A Phase 1b, Randomized, Double-blind, Placebo-controlled, Dose-escalation Study to Evaluate the Safety and Immunogenicity of the ID93 + GLA-SE Vaccine in BCG-Vaccinated Healthy Adults
Phase: PHASE1
Conditions: Pulmonary Tuberculosis
Sponsor: Access to Advanced Health Institute (AAHI)

 
 
Page 1 of 55 
 
 
ID93 + GLA-SE 
 
Protocol IDRI-TBVPX-114 
 
CONFIDENTIAL 
08/Feb/2013; Final Version 1.0 
 
Aeras Clinical Protocol Template Edition 01.4; Reference SOP CLD-136 rev. 01, ATT-CLD136-B 
  
 
 
A Phase 1b, Randomized, Double-blind, Placebo-controlled, Dose-escalation 
Study to Evaluate the Safety and Immunogenicity of the ID93 + GLA-SE Vaccine in 
BCG-Vaccinated Healthy Adults 
 
Investigational Product:  
 
ID93 + GLA-SE 
 
IDRI Protocol Number: 
 
 
IDRI-TBVPX-114 
 
US FDA IND Number: 
 
 
BB-IND 15101 
 
 
 
 
 
Sponsor: 
Infectious Disease Research Institute (IDRI) 
1124 Columbia St #400 
Seattle, WA 98104-2053 
U.S.A. 
Phone: (206) 381-0883 
Fax: 
(206) 381-3678 
 
 
 
Sponsor's Authorized Representative: 
Franco Piazza, MD, MPH 
Medical Director 
 
 
 
 
 
 
 
 
Principal Investigator Agreement: 
I, the undersigned, have reviewed this protocol and agree to conduct this protocol in accordance 
with Good Clinical Practices (ICH-GCP), the ethical principles set forth in the Declaration of 
Helsinki, and with local regulatory requirements.   
 
Signature 
 
 
 
 
 
 
 
Date 
 
 
Printed Name  

 
 
Page 2 of 55 
 
 
ID93 + GLA-SE 
 
Protocol IDRI-TBVPX-114 
 
CONFIDENTIAL 
08/Feb/2013; Final Version 1.0 
 
Aeras Clinical Protocol Template Edition 01.4; Reference SOP CLD-136 rev. 01, ATT-CLD136-B 
  
 
 TABLE OF CONTENTS 
 
STUDY ABSTRACT .................................................................................................................... 7 
1 
INTRODUCTION............................................................................................................. 9 
1.1 
Background ............................................................................................................... 9 
1.2 
Description of ID93 + GLA-SE ................................................................................ 9 
1.3 
Nonclinical Experience with ID93 + GLA-SE ......................................................... 9 
1.4 
Clinical Experience with ID93 + GLA-SE ............................................................. 10 
1.5 
Clinical Experience with GLA-SE .......................................................................... 10 
1.6 
Rationale for Study .................................................................................................. 10 
2 
STUDY OBJECTIVES AND DESIGN ......................................................................... 11 
2.1 
Objectives ................................................................................................................ 11 
2.2 
Design ...................................................................................................................... 11 
3 
STUDY PROCEDURES ................................................................................................ 12 
3.1 
Schedule of Participant Evaluations ........................................................................ 12 
3.2 
Participant Selection ................................................................................................ 15 
3.2.1 
Recruitment and Informed Consent .......................................................... 15 
3.2.2 
Screening................................................................................................... 15 
3.2.3 
Inclusion Criteria ...................................................................................... 15 
3.2.4 
Exclusion Criteria ..................................................................................... 16 
3.2.5 
Screening Clinical Assessments and Laboratory Tests ............................ 17 
3.3 
Study Randomization .............................................................................................. 17 
3.4 
Blinding ................................................................................................................... 18 
3.4.1 
Unblinding for Clinical Emergencies ....................................................... 19 
3.5 
Study Injection Administration ............................................................................... 19 
3.6 
Study Evaluations .................................................................................................... 20 
3.6.1 
Immunology Laboratory Evaluations ....................................................... 20 
3.6.2 
Safety Evaluations .................................................................................... 21 
3.6.2.1 
Pre-vaccination and Post-vaccination Monitoring of 
Participants ............................................................................... 21 
3.6.2.2 
Clinical Assessments and Laboratory Tests ............................. 21 
3.6.2.3 
Adverse Events......................................................................... 21 
3.6.2.4 
Concomitant Medications ........................................................ 22 
3.6.3 
Participant Follow-up and Contact ........................................................... 22 
3.6.4 
Loss to Follow-up ..................................................................................... 23 
4 
STUDY VACCINES ....................................................................................................... 23 
4.1 
Supplies ................................................................................................................... 23 
4.2 
Accountability ......................................................................................................... 24 
4.3 
Receipt and Storage ................................................................................................. 24 
4.4 
Vaccine Preparation ................................................................................................ 24 
4.5 
Disposal of Unused Supplies ................................................................................... 24 

 
 
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ID93 + GLA-SE 
 
Protocol IDRI-TBVPX-114 
 
CONFIDENTIAL 
08/Feb/2013; Final Version 1.0 
 
Aeras Clinical Protocol Template Edition 01.4; Reference SOP CLD-136 rev. 01, ATT-CLD136-B 
  
 
5 
SAFETY ........................................................................................................................... 24 
5.1 
Responsibilities for Ensuring the Safety of Trial Participants ................................ 24 
5.1.1 
Principal Investigator ................................................................................ 25 
5.1.2 
Study Sponsor ........................................................................................... 25 
5.1.3 
Local Medical Monitor ............................................................................. 25 
5.1.4 
Safety Monitoring Committee .................................................................. 25 
5.1.5 
Institutional Review Boards and Ethics Committees................................ 26 
5.1.6 
National Regulatory Authority ................................................................. 26 
5.2 
Safety Surveillance During the Study ..................................................................... 26 
5.3 
Definition of Adverse Event ................................................................................... 26 
5.4 
Assessing Severity ................................................................................................... 27 
5.5 
Assessing Causal Relationship (Relatedness) ......................................................... 28 
5.6 
Definition of Adverse Reaction ............................................................................... 29 
5.7 
Solicited Adverse Events and Injection Site Reactions .......................................... 29 
5.8 
Adverse Events of Special Interest (AESIs) ........................................................... 30 
5.9 
Assessing "Seriousness" and Serious Adverse Events ............................................ 30 
5.10 Assessing Expectedness .......................................................................................... 31 
5.11 Definition of Suspected Unexpected Serious Adverse Reaction (SUSAR) ............ 31 
5.12 Reporting of Serious Adverse Events ..................................................................... 31 
5.13 Other Events Requiring Immediate Reporting ........................................................ 32 
5.14 Adverse Event Treatment, Follow-up, and Outcome .............................................. 33 
5.15 Follow-up of Participants Who Become Pregnant .................................................. 33 
5.16 Dose Escalation ....................................................................................................... 34 
6 
CRITERIA FOR INTERRUPTING THE TRIAL ...................................................... 35 
6.1 
Rules for Discontinuing Study Injections in an Individual Participant ................... 35 
6.2 
Rules for Suspension of the Entire Study ................................................................ 35 
7 
STATISTICAL CONSIDERATIONS .......................................................................... 36 
7.1 
Participant Populations ............................................................................................ 36 
7.2 
Demographics and Protocol Compliance ................................................................ 36 
7.3 
Efficacy Analyses .................................................................................................... 36 
7.4 
Immunology Analyses ............................................................................................. 37 
7.4.1 
Primary Immunology Analyses ................................................................ 37 
7.4.2 
Exploratory Immunology Analyses .......................................................... 37 
7.5 
Safety Analyses ....................................................................................................... 37 
7.5.1 
Adverse Events ......................................................................................... 38 
7.5.2 
Clinical Laboratory and Vital Sign Parameters ........................................ 38 
7.6 
Sample Size Considerations .................................................................................... 38 
7.7 
Plan for Statistical Summaries and Analyses .......................................................... 39 
7.7.1 
Preliminary Data Reviews ........................................................................ 39 
7.7.2 
Dose response ........................................................................................... 39 
7.7.3 
Final Study Report .................................................................................... 39 
7.8 
Computer Methods .................................................................................................. 40 
8 
DATA COLLECTION, MONITORING, AND RECORD RETENTION................ 40 

 
 
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ID93 + GLA-SE 
 
Protocol IDRI-TBVPX-114 
 
CONFIDENTIAL 
08/Feb/2013; Final Version 1.0 
 
Aeras Clinical Protocol Template Edition 01.4; Reference SOP CLD-136 rev. 01, ATT-CLD136-B 
  
 
9 
HUMAN SUBJECTS ...................................................................................................... 40 
9.1 
Ethics and Regulatory Considerations .................................................................... 40 
9.2 
Institutional Review Board or Independent Ethics Committee ............................... 41 
9.3 
Informed Consent .................................................................................................... 41 
10 
STUDY COMPLETION ................................................................................................ 42 
11 
PUBLICATIONS ............................................................................................................ 43 
12 
CHANGES IN THE PROTOCOL ................................................................................ 43 
13 
REFERENCES ................................................................................................................ 44 
APPENDIX A 
Detailed Description of Study Visits ...................................................... 45 
APPENDIX B 
Reporting Schemes for SAEs, Immediately Reportable 
Events, and SUSARs ............................................................................... 50 
APPENDIX C 
Toxicity Table .......................................................................................... 52 
APPENDIX D 
Adverse events of Special Interest ......................................................... 54 
 
 
LIST OF TABLES 
 
Table 0-1 
Dose Cohorts and Treatment Regimen ..................................................................... 8 
Table 2-1 
Dose Cohorts and Treatment Regimen ................................................................... 12 
Table 3-1 
Summary Schedule of Participant Evaluations ....................................................... 13 
Table 3-2 
Summary of Immunology Laboratory Evaluations ................................................. 20 

 
 
Page 5 of 55 
 
 
ID93 + GLA-SE 
 
Protocol IDRI-TBVPX-114 
 
CONFIDENTIAL 
08/Feb/2013; Final Version 1.0 
 
Aeras Clinical Protocol Template Edition 01.4; Reference SOP CLD-136 rev. 01, ATT-CLD136-B 
  
 
LIST OF ABBREVIATIONS 
 
βHCG 
beta human chorionic gonadotropin 
µg 
microgram(s) 
Ab 
antibody 
AE 
adverse event(s) 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST  
aspartate aminotransferase 
BCG 
bacillus Calmette-Guérin 
BMI 
body mass index 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CFR 
Code of Federal Regulations (US) 
CIOMS 
Council for International Organizations of Medical Sciences 
CRF 
case report form(s) 
CRO 
contract research organization 
CRP 
C-reactive protein 
EDC 
electronic data capture 
ELISA 
enzyme-linked immunosorbent assay 
ELISPOT 
enzyme-linked immunospot 
FDA 
United States Food and Drug Administration 
GCP 
good clinical practices 
GMP 
good manufacturing practices 
HIV 
human immunodeficiency virus 
ICH 
International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use 
ICS 
intracellular cytokine staining 
IEC 
Independent Ethics Committee 
IFN-γ 
interferon gamma 
IL-2 
interleukin-2 
IM 
intramuscular 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
MAF 
medical assessment form 
MDR 
multidrug-resistant 
MedDRA 
Medical Dictionary for Regulatory Activities 
mL 
milliliter(s) 
Mtb 
Mycobacterium tuberculosis  
PBMC 
peripheral blood mononuclear cell(s) 
PI 
principal investigator 
PPD 
purified protein derivative 
PRBC 
packed red blood cells 
PT 
preferred term  

 
 
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ID93 + GLA-SE 
 
Protocol IDRI-TBVPX-114 
 
CONFIDENTIAL 
08/Feb/2013; Final Version 1.0 
 
Aeras Clinical Protocol Template Edition 01.4; Reference SOP CLD-136 rev. 01, ATT-CLD136-B 
  
 
QFT 
QuantiFERON-TB Gold 
RNA 
ribonucleic acid 
SAE 
serious adverse event(s) 
SAER 
supplemental serious adverse event report 
SE 
stable emulsion 
SMC 
Safety Monitoring Committee 
SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse reaction(s) 
TB 
tuberculosis 
TLR 
toll-like receptor 
TNF-α 
tumor necrosis factor alpha 
ULN 
upper limit of normal 
US 
United States 
WBC 
white blood cell 
WHO 
World Health Organization 

 
 
Page 7 of 55 
 
 
ID93 + GLA-SE 
 
Protocol IDRI-TBVPX-114 
 
CONFIDENTIAL 
08/Feb/2013; Final Version 1.0 
 
Aeras Clinical Protocol Template Edition 01.4; Reference SOP CLD-136 rev. 01, ATT-CLD136-B 
  
 
STUDY ABSTRACT 
 
TITLE: 
A Phase 1b, Randomized, Double-blind, Placebo-controlled, Dose-escalation Study to Evaluate 
the Safety and Immunogenicity of the ID93 + GLA-SE Vaccine in BCG-Vaccinated Healthy 
Adults 
 
RATIONALE: 
The initial target population for the vaccine is previously BCG-vaccinated adults who may be 
latently infected with Mtb.  With the demonstration of initial safety in non-BCG-vaccinated, 
QFT-negative adults, safety and immunogenicity data in BCG-vaccinated adults are needed prior 
to further studies in Mtb-exposed populations. 
 
OBJECTIVES: 
Primary Objective 
To describe the safety profile of ID93 + GLA-SE in BCG-vaccinated, QuantiFERON TB-Gold 
(QFT) negative and positive healthy adults. 
 
Secondary Objective(s) 
To describe the immunogenicity of ID93 + GLA-SE in BCG-vaccinated, QFT negative and 
positive healthy adults. 
 
To identify one or more ID93 + GLA-SE vaccination regimens for further evaluation in BCG-
vaccinated, QFT negative and positive healthy adults. 
 
DESIGN: 
This is a Phase 1b, randomized, double-blind, placebo-controlled, dose-escalation evaluation of 
two dose levels of the ID93 antigen administered intramuscularly (IM) in combination with two 
dose levels of the GLA-SE adjuvant.  This study will be conducted in 66 HIV-negative, healthy 
South African adults with previous BCG vaccination.  For safety reasons, participants who are 
QFT negative (not latently infected with Mtb) at screening will be enrolled first; successive 
cohorts will enroll both QFT negative and positive participants.  The study will be conducted at 
one or more clinical research sites in South Africa.  Participants will be followed for 6 months 
following the last study injection.  Solicited and unsolicited adverse events (AEs) will be 
recorded for 28 days following each study injection; serious adverse events and adverse events of 
special interest will be recorded for the duration of the study.  Immune responses (cellular and 
antibody) will be assessed at baseline and periodically after study injections. 
 
Table 0-1 shows the dose cohorts and treatment regimen.  Entry of participants in successive 
cohorts will occur after the principal investigator(s) and the local medical monitor have reviewed 
cumulative safety data following the first two study injections (up to and including Study Day 
35) of all participants in the preceding cohort(s). 
 

