Clinical trial NCT05592223
Conditions: Tuberculosis
Sponsor: Fred Hutchinson Cancer Center
Start date: 2022-12-06; Completion date: 2023-12-01
Enrollment: 20 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to develop a BCG challenge model for use in short term Phase I human trials capable of assessing the ability of TB drugs and/or vaccine-induced immune responses to impact in vivo mycobacterial replication as a method of assessing antimycobacterial agents and/or protective immunity elicited by vaccines or host-directed therapy. The trial will illuminate the nature of local and systemic immune responses to BCG and treatment response, as well as demonstrate our local capacity for newer, more innovative study designs.

Detailed description:
This is phase 1, open-label, randomized clinical protocol to develop a human challenge model using the licensed and available BCG VACCINE USP (TICE® strain) with and without INH or Rifampin (RIF). Part 1 will involve 10 participants who will be screened and consented, given an intradermal injection of BCG; five of these participants will receive oral INH for 3 days. Part 2 will involve 10 participants who will be screened and consented, given an intradermal injection of BCG; five of these participants will receive oral RIF for 7 days. All participants will undergo physical exams, clinical evaluations, blood draws, urine collections, skin biopsies, and pregnancy tests. This study will measure the rate of replication by utilizing qPCR and in vitro culture, systemic innate and adaptive immune responses, including humoral and cellular assay analyses and the evaluation and PPD/IGRA status.

Arms: arm 1: Will receive INH in the dose of 300 mg for three days post BCG injection. arm 2: Will not receive any INH or RIF dose. arm 3: Will receive RIF in the dose of 600 mg for seven days post BCG injection.
Interventions: intervention 1: BCG Vaccine USP intervention 2: Isoniazid intervention 3: Rifampin
Intervention descriptions: intervention 1: 2x10\^6 cfu Tice® BCG (ID) intervention 2: INH in the dose of 300 mg for three days post BCG injection. intervention 3: RIF in the dose of 600 mg for seven days post BCG injection.

Protocol documents:
Prot_SAP_001.pdf: 
Kublin_Phase I human BCG challenge trial     
           Page 1 of 41  
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FRED HUTCHINSON CANCER CENTER 
UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE 
Current version: 03/29/2022 
Previous version:  
Title of Protocol: 
A Phase I single site open label clinical trial for the development of a human BCG challenge model to assess TB 
drugs and vaccines 
Investigators List 
Professional Title 
Phone Number 
Principal Investigator 
James Kublin, MD, MPH 
Executive Director, HVTN 
Medical Director, Seattle MCTC 
Principal Staff Scientist, VIDD 
Clinical Professor, UW Global health 
(206)-667-1970 
Investigators 
Chetan Seshadri, MD 
Associate Professor, UW Department of Medicine 
Associate Medical Staff, UW Medical Center and Harborview 
Medical Center 
Affiliate Investigator, VIDD, FHCRC 
Adjunct Professor, UW Department of Global Health 
(206) 543-6709
E. Chandler Church, MD, MSc
Acting Instructor, UW Department of Medicine 
Senior Fellow, VIDD 
(206) 667-6982
Thomas R. Hawn, MD, PhD 
Professor, UW Department of Medicine 
Adjunct Associate Professor, UW Department of Global 
Health 
(206) 616-4124
Sean C. Murphy, MD, PhD 
Associate Professor, UW Laboratory Medicine 
Assistant Director, UW Medical Center 
Member, UW CERID 
Clinical Investigator, Seattle MCTC 
Medical Director, Human Challenge Center, Seattle Children’s 
Research Institute 
(206) 685-6162
Jay Vary, MD, PhD 
Associate Professor, UW Division of Dermatology 
(206)-598-5065 
David Sherman, PhD 
Professor and Chair, UW Microbiology 
Affiliate Professor, UW Global Health 
(206)-543-4547 
Julie McElrath, MD, PhD 
Senior Vice President and Director, VIDD; Member, VIDD 
Member, CRD 
Professor of Medicine, UW 
Adjunct Professor, Pathobiology, Global Health, and 
Laboratory Medicine, UW 
Joel D. Meyers Endowed Chair, FHCRC 
(206)-667-6704 
Medical Monitor: 
Chetan Seshadri, MD 
Associate Professor, UW Department of Medicine; Associate 
Medical Staff, UW Medical Center and Harborview Medical 
Center 
Affiliate Investigator, VIDD, FHCRC 
Adjunct Professor, UW Department of Global Health 
(206) 543-6709
Biostatistician: 
Andrew Fiore-Gartland, PhD 
Staff Scientist, VIDD 
(206) 667-1228
IRO received 05/20/22
FHCRC IRB Approval  
05/25/2022 
Document Released Date


