome of all treatment emergent AEs will 
be tabulated by treatment arm, system organ class and preferred term. Separate tables will be 
provided for fatal events, events leading to withdrawal, serious events and SUSARs.  
Treatment emergent AEs will be flagged in the subject data listings. 
 

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10.9.3 Local tolerability 
Injection site tolerability will be tabulated by treatment group, time point, reaction, grade (Section 
7.6.1.7). 
 
10.9.4 Vital signs 
Vital signs test results will be presented using the standard summary statistics and shift tables. 
Listings of safety laboratory results and vital signs will have assessments below and above the 
reference range highlighted, together with an indicator for clinical significance. 
 
10.9.5 ECG 
ECG assessments will be tabulated by treatment arm, time point and whether the ECG trace was 
normal, abnormal (not clinically significant) and abnormal (clinically significant). 12-lead ECG 
parameters will be tabulated using the standard summary statistics. 
 
10.9.6 Safety laboratory assessments 
Safety laboratory assessments will be presented using the standard summary statistics and shift 
tables.  
Listings of safety laboratory results from local laboratories will have assessments below and above the 
reference range highlighted, together with an indicator for clinical significance. 
 
10.9.7 Other safety assessments 
The Physical Examination will be summarised by treatment arm and time point. 
Concomitant medications will be summarised by treatment arm, WHO drug class, generic name and 
indication.  
 
10.10  Immunogenicity analysis 
Immunological outcome variables will be summarised by treatment arm and by time point tabulated 
using the standard summary statistics over the immunogenicity analysis set. 
A detailed description of the planned analysis of each immunogenicity and virological endpoint will be 
presented in a separate SAP. 
 
10.11 Timing of analysis  
After all participants have completed Day 85, the primary analysis of the safety data collected up to 
Day 85, immunogenicity (except HLA genotyping) and virology data will be performed. A secondary 
follow-up analysis of the immunology and safety data collected between Day 86 and Day 225 will be 
conducted. The Investigators, all site staff, the subjects and trial monitors will remain blinded between 

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the two analyses. Details of the analyses will be documented in the SAP. The information from the 
primary analysis is required to inform the design of the next clinical study and confirm the formulation 
and dose to use.  
 
11  DATA HANDLING 
11.1 Data collection tools and source document identification 
All the information collected during the study will be recorded in the eCRFs, patient diaries or other 
source documents, if applicable, which are identified by subject number. The Investigator will ensure 
that the eCRFs are correctly completed.  
 
11.2 Data handling and record keeping 
Clinical data will be entered into DataLabs. PRA processes allow adherence to 21 CFR Part 11. 
DataLabs is part of that process, and is therefore compliant with Part 11. DataLabs includes password 
protection and internal quality checks, such as range checks, to identify data that appear inconsistent, 
incomplete, or inaccurate. Data reported in the eCRF, derived from source documents, should be 
consistent with the source documents or the discrepancies should be explained. Where the data 
violate validation checks, queries will be generated for resolution by clinical staff. All edits made to the 
database upon resolution of queries will be recorded in an electronic audit trail. 
eCRFs will be used for all patients. The Investigator’s data will be accessible from the Investigator’s 
site throughout the trial. eCRFs must be kept current to reflect patient status at each phase during the 
course of the trial. The eCRF will not capture personalised data. The Investigator must make a 
separate confidential record of personalised details (name and initials) on the subject identification and 
screening enrolment log. 
It is the responsibility of the PI of the respective site to ensure that all subject discontinuations or 
changes in study or other medications entered on the subject’s eCRF are also made on the subject’s 
medical records. 
The eCRFs for any subject leaving the study should be completed at the time of the final visit or 
shortly thereafter. 
 
11.3 Access to Data 
Direct access will be granted to authorised representatives from the Sponsor, host institution and the 
regulatory authorities to permit trial-related monitoring, audits and inspections. 
 
11.4 Archiving 
Records and documents pertaining to the conduct of the study and the distribution of the 
investigational product (e.g. ICFs, eCRFs (if used), laboratory slips, medication inventory records, and 
other pertinent information) must be retained by the Investigator according to local requirements. 
 