 
 
Page 8 of 55 
 
 
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Protocol IDRI-TBVPX-114 
 
CONFIDENTIAL 
08/Feb/2013; Final Version 1.0 
 
Aeras Clinical Protocol Template Edition 01.4; Reference SOP CLD-136 rev. 01, ATT-CLD136-B 
  
 
Table 0-1 
Dose Cohorts and Treatment Regimen 
Cohort/ 
QFT status 
Group 
Number 
of 
participants 
Study injections 
ID93 
Dose 
GLA-SE 
Dose 
Dosing 
Schedule 
1 (QFT-) 
1 
9 
ID93 + GLA-SE 
10 µg 
2 µg 
Days 0, 28, 112 
2 
3 
Placebo (saline) 
- 
- 
2 (QFT -/+) 
3 
15 
ID93 + GLA-SE 
2 µg 
2 µg 
Days 0, 28, 112 
4 
3 
Placebo (saline) 
- 
- 
3 (QFT -/+) 
5 
15 
ID93 + GLA-SE 
10 µg 
2 µg 
Days 0, 28, 112 
6 
3 
Placebo (saline) 
- 
- 
4 (QFT -/+) 
7 
15 
ID93 + GLA-SE 
10 µg 
5 µg 
Days 0, 28, 112 
8 
3 
Placebo (saline) 
- 
- 
Total number of participants 66 (54 receiving ID93 + GLA-SE, 12 receiving saline placebo) 
 
ANALYSIS OF IMMUNOLOGY 
The primary variables of interest for assessment of the immune response to the vaccine will be 
the percentage of CD4+ and CD8+ T cells that produce any of selected cytokines following 
stimulation with peptide pools derived from and representing the entire amino acid sequences of 
the mycobacterial antigens Rv2608, Rv3619, Rv3620, and Rv1813.  Response will be measured 
using PBMCs by flow cytometry in the intracellular cytokine staining (ICS) assay, and will be 
presented using median DMSO-subtracted cytokine responses and associated 95% CIs by 
treatment regimen.  Positivity of T cell responses from the ICS assay will be determined 
according to a pre-specified methodology, to be described in the statistical analysis plan, and will 
be summarized as number (percentage) of responders by treatment regimen.  Separate summaries 
will also be presented by treatment regimen and by baseline QFT status. 
 
ANALYSIS OF SAFETY 
The primary variable for evaluation of the safety profile will be the number and percentage of 
unsolicited and solicited adverse events recorded at all available post-vaccination time points, 
summarized by MedDRA system organ class (SOC) and preferred term (PT).  Additional 
summaries will present the number (percentage) of participants with adverse events by severity 
and by relationship to study injection. 

 
 
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ID93 + GLA-SE 
 
Protocol IDRI-TBVPX-114 
 
CONFIDENTIAL 
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Aeras Clinical Protocol Template Edition 01.4; Reference SOP CLD-136 rev. 01, ATT-CLD136-B 
  
 
1 
INTRODUCTION 
1.1 
Background 
Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb).  
Despite progress in reducing the number of deaths due to TB, the global burden of disease 
remains enormous, with an estimated 8.7 million new cases and 1.4 million deaths from TB in 
2011.  Worldwide, 3.7% of new cases and 20% of previously treated cases were estimated to 
have multidrug-resistant (MDR) TB, with 60% of those cases in India, China, or South Africa; 
extensively drug resistant TB has been reported in 84 countries (1). 
 
BCG is the only TB vaccine currently licensed for use in humans and appears to be effective at 
preventing severe disseminated disease in newborns and young children, but fails to protect 
against pulmonary TB in adults (2).  Even though variable efficacy has been shown with BCG 
vaccination in human trials, BCG is unlikely to be replaced in the near future and is the reference 
standard to which all other experimental vaccines are compared.  A number of countries with a 
lower incidence of TB, including the United States, have not adopted or have withdrawn from 
routine BCG vaccination, preferring to screen for and treat TB with antibiotics.  Therefore, ID93 
+ GLA-SE is being developed as a TB vaccine that is safe and efficacious for the prevention of 
pulmonary TB in both BCG- and non-BCG-primed individuals. 
 
1.2 
Description of ID93 + GLA-SE 
Protective immunity to TB may be conferred by Th1 CD4 and CD8 T cells (3), and TB animal 
models have demonstrated that an effective vaccine requires the generation of a T cell-mediated 
immune response.  Mtb antigens have been identified which are recognized by human T cells and 
are capable of eliciting dominant Th1 responses associated with reduced bacterial burden in a 
mouse model of TB (4).  A recombinant subunit vaccine antigen, called ID93, has been 
developed in response to these findings.  ID93 combines four antigens belonging to families of 
Mtb proteins associated with virulence (Rv2608, Rv3619, Rv3620) and latency (Rv1813) (4, 5, 
6). 
 
As recombinant proteins are known to demonstrate poor immunogenicity alone and require an 
adjuvant to elicit adaptive immune responses, a synthetic Toll-like Receptor (TLR) 4 adjuvant 
has been developed and formulated in a stable oil-in-water emulsion (GLA-SE) (7).  This 
adjuvant system has been successfully combined with recombinant protein antigens for the 
induction of high antibody titers (8, 9) and of Th1 immune responses that have been associated 
with protection in Mtb and Leishmania challenge models (10, 11). 
 
1.3 
Nonclinical Experience with ID93 + GLA-SE 
Several nonclinical studies in human cells, mice, guinea pigs, non-human primates, and rabbits 
have demonstrated the safety and immunogenicity of ID93 + GLA-SE.    
 
Observed effects of ID93 + GLA-SE in toxicity and safety studies in nonhuman primates and 
rabbits include: 

 
 
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Aeras Clinical Protocol Template Edition 01.4; Reference SOP CLD-136 rev. 01, ATT-CLD136-B 
  
 
 
• Elevation of CRP and fibrinogen levels; and, 
• Changes in hematologic values 
 
These mild and reversible effects are considered related to treatment and the intramuscular 
injection route of administration.  Previous toxicity studies with other vaccine antigens and 
GLA-SE have indicated the potential for mild and reversible injection site reactogenicity.  
Further details can be found in the ID93 + GLA-SE Investigator's Brochure, and in the GLA-SE 
Investigator's Brochure (attached as an appendix to the ID93 + GLA-SE Investigator's Brochure). 
 
1.4 
Clinical Experience with ID93 + GLA-SE 
Aeras (a non-profit organization dedicated to the development of new TB vaccines) is partnering 
with IDRI in the clinical development of ID93 + GLA-SE.  A Phase 1 study is currently being 
conducted at Johnson County Clin-Trials in Lenexa, Kansas, USA.  Sixty BCG-naïve, HIV-
negative, QuantiFERON-TB Gold (QFT)-negative healthy adults are being randomized to 
receive ID93 + GLA-SE or ID93 alone given intramuscularly on Days 0, 28, and 56 and are 
being followed through Day 420.  Four dose cohorts will escalate ID93 from 2 µg to 10 µg and 
GLA-SE from 2 µg to 5 µg.  To date, vaccinations in Cohort 1 (2 µg ID93 with or without 2 µg 
GLA-SE) and Cohort 2 (10 µg ID93 with or without 2 µg GLA-SE) have been well tolerated.  
Local reactogenicity has been mostly mild pain and swelling and related systemic AEs have been 
mostly mild.  See the ID93 + GLA-SE Investigator's Brochure for further details.  
  
1.5 
Clinical Experience with GLA-SE 
GLA-SE has been used in clinical trials of vaccines targeting schistosomiasis, malaria, 
leishmaniasis, and influenza.  Dose levels of GLA-SE have ranged from <2 to 10 µg, with up to 
3 injections administered.  Injections of vaccines containing GLA-SE have generally been well-
tolerated, adverse events have been mostly mild, and no serious adverse events related to GLA-
SE have been observed.  See the GLA-SE Investigator's Brochure for further details. 
 
1.6 
Rationale for Study 
The initial target population for the vaccine is remotely BCG-vaccinated adults (i.e., vaccinated 
as infants) who may be latently infected with Mtb.  With the demonstration of initial safety in 
non-BCG-vaccinated, QFT-negative adults, safety and immunogenicity data in BCG-vaccinated 
adults are needed prior to further studies in Mtb-exposed populations.  The current study, to be 
conducted in South Africa, will begin with QFT-negative adults (who are less likely to be 
latently infected with Mtb) at a dosing level shown to be safe in US adults.  If no safety issues 
are identified, successive cohorts will enroll both QFT-negative and positive adults beginning 
with a lower dose and separately escalating both ID93 and GLA-SE.  The dose levels of the ID93 
antigen and the GLA-SE adjuvant and the intramuscular route of administration chosen for this 
clinical protocol have been selected based on the initial safety data in the US Phase 1 study, pre-
clinical studies of ID93 + GLA-SE in animals, and clinical trials of other vaccines adjuvanted 
with GLA-SE.  In this study vaccinations will be administered at Study Days 0, 28, and 112; the 
longer interval between the 2nd and 3rd doses of vaccine, as compared to the Phase 1 study, may 

 
 
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ID93 + GLA-SE 
 
Protocol IDRI-TBVPX-114 
 
CONFIDENTIAL 
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Aeras Clinical Protocol Template Edition 01.4; Reference SOP CLD-136 rev. 01, ATT-CLD136-B 
  
 
increase the boosting effect of the third dose.  If safety and immunogenicity are demonstrated in 
QFT-negative and positive, BCG-vaccinated adults, subsequent studies using either a 2 or 3-dose 
regimen will evaluate safety in adults recently treated for tuberculosis (Phase 2a), and efficacy 
against pulmonary tuberculosis (Phase 2b).  Data from the Phase 1 (US adults) and Phase 1b 
(South African adults) studies will be used for selection of the dose and regimen to be taken 
forward in clinical development. 
 
2 
STUDY OBJECTIVES AND DESIGN 
2.1 
Objectives 
Primary Objective 
To describe the safety profile of ID93 + GLA-SE in BCG-vaccinated, QuantiFERON TB-Gold 
(QFT) negative and positive healthy adults. 
 
Secondary Objective(s) 
To describe the immunogenicity of ID93 + GLA-SE in BCG-vaccinated, QFT negative and 
positive healthy adults. 
 
To identify one or more ID93 + GLA-SE vaccination regimens for further evaluation in BCG-
vaccinated, QFT negative and positive healthy adults. 
 
2.2 
Design 
This is a Phase 1b, randomized, double-blind, placebo-controlled, dose-escalation evaluation of 
two dose levels of the ID93 antigen administered intramuscularly (IM) in combination with two 
dose levels of the GLA-SE adjuvant.  This study will be conducted in 66 HIV-negative, healthy 
South African adults with previous BCG vaccination.  For safety reasons, participants who are 
QFT negative (not latently infected with Mtb) at screening will be enrolled first; successive 
cohorts will enroll both QFT negative and positive participants.  The study will be conducted at 
one or more clinical research sites in South Africa.  
 
Participants will be sequentially assigned to a dose cohort based on timing of completion of 
screening and on QFT status at screening.  Participants will be randomized in a 3:1 ratio (Cohort 
1) or 5:1 ratio (Cohorts 2–4) to receive ID93 + GLA-SE or saline placebo on Days 0, 28, and 
112.  Participants and site personnel involved in observing the participants will be blinded as to 
treatment regimen.  Participants will be followed for 6 months following the last study injection.  
Solicited and unsolicited adverse events (AEs) will be recorded for 28 days following each study 
injection; serious adverse events and adverse events of special interest will be recorded for the 
duration of the study.  Immune responses (cellular and antibody) will be assessed at baseline and 
periodically after study injections.  Primary endpoints will be the frequency and severity of AEs.  
Secondary endpoints will be cellular responses to the vaccine antigens as assessed by 
intracellular cytokine staining (ICS). 
 
Table 2-1 shows the dose cohorts and treatment regimens.  The first 4 participants vaccinated in 
any dose cohort must be evaluated at their second post-vaccination follow-up visit (Study Day 3) 

 
 
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Aeras Clinical Protocol Template Edition 01.4; Reference SOP CLD-136 rev. 01, ATT-CLD136-B 
  
 
before any additional participants in that cohort may be vaccinated.  If the principal investigator 
determines that there is no reason to pause the study, based on the study suspension rules as 
outlined in Section 6.2, then the site may proceed to enroll the remainder of the participants in 
the cohort.  Entry of participants in successive cohorts will occur after the principal 
investigator(s) and the local medical monitor have reviewed cumulative safety data following the 
first two study injections (up to and including Study Day 35) of all participants in the preceding 
cohort(s). 
 
Table 2-1 
Dose Cohorts and Treatment Regimen 
Cohort/ 
QFT status 
Group 
Number 
of 
participants 
Study injections 
ID93 
Dose 
GLA-SE 
Dose 
Dosing 
Schedule 
1 (QFT-) 
1 
9 
ID93 + GLA-SE 
10 µg 
2 µg 
Days 0, 28, 112 
2 
3 
Placebo (saline) 
- 
- 
2 (QFT -/+) 
3 
15 
ID93 + GLA-SE 
2 µg 
2 µg 
Days 0, 28, 112 
4 
3 
Placebo (saline) 
- 
- 
3 (QFT -/+) 
5 
15 
ID93 + GLA-SE 
10 µg 
2 µg 
Days 0, 28, 112 
6 
3 
Placebo (saline) 
- 
- 
4 (QFT -/+) 
7 
15 
ID93 + GLA-SE 
10 µg 
5 µg 
Days 0, 28, 112 
8 
3 
Placebo (saline) 
- 
- 
Total number of participants 66 (54 receiving ID93 + GLA-SE, 12 receiving saline placebo) 
 
3 
STUDY PROCEDURES 
3.1 
Schedule of Participant Evaluations 
A Summary Schedule of Evaluations depicting all visit-specific procedures is provided in Table 
3-1.  See Appendix A for a more detailed description of the evaluations.  
 

 
 
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Table 3-1 
Summary Schedule of Participant Evaluations 
Study Visit Day → 
Scra 
0 
1 
3 
7 
14 
28 
29 
31 
35 
42 
56 
112 113 
115 
119 126 
140 
196 
294 
Written informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria verification 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine toxicology screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine βHCG (all females) 
X 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
QuantiFERON-TB Gold (mL) 
3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3 
Hepatitis B, C (mL) 
3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV (mL)e  
3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum chemistry (mL)b 
5 
 
 
 
5 
 
 
 
 
5 
 
 
 
 
 
5 
 
 
 
 
CBC, differential (mL)c 
5 
 
 
 
5 
 
 
 
 
5 
 
 
 
 
 
5 
 
 
 
 
Study injection administration 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Study Day 0 site of injection 
examination and photographd 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Day 28 site of injection 
examination and photographd 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Study Day 112 site of injection 
examination and photographd 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
Vital signs 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Interval history 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Focused physical examination 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Whole blood (mL) for: 
- Primary immuno PBMCs (Flow 
cytometry, ICS) 
- Exploratory immuno PBMCs (IFN-γ 
ELISPOT) 
 
30 
 
 
 
30 
 
 
 
 
30 
 
30 
 
 
 
30 
 
30 
30 
Whole blood (mL) for: 
- Exploratory immuno (ICS)  
 
10 
 
 
 
10 
 
 
 
 
10 
 
10 
 
 
 
10 
 
10 
10 
Serum (mL) for: 
- Exploratory immuno (antigen-
specific IgG ELISA) 
 
4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4 
 
 
4 
Serum (mL) for: 
- Exploratory immuno (autoimmune 
Ab ELISA) 
 
2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 
Whole blood (mL) for: 
- Exploratory RNA extraction 
(microarray) 
 
2.5 
2.5 
2.5 
2.5 
 
 
 
 
 
 
 
 
 
 
 
2.5 
 
 
 

 
 
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CONFIDENTIAL 
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Aeras Clinical Protocol Template Edition 01.4; Reference SOP CLD-136 rev. 01, ATT-CLD136-B 
  
 
Study Visit Day → 
Scra 
0 
1 
3 
7 
14 
28 
29 
31 
35 
42 
56 
112 113 
115 
119 126 
140 
196 
294 
Solicited adverse events (incl. con. 
meds.) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Unsolicited adverse events (incl. con. 
meds.) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Serious adverse events and adverse 
events of special interest (incl. con. 
meds.) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Per visit phlebotomy volume (mL) 
19 
48.5 
2.5 
2.5 
12.5 
40 
0 
0 
0 
10 
40 
0 
40 
0 
0 
10 
46.5 
0 
40 
49 
Cumulative phlebotomy volume (mL) 
19 
67.5 
70 
72.5 
85 
125 
125 
125 
125 
135 
175 
175 
215 
215 
215 
225 271.5 271.5 311.5 360.5 
a. 
Screening evaluations must be completed within 30 days prior to randomization.  
b. Serum chemistry includes AST, ALT, alkaline phosphatase, total bilirubin, creatinine, and BUN. 
c. 
Includes hemoglobin, hematocrit, white blood cell count with differential, and platelet count. 
d. Site of injection will be photographed only if there is a visible injection-site abnormality; on vaccination days, the photograph will be taken (if applicable) at 
60 minutes post-vaccination. 
e. 
Rapid test with ELISA confirmation 
 

 
 
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CONFIDENTIAL 
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3.2 
Participant Selection 
3.2.1 
Recruitment and Informed Consent 
Various methods of recruitment may be used such as advertising, referrals, or solicitation of 
participants previously known to the clinical site.  Interested potential participants will be invited 
to participate in the informed consent process.  Informed consent will be obtained by the use of a 
written consent form approved by the Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) and signed and dated by the participant at the time of consent.  Potential 
participants will be interviewed to ensure that they meet all entry criteria relating to history.  The 
clinical investigator or designee will conduct the consent discussion on an individual basis with 
each participant and will allow adequate time for all questions to be addressed.  Written informed 
consent will be obtained prior to conducting any study-related procedures.  A copy of the signed 
consent form shall be given to the participant prior to Study Day 0. 
 