 
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Contents 
1.0 
PROTOCOL SYNOPSIS ........................................................................................................................................................ 5 
2.0 
STATEMENT OF COMPLIANCE ........................................................................................................................................... 6 
3.0 
SIGNATURE PAGE .............................................................................................................................................................. 7 
4.0 
LIST OF ABBREVIATIONS ................................................................................................................................................... 8 
5.0 
BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ............................................................................................ 9 
5.1 
Background Information ...................................................................................................................................... 9 
5.1.1 
The Challenge of Achieving TB Control ................................................................................................................ 9 
5.1.2 
Evaluating New Vaccines for TB ........................................................................................................................... 9 
5.1.3 
Evaluating New Drugs for TB ............................................................................................................................. 10 
5.1.4 
The Need for a Human Challenge Model ........................................................................................................... 10 
5.2 
Rationale ............................................................................................................................................................ 11 
5.3 
Preclinical Data .................................................................................................................................................. 11 
5.3.1 
BCG .................................................................................................................................................................... 11 
5.3.2 
Isoniazid (INH) .................................................................................................................................................... 11 
5.3.3 
Novel Pre-ribosomal RNA Assay to Assess the Viable BCG Bacterial Burden in Skin Biopsies........................... 11 
5.4 
Clinical Data to Date .......................................................................................................................................... 12 
5.5 
Protocol Agents .................................................................................................................................................. 12 
5.6 
Handling, Storage and Accountability and Preparation ..................................................................................... 12 
5.7 
Study Compliance .............................................................................................................................................. 13 
5.8 
Potential Risks and Benefits ............................................................................................................................... 13 
5.8.1 
Known Potential Risks ........................................................................................................................................ 13 
5.8.2 
Known Potential Benefits................................................................................................................................... 14 
6.0 
OVERVIEW OF CLINICAL TRIAL ........................................................................................................................................ 14 
6.1 
Study Objectives ................................................................................................................................................ 14 
6.1.1 
Primary Objectives ............................................................................................................................................. 14 
6.1.2 
Secondary Objectives ......................................................................................................................................... 14 
6.2 
Study Design ...................................................................................................................................................... 14 
7.0 
STUDY POPULATION ....................................................................................................................................................... 15 
8.0 
SUBJECT ELIGIBLITY ......................................................................................................................................................... 15 
8.1 
Inclusion Criteria ................................................................................................................................................ 15 
8.2 
Exclusion Criteria ............................................................................................................................................... 16 
9.0 
RECRUITMENT ................................................................................................................................................................. 18 
10.0 
STUDY PROCEDURES AND EVALUATIONS ....................................................................................................................... 18 
10.1 
Consent .............................................................................................................................................................. 18 
10.2 
Screening ........................................................................................................................................................... 18 
10.3 
Group Assignment ............................................................................................................................................. 19 
10.4 
Study Drug Administration................................................................................................................................. 19 
10.4.1 
BCG injection (all participants) .......................................................................................................................... 19 
10.4.2 
INH (Group 1 only) ............................................................................................................................................. 19 