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11.5 Clinical study report 
After completion of the study, the results will be tabulated, evaluated and issued as a complete final 
clinical study report according to the ICH-E3 Note for guidance on structure and content of clinical 
study reports.  
The Sponsor will send a summary of this clinical study report to the ECs and CAs within one year after 
the end of the trial. 
 
12 MONITORING, AUDIT & INSPECTION 
The Investigator will permit trial-related monitoring, IEC review, and regulatory inspections, providing 
direct access to source data/documents. Sponsor-authorised quality assurance personnel may carry 
out audits for which the Investigator must provide support. 
The study will be supervised by a monitor. The study monitor will contact the Investigator regularly to 
discuss the progress of the study and to check the study documents including the ICFs for 
completeness and consistency. In regards to an unblinded monitor, the monitor will review the drug 
delivery information at the pharmacy. 
The Sponsor, or delegate, will conduct pre-study and start-up meeting site visits. The study monitor, or 
a representative of the Sponsor, will cross-check the data entered in the eCRFs with the source data 
at the study site and observe the study procedures in order to verify adherence to the study protocol. 
The eCRFs will be checked for completeness and correctness by the monitor and data management 
department of the CRO and any queries will be resolved by the Investigator. The Sponsor, or 
delegate, will conduct post study site visits. 
 
13 ETHICAL AND REGULATORY CONSIDERATIONS 
13.1 Ethics Committee (EC) review & reports 
Favourable opinions from the relevant ECs will be obtained for the trial protocol, ICFs and other 
relevant documents prior to the start of the study. 
The ECs will be notified about the end of the trial by the CI within 90 days of its completion and a 
report summarising the study results will be sent to the ECs within one year after the end of the trial. If 
the trial is terminated early, the ECs will be notified within 15 days. Periodic Reports to CAs and ECs 
will be submitted as required by local regulations. 
 
13.2 Peer review 
The protocol has been reviewed by representatives of the Sponsor, the Sponsor’s Medical advisor, the 
Sponsor’s Statistician, the CI, and a CRO assigned by the Sponsor.  
 
13.3 Public and Patient Involvement 
The public and study participants will not be involved in the research. 
 

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13.4 Regulatory Compliance 
Prior to the start of the study, appropriate regulatory authority approvals will be obtained, according to 
local country requirements. This study will be conducted in accordance with the protocol and ethical 
principles stated in the applicable guidelines on Good Clinical Practice (GCP), and all applicable local 
and/or regional laws, rules, and regulations.  
The Investigator will provide the Sponsor or its designee with documentation of the Institutional 
Review Board/Independent Ethics Committee approval of the protocol and the informed consent 
document before the study may begin at the investigative site(s). 
 
13.5 Protocol compliance  
The Investigator agrees to conduct the trial in compliance with the protocol. Any amendments should 
be agreed by both the Sponsor and the CI, with the appropriate written and approved protocol 
amendments made to reflect the changes agreed upon. 
Any deviation from the clinical study protocol in the conduct of the clinical trial will be notified to the 
monitor on an ongoing basis. 
 
13.6 Notification of Serious Breaches to GCP and/or the protocol  
A “serious breach” is a breach which is likely to affect to a significant degree  
 
the safety or physical or mental integrity of the subjects of the trial; or 
 
the scientific value of the trial 
The Sponsor will be notified immediately of any case where the above definition applies during the trial 
conduct phase. The Sponsor will notify the licensing authority in writing of any serious breach of the 
conditions and principles of GCP in connection with that trial; or the protocol relating to that trial, as 
amended from time to time, within 7 days of becoming aware of that breach. 
 
13.7 Data protection and patient confidentiality  
The ICF will incorporate wording that complies with relevant local data protection and privacy 
legislation. Records containing patient medical information will be handled in accordance with local 
and national laws, rules, and regulations and consistent with the terms of the patient authorisation 
contained in the informed consent document for the study. 
The Investigators and trial site staff will comply with these requirements with regard to the collection, 
storage, processing and disclosure of personal information.  
For the purposes of the study (recording of data in the eCRF or other documents), personal subject 
data such as name, birth date or address will be replaced by an identification number (pseudonymous 
data recording). The Investigator makes and archives a decode list, by means of which the 
pseudonymous data can be allocated to the subject if necessary in accordance with legal 
requirements. Only pseudonymous study data may be transferred to the Sponsor or a CRO for the 
purpose of analysis and to the relevant authorities according to legal requirements. 