3.2.2 
Screening 
After informed consent is obtained, a screening number will be assigned to each participant for 
identification purposes, and the participant will be screened to assess eligibility for the study.  A 
screening log will be maintained by the site that records all participants for whom consent was 
obtained and who entered the screening process.  At a minimum, the screening log will 
document the participant’s date of consent, screening number, initials, and date of birth.  For 
screened participants who do not subsequently enter the study, the screening log will provide 
details as to why the participant did not enter the study (e.g., ineligibility due to screening 
laboratory abnormality, new illness, or new clinical finding; withdrawal of consent; or failure to 
return to the study site).  For screened participants who subsequently enter the study, the date of 
study entry (date participant is assigned to a study group) will also be recorded.  Abnormal 
results and findings resulting in ineligibility will be discussed with the participant, who will be 
referred for follow-up care with their healthcare provider if necessary. 
 
Eligibility for entry into the study will be based on the inclusion and exclusion criteria described 
below.  The investigator must document confirmation of eligibility prior to randomization. 
 
3.2.3 
Inclusion Criteria 
Participants must meet all of the following criteria: 
 
1. Has completed the written informed consent process prior to start of screening evaluations 
2. Male or female who is ≥18 years and ≤50 years of age at the time of randomization  
3. Agrees to stay in contact with the study site for the duration of the study, provide updated 
contact information as necessary, and has no current plans to move from the study area for 
the duration of the study 
4. Agrees to avoid elective surgery for the full duration of the study 
5. For female participants:  agrees to avoid pregnancy from 21 days prior to Study Day 0 and 
for the full duration of the study.  Women physically capable of pregnancy (not sterilized and 
still menstruating or within 1 year of the last menses if menopausal) in sexual relationships 
with men must use an acceptable method of avoiding pregnancy during this period.  
Acceptable methods of avoiding pregnancy include a sterile sexual partner, sexual abstinence 

 
 
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(not engaging in sexual intercourse), hormonal contraceptives (oral, injection, transdermal 
patch, or implant), vaginal ring, intrauterine device (IUD), or the combination of a condom or 
diaphragm with spermicide gel 
6. Has general good health, confirmed by medical history and physical examination 
7. Has body mass index (BMI) between 19 and 33 (weight/height2) by nomogram 
8. Had BCG vaccination at least 5 years ago, documented through medical history or presence 
of scar 
 
3.2.4 
Exclusion Criteria 
Participants must have none of the following: 
1. Acute illness at the time of randomization 
2. Oral temperature ≥37.5°C at the time of randomization 
3. Clinically significant abnormal laboratory values for any of the following screening 
laboratory parameters, per local laboratory normal ranges from blood collected within 30 
days prior to Study Day 0 randomization as follows: 
• hemoglobin, hematocrit, absolute neutrophil count, absolute lymphocyte count, or 
platelet count below lower limit of normal (LLN)  
• white blood cell count above upper limit of normal (ULN) or below LLN (i.e., must be 
within normal limits)  
• ALT, AST, total bilirubin, alkaline phosphatase, creatinine, or blood urea nitrogen (BUN) 
above ULN  
4. Evidence of systemic or local disease process on screening urinalysis 
5. Evidence of significant active infection 
6. History of treatment for active or latent tuberculosis or evidence of active tuberculosis 
7. Shared a residence within the last year prior to randomization with an individual on anti-
tuberculosis treatment or with culture or smear positive tuberculosis 
8. History of autoimmune disease or immunosuppression 
9. Used immunosuppressive medication within 42 days before randomization (inhaled and 
topical corticosteroids are permitted)  
10. Received immunoglobulin or blood products within 42 days before randomization 
11. Received any investigational drug therapy or investigational vaccine within 182 days before 
randomization, or planned participation in any other investigational study during the study 
period 
12. Received investigational Mtb vaccine at any time prior to randomization 
13. Received a live vaccine within past 4 weeks or a killed vaccine within past 2 weeks prior to 
randomization. 
14. Unable to discontinue current chronic prescription drug therapy that can be hepatotoxic or 
toxic to the bone marrow or kidneys.   
15. History or laboratory evidence of immunodeficiency state including but not limited to any 
laboratory indication of HIV-1 infection 
16. History of allergic disease or reactions (including allergy to kanamycin-related antibiotics, 
allergic reaction to eggs, and severe eczema), likely to be exacerbated by any component of 
the study vaccine 

 
 
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17. Previous medical history that may compromise the safety of the participant in the study, 
including but not limited to:  severe impairment of pulmonary function from pulmonary 
disease; chronic illness with signs of cardiac or renal failure; suspected progressive 
neurological disease; or uncontrolled epilepsy  
18. Evidence of chronic hepatitis (e.g., hepatitis B surface antigen or hepatitis C antibody) 
19. Chronic heavy ethanol intake which, in the opinion of the investigator, may compromise the 
safety of the participant or interfere with the evaluation of the safety of the vaccine  
20. Cannabis smoking 3 or more days per week 
21. Positive urine test for illicit drugs (opiates, cocaine, amphetamines) 
22. History or evidence on physical examination of any systemic disease or any acute or chronic 
illness that, in the opinion of the investigator, may interfere with the evaluation of the safety 
or immunogenicity of the vaccine 
23. All female participants:  currently pregnant or lactating/nursing; or positive urine pregnancy 
test during screening or on the day of study injection  
24. Received a tuberculin skin test within 3 months (90 days) prior to Study Day 0   
25. Any current medical, psychiatric, occupational, or substance abuse problems that, in the 
opinion of the investigator, will make it unlikely that the participant will comply with the 
protocol or may compromise the safety of the participant 
 
3.2.5 
Screening Clinical Assessments and Laboratory Tests 
Unless noted otherwise, the window period within which all screening evaluations must be 
completed, and the results reviewed by the investigator to confirm eligibility of participants, is 
30 days prior to Study Day 0.   
 
Participants will provide a detailed medical history and will undergo a physical examination.  
The assessment will include the determination of any surgeries or medically significant 
procedures planned to occur during the entire study period.  Demographic characteristics (date of 
birth, gender, and race/ethnicity) will also be collected.  Any new abnormal findings will be 
discussed with the participant and referral will be made for follow-up care if necessary. 
 
Screening laboratory tests (hemoglobin, hematocrit, white blood cell count with differential, 
platelet count, AST, ALT, alkaline phosphatase, total bilirubin, creatinine, BUN, urinalysis, 
hepatitis B and C, HIV, QFT) will be performed during the screening process.  Results from 
these laboratory tests will serve as study-entry baseline values.  Abnormal results and findings 
that make the participant ineligible will be discussed with the participant and the participant will 
be referred for follow-up care with their healthcare provider if necessary.  All screening 
laboratory specimens will be processed according to laboratory SOPs available from the clinical 
laboratory(ies) designated for the study.  Information about the laboratory(ies), including any 
instructions for performing and interpreting specific tests, will be maintained in the investigator’s 
study files. 
 
3.3 
Study Randomization 
Participants will be sequentially assigned to a Dose Cohort based on time of completion of 
screening and then randomized within each Dose Cohort to a treatment regimen based on a 

 
 
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sequential series of two-digit randomization numbers linked to a randomly-generated sequence 
of treatment assignments (randomization schedule).  The subject identification number consists 
of the screening number plus the randomization number, which allows for linking of results and 
samples obtained before randomization.  
 
In order to maintain the blind of the team at the study site(s), the study vaccine manager must be 
a designated study team member who will have no clinical or regulatory responsibilities 
associated with the conduct of the study during the entire study period, other than managing the 
vaccine. 
 
A participant is considered randomized when the study vaccine manager assigns that participant 
to the treatment group corresponding to the participant’s assigned randomization number.  If a 
participant does not meet all study entry criteria, randomization of the participant should not 
occur on that day.  If the situation permits, participants may be reconsidered for randomization at 
a later date, e.g., pending resolution of an acute illness or after a repeated clinical laboratory 
evaluation result is shown to be within normal limits, within the allowed time frame for complete 
screening evaluations.    
 
For each randomization number on the randomization schedule there will be a corresponding 
“back-up” randomization number to be used in the event that a participant needs to be replaced.  
If a participant withdraws consent or is removed from the study AFTER being randomized but 
BEFORE receiving any study injection, that participant will be replaced; the next participant 
randomized will be assigned the “back-up” randomization number and thus the same treatment 
assignment as the participant who was replaced.  If a participant withdraws consent or is 
removed from the study AFTER receiving any study injection, that participant will not be 
replaced and that participant’s “back-up” randomization number will not be used. 
 
3.4 
Blinding 
Personnel at the study site(s) will be blinded to participant treatment assignments, with the 
exception of the study vaccine manager (and designee, if appointed) and QA/QC site staff 
responsible for reviewing pharmacy records (if appointed).  In addition, since ID93 + GLA-SE 
and saline for injection (comparator) have different appearances, the study injection 
administrator (the study team member in the clinic who will be administering the injections) will 
also be unblinded.  To avoid unblinding of the study participants, the syringes containing study 
vaccine or comparator will be masked.  All unblinded persons must take care to not reveal 
individual participant treatment regimen assignments to any other member of the study team, 
including the immunologists.  Unblinded study personnel must not participate in the evaluation 
of adverse events.  A Delegation of Authority Log will be maintained by the site and will 
identify the individual(s) authorized to function as the study vaccine manager and study injection 
administrator, i.e., individuals with access to study blinding information.  The pharmacy 
reconciliation monitor(s) and the Aeras investigational product manager will also have access to 
unblinded information.   
 
The randomization schedule will be provided by the unblinded statistician to the study vaccine 
manager in a sealed tamper-evident envelope, or randomization will be administered via a 

 
 
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validated IVRS/IWRS (interactive voice/web response system).  Access to the randomization 
schedule during the study will be provided to the study vaccine manager (and designee) and the 
unblinded pharmacy reconciliation monitor(s).  The randomization schedule and all pharmacy 
source documents and dose preparation records that can link a subject identification number with 
a treatment assignment must remain secure (e.g., in the pharmacy with access limited to only 
authorized unblinded persons) until notification from the sponsor or its designee that the study 
has been unblinded.   
 
3.4.1 
Unblinding for Clinical Emergencies  
If there is an urgent clinical requirement to know a participant’s treatment assignment, the 
investigator (in consultation with the local medical monitor, if possible) will make a written 
request to the vaccine manager for urgent unblinding of a participant’s treatment.  The request 
must include the subject identification number, the date, a brief justification of the clinical 
requirement for unblinding, and the investigator’s signature.  The request will be kept in the 
study file.  
 
Upon receipt of proper written request, the vaccine manager or designee will disclose the 
treatment group to the investigator.  Aeras must be notified immediately of any clinically 
required break of the study blind on an Immediately Reportable Event Form. 
 
3.5 
Study Injection Administration 
On Study Day 0, participants will receive their study injection as soon as possible after 
assignment of a subject identification number, and after their baseline immunology blood 
collection.  On Study Day 28, participants who have not met any of the criteria for 
discontinuation of study injections (see Section 6.1) will receive a second study injection.  In 
cases of short term, reversible conditions, such as acute febrile or respiratory illness or evidence 
of significant active infection, the second study injection should be deferred until the participant 
has recovered; the allowable time period for deferral of the second dose is 5 days (i.e., Study Day 
28+5 days; see Appendix A).  On Study Day 112, participants who have not met any of the 
criteria for discontinuation of study injections (see Section 6.1) will receive a third study 
injection.  Again, in cases of short term, reversible conditions, such as acute febrile or respiratory 
illness or evidence of significant active infection, the third study injection should be deferred 
until the participant has recovered; the allowable time period for deferral of the third dose is 14 
days (i.e., Study Day 112+14 days).   
 
The study vaccine manager will send the study injection to the clinic as a unit-dose syringe, 
which will be identified with the subject identification number, participant’s initials, date and 
time of dose preparation, and the volume prepared.  The syringe will contain 0.5 mL of the study 
vaccine or saline placebo (the comparator).  A medically qualified study team member must be 
present in the clinic at the time of all study injection administrations.   
 
Before administering the injection, the study injection administrator must inspect the syringe and 
vaccine volume, checking that the syringe is identified with the correct subject identification 
number and initials and checking the date and time the dose was prepared.  The vaccine must be 

 
 
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administered within 6 hours of being prepared.  If circumstances result in a delay of 
administration beyond the allotted time, an explanation must be entered into the source 
documents and the expired syringe must be returned to the study vaccine manager, who will 
prepare a replacement syringe using a new vial(s).   
 
The study injection will be administered IM by the study injection administrator into the deltoid 
area using standard aseptic technique.  The Study Day 28 injection should be administered in the 
opposite arm to the Study Day 0 injection.  The Study Day 112 injection can be administered in 
either arm. 
 
The study vaccine manager will refer to the IDRI-TBVPX-114 Vaccine Management Manual 
(provided under separate cover) for detailed instructions for study vaccine storage and 
preparation. 
 
3.6 
Study Evaluations 
3.6.1 
Immunology Laboratory Evaluations 
A summary of immunologic assays to be performed on blood specimens is shown in Table 3-2.  
Staff at the clinical research site will refer to the most current version of the Specimen 
Management Manual (provided under separate cover) for further instructions and additional 
information on specimen collection and processing. 
 
Table 3-2 
Summary of Immunology Laboratory Evaluations 
Sample type 
 
Location 
Assay 
Purpose of 
Assay 
 
Study Days 
Primary Immunology:  
Peripheral Blood 
Mononuclear Cells 
(PBMCs) 
Aeras 
Flow cytometry, 
Intracellular cytokine 
staining (ICS) 
Determine cellular 
immune response 
to study vaccine 
Days 0, 14, 42, 
112, 126, 196, 
294 
Exploratory Immunology 
Cells (PBMCs) 
Aeras 
IFN-γ ELISPOT 
Determine cellular 
immune response 
to study vaccine 
Days 0, 14, 42, 
112, 126, 196, 
294 
Exploratory Immunology 
Whole Blood 
Study site 
Whole blood ICS 
Determine cellular 
immune response 
to study vaccine 
Days 0, 14, 42, 
112, 126, 196, 
294 
Exploratory Immunology 
Serum  
Aeras or 
designee 
Antigen-specific IgG 
Determine humoral 
response to study 
vaccine 
Days 0, 126, 
294 
Exploratory Immunology 
Serum 
NA (to be 
stored) 
Autoimmune antibodies 
(ELISA) 
Determination of 
vaccine-induced 
autoimmunity 
Days 0, 294 
Exploratory Immunology 
Whole Blood for RNA 
Extraction 
Aeras or 
designee 
Microarray 
transcriptional profiling 
or RNA sequencing 
Determine immune 
response to study 
vaccine 
Days 0, 1, 3, 7, 
126 
 

 
 
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A 13-color ICS assay using frozen PBMC will be performed at Aeras’ immunology laboratory in 
the US, where the reagents, equipment, and training of personnel have all been standardized to 
provide consistent results.  The IFN-γ ELISpot assay using frozen PBMC will also be conducted 
at Aeras’ immunology laboratory using a qualified assay.  Conducting both the ICS and IFN-γ 
ELISpot assays in the same laboratory using the same material will reduce the assay variability, 
particularly when determining the correlation between the 2 assays.  The whole blood assay is an 
exploratory assay and will be conducted at the study site(s) if the capacity exists to conduct the 
assay there.  
 