 
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10.5 
Study Duration ................................................................................................................................................... 19 
10.6 
Evaluations ......................................................................................................................................................... 19 
10.6.1 
Physical Examination and Clinical Assessments ................................................................................................. 19 
10.6.2 
Participant Self-monitoring AEs/SAEs and Health Status Records ..................................................................... 19 
10.6.3 
Concomitant Medication and Supportive Care Guidelines ................................................................................ 20 
10.6.4 
Laboratory Evaluations/Assays .......................................................................................................................... 20 
10.7 
Photographs ....................................................................................................................................................... 21 
10.8 
PPD Skin Test ..................................................................................................................................................... 21 
10.9 
Memory Aid eCRF Device and AE/SAE Recording Training ................................................................................ 21 
11.0 
STUDY SCHEDULE ............................................................................................................................................................ 21 
11.1 
Participant Procedures Schedule ....................................................................................................................... 21 
11.2 
Clinic Visit Schedule ........................................................................................................................................... 21 
11.3 
Abnormal BCG Injection Site Procedures ........................................................................................................... 24 
11.4 
Withdrawal Procedures ..................................................................................................................................... 24 
12.0 
LABORATORY TESTING AND ASSAY SCHEDULE ............................................................................................................... 24 
13.0 
SAFETY MONITORING COMMITTEE ................................................................................................................................ 25 
13.1 
Primary Endpoint ............................................................................................................................................... 25 
13.2 
Secondary Endpoint ........................................................................................................................................... 25 
14.0 
SUBJECT DISCONTINUATION OF ACTIVE TREATMENT .................................................................................................... 25 
15.0 
ASSESSMENT OF SAFETY ................................................................................................................................................. 26 
15.1 
Specification of Safety Parameters .................................................................................................................... 26 
15.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters ........................................... 26 
15.2.1 
Adverse Events ................................................................................................................................................... 26 
15.2.2 
Reactogenicity .................................................................................................................................................... 27 
15.2.3 
Additional Adverse Event Characterization and Severity Grading ..................................................................... 29 
15.3 
Reporting Procedures ........................................................................................................................................ 31 
16.0 
DATA AND SAFETY MONITORING PLAN .......................................................................................................................... 32 
17.0 
DATA MANAGEMENT/CONFIDENTIALITY ....................................................................................................................... 32 
17.1 
Data Management Responsibilities ................................................................................................................... 32 
17.2 
Data Capture Methods ...................................................................................................................................... 32 
17.3 
Types of Data ..................................................................................................................................................... 33 
17.4 
Study Records Retention ................................................................................................................................... 33 
17.5 
Quality Control ................................................................................................................................................... 33 
18.0 
STATISTICAL CONSIDERATIONS ....................................................................................................................................... 33 
18.1 
Sample Size and Power for Outcome Measures ................................................................................................ 33 
18.2 
Randomization ................................................................................................................................................... 34 
18.3 
Ethnic and Gender Distribution Chart ................................................................................................................ 34 
19.0 
ETHICS/PROTECTION OF HUMAN SUBJECTS................................................................................................................... 35 
19.1 
Institutional Review Board ................................................................................................................................. 35 
19.2 
Informed Consent Process ................................................................................................................................. 35 


 
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19.3 
Exclusion of Minors ............................................................................................................................................ 35 
19.4 
Subject Confidentiality ....................................................................................................................................... 36 
19.5 
Future Use of Stored Specimens and Data ........................................................................................................ 36 
20.0 
PUBLICATION POLICY ...................................................................................................................................................... 36 
21.0 
REFERENCES .................................................................................................................................................................... 36 
22.0 
APPENDICES .................................................................................................................................................................... 39 
Appendix A: Lab Procedures Table ...................................................................................................................................... 40 
Appendix B: Participant Procedures Table .......................................................................................................................... 41 
 
 
 
 


 
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1.0 PROTOCOL SYNOPSIS 
Protocol Title 
A Phase I single site open label clinical trial for the development of a human 
BCG challenge model to assess TB drugs and vaccines 
Trial Phase 
Phase 1 
Study Objectives 
Primary: 
1. Evaluate the safety and tolerability of Intradermal Tice® BCG 
followed by a short course (3 days) of isoniazid (INH). 
2. Assess the BCG bacterial burden in skin biopsies as measured by 
culture. 
Secondary: 
1. Assess the BCG bacterial burden in skin biopsies as measured by a 
novel qPCR assay. 
2. Evaluate peripheral blood cellular frequencies (Trucount) after 
intradermal BCG.  
3. Evaluate adaptive immune response after intradermal BCG 
(validated intracellular cytokine staining after stimulation). 
Exploratory 
1. To conduct analyses related to furthering the understanding of TB, 
immunology, vaccines, and clinical trial conduct. 
 