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Authorised representatives from the Sponsor or an institution assigned by the Sponsor and the 
responsible authorities may review the subjects’ personal data stored at the study site as far as this is 
necessary for the inspection of the proper conduct of the study. All persons involved in the review of 
personal data will guarantee complete confidentiality. 
The study results will be analysed by the Sponsor and may be published in a professional scientific 
journal. However, in no case can the subject be identified from this data. 
 
13.8 Financial and other competing interests for the CI, PIs at each site and committee 
members for the overall trial management  
The disclosed financial interest of the Investigator must be collected before screening of the first 
patient, following study completion at the Investigator site and 1 year following overall study 
completion. The Investigator should promptly update this information if any relevant changes occur 
during this period. 
 
13.9 Indemnity 
In accordance with Statutory Instrument 1031 and amendments section 15 (5i, j) and the EU Clinical 
Trials Directive 2000/20/EC Article 3 (2f), provision is to be made for: 
 
The indemnity or compensation in the event of injury or death attributable to the clinical trial; 
and  
 
Insurance or indemnity to cover the liability of the Investigator or Sponsor. 
Therefore the Sponsor, Altimmune, will indemnify the CI/PI from all and any claims arising out of this 
study except for those that arise from their negligence or malpractice and providing that the study is 
conducted according to the standards established by the protocol. 
In the event that it can be demonstrated that a subject suffers any significant deterioration in health or 
well-being or any harmful susceptibility or toxicity as a direct result of their participation in this study 
then Altimmune will agree to abide by the current Association of the British Pharmaceutical Industry 
Guidelines with regard to compensation payable to the subject. The amount of compensation will be 
calculated by reference to the level of damages commonly awarded in local law for similar injuries at 
the time when such injury occurred. 
The Investigator declares to having insurance cover for the malpractice and/or negligence of their 
employees and agents. 
 
13.10 Amendments  
Amendments to this study protocol may be made following the procedures specified by local laws and 
regulations. Substantial amendments to this study protocol may be implemented only if the approval of 
the CA and a favourable opinion of the EC(s) have been obtained. 
Substantial amendments to the conduct of the clinical trial may arise from changes to the protocol or 
from new information relating to the scientific documents in support of the trial. Amendments to the 
trial are regarded as “substantial” where they are likely to have a significant impact on: 
 
the safety, physical health and mental integrity of the subjects; 

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 
the scientific value of the trial; 
 
or be otherwise significant. 
If a new event occurs related to the conduct of the trial or the development of the investigational 
product, which may affect the safety of the subjects, the Sponsor and the Investigator will take 
appropriate safety measures to protect the subjects against any immediate hazard. The Sponsor will 
immediately inform the CAs and EC(s) of the new events and the measures taken. 
 
13.11 Post-trial care 
After the end of the trial, the study participants will return to the care of their treating physician(s).  
 
13.12 Access to the final trial dataset 
The original eCRFs and the data generated from the eCRFs or otherwise obtained during the study 
under this study protocol will become the property of the Sponsor. Access to the final trial dataset will 
be restricted to the Sponsor or authorised representatives of the Sponsor. 
 
13.13 Authorship eligibility guidelines and any intended use of professional writers 
Authorship of scientific publications will be in accordance with the guidelines of the International 
Committee of Medical Journal Editors. Publication of the results of this study by the Investigator is 
possible only after written consent has been obtained from the Sponsor. Any material intended for 
publication will be given to the Sponsor at least 4 weeks before submission for publication. The 
Sponsor will have the right to comment on the intended publication and to take any reasonable 
measures for patent protection. 
 
13.14 Ethical conduct of the study  
The study will be conducted in accordance with the ethical principles set forth in the Declaration of 
Helsinki (including amendments). The Sponsor will ensure that the study complies with all local, 
federal, or country regulatory requirements as applicable. 
 