3.6.2 
Safety Evaluations 
3.6.2.1 Pre-vaccination and Post-vaccination Monitoring of Participants 
Participants will have vital signs taken prior to each study vaccination.  Participants will remain 
in the clinic under close observation for at least 60 minutes after receiving each study injection.  
Vital signs will be repeated before participants leave the clinic.  Allergic reactions to vaccination 
are possible, therefore, appropriate drugs and medical equipment to treat acute anaphylactic 
reactions must be immediately available and a medically qualified study team member trained to 
recognize and treat anaphylaxis must be present in the clinic during the entire vaccination 
procedure and post-vaccination monitoring period. 
 
3.6.2.2 Clinical Assessments and Laboratory Tests 
Clinical assessments and laboratory tests are summarized in Appendix A.  
 
Assessment of Abnormal Clinical Laboratory Test Results 
Results from clinical laboratory tests obtained on the study must be reviewed by the investigator 
(or a designee who is a medically qualified study team member) within 72 hours of receiving the 
results to determine if abnormalities exist.  If the laboratory value is abnormal and has increased 
in toxicity grade (see Appendix C for toxicity grading scales) from pre-vaccination values, it 
must be reported as an adverse event and repeated promptly to demonstrate resolution.  
Additional laboratory tests may be performed if the investigator deems them to be necessary to 
fully evaluate an adverse event.  In the event that the investigator elects to order non-protocol-
specified laboratory tests, the investigator must record the rationale for the tests and a 
determination of clinical significance of the result in the source documents.  The investigator 
must keep the local medical monitor informed of adverse events of clinical significance.   
 
Abnormal results and findings will be discussed with the participant, and the participant will be 
referred for follow-up with their healthcare provider if necessary. 
 
3.6.2.3 Adverse Events 
The collection periods for adverse events are: 
Unsolicited adverse events: 28 days post-vaccination 
Solicited adverse events: 
28 days post-vaccination 
Serious adverse events: 
Entire study period (i.e., 294 days) 

 
 
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Adverse events of special interest:  Entire study period (i.e., 294 days) 
 
Solicited adverse events to be collected include the following: pain, redness (erythema) and 
swelling (induration) at the site of injection; fever; myalgia (muscle pain); arthralgia (joint pain); 
fatigue; headache; anorexia (loss of appetite); hives; chills.  
 
Adverse events of special interest (see Appendix D) will be collected passively during 
participant safety evaluations. 
 
3.6.2.4 Concomitant Medications 
The collection of information on concomitant medications used by participants following 
vaccination will coincide with the collection period of adverse events.  The collection period for 
concomitant medications associated with the treatment of adverse events will be 28 days 
following each vaccination.  The collection period for concomitant medications associated with 
the treatment of serious adverse events will be Study Days 0-294.   
 
Concomitant medication includes prescription and non-prescription drugs or other treatments, 
and any vaccines other than the study vaccine.  The name of the medication, treatment start and 
stop dates (or ‘ongoing’), route of administration, and indication must be recorded on the 
Concomitant Medications case report form (CRF).  The indication recorded on the Concomitant 
Medications CRF must correspond to a medical term/diagnosis recorded on the adverse event 
(AE) CRF, or to a pre-existing condition noted in the participant’s medical history, or be noted as 
prophylaxis, e.g., dietary supplement. 
 
3.6.3 
Participant Follow-up and Contact 
All participants who are assigned a subject identification number and receive study injection(s) 
will be followed according to the protocol unless consent is withdrawn.   
 
Participants will be instructed to contact a study team member to report new diagnoses or new or 
worsening adverse events and to come to the study clinic if medical attention is needed, provided 
the urgency of the situation permits.  For emergencies and other unscheduled visits to a medical 
facility other than the study clinic, medical records will, to the extent possible, be obtained by the 
investigator.   
 
During each clinic visit, participants will be reminded to notify a study team member of the 
following:   
• 
The occurrence of AEs and SAEs during the respective reporting periods  
• 
Receipt of any concomitant medications during the applicable reporting period 
• 
Plans to move or if contact information changes  
• 
If participant has decided to withdraw from the study 
• 
Change in general health status  
• 
Any other change in status that may affect the participant’s continuation (e.g., plan to 
participate in another investigational study) 
 

 
 
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All deviations from protocol procedures, evaluations, and/or visits must be categorized and 
documented as they occur.  Each deviation must be documented on a Protocol Deviation Form.  
When possible, missed visits and procedures must be rescheduled and performed at the nearest 
possible time point to the original schedule.  In cases where the visit at which the second or third 
study injection is to be administered (i.e., Study Day 28 or 112) would fall outside of the 
allowable visit window (see Appendix A), scheduling of the visit should be done in consultation 
with the sponsor or designee. 
 
3.6.4 
Loss to Follow-up 
If the site’s study team members are unable to establish contact with participant who misses a 
scheduled study visit, the clinical site must make every possible effort to re-establish contact and 
document such efforts.  If contact is re-established, then the participant will resume participation 
in the study. 
 
If contact with the participant cannot be re-established by the participant’s calculated Study Day 
294 visit date, then a determination of “lost to follow-up” should be made. 
 
4 
STUDY VACCINES 
4.1 
Supplies 
ID93 antigen, GLA-SE adjuvant, and SE (stable emulsion) will be supplied by IDRI in separate 
vials for admixture at the site.   
 
ID93 recombinant protein is produced by fermentation and purified following cGMP guidelines 
at the University of Iowa Center for Biocatalysis and Bioprocessing (Iowa City, Iowa).  The 
ID93 Purified Bulk Protein is formulated and lyophilized following cGMP guidelines at the 
University of Iowa Pharmaceuticals (Iowa City, Iowa) to yield the final vaccine fusion antigen, 
ID93 for Injection.  ID93 for Injection is formulated as a lyophilized solid and appears as a white 
to off-white cake. 
 
GLA-SE is manufactured at IDRI.  SE, also referred to as EM060G in the ID93 + GLA-SE 
Investigator's Brochure, contains the same components as GLA-SE but without GLA and is also 
manufactured at IDRI.  SE will be used to dilute the GLA-SE to the appropriate dose for the 
clinical study while maintaining the 2% oil concentration in the final dose.  Both GLA-SE and 
SE were formulated by IDRI under cGMP guidelines.  Bulk GLA was manufactured for IDRI by 
Avanti Polar Lipids (Alabaster, Alabama). 
 
Further details regarding clinical supplies, including the composition of ID93 for Injection and 
GLA-SE, are provided in the ID93 + GLA-SE Investigator's Brochure and/or the Vaccine 
Management Manual. 
 
The normal saline placebo (comparator) will be sourced by the study vaccine manager in sterile 
10 mL vials.  A separate vial will be used for each participant in order to ensure sterility. 
 

 
 
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4.2 
Accountability 
The study vaccine manager is required to maintain accurate study vaccine accountability records.  
Instructions and forms to be completed and kept for accountability will be provided to the study 
vaccine manager.  If the study vaccine manager wishes to use site-specific accountability forms, 
these must be reviewed and approved in advance by the sponsor or its designee.  Upon 
completion of the study, all study vaccine management records will be copied and the copies 
returned to the sponsor or its designee.  The originals must be maintained at the clinical site with 
the rest of the study records. 
 
4.3 
Receipt and Storage 
Upon receipt of study vaccine supplies, the study vaccine manager must immediately inspect all 
vials for damage.  ID93 antigen, GLA-SE adjuvant, and SE will be shipped with a continuous 
temperature-monitoring device.  Any damage or discrepancies from the packing list must be 
documented and promptly discussed with the sponsor or its designee and the study monitor to 
determine the appropriate action.  
 
Lyophilized ID93 for Injection, GLA-SE adjuvant, and SE must be stored at 2-8°C in a 
monitored secure location with no access for unauthorized personnel.  The normal saline placebo 
will be stored at room temperature in the study pharmacy. 
 
Refer to the most recent version of the Vaccine Management Manual for detailed instructions 
regarding study vaccine storage. 
 
4.4 
Vaccine Preparation 
The procedure for reconstitution and admixture of ID93 + GLA-SE for each treatment regimen is 
described in the Vaccine Management Manual.  Refer to the most recent version of the Vaccine 
Management Manual for detailed instructions regarding study vaccine preparation.  The 
antigen/adjuvant mixture is stable for 6 hours at room temperature; hence, the 
antigen/adjuvant mixture must be freshly prepared at the beginning of each injection time point. 
 
4.5 
Disposal of Unused Supplies 
Upon completion of the study, the sponsor or its designee must provide authorization for any 
unused study vaccine and supplies to be disposed of or returned to the sponsor.  Any disposal of 
study vaccine conducted at the clinical site must be done according to the facility’s SOPs for 
destruction and documented in the study file. 
 
5 
SAFETY 
5.1 
Responsibilities for Ensuring the Safety of Trial Participants 
The national regulatory authority, the study sponsor or its designee, the institution through which 
the research is performed and all members of the principal investigator’s clinical team share 

 
 
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responsibility for ensuring that participants in this trial are exposed to the least possible risk of 
adverse events that may result from participation in this trial.  
 
5.1.1 
Principal Investigator 
The principal investigator has a personal responsibility to closely monitor trial participants and 
an inherent authority to take whatever measures necessary to ensure their safety.  The principal 
investigator has the authority to terminate, suspend or require changes to a clinical trial for safety 
concerns and may delay an individual’s study injection administration or pause study injection 
administration in the whole trial if the investigator has some suspicion that the study injection 
might place a participant at significant risk.  The principal investigator determines severity and 
causality with respect to the study injection for each adverse event.  For blinded studies the 
principal investigator is blinded.  
 
5.1.2 
Study Sponsor 
The sponsor or its designee also has an institutional responsibility to ensure participant safety.  
This responsibility is vested in the local medical monitor and a safety monitoring committee 
(SMC).   
 
5.1.3 
Local Medical Monitor 
The local medical monitor is the sponsor’s representative and is a credentialed physician or 
surgeon in their country of residence with the necessary expertise to act in such capacity.  The 
local medical monitor reviews the safety of the product for protocols in a specific region and 
determines expectedness of the adverse event.  The local medical monitor may make a sponsor’s 
assessment of severity and causality for adverse events that may upgrade the degree of severity 
and causality determined by the principal investigator.  The local medical monitor, like the 
principal investigator, is blinded for a blinded study.  
 
5.1.4 
Safety Monitoring Committee 
A Safety Monitoring Committee (SMC) will be formed and its composition will be described in 
an SMC charter.  If study injection administration is paused (see rules for suspension of entire 
study in Section 6.2) by the principal investigator or the local medical monitor, the SMC will be 
convened.  The voting members cannot be directly involved with the conduct of the study.  
Voting members cannot be employees of the sponsor or the sponsor's designee (e.g., CRO).  
Additional subject area experts may be present to provide expertise if requested by the SMC.  
The SMC may review an individual SAE or it may choose to review adverse events, serious 
adverse events, solicited adverse events, and laboratory and vital signs data.  The SMC may 
unblind any amount of safety information needed to conduct their assessment.  All procedures 
associated with this review, including objectives, data handling, and elements to be included for 
review will be documented in SMC minutes.  
 
Based on its review and the protocol stopping rules (Section 6) the SMC will make 
recommendations in the SMC minutes to the sponsor or its designee regarding further conduct of 
the study and further administration of study injections.  The conclusions of the SMC, along with 

 
 
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the final decision of the sponsor or its designee, will be communicated to the investigators and 
the Institutional Review Boards and the national regulatory authority.  The sponsor or its 
designee agrees to abide by any directives issued by the national regulatory authority or the 
Institutional Review Board.   
 
5.1.5 
Institutional Review Boards and Ethics Committees 
The Institutional Review Board or Ethics Committee has institutional responsibility for the safety 
of research participants.  The Institutional Review Board or Ethics Committee has the authority 
to terminate, suspend or require changes to a clinical trial.   
 
5.1.6 
National Regulatory Authority 
Since the national regulatory authority (such as the Food and Drug Administration [FDA] and 
Medicines Control Council [MCC]) receives all expedited safety reports it also has the authority 
to terminate, suspend or require changes to a clinical trial.   
 
5.2 
Safety Surveillance During the Study 
Participants will be evaluated on Days 1, 3, 7, 14, and 28 after each vaccination.  Safety data will 
be collected by way of clinical interviews and examinations, and through evaluation of 
laboratory results.  Time points and the specific data collected for each of these evaluations are 
described in Section 3 and the protocol appendices.   
 
5.3 
Definition of Adverse Event 
Adverse event means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related.  An adverse event (also referred to as an adverse 
experience) can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a drug, and does not imply any 
judgment about causality.  An adverse event can arise with any use of the drug (e.g., off-label 
use, use in combination with another drug) and with any route of administration, formulation, or 
dose, including an overdose. 
 
All conditions that exist prior to administration of the study injection (pre-existing conditions) 
will be recorded in the participant’s medical history to establish baseline.  Day-to-day 
fluctuations in pre-existing conditions that do not represent a clinically significant change in the 
participant’s status will not necessarily be reported as adverse events. 
 
Any adverse change from the participant’s baseline condition (determined from screening 
evaluations conducted to confirm study eligibility) that occurs following the administration of 
the study injection will be considered an adverse event.  This includes the occurrence of a new 
adverse event or the worsening of a baseline condition, whether or not considered related to the 
study injection.  Intermittent conditions such as headaches in adults or irritability in infants may 
be present on Study Day 0 but may represent an adverse event if the intensity or duration of the 
event is worse than usual following receipt of study injection.  Adverse events include but are 
not limited to: adverse changes from baseline that represent increases in toxicity grade according 

 
 
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to the Toxicity Table (see protocol appendices), adverse changes in the general condition of the 
participant, signs and symptoms noted by the participant, concomitant disease with onset or 
increased severity after study injection administration, and changes in laboratory safety 
parameters occurring after study injection administration.   
 
The reporting period for all adverse events is specified in Section 3.  Adverse events will be 
reported on the Adverse Event CRF using a recognized medical term or diagnosis that accurately 
reflects the event.  Adverse event evaluations will be reviewed by the principal investigator or by 
a designated medically qualified practitioner.  Adverse event CRF pages are to be completed by 
members of the study team designated in writing by the principal investigator.  The onset and 
resolution dates of the event and action taken in response to the event will be documented.  All 
adverse events must be followed until resolution is demonstrated.  The resolution date will be 
recorded on the CRF as the last date on which the participant experienced the adverse event.  If 
an adverse event resolution date is uncertain the principal investigator should estimate the 
completion date based on medical judgment and interview of the participant.  Approximate dates 
of resolution from interviews may be taken as adverse event resolution dates.  Some examples of 
estimation of adverse event resolution are:  1) an asymptomatic laboratory abnormality on one 
visit that has not been followed-up between visits but has resolved by the next visit may be 
assumed to have resolved by the midpoint of the inter-visit interval; 2) A resolved adverse event 
that was treated may be assumed to have been resolved by the end of treatment.  Adverse events 
that are still present at the end of the trial should be recorded as ongoing.  Information recorded 
on the CRF must be substantiated in the source documents.  If an adverse event evolves into a 
condition that becomes “serious,” it will be designated as serious on the Adverse Event CRF and 
a Supplemental SAE Report (SAER) form will be completed.  
 
5.4 
Assessing Severity 
The safety concepts of “severity” and “seriousness” are distinct concepts (see Section 5.8).  
Severity refers to a degree of clinical manifestation.  “Seriousness” refers to defined outcomes 
from an adverse event.  A severe adverse event is not always serious and a serious adverse event 
is not always severe.  
 
For all adverse events, the investigator (or designee, who is a healthcare professional; is someone 
the investigator deems qualified to review adverse event information, to provide a medical 
evaluation of the event, and to classify the event based upon medical judgment and the severity 
categories described below) is responsible for assessing the severity of the event and the causal 
relationship of the event to the study injection. 
 