 

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14 REFERENCES 
1 
Betancourt AA, Delgado CA, Estévez ZC, et al. Phase I clinical trial in healthy adults of a nasal 
vaccine candidate containing recombinant hepatitis B surface and core antigens. Int J Infect Dis. 
2007 Sep;11(5):394-401 
2 
Boni C, Laccabue D, Lampertico P, et al. Restored function of HBV-specific T cells after long-term 
effective therapy with nucleos(t)ide analogues. Gastroenterology. 2012 Oct;143(4):963-73.e9.  
3 
Fisicaro P, Valdatta C, Massari M, et al. Antiviral intrahepatic T-cell responses can be restored by 
blocking programmed death-1 pathway in chronic hepatitis B. Gastroenterology. 2010 
Feb;138(2):682-93.693.e1-4 
4 
Francis JN, Bunce CJ, Horlock C, et al. A novel peptide-based pan-influenza A vaccine: a double 
blind, randomised clinical trial of immunogenicity and safety. Vaccine. 2015 Jan 3;33(2):396-402 
5 
Francis JN, Thaburet JF, Bonnet D, et al. Increasing cellular immunogenicity to peptide-based 
vaccine candidates using a fluorocarbon antigen delivery system. Vaccine. 2015 Feb 
18;33(8):1071-6 
6 
Grimm D, Heeg M, and Thimme R. Hepatitis B virus: from immunobiology to immunotherapy. Clin 
Sci (Lond). 2013 Jan;124(2):77 -84 
7 
Mahtab MA, Akbar F, Uddin H, et al. A phase III clinical study with nasal vaccine containing both 
HBsAg and HBcAg in patients with chronic hepatitis B. Journal of Hepatology, April 2013 Volume 
58, Supplement 1, Page S309 
8 
Pol S, Nalpas B, Driss F, et al. Efficacy and limitations of a specific immunotherapy in chronic 
hepatitis B. J Hepatol. 2001 Jun;34(6):917-21. 
9 
Reither K et al. Safety and Immunogenicity of H1/IC31H, an Adjuvanted TB Subunit Vaccine, in 
HIV-Infected Adults with CD4+ Lymphocyte Counts Greater than 350 cells/mm3: A Phase II, Multi-
Centre, Double-Blind, Randomized, Placebo-Controlled Trial. PLoS One. 2014 Dec 
9;9(12):e114602 
10 Riedl K, Riedl R, von Gabain A, et al. The novel adjuvant IC31 strongly improves influenza 
vaccine-specific cellular and humoral immune responses in young adult and aged mice. Vaccine. 
2008 Jun 25;26(27-28):3461-8 
11 Salmon-Ceron D, Rosenthal E, Lewden C, et al. ANRS EN19 Mortalité Study Group and Mortavic. 
Emerging role of hepatocellular carcinoma among liver-related causes of deaths in HIV-infected 
patients: The French national Mortalité 2005 study. J Hepatol. 2009 Apr;50(4):736-45. 
12 Schellack C1, Prinz K, Egyed A, et al. IC31, a novel adjuvant signaling via TLR9, induces potent 
cellular and humoral immune responses. Vaccine. 2006 Jun 29;24(26):5461-72 
13 Tang C-M, Yau TO and Yu J. Management of chronic hepatitis B infection: Current treatment 
guidelines, challenges, and new developments. World J. Gastroenterol. 2014; 20 (20): 6262-6278 
14 Van Dissel JT et al. Ag -84B-ESAT-6 adjuvanted with IC31® promotes strong and long-lived 
Mycobacterium tuberculosis specific T cell responses in volunteers with previous BCG vaccination 

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or tuberculosis infection. Vaccine. 2011 Mar 3;29(11):2100-9 
15 Vandepapelière P, Lau GK, Leroux-Roels G, et al. Therapeutic vaccination of chronic hepatitis B 
patients with virus suppression by antiviral therapy: a randomized, controlled study of co-
administration of HBsAg/AS02 candidate vaccine and lamivudine. Vaccine. 2007 Dec 
12;25(51):8585-97