The severity of all adverse events, including clinical findings and abnormal laboratory values, 
will be classified as one of the following grades:  
1. Mild  
2. Moderate  
3. Severe   
 
A Toxicity Table is provided in the protocol appendices for the assessment of severity of 
specified adverse events.  The Toxicity Table Adverse Event Grades do not correlate directly 

 
 
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with the classical severity grades of mild, moderate and severe.  For the purposes of recording 
events on the CRF, Toxicity Table Grade 1 events will be considered mild in severity, Toxicity 
Table Grade 2 events will be considered moderate in severity, and both Toxicity Table Grade 3 
and 4 events will be considered as severe.  In the Toxicity Table certain local reactions such as 
erythema (redness) and swelling (induration) are graded according to size.  Laboratory values are 
graded according to level of deviation from the normal range.   
 
For adverse events not listed in the Toxicity Table determination of severity requires some level 
of interpretation as outlined below.  The degree of incapacity caused by the adverse event and 
the level of medical intervention required for treatment may be helpful in assessing the overall 
severity of the adverse event.  
For example: 
• 
“Mild” events are generally regarded as noticeable but have no impact on normal activities; 
they may or may not require over-the-counter treatment managed by the participant.   
• 
“Moderate” events generally have some impact on an individual’s normal activities and may 
require general symptomatic medical intervention by a healthcare professional or by the 
participant.   
• 
“Severe” adverse events may be incapacitating, leading to suspension of normal daily 
activities, and would generally require more immediate medical evaluation and intervention 
by a healthcare professional.   
 
A change in severity of an adverse event will not be recorded as a new adverse event.  Only the 
highest severity level that occurs during the entire period of the adverse event will be recorded 
on the CRF with the onset and resolution dates encompassing the entire duration of the event.   
 
5.5 
Assessing Causal Relationship (Relatedness) 
For all adverse events, the investigator will determine a causal relationship to the study 
injection without knowledge, for blinded studies, of whether ID93 + GLA-SE or placebo was 
administered.  A number of factors will be considered in making this assessment, including:  1) 
the temporal relationship of the event to the administration of the study injection 2) whether an 
alternative etiology has been identified and 3) biological plausibility.  The investigator will use 
the following guidelines to assess the causal relationship of an adverse event to study injection:   
 
• 
Not Related to study injection (i.e., there is no evidence of a causal relationship; another 
etiology is known to have caused the adverse event.  The alternative etiology should be 
documented in the participant’s study record). 
• 
Unlikely Related to study injection (i.e., there is less than a reasonable possibility that the 
adverse event was caused by study injection). 
• 
Possible relationship to study injection (i.e., there is a reasonable possibility that the adverse 
event was caused by study injection.  There must be a plausible mechanism for the event to 
be related to study injection.  The evidence is inadequate to accept or reject, or favors 
rejection of, a causal relationship; an association exists between the event and the study 
injection but there may also be an alternative etiology, such as characteristics of the 
participant’s clinical status or underlying condition).   

 
 
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• 
Probable relationship to study injection (i.e., it is likely that the adverse event was caused by 
administration of the study injection.  The evidence favors acceptance of a causal 
relationship; an association exists between the event and receipt of the study injection and 
there is a plausible mechanism for the event to be related to the study injection, and an 
alternative etiology is not apparent). 
• 
Definite relationship to study injection (i.e., the study injection is known to be the cause of 
the adverse event.  The evidence establishes a causal relationship; an association exists 
between the event and receipt of the study injection and there is a plausible mechanism for 
the event to be related to the study injection, and causes other than the study injection have 
been ruled out).  
 
Definite, probable and possible are considered to be related to study injection.  Not related and 
unlikely related are considered to be unrelated.  
 
For adverse events requiring immediate reporting, the principal investigator and the local 
medical monitor both determine causality.  It is expected that communication and consultation 
may occur in the assessment of the causality of adverse events.  The greatest degree of causal 
relationship (definite > probable > possible > unlikely related > not related) determined by either 
the investigator or local medical monitor after their discussions will determine the ultimate 
classification of the adverse event.   
 
Every effort should be made by the investigator to determine the existence of any pre-existing 
conditions (e.g., headache in adults or rashes in infants on Study Day 0 with onset prior to study 
vaccination) that must be taken into consideration when assessing causal relationship of an 
adverse event.  Pre-existing conditions should be recorded in the CRF as baseline history and 
substantiated by appropriate source documentation.  Intermittent conditions such as headaches in 
adults or irritability in infants may not be present on Study Day 0 but may represent an adverse 
event if the intensity or duration of the event is worse than usual following study injection. 
 
5.6 
Definition of Adverse Reaction 
An adverse reaction is an adverse event judged to be related to study injection (see Section 5.3 
for adverse event definition). 
 
Related adverse events (adverse reactions) are defined as those judged by the investigator or 
local medical monitor to be possibly, probably, or definitely related to study injection.  
 
5.7 
Solicited Adverse Events and Injection Site Reactions 
Solicited adverse events are events the participant is specifically asked about.  These adverse 
events are commonly observed soon after receipt of vaccines.  For this study, solicited adverse 
events to be collected include: pain, redness and swelling at the site of injection; fever; myalgia; 
arthralgia; fatigue; headache; anorexia, hives, chills.  Solicited adverse events of local injection 
site reactions (i.e., pain at injection site, redness at injection site, or swelling at injection site) will 
be considered causally related to study injection (adverse reaction). 
 

 
 
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The reporting period during which solicited adverse events will be evaluated is specified in 
Section 5.2.  The solicited adverse event reporting period begins with the day of vaccination.      
 
Adverse events and solicited adverse events including assessment of local injection site reactions 
will be assessed by the investigator for severity, causal relationship to the study injection, 
possible etiologies, and whether the event meets criteria as a serious adverse event (and therefore 
requires immediate notification to the local medical monitor).   
 
Presence of ulceration and/or scarring at the site of injection and axillary lymphadenopathy of 
the injection arm(s) are considered to be adverse events that are causally related to the study 
injection and are of special interest.  Site of injection ulceration (including presence of drainage) 
and axillary lymphadenopathy will be actively evaluated during each clinic visit through the end 
of the study.  These events will be recorded on the Adverse Event CRF. 
 
In the event that the clinical presentation meets the definition of a serious adverse event, an 
SAER form must be completed and the event reported per protocol instructions.  
  
5.8 
Adverse Events of Special Interest (AESIs) 
Adverse events of special interest (AESIs) are clinical events which are potentially immune 
mediated, and are listed in Appendix D.   
 
5.9 
Assessing "Seriousness" and Serious Adverse Events 
Seriousness refers to the outcome of an adverse event.  Seriousness is determined by both the 
principal investigator and the local medical monitor.  If either principal investigator or local 
medical monitor determines an event to be serious, it will be classified as such.  If any of the 
following outcomes are present then the adverse event is serious: 
 
• 
It results in death (i.e., the AE caused or led to the fatality).  Serious does not describe an 
event which hypothetically might have caused death if it were more severe. 
• 
It was immediately life-threatening (i.e., the AE placed the subject at immediate risk of 
dying.  It does not refer to an event which hypothetically may have led to death if it were 
more severe).  
• 
It required inpatient hospitalization or prolonged hospitalization beyond the expected length 
of stay.  Hospitalizations for scheduled treatments and elective medical/surgical procedures 
related to a pre-existing condition that did not increase in severity or frequency following 
receipt of study injection, are not serious by this criterion.  Hospitalization is defined as 
either 1) a hospital admission, or 2) an emergency room visit for a period greater than 24 
hours.  
• 
It resulted in a persistent or significant disability/incapacity (i.e., substantial reduction of the 
subject’s ability to carry out activities of daily living). 
• 
It resulted in a congenital anomaly or birth defect (i.e., an adverse finding in a child or 
fetus of a subject exposed to the study vaccine prior to conception or during pregnancy). 
• 
Other medically important conditions that may not result in death, threaten life or require 
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considered a serious adverse event when, based on appropriate medical judgment, they may 
jeopardize the subject and require medical or surgical intervention to prevent one of the 
serious outcomes listed in these criteria (e.g., allergic bronchospasm requiring intensive 
treatment in an emergency room or at home; blood dyscrasias or convulsions that do not 
result in hospitalization, or the development of drug dependency or drug abuse). 
 
A serious adverse event is an adverse event meeting the outcome criteria for seriousness 
regardless of relationship to an administered medicinal product. 
 
5.10 
Assessing Expectedness 
Expected adverse events are adverse events consistent with the applicable product information 
provided by the sponsor (the investigator’s brochure for an investigational product).  The 
sponsor, in the person of the local medical monitor, determines expectedness.  If the assessment 
is that the adverse event is expected no further action is required.  If the local medical monitor’s 
assessment is that the adverse event is unexpected, then the event may represent a SUSAR or 
expedited SAE (see Sections 5.11 and 5.12). 
 
5.11 
Definition of Suspected Unexpected Serious Adverse Reaction (SUSAR) 
When an adverse event is judged to be related to an investigational product, such as ID93 + 
GLA-SE, and also is judged to be serious and unexpected, it is a SUSAR (suspected unexpected 
serious adverse reaction) and is subject to expedited reporting. 
 
5.12 
Reporting of Serious Adverse Events 
Serious adverse events, which include SUSARs, are reported to the sponsor or its designee 
and to the World Wide Safety Center for the entire study period (see Appendix B).  
SUSARs are reported even after the trial is over, if the sponsor or its designee, local 
medical monitor or principal investigator becomes aware of them.  The site will be provided 
with specific reporting procedures including the Adverse Event CRF and any supplemental 
reporting forms to be used.  Serious adverse events will be reported on the Adverse Event CRF 
using a recognized medical term or diagnosis that accurately reflects the event.   
 
Serious adverse events will be assessed by the investigator and the local medical monitor 
according to their roles (as described in Sections 5.1.1 and 5.1.3) for severity, causal relationship 
to the study injection, and expectedness.  The onset and resolution dates of the event and the 
action taken in response to the event will be documented.  If the event has not resolved by the 
final study visit, it will be documented as “ongoing” on the CRF, however, follow-up of the SAE 
must continue until resolved.  Information recorded on the CRF must be substantiated in the 
source documents. 
 
The SAE Report form completed for that event must be scanned and emailed, or faxed, by 
the principal investigator or his/her designee, within one business day of the clinical site 
becoming aware of the event, to the local medical monitor, study monitor, and the World 
Wide Safety Center.  The AE CRF should be completed with all information known at the 

 
 
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time; the SAE Report (paper form) should be completed and both forms scanned and 
emailed, or faxed (even if all information concerning the event is not yet known) within one 
business day of awareness of the event.    
 
Fatal or life-threatening serious adverse events that the investigator suspects are related to 
the study injection should be telephoned to the local medical monitor immediately upon the 
investigator’s awareness of the event.  If the local medical monitor is required by the 
protocol or chooses to suspend enrollment s/he shall immediately create a written 
memorandum for record to the study file and telephonically notify the sponsor or its 
designee of this act. 
 
Contact information for all safety personnel are contained in the Team Contact List which 
will be stored on site in the Site Regulatory Binder and maintained by the study sponsor or 
its designee.   
 
Investigators must not wait to collect additional information to fully document the event before 
notifying the local medical monitor and World Wide Safety Center of a serious adverse event.  
The initial notification should include the following (at minimum):  
 
• 
Protocol number and name and contact number of the investigator 
• 
Subject ID number (and initials and date of birth, if available) 
• 
Date(s) participant received study injection(s)     
• 
Serious adverse event(s) and date of event onset 
• 
Current status of participant  
 
The sponsor or its designee has authorized the World Wide Safety Center to execute its 
responsibilities for safety report submission to the appropriate regulatory authorities within 
specific time periods of being notified of the event (within 7 or 15 calendar days depending the 
character of the SUSAR); therefore, it is important that the investigator submit additional 
information requested as soon as it becomes available.   
 
The sponsor or its designee will notify the SMC of all SUSARs within 3 working days of 
becoming aware of an event and will provide all follow-up information in a timely manner. 
 
5.13 
Other Events Requiring Immediate Reporting 
The investigator must report the following events by scanning and emailing, or faxing, the 
appropriate form to the local medical monitor within one business day of becoming aware of the 
event:   
 
• 
Emergency unblinding (Immediately Reportable Event Form) 
• 
Protocol violation affecting the safety of a participant or involving the vaccination process 
(Immediately Reportable Event Form) 
• 
Any event that, according to the protocol or in the opinion of the investigator, precludes 
further administration of the study injections (Immediately Reportable Event Form, unless 
meets SAE criteria)  
• 
Pregnancy (Immediately Reportable Event Form, and Pregnancy Notification Form) 

 
 
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5.14 
Adverse Event Treatment, Follow-up, and Outcome 
Treatment of any adverse events will be determined by the investigator using his/her best 
medical judgment and according to local clinical practice guidelines.  All applied measures as 
well as follow-up will be recorded in the appropriate CRF.   
 
Adverse events will be considered resolved when the condition returns to normal or returns to 
the participant’s baseline status as established on Study Day 0, or when the condition has 
stabilized with the expectation that it will remain chronic. 
 
The investigator will continue follow-up on adverse events, including laboratory abnormalities 
and solicited adverse events, until the event has resolved, is otherwise satisfactorily explained, or 
the participant completes the study. 
  
Follow-up for serious adverse events must continue until resolution and the outcome reported to 
Aeras, even if this extends beyond the serious adverse event reporting period (i.e., after the final 
study visit).  For analysis purposes, the outcome for serious adverse events will be determined on 
the final study visit. 
 
Outcome of all adverse events will be classified as one of the following: 
• 
Resolved  
• 
Resolved with sequelae 
• 
Ongoing 
• 
Death 
 
If at any time after completion of the serious adverse event reporting period (the final study visit) 
the investigator becomes aware of a serious adverse event that is suspected by the investigator to 
be related to the study injection, the event must be reported to Aeras. 
 
5.15 
Follow-up of Participants Who Become Pregnant 
If a participant becomes pregnant during the study, she will not receive any further study 
injections but should be encouraged to continue in the study for safety follow-up.  Follow-up 
should continue for pregnancy outcome including premature terminations, and data are to be 
included in the safety reports.  
 
The investigator must notify the local medical monitor and the World Wide Safety Center of the 
pregnancy immediately (even if already known to have resulted in spontaneous or elective 
abortion) by emailing the scanned copy or faxing the Pregnancy Notification Form.  At a 
minimum, the estimated date of conception, the estimated due date, and the date the participant 
received the study injection(s) should be provided.   
 
If a participant becomes pregnant, she will not have any interventions done as normally 
mandated by the protocol.  The participant will undergo all other evaluations according to the 
Summary Schedule(s) of Evaluations.      

 
 
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The health status of the mother and child, the date of delivery, and the child’s sex, birth weight 
and parity should be reported to the safety monitor after delivery, using a Pregnancy Notification 
Form.  If delivery occurs before the final study visit, the participant should continue to be 
followed for SAEs through the final study visit unless withdrawal of consent has occurred.  If 
delivery occurs after the final study visit, the investigator should attempt to maintain contact with 
the participant to obtain information after delivery.       
 
Pregnancy will not be recorded as an adverse event.  However, pregnancy outcomes will be 
recorded in the World Wide Safety Database.  If the pregnancy results in a miscarriage or a 
planned termination, the event (spontaneous abortion or elective abortion) will be reported as an 
adverse event or serious adverse event per the investigator's judgment (e.g., if it was a medically 
important or life-threatening event that meets the definition of a serious adverse event).  
 
A congenital anomaly or birth defect (i.e., an adverse finding in a child or fetus of a participant 
exposed to the study vaccine before conception or during pregnancy) must be reported as a 
serious adverse event. 
 
If it is determined after completion of the study that a participant became pregnant during the 
study, the participant should notify the investigator.  The pregnancy must be reported to the local 
medical monitor and the World Wide Safety Center and the status of the mother and child after 
delivery will be obtained and reported, when possible.     
 
5.16 
Dose Escalation  
Entry of participants into the next dose cohort may be permitted after the completion and review 
by the principal investigator and local medical monitor of cumulative safety data, including the 
specified post-vaccination adverse event reporting period for the most recently completed dose 
cohort, and the local medical monitor has confirmed: 
 
• That rules for suspension of the entire study (Section 6.2) have not been met  
 
 
 
AND  
 
• The absence of a pattern of significant symptoms, physical findings or laboratory 
abnormalities (adverse events) that, although individually minor, collectively represent a 
safety concern in the opinion of the investigator or the local medical monitor for the most 
recently completed randomized blinded dose cohort.  
 
If the above confirmation occurs, dose escalation to the next dose cohort may take place 
following completion and review of safety data by the local medical monitor from the specified 
post-vaccination adverse event reporting period.  The local medical monitor will confirm this in 
a memorandum to the study file and inform the principal investigator(s) before enrollment of the 
next dose cohort proceeds.  
 

 
 
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If rules for suspension are met or an adverse event pattern of concern is determined to be related 
to study injection, enrollment and study injection administration will be paused pending review 
by the SMC. 
6 
CRITERIA FOR INTERRUPTING THE TRIAL 
6.1 
Rules for Discontinuing Study Injections in an Individual Participant 
Administration of additional study injections will be discontinued for an individual participant if 
he/she has any of the following immediately reportable adverse events: 
 
• A clinical or laboratory parameter change which meets Grade 3 or Grade 4 severity, as 
defined in the protocol toxicity table, AND is judged to be possibly, probably, or definitely 
related to study injection 
• Fever (oral temperature ≥102.1˚F/39˚C) within 1 week following study injection which is 
associated with constitutional symptoms (myalgia, arthralgia, fatigue, headache, anorexia, 
hives, chills) AND is judged to be possibly, probably, or definitely related to study injection 
• Injection site reactogenicity that involves Grade 3 or Grade 4 induration (swelling), or pain  
as defined in the protocol toxicity table 
• Adverse event occurring within 4 hours of injection thought to be an allergic reaction to the 
study injection, including anaphylaxis or bronchospasm  
• Any extensive rash (>40% body surface) on the thorax, abdomen, or limbs, including but not 
limited to urticaria, generalized petechiae, or erythema multiforme judged to be possibly, 
probably, or definitely related to study injection 
• Development of active tuberculosis 
• Development of autoimmune disease or immunosuppression, or an adverse event of special 
interest 
• Receipt of investigational drug therapy or investigational vaccine (other than study injections 
received as part of this study) 
• Missed study injection 
• Any event that in the opinion of the principal investigator precludes administration of any 
further study injections 
• Pregnancy 
 
6.2 
Rules for Suspension of the Entire Study 
The study will be immediately suspended and no additional study injections administered 
pending review and discussion by the SMC of all appropriate safety data in the event of any of 
the following immediately reportable adverse events judged to be possibly, probably, or 
definitely related to study injection: 
 
• One or more SAE(s) 
• Two or more participants in any dose cohort experience the same Grade 2 or higher 
laboratory abnormality, or one or more participants in any dose cohort experience a toxicity 
Grade 3 systemic AE lasting more than 24 hours or toxicity Grade 3 laboratory abnormality   

 
 
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• Anaphylaxis or bronchospasm within 4 hours of injection, indicative of an immediate 
hypersensitivity reaction to the study injection 
• Any extensive rash (>40% body surface) on the thorax, abdomen, or limbs, including but not 
limited to urticaria, generalized petechiae, or erythema multiforme 
 
The study will also be immediately suspended and no additional study injections administered 
pending SMC review and discussion of all appropriate safety data if 3 or more participants fulfill 
the criteria for discontinuation of further injections due to an AE or SAE. 
 
If the principal investigator or medical monitor interrupts administration of study injections in 
the study, he or she will record this in a memorandum to the study file and notify the sponsor or 
its designee who will then convene the Safety Monitoring Committee (SMC).  The 
administration of study injections may resume only after SMC review of safety data.  Any 
changes to the protocol recommended by the SMC as a condition of study injection resumption 
must be approved by the Institutional Review Board or Independent Ethics Committee. 
 
7 
STATISTICAL CONSIDERATIONS 
The planned statistical analyses for this study are outlined below.  A detailed statistical analysis 
plan will be created and finalized prior to database lock and preparation of any unblinded 
preliminary data review and for preparation of the final study report. 
 
7.1 
Participant Populations 
The safety population will consist of all randomized participants who received at least one study 
injection.    
 
7.2 
Demographics and Protocol Compliance 
Demographic parameters (age, gender, and race/ethnicity) and other baseline characteristics will 
be summarized by treatment group for all participants in the safety population. 
 
As participant enrollment to each dose cohort will be conducted based on timing of completion 
of study eligibility requirements, any imbalance in baseline characteristics between dose cohorts 
will also be examined.  
 
Listings of randomized participants who missed any study injection and of participants with 
protocol deviations (to be defined in the statistical analysis plan) will be provided. 
 
7.3 
Efficacy Analyses 
There will be no efficacy analyses performed in this study.  
 

 
 
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7.4 
Immunology Analyses 
7.4.1 
Primary Immunology Analyses 
The primary variables of interest for assessment of the immune response to the vaccine will be 
the percentage of CD4+ and CD8+ T cells that produce any of selected cytokines following 
stimulation with peptide pools derived from and representing the entire amino acid sequences of 
the mycobacterial antigens Rv2608, Rv3619, Rv3620, and Rv1813.  Response will be measured 
using PBMCs by flow cytometry in the intracellular cytokine staining (ICS) assay, and will be 
presented using median DMSO-subtracted cytokine responses and associated 95% CIs by 
treatment regimen.  DMSO (background) values in vaccine recipients with respective antigen-
stimulated responses and responses in the placebo recipients will be presented for comparison.  
Separate summaries will be presented by treatment regimen and by baseline QFT status.   
 
Positivity of T cell responses from the ICS assay will be determined according to a pre-specified 
methodology (12), to be described in the statistical analysis plan, and will be summarized as 
number (percentage) of responders by treatment regimen.  Separate summaries will also be 
presented by treatment regimen and by baseline QFT status.   
 
7.4.2 
Exploratory Immunology Analyses 
Immune sera will be analyzed for the presence of antigen-specific IgG antibodies by enzyme-
linked immunosorbent assay (ELISA) techniques.  Responses will be summarized using 
geometric mean titers and associated 95% CIs by treatment regimen and by baseline QFT status, 
at all available time points. 
 
A qualified enzyme-linked immunospot (ELISPOT) assay will be used to detect and quantify the 
number of antigen-specific IFN-γ-secreting cells in the peripheral blood mononuclear cells 
collected from patients prior to and following vaccination.  Positivity of T cell responses from 
the ELISPOT assay will be determined according to pre-specified methodologies and will be 
summarized as described above for the ICS assay. 
 
Cellular responses will also be assessed using a whole blood assay and RNA will be obtained for 
microarray transcriptional profiling or RNA sequencing. 
 
7.5 
Safety Analyses 
The safety profile will be described by treatment regimen for all participants who received at 
least one study injection.  Listings will be provided for all participants with adverse events 
(AEs), serious adverse events (SAEs) and adverse events of special interest (AESIs).  All AEs 
and clinically relevant laboratory results will be summarized to examine the relationship between 
treatment regimen and key safety endpoints including number (percentage) of participants with 
solicited and unsolicited adverse events and number (percentage) of participants with newly 
abnormal post-vaccination laboratory values based on predefined toxicity criteria.  Adverse 
events will also be summarized by severity and by relationship to study injection, by treatment 
regimen, and by baseline QFT status. 
 

 
 
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7.5.1 
Adverse Events 
The safety profile of the dose levels of ID93 + GLA-SE will be described.  The primary variable 
for evaluation of the safety profile will be the number and percentage of unsolicited and solicited 
adverse events recorded at all available post-vaccination time points.  For all presentations of 
adverse events, additional summaries based on reporting period of adverse events following each 
study injection may also be presented.   
 
The number (percentage) of participants with adverse events will be summarized by MedDRA 
system organ class (SOC) and preferred term (PT).  Additional summaries will present the 
number (percentage) of participants with adverse events by severity and by relationship to study 
injection; each participant will be counted once per preferred term at the greatest severity or most 
related state recorded for that term.   
 
Separate summaries of the number (percentage) of participants with solicited adverse events will 
also be presented.  Solicited adverse events will also be summarized by severity and relationship 
to study injection; each participant will be counted once per preferred term at the greatest 
severity or most related state recorded for that term.   
 
Separate summaries of the number (percentage) of participants with adverse events of special 
interest will also be presented. 
 
Listings will be provided for participants with adverse events. 
 
Serious adverse events will be recorded through the final study visit for all participants.  Listings 
will be provided for participants with serious adverse events. 
 
Listings will be provided for participants who have discontinued prematurely due to an adverse 
event.    
 
7.5.2 
Clinical Laboratory and Vital Sign Parameters 
For each clinical laboratory parameter and vital sign parameter pre-specified in the protocol, 
summary statistics for continuous parameters will be presented by treatment regimen for all pre- 
and post-vaccination assessments and for change from pre-vaccination to post-vaccination 
assessments.   
 
The number (percentage) of participants with post-vaccination clinical laboratory values or vital 
sign values recorded as newly abnormal following study injection and meeting toxicity mild 
criteria (Grade 1) or above as specified in the Toxicity Table (Appendix C) will be tabulated at 
each post-vaccination time point and overall.  Clinical laboratory and vital sign abnormalities 
will also be reported as adverse events and will be included in the summary of adverse events. 
 
7.6 
Sample Size Considerations 
The sample size for this study was selected as adequate to detect frequent adverse events.  Given 
a total sample size of 54 participants receiving ID93 + GLA-SE at any dose level, the study will 

 
 
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have an 80 percent chance of observing at least one adverse event which occurs at a rate of 3 
percent.  Alternatively, if no events are observed in 54 participants who receive ID93 + GLA-SE 
at any dose level, the upper bound of the one-sided 95 percent confidence interval on the rate of 
event occurrence is approximately 5.4 percent.   
 
Given the dose-escalation design (15 participants in Cohorts 2, 3, and 4), there is nearly 80% 
probability of observing an event that occurs at a rate of 10 percent in each individual ID93 + 
GLA-SE antigen/adjuvant study group/cohort.  Additionally, if the single-stage procedure 
proposed by Sobel and Huyett were to be used for the dose response analysis of immunogenicity 
data based on number of vaccine responders, given 15 participants per vaccine dose group, this 
study will allow for selection of the correct dose group with the largest true response rate with an 
85% confidence if the observed difference in response rate between the highest response dose 
group and the next best is at least 25 percentage points (13). 
 
7.7 
Plan for Statistical Summaries and Analyses 
7.7.1 
Preliminary Data Reviews 
A preliminary unblinded review of  Th-1 and Th-2 cytokine response, based on ICS data, may be 
conducted following completion of Study Day 42 (i.e., 14 days after the second study injection) 
for each dose cohort.  The purpose of these preliminary reviews is to obtain preliminary 
immunogenicity data for use in the decision-making process regarding vaccine dose level and 
dosing regimens to be employed in future studies of the vaccine.  Study procedures and 
monitoring practices will not change following the unblinded preliminary data reviews.  No 
decision cut points or stopping rules will be stipulated.  No hypothesis testing will be performed.  
Personnel involved in assessment of adverse events and at the immunology laboratories will 
remain blinded to all study results and to treatment assignments until after the Study Day 294 
data have been collected, reviewed and queries resolved. 
 
7.7.2 
Dose response 
A dose response analysis of safety and immunogenicity data from Cohorts 2-4 will also be 
performed.  The details on the statistical method for the dose response analysis will be provided 
in the statistical analysis plan. 
 
7.7.3 
Final Study Report 
The final study report will include all available safety data, primary immunogenicity data, 
clinical assessments, and concomitant medications through the final study visit.  The database 
will be locked prior to preparation of the final study report when all of the above data have been 
entered, reviewed, and all queries related to the data have been addressed.   
 
Modifications or additions to the analyses described above will be included in the relevant 
statistical analysis plan(s).  Any decisions to deviate from the planned analyses described in the 
protocol and in the statistical analysis plan will be described in detail in the final study report. 
 

 
 
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7.8 
Computer Methods 
Statistical analyses will be performed using SAS® version 9.1.3 or later under a Windows 
operating system. 
 
8 
DATA COLLECTION, MONITORING, AND RECORD RETENTION 
For the purpose of monitoring and auditing the study, source documentation will consist of 
existing medical records and/or study records developed and maintained by the investigator.  
Any source document templates provided by Aeras or its designee will serve as supplements to 
the participant’s study record.  
 
Data recorded on source documents will be transcribed onto case report forms (CRFs) provided 
by Aeras or entered using electronic case report forms (eCRFs) using an Electronic Data Capture 
(EDC) system provided and approved by Aeras.  Completed, original CRFs will be retrieved by 
Aeras or its designee and a copy of each completed CRF will be retained at the clinical site as 
part of the study records.   
 
The study will be monitored regularly by Aeras or its designee throughout the study period.  For 
studies of unapproved investigational products, all study records (source documents, signed 
informed consent forms, copies of CRFs, IRB/IEC correspondence and approval letters, national 
regulatory authority correspondence and approval letters, study vaccine management records) 
will be kept secured for a minimum of 2 years following the marketing of the investigational 
product or for 2 years after the discontinuation of the IND (or CTA, etc.).  Records will be kept 
for longer than 2 years if required by local regulations.  The investigator will ensure that study 
records are not disposed of or removed from the clinical site without prior notification and 
approval from Aeras or its designee. 
 
9 
HUMAN SUBJECTS 
9.1 
Ethics and Regulatory Considerations 
The study will be conducted according to the ethical principles set forth in the Declaration of 
Helsinki, ICH-GCP, Protection of Human Subjects (21 CFR 50), Institutional Review Boards 
(21 CFR 56), Obligations of Clinical Investigators (21 CFR 312), Guidelines for Good Practice 
in the Conduct of Clinical Trials in Human Participants in South Africa, and local regulatory 
requirements.  
 
The protocol and informed consent form will be reviewed and approved by the local national 
regulatory authority and the IRB or IEC of each participating clinical site prior to any protocol-
specified procedures being conducted.  The investigator will inform the IRB/IEC as to the 
progress of the study on a regular basis, or at minimum, once a year. 
 
Written informed consent will be obtained from each participant prior to any protocol-specified 
procedures being conducted.   
 

 
 
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To maintain confidentiality, subject identification numbers will be used to identify the 
participant’s laboratory specimens, source documents, CRF, study reports, etc.  All study records 
will be maintained in a secured location.  Clinical information will not be released without 
written permission from the participant except as necessary for monitoring or auditing of the 
study by Aeras or its designee or applicable regulatory authorities. 
 
After the study has been unblinded, the participant should be informed which treatment (ID93 + 
GLA-SE or placebo) the participant received. 
 
9.2 
Institutional Review Board or Independent Ethics Committee 
All the documents the IRB/IEC may need to fulfill its responsibilities, such as the protocol, 
protocol amendments, informed consent forms, information concerning participant recruitment, 
payment or compensation procedures, etc., will be submitted to the IRB/IEC by the investigator.  
The IRB’s/IEC’s written, unconditional approval of the study protocol and the informed consent 
form will be in the possession of the investigator/clinical site staff prior to the conduct of any 
protocol-specified procedures.  
 
Modifications to the protocol may not be implemented without prior written IRB/IEC approval 
except when necessary to eliminate immediate hazards to the participants or when the 
modification involves only logistical or administrative aspects of the study.  Such logistical or 
administrative modifications will be submitted to the IRB/IEC in writing by the investigator, and 
a copy of the correspondence to verify the submission will be maintained.   
 
The investigator must inform the IRB/IEC of modifications to the informed consent form or any 
other documents previously submitted for review/approval, of any new information that may 
adversely affect the safety of the participants or the conduct of the study, provide an annual 
update and/or request for re-approval according to local requirements, and advise the IRB/IEC 
when the study has been completed.  
 
Any documents or forms to be provided to the participant (e.g., information cards, form letters 
from the investigator), and all forms of study advertising (flyers, brochures, print advertisements, 
radio or television scripts, etc.) must be approved by Aeras or its designee prior to the clinical 
site submitting them to the IRB/IEC.  Approval from the IRB/IEC must be obtained prior to 
providing the documents or forms to the participant.  
 
9.3 
Informed Consent 
The principles of informed consent in the current edition of the Declaration of Helsinki, ICH-
GCP/21 CFR 50.25, South Africa GCP, and local regulations should be implemented prior to 
any protocol-specified procedures being conducted.  Informed consent will be documented in 
writing on a consent form approved by the IRB/IEC. 
 
All relevant information should be provided in both oral and written form in a way that is 
understandable to the participant.  Ample time and opportunity must be given for the participant 
to inquire about details of the study.  The written consent document will embody the elements of 

 
 
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informed consent as described in the Declaration of Helsinki and will also comply with local 
regulations.    
 
The investigator or the investigator’s qualified designee will explain the nature of the study and 
inform the participant that participation is voluntary and that he or she can leave the study at any 
time, without penalty or loss of benefits to which they are otherwise entitled.  The participant 
must be informed about the study’s purpose including why the participant was selected to 
participate, study goals, expected benefits and risks, potential risks, and that some potential risks 
are unforeseeable.  The participant must be provided with a description of the procedures and the 
estimated duration of time required for participation in the study, as well as alternative 
interventions or courses of treatment, if applicable.   
 
The participant must receive an explanation as to whether any compensation and any medical 
treatments are available if injury occurs and, if so, what they are, where further information may 
be obtained, and who to contact in the event of a study-related injury.  Participants must be told 
who to contact for answers to any questions related to the study.  The extent of the 
confidentiality of participant records must be defined and the participant must be informed that 
applicable data protection legislation applies. 
 
The participant must be informed that the monitor(s), auditor(s), IRB/IEC members, and the 
applicable regulatory authorities will be granted direct access to the participant’s original study 
medical records for verification of protocol-specified procedures and/or data, without violating 
the confidentiality of the participant to the extent permitted by the applicable laws and 
regulations.  The participant must be informed that his/her signature on the informed consent 
form indicates that he/she has decided to participate in the study, having read and discussed the 
information presented.  
 
Modifications made by the investigator to an informed consent form template provided to the 
investigator by Aeras or its designee will be reviewed and approved by Aeras or its designee 
prior to being submitted to the IRB/IEC.   
 
The original, signed informed consent form for each participant will be maintained by the 
investigator as part of the participant’s study records.  A copy of the signed informed consent 
form will be provided to each participant. 
 
10 
STUDY COMPLETION 
At the discretion of the sponsor or its designee, all materials and supplies provided to the 
investigator will be returned or disposed of in compliance with local regulatory requirements 
upon authorization from Aeras, upon study completion.  The investigator or designated clinical 
site staff will notify the IRB/IEC when the study has been completed. 
 

 
 
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11 
PUBLICATIONS 
All information contained in this clinical study protocol and accompanying documents is 
confidential.  All data collected during the course of this study are confidential and considered 
the sole property of IDRI.  The investigators agree to use this information and data only in 
accomplishing this study, including for benchmarking and other analytical purposes in future 
clinical trials, and will not use it for other purposes without the written permission of IDRI.  
IDRI encourages publication in peer-reviewed medical journals and will not unduly withhold 
permission to publish.  However, all proposed publications, papers, abstracts, or written 
materials related to the study, or an outline or poster of any oral presentation, shall be submitted 
to and coordinated by IDRI for review not less than eight (8) weeks in advance of the planned 
submission date or presentation.  In regard to all proposed public disclosures, IDRI has the right 
to do the following: request changes to the manuscript in accordance with scientific custom; 
request changes for patent purposes and/or inadvertent disclosure of IDRI’s confidential 
information; request changes that could reasonably be expected to materially or negatively 
impact IDRI’s intellectual property rights; and access patentability of any invention disclosed 
and delay submission for up to sixty (60) days to allow IDRI to file a patent.    
 
IDRI may request in writing that the proposed publication or presentation be delayed or 
modified, specifying in reasonable detail the reasons for the request.  If IDRI objects to a 
proposed publication or presentation on the basis that it would disclose confidential information, 
the investigator shall remove the objectionable information from such proposed publication or 
presentation.  If the parties disagree concerning whether certain information should be deleted or 
modified, the parties agree to meet for the purpose of making good faith efforts to discuss and 
resolve any such issues or disagreements.  IDRI will work with the Institution in a collaborative 
manner to make certain that the clinical study results contained within such presentation or 
publication (whether positive or negative) are accurate. 
 
If IDRI determines that the proposed presentation or publication contains patentable subject 
matter that requires protection, IDRI may require an additional delay and the Institution shall 
delay such publication or presentation for an additional period (not to exceed sixty (60) days) for 
the purpose of filing a patent application(s).  In no event shall IDRI unreasonably delay such 
publication or presentation. 
 
All publications and presentations must acknowledge IDRI’s sponsorship of the clinical study. 
 
12 
CHANGES IN THE PROTOCOL 
The protocol may not be modified without written approval from the sponsor or its designee.  All 
changes to the protocol must be submitted to the IRB/IEC and must be approved by the IRB/IEC 
prior to their implementation.   
 

 
 
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13 
REFERENCES 
 
1. WHO, Global Tuberculosis Report 2012.  
http://www.who.int/tb/publications/global_report/en/ 
2. Andersen P, Doherty TM.  The success and failure of BCG - implications for a novel 
tuberculosis vaccine.  Nat Rev Microbiol 2005; 3:656-662. 
3. Flynn JL, Chan J. Immunology of tuberculosis.  Annu Rev Immunol 2001; 19:93-129. 
4. Bertholet S, Ireton GC, Kahn M, et al. Identification of human T cell antigens for the 
development of vaccines against Mycobacterium tuberculosis.  J Immunol 2008; 181:7948-
7957. 
5. Baldwin S, Bertholet S, Reese VA, Ching LK, Reed SG, Coler RN.  The importance of 
adjuvant formulation in the development of a tuberculosis vaccine.  J. Immunol 2012; 
188(5):2189-97. 
6. Bertholet SI, Ireton G, Ordway D, et al. A defined tuberculosis vaccine candidate to boost 
BCG and protect against multidrug resistant Mycobacterium tuberculosis.  Science 
Translational Medicine 2010; 2(53):53ra74. 
7. Anderson RC, Fox CB, Dutill TS, et al.  Physicochemical characterization and biological 
activity of synthetic TLR4 agonist formulations.  Colloids Surf B Biointerfaces 2010; 75:123-
132. 
8. Baldwin SL, Shaverdian N, Goto Y, et al.  Enhanced humoral and Type 1 cellular immune 
responses with Fluzone® adjuvanted with a synthetic TLR4 agonist formulated in an 
emulsion.  Vaccine 2009; 27:5956–5963. 
9. Lousada_Dietrich S, Jogdand PS, Jepsen S, et al.  A synthetic TLR4 agonist formulated in an 
emulsion enhances humoral and Type 1 cellular responses against GMZ2 – A GLURP-MSP3 
fusion protein malaria vaccine candidate.  Vaccine 2011; 29:3284-3292. 
10. Baldwin SL, Bertholet S, Kahn M, et al. Intradermal immunization improves protective 
efficacy of a novel TB vaccine candidate.  Vaccine 2009; 27:3063-3071. 
11. Bertholet S, Goto Y, Carter L, et al.  Optimized subunit vaccine protects against experimental 
leishmaniasis.  Vaccine 2009; 27:7036-7045. 
12. Horton H, Thomas EP, Stucky JA, et al.  Optimization and validation of an 8-color 
intracellular cytokine staining (ICS) assay to quantify antigen-specific T cells induced by 
vaccination.  J Immunol Methods.  2007 May 31;323(1):39-54.  Epub 2007 Apr 3. 
13. Sobel M, Huyett MJ.  Selecting the best one of several binomial populations.  Bell Syst Tech 
J 1957; 36:537–76. 
 

 
 
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APPENDIX A 
Detailed Description of Study Visits 
Screening Visit(s)  
 
1. 
Written informed consent process  
2. 
Assignment of screening  number 
3. 
Verify study entry eligibility criteria are met 
4. 
Medical history 
5. 
Physical examination  
6. 
Urine collection for urinalysis, toxicology screen, and (for females) βHCG 
7. 
Blood collection for  
• QuantiFERON®-TB Gold In-Tube 
• Hepatitis B, C 
• HIV-1 
• Serum chemistry (AST, ALT, alkaline phosphatase, total bilirubin, creatinine, BUN) 
• Hematology (hemoglobin, hematocrit, white cell count with differential and platelet count) 
 
Study Day 0 
 
Pre- injection: 
1. 
Urine collection (females) for βHCG 
2. 
Obtain pre-immunization vital signs (blood pressure, pulse, oral temperature)  
3. 
Interval medical history and focused physical examination.  Note: focused physical examination to include 
axillary lymph node examination. 
4. 
Verify study entry eligibility criteria are met 
5. 
Assign subject ID number (randomize) 
6. 
Blood collection for 
• PBMCs for flow cytometry, ICS, and ELISPOT 
• Serum for antigen-specific IgG ELISA 
• Whole blood for exploratory immunology (ICS) 
• Serum for autoimmune Ab ELISA 
• Whole blood for RNA extraction (microarray) 
 
Injection: 
7. 
Administer study injection by intramuscular injection into deltoid area.  Record date and time of injection and 
which arm was injected. 
 
Post-injection: 
8. 
Monitor participant for solicited, unsolicited, and serious adverse events (including adverse events of special 
interest) for at least 60 minutes after injection; record concomitant medications 
9. 
Obtain 30±5-minute and 60±5-minute post-immunization vital signs  
10. Complete Study Day 0 study injection site examination (with photograph at 60±5 minutes post-injection if 
there is a visible injection-site abnormality) 
 
Study Day 1 - Allowable window for clinic visit is 1±0 days from Study Day 0. 
1. 
Interval medical history and focused physical examination.  Note: focused physical examination to include 
axillary lymph node examination. 
2. 
Monitor participant for solicited, unsolicited, and serious adverse events (including adverse events of special 
interest), and record concomitant medications 
3. 
Complete Study Day 0 study injection site examination (with photograph if there is a visible injection-site 
abnormality) 
4. 
Blood collection for 

 
 
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• Whole blood for RNA extraction (microarray) 
 
Study Day 3 - Allowable window for clinic visit is 3+1 days from Study Day 0. 
1. 
Interval medical history and focused physical examination.  Note: focused physical examination to include 
axillary lymph node examination. 
2. 
Monitor participant for solicited, unsolicited, and serious adverse events (including adverse events of special 
interest), and record concomitant medications 
3. 
Complete Study Day 0 study injection site examination (with photograph if there is a visible injection-site 
abnormality) 
4. 
Blood collection for 
• Whole blood for RNA extraction (microarray) 
 
Study Day 7 - Allowable window for clinic visit is 7±1 days from Study Day 0. 
1. 
Interval medical history and focused physical examination.  Note: focused physical examination to include 
axillary lymph node examination. 
2. 
Monitor participant for solicited, unsolicited, and serious adverse events (including adverse events of special 
interest), and record concomitant medications 
3. 
Complete Study Day 0 study injection site examination (with photograph if there is a visible injection-site 
abnormality) 
4. 
Blood collection for 
• Serum chemistry (AST, ALT, alkaline phosphatase, total bilirubin, creatinine, BUN) 
• Hematology (hemoglobin, hematocrit, white cell count with differential and platelet count) 
• Whole blood for RNA extraction (microarray) 
 
Study Day 14 - Allowable window for clinic visit is 14±2 days from Study Day 0. 
1. 
Interval medical history and focused physical examination.  Note: focused physical examination to include 
axillary lymph node examination. 
2. 
Monitor participant for solicited, unsolicited and serious adverse events (including adverse events of special 
interest), and record concomitant medications 
3. 
Complete Study Day 0 study injection site examination (with photograph if there is a visible injection-site 
abnormality) 
4. 
Blood collection for 
• PBMCs for flow cytometry, ICS, and ELISPOT 
• Whole blood for exploratory immunology (ICS) 
 
Study Day 28 - Allowable window for clinic visit is 28-2/28+5 days from Study Day 0. 
 
Pre- injection: 
1. 
Urine collection (females) for βHCG 
2. 
Obtain pre-immunization vital signs (blood pressure, pulse, oral temperature)  
3. 
Interval medical history and focused physical examination.  Note: focused physical examination to include 
axillary lymph node examination. 
4. 
Monitor participant for solicited, unsolicited, and serious adverse events (including adverse events of special 
interest), and record concomitant medications 
 
Injection: 
5. 
Administer study injection by intramuscular injection into deltoid area of opposite arm from Study Day 0 
injection.  Record date and time of injection and which arm was injected. 
 
Post-injection: 
6. 
Monitor participant for solicited, unsolicited, and serious adverse events (including adverse events of special 
interest) for at least 60 minutes after injection; record concomitant medications 
7. 
Obtain 30±5-minute and 60±5-minute post-immunization vital signs  

 
 
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8. 
Complete Study Day 0 study injection site examination 
9. 
Complete Study Day 28 study injection site examination (with photograph at 60±5 minutes post-injection if 
there is a visible injection-site abnormality) 
 
Study Day 29 - Allowable window for clinic visit is 1±0 days from Study Day 28. 
1. 
Interval medical history and focused physical examination.  Note: focused physical examination to include 
axillary lymph node examination. 
2. 
Monitor participant for solicited, unsolicited, and serious adverse events (including adverse events of special 
interest), and record concomitant medications 
3. 
Complete Study Day 28 study injection site examination (with photograph if there is a visible injection-site 
abnormality) 
 
Study Day 31 - Allowable window for clinic visit is 3+1 days from Study Day 28. 
1. 
Interval medical history and focused physical examination.  Note: focused physical examination to include 
axillary lymph node examination. 
2. 
Monitor participant for solicited, unsolicited, and serious adverse events (including adverse events of special 
interest), and record concomitant medications 
3. 
Complete Study Day 28 study injection site examination (with photograph if there is a visible injection-site 
abnormality) 
 
Study Day 35 - Allowable window for clinic visit is 7±1 days from Study Day 28. 
1. 
Interval medical history and focused physical examination.  Note: focused physical examination to include 
axillary lymph node examination. 
2. 
Monitor participant for solicited, unsolicited, and serious adverse events (including adverse events of special 
interest), and record concomitant medications 
3. 
Complete Study Day 28 study injection site examination (with photograph if there is a visible injection-site 
abnormality) 
4. 
Blood collection for 
• Serum chemistry (AST, ALT, alkaline phosphatase, total bilirubin, creatinine, BUN 
• Hematology (hemoglobin, hematocrit, white cell count with differential and platelet count) 
 
Study Day 42 - Allowable window for clinic visit is 14±2 days from Study Day 28. 
1. 
Interval medical history and focused physical examination.  Note: focused physical examination to include 
axillary lymph node examination. 
2. 
Monitor participant for solicited, unsolicited and serious adverse events (including adverse events of special 
interest), and record concomitant medications 
3. 
Complete Study Day 28 study injection site examination (with photograph if there is a visible injection-site 
abnormality) 
4. 
Blood collection for 
• PBMCs for flow cytometry, ICS, and ELISPOT) 
• Whole blood for exploratory immunology (ICS) 
 
Study Day 56 - Allowable window for clinic visit is 28±5 from Study Day 28. 
1. 
Interval medical history and focused physical examination.  Note: focused physical examination to include 
axillary lymph node examination. 
2. 
Monitor participant for solicited, unsolicited, and serious adverse events (including adverse events of special 
interest), and record concomitant medications 
3. 
Complete Study Day 28 study injection site examination (with photograph if there is a visible injection-site 
abnormality) 

 
 
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Study Day 112 – Allowable window for clinic visit is 112-2/112+14 days from Study Day 0. 
 
Pre- injection: 
1. 
Urine collection (females) for βHCG 
2. 
Obtain pre-immunization vital signs (blood pressure, pulse, oral temperature)  
3. 
Interval medical history and focused physical examination.  Note: focused physical examination to include 
axillary lymph node examination. 
4. 
Blood collection for 
• PBMCs for flow cytometry, ICS, and ELISPOT 
• Whole blood for exploratory immunology (ICS) 
 
Injection: 
5. 
Administer study injection by intramuscular injection into deltoid area of either arm.  Record date and time of 
injection and which arm was injected. 
 
Post-injection: 
6. 
Monitor participant for solicited, unsolicited, and serious adverse events (including adverse events of special 
interest) for at least 60 minutes after injection; record concomitant medications 
7. 
Obtain 30±5-minute and 60±5-minute post-immunization vital signs  
8. 
Complete Study Day 28 study injection site examination 
9. 
Complete Study Day 112 study injection site examination (with photograph at 60±5 minutes post-injection if 
there is a visible injection-site abnormality) 
 
Study Day 113 - Allowable window for clinic visit is 1±0 days from Study Day 112. 
1. 
Interval medical history and focused physical examination.  Note: focused physical examination to include 
axillary lymph node examination. 
2. 
Monitor participant for solicited, unsolicited, and serious adverse events (including adverse events of special 
interest), and record concomitant medications 
3. 
Complete Study Day 112 study injection site examination (with photograph if there is a visible injection-site 
abnormality) 
 
Study Day 115 - Allowable window for clinic visit is 3+1 days from Study Day 112. 
1. 
Interval medical history and focused physical examination.  Note: focused physical examination to include 
axillary lymph node examination. 
2. 
Monitor participant for solicited, unsolicited, and serious adverse events (including adverse events of special 
interest), and record concomitant medications 
3. 
Complete Study Day 112 study injection site examination (with photograph if there is a visible injection-site 
abnormality) 
 
Study Day 119 - Allowable window for clinic visit is 7±1 days from Study Day 112. 
1. 
Interval medical history and focused physical examination.  Note: focused physical examination to include 
axillary lymph node examination. 
2. 
Monitor participant for solicited, unsolicited, and serious adverse events (including adverse events of special 
interest), and record concomitant medications 
3. 
Complete Study Day 112 study injection site examination (with photograph if there is a visible injection-site 
abnormality) 
4. 
Blood collection for 

 
 
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• Serum chemistry (AST, ALT, alkaline phosphatase, total bilirubin, creatinine, BUN) 
• Hematology (hemoglobin, hematocrit, white cell count with differential and platelet count) 
 
Study Day 126 - Allowable window for clinic visit is 14±2 days from Study Day 112. 
1. 
Interval medical history and focused physical examination.  Note: focused physical examination to include 
axillary lymph node examination. 
2. 
Monitor participant for solicited, unsolicited and serious adverse events (including adverse events of special 
interest), and record concomitant medications 
3. 
Complete Study Day 112 study injection site examination (with photograph if there is a visible injection-site 
abnormality) 
4. 
Blood collection for 
• PBMCs for flow cytometry, ICS, and ELISPOT 
• Serum for antigen-specific IgG ELISA 
• Whole blood for exploratory immunology (ICS) 
• Whole blood for RNA extraction (microarray) 
 
Study Day 140 - Allowable window for clinic visit is 28±5 days from Study Day 112. 
1. 
Interval medical history and focused physical examination.  Note: focused physical examination to include 
axillary lymph node examination. 
2. 
Monitor participant for solicited, unsolicited and serious adverse events (including adverse events of special 
interest), and record concomitant medications 
3. 
Complete Study Day 112 study injection site examination (with photograph if there is a visible injection-site 
abnormality) 
 
Study Day 196 - Allowable window for clinic visit is 196±14 from Study Day 0. 
1. 
Interval medical history and focused physical examination.  Note: focused physical examination to include 
axillary lymph node examination. 
2. 
Monitor participant for serious adverse events (including adverse events of special interest), and record 
concomitant medications 
3. 
Blood collection for 
• PBMCs for flow cytometry, ICS, and ELISPOT 
• Whole blood for exploratory immunology (ICS) 
 
 
Study Day 294 - Allowable window for clinic visit is 294±14 days from Study Day 0. 
1. 
Interval medical history and focused physical examination.  Note: focused physical examination to include 
axillary lymph node examination. 
2. 
Monitor participant for serious adverse events (including adverse events of special interest), and record 
concomitant medications 
3. 
Blood collection for 
• QuantiFERON®-TB Gold In-Tube 
• PBMCs for flow cytometry, ICS, and ELISPOT 
• Whole blood for exploratory immunology (ICS) 
• Serum for antigen-specific IgG ELISA 
• Serum for autoimmune Ab ELISA 

 
 
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APPENDIX B 
Reporting Schemes for SAEs, Immediately Reportable Events, 
and SUSARs 
 
Reporting Scheme for SAEs and Immediately Reportable Events (IREs) 
 
 
 
 
SAE 
occurs at 
Study Site
Site
• Completes SAER/IRE Form 
• PI determines causality & severity
• Fax/email SAER/IRE to Worldwide Safety
• Fax/email SAER/IRE to Local Medical Monitor
(+ phone call if event is life-threatening or death)
• Enters SAE/IRE into clinical database (as applicable)
• Notifies Local Ethics, as required
Local Medical Monitor
• Receives SAER/IRE fax/email
• Reviews SAE/IRE
• Provides medical assessment of SAE/IRE
• In conjuction with IDRI and Aeras, 
determines expectedness of SAE
• Communicates with Worldwide Safety, 
IDRI, Aears, PI, if needed SMC
World-Wide Safety
•
Safety Team
•Receives SAER/IRE fax/email
•Processes SAE/IRE
•Notifies Sponsor/Aeras
•
Unblinding Team
•Manages unblinding information
IDRI / Aeras
One business day
One business day
Study Monitors
One business day

 
 
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Reporting Scheme for SUSARs 
 
 
 
SAE 
occurs at 
Study Site
PI assesses AE as Serious and Related
(Possible, Probable, Definite)
World-Wide Safety + 
IDRI regulatory
National Regulatory
Authority & EC
Study Monitors
SUSAR
Local Medical Monitor assesses the SAE as 
unexpected
Unblinded SUSAR 
paper CIOMS
IDRI / Aeras
Blinded SUSAR 
paper CIOMS
Blinded SUSAR 
paper CIOMS
Blinded SUSAR 
paper CIOMS
Blinded SUSAR 
paper CIOMS
FDA
Unblinded SUSAR 
paper CIOMS
 
 

 
 
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APPENDIX C 
Toxicity Table 
Note: From final US FDA guidance: Toxicity Grading Scale for Healthy Adult and Adolescent Subjects Enrolled in Preventive Vaccine Clinical 
Trials (September 2007); laboratory values are in conventional and SI units.  The laboratory values provided in the tables serve as guidelines 
and are dependent upon institutional normal parameters.  Institutional normal reference ranges should be provided to demonstrate that they are 
appropriate. 
 
Local Site of 
Injection Symptoms 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Potentially Life 
Threatening (Grade 4) 
Pain 
Does not interfere 
with activity 
Repeated use of  
non-narcotic pain reliever > 
24 hours or interferes with 
activity 
Any use of narcotic pain 
reliever or prevents daily 
activity 
ER visit or hospitalization 
Erythema/Redness * 
2.5 - 5 cm 
5.1 - 10 cm 
>10 cm 
Necrosis (ulceration) or 
exfoliative dermatitis 
Induration/Swelling * 
2.5 - 5 cm 
5.1 - 10 cm 
>10 cm 
Necrosis (ulceration) 
* In addition to grading the local reaction at the greatest single diameter, the measurement should be recorded as a continuous variable. 
 
Vital Signs* 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Potentially Life 
Threatening (Grade 4) 
Fever** 
38.0 – 38.4°C 
100.4 – 101.1°F 
38.5 - 38.9°C 
101.2 - 102.0°F 
39.0 - 40°C 
102.1 - 104°F 
>40°C 
>104°F 
Tachycardia – beats per 
minute 
101 – 115 
116 – 130 
>130 
ER visit or hospitalization for 
arrhythmia 
Bradycardia – beats per 
minute 
50 – 54 
45 –  49 
<45 
ER visit or hospitalization for 
arrhythmia 
Hypertension (systolic) 
– mm Hg 
141 – 150 
151 – 155 
>155 
ER visit or hospitalization for 
malignant hypertension 
Hypertension (diastolic) 
– mm Hg 
91 – 95 
96 – 100 
>100 
ER visit or hospitalization for 
malignant hypertension 
Hypotension (systolic) – 
mm Hg 
85 - 89 
80 – 84 
<80 
ER visit or hospitalization for 
hypotensive shock 
Respiratory rate – 
breaths per minute 
17 – 20 
21 – 25 
>25 
Intubation 
* Subject should be at rest for all vital sign measurements.  ** Oral temperature; no recent hot or cold beverages or smoking.  
 
Systemic (General) 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Potentially Life 
Threatening (Grade 4) 
Nausea/vomiting 
No interference 
with activity or  
1 - 2 episodes/24 
hours 
Some interference with 
activity or  >2 episodes/24 
hours 
Prevents daily activity, 
requires outpatient IV 
hydration 
ER visit or hospitalization for 
hypotensive shock 
Diarrhea 
2 - 3 loose stools or 
< 400 grams/ 24 
hours 
4 - 5 stools or 400 - 800 
grams/24 hours 
6 or more watery stools or 
> 800 grams/24 hours or 
requires outpatient IV 
hydration 
ER visit or hospitalization for 
hypotensive shock 
Headache 
No interference 
with activity 
Repeated use of non-narcotic  
pain reliever > 24 hours or 
some interference with 
activity  
Significant; any use of 
narcotic pain reliever or 
prevents daily activity  
ER visit or hospitalization 
Fatigue 
No interference 
with activity 
Some interference with 
activity 
Significant; prevents daily 
activity 
ER visit or hospitalization 
Myalgia (muscle pain) 
No interference 
with activity 
Some interference with 
activity 
Significant; prevents daily 
activity 
ER visit or hospitalization 
Illness or clinical 
adverse event (as defined 
according to applicable 
regulations) 
No interference 
with activity 
Some interference with 
activity not requiring medical 
intervention 
Prevents daily activity and 
requires medical 
intervention 
ER visit or hospitalization 
 
 

 
 
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Serum 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Potentially Life 
Threatening (Grade 4) 
Blood urea nitrogen (BUN) 
– mg/dL: 
mmol/L: 
 
23 – 26 
8.3 – 9.5 
 
27 – 31 
9.6 – 11.2 
 
>31 
>11.2 
Requires dialysis 
Creatinine – elevated 
mg/dL: 
umol/L: 
 
1.5 – 1.7 
121 - 145 
 
1.8 – 2.0 
146 – 170 
 
2.1 – 2.5 
171 – 208 
 
>2.5 or requires dialysis 
>208 or requires dialysis 
Alkaline phosphatase (ALP) 
– increased 
1.1 – 2.0 x ULN 
2.1 – 3.0 x ULN 
3.1 – 10 x ULN 
>10 x ULN 
Liver Function Tests (LFT): 
AST, ALT – increased 
1.1 – 2.5 x ULN 
2.6 – 5.0 x ULN 
5.1 – 10 x ULN 
>10 x ULN 
Bilirubin (with any increase 
in LFT) - increased 
1.1 – 1.25 x ULN 
1.26 – 1.5 x ULN 
1.51 – 1.75 x ULN 
>1.75 x ULN 
Bilirubin (with normal LFT) 
- increased 
1.1 – 1.5 x ULN 
1.6 – 2.0 x ULN 
2.1 – 3.0 – x ULN 
>3.0 x ULN 
ULN (upper limit of normal) dependent on normal reference ranges per institutional parameters.  
 
 
Hematology 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Potentially Life 
Threatening (Grade 4) 
Hemoglobin (Female) – 
g/dL: 
g/L: 
 
11.0 – 12.0 
110 – 120 
 
9.5 – 10.9 
95 – 109 
 
8.0 – 9.4 
80 – 94 
 
<8.0 
<80 
Hemoglobin (Male) –  
g/dL: 
g/L: 
 
12.5 – 13.5 
125 – 135 
 
10.5 – 12.4 
105 - 124 
 
8.5 – 10.4 
85 – 104 
 
<8.5 
<85 
WBC – increased 
cells/mm3: 
cells x 109/L: 
 
10,800 – 15,000 
10.8 – 15.0 
 
15,001 – 20,000 
15.1 – 20.0 
 
20,001 – 25,000 
20.1 – 25.0 
 
>25,000 
>25.0 
WBC – decreased 
 cells/mm3: 
cells x 109/L: 
 
2,500 – 3,500 
2.5 – 3.5 
 
1,500 – 2,499 
1.5 – 2.4 
 
1,000 – 1,499 
1.0 – 1.4 
 
<1,000 
<1.0 
Lymphocytes – decreased 
cells/mm3: 
cells x 109/L: 
 
750 – 1,000 
0.8 – 1.0 
 
500 – 749 
0.5 – 0.7 
 
250 – 499 
0.3 – 0.4 
 
<250 
<0.3 
Neutrophils – decreased 
cells/mm3: 
cells x 109/L: 
 
1,500 – 2,000 
1.5 – 2.0 
 
1,000 – 1,499 
1.0 – 1.4 
 
500 – 999 
0.5 – 0.9 
 
<500 
<0.5 
Platelets – decreased 
cells/mm3: 
cells x 109/L: 
 
125,000 – 140,000 
125 – 140 
 
100,000 – 124,000 
100 – 124 
 
25,000 – 99,000 
25 – 99 
 
<25,000 
<25 
ULN (upper limit of normal) dependent on normal reference ranges per institutional parameters.  
  
 
 
 

 
 
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APPENDIX D 
Adverse events of Special Interest 
 
Adverse events of special interest (AESIs) are events which are potentially immune mediated 
and include: 
 
Acute disseminated encephalomyelitis (ADEM) 
Addison's Disease 
Anti-neutrophil Cytoplasmic Antibody (ANCA)-associated Vasculitis 
Ankylosing Spondylitis 
Anti-phospholipid Syndrome 
Autoimmune Bullous Skin Diseases 
Autoimmune Hemolytic Anemia 
Autoimmune Hepatitis 
Basedow’s Disease 
Behcet’s Syndrome 
Bell's Palsy 
Carditis 
Celiac Disease 
Crohn’s Disease 
Cutaneous Lupus 
Demyelinating Disease 
Dermatomyositis 
Diabetes Mellitus, Insulin Dependent (IDDM) 
Erythema Nodosum 
Glomerulonephritis 
Guillain Barre Syndrome 
Grave’s Disease 
Idiopathic Thrombocytopenic Purpura (ITP) 
Inflammatory Bowel Disease (non-specific) 
Juvenile Rheumatoid Arthritis 
Mixed Connective Tissue Disease 
Multiple Sclerosis 
Myasthenia Gravis 
Myelitis/Transverse Myelitis 
Myocarditis 
Nephritis 
Optic neuritis 
Pericarditis 
Polymyalgia Rheumatica 
Polymyositis 
Primary Biliary Cirrhosis 
Primary Sclerosing Cholangitis 
Psoriasis 
Psoriatic Arthritis 

 
 
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Raynaud's Phenomenon 
Rheumatoid Arthritis 
Sarcoidosis 
Scleroderma 
Sjogren’s Syndrome 
Spondylo-arthropathy 
Stevens-Johnson Syndrome 
Systemic Lupus Erythematosus 
Temporal Arteritis 
Thyroiditis 
Ulcerative Colitis 
Ulcerative Proctitis 
Uveitis 
Vasculitis 
Vitiligo 
Wegener’s Granulomatosis