Outcome Measures 
Primary Endpoints:  
1. The rate of AE’s/SAE’s 
2. Colony forming units (CFU) from culture 
Secondary Endpoints: 
1. Quantitative bacterial 16S ribosomal DNA PCR 
2.  Microbial viability testing pre-ribosomal RNA RT-PCR 
3. Humoral and cellular immune responses after BCG immunization 
Summary of Study Design 
This is phase 1, open-label, randomized clinical protocol to develop a human 
challenge model using the licensed and available BCG VACCINE USP (TICE® 
strain) with and without antibacterial Isoniazid (INH).  It will involve 10 
participants who will be screened and consented, given an intradermal 
injection of BCG; five of these participants will receive oral INH for 3 days.  
Participants will undergo physical exams, clinical evaluations, blood draws, 
urine collections, skin biopsies, and pregnancy tests.  This study will measure 
the rate of replication by utilizing qPCR and in vitro culture, systemic innate 
and adaptive immune responses, including humoral and cellular assay 
analyses and the evaluation and PPD/IGRA status. 
Population 
10 healthy male and non-pregnant female individuals, HIV and TB 
uninfected, aged 18 to 45 years, with no extensive residence in high TB 
endemic country. 


 
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Drugs 
• 
BCG VACCINE USP (TICE® strain) has been licensed for percutaneous use 
and is an attenuated, live culture preparation of the Bacillus of 
Calmette and Guerin (BCG) strain of Mycobacterium bovis. 
• 
Isoniazid is a licensed antibacterial available as 100mg and 300mg 
tablets for oral administration. 
Dose 
Ten participants will receive one intradermal injection of 2x106 cfu Tice® BCG 
(ID), and five of these participants will receive oral tablet(s): either three 
tablets of 100mg or one tablet of 300mg of INH each day for 3 days 
following the injection of BCG vaccine. 
Duration of Participation 
16 to 24 weeks (screening up to 8 weeks prior to enrollment, study follow up 
for 16 weeks after enrollment) 
2.0 STATEMENT OF COMPLIANCE 
 
The trial will be conducted in accordance with International Conference on Harmonisation Good Clinical Practice 
(ICH GCP), applicable United States (US) Code of Federal Regulations (CFR), Office for Human Research 
Protections (OHRP), IRB policies of Fred Hutchinson Cancer Center, and collaborating institutions.  The Principal 
Investigator will assure that no deviation from, or changes to the protocol will take place without prior 
agreement from the Investigational New Drug (IND) (If applicable), funding agency and documented approval 
from the Institutional Review Board (IRB), except where necessary to eliminate an immediate hazard(s) to the 
trial participants.  All personnel involved in the conduct of this study have completed Human Subjects Protection 
and ICH GCP Training. 
 
The protocol, informed consent form, recruitment materials, and all participant materials will be submitted to 
the IRB for review and approval.  Approval of both the protocol and the consent form must be obtained before 
any participant is enrolled.  Any amendment to the protocol will require review and approval by the IRB before 
the changes are implemented to the study.  All changes to the consent form will be IRB approved; a 
determination will be made regarding whether a new consent needs to be obtained from participants who 
provided consent using a previously approved consent form. 
 
 
 


 
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3.0 SIGNATURE PAGE 
 
The signature below constitutes the approval of this protocol and the attachments and provides the necessary 
assurances that this trial will be conducted according to all stipulations of the protocol, including all statements 
regarding confidentiality, and according to local legal and regulatory requirements and applicable US federal 
regulations and ICH guidelines. 
 
 
 
 
James Kublin, MD., MPH. 
Principal Investigator 
 
Date 
 
 
 


 
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4.0 LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
BCG 
Bacillus Calmette-Guerin 
BMI 
Body Mass Index 
CFR 
Code of Federal Regulations 
CFU 
Colony Forming Unit 
CRS 
Clinical Research Support 
DSMC 
Data and Safety Monitoring Committee 
EBA 
Early Bactericidal Activity 
eCRF 
Electronic Case Report Form 
FDA 
Food and Drug Administration 
FHCRC  
Fred Hutchinson Cancer Center 
FWA 
Federal-Wide Assurance 
GCP 
Good Clinical Practice 
HIV 
Human Immunodeficiency Virus 
IA 
Immunoassay 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
ID 
Intradermal 
IEC 
Independent or Institutional Ethics Committee 
INH 
Isoniazid 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
MDR/RR-TB 
Multidrug and Rifampicin-resistant Tuberculosis 
MOP 
Manual of Procedures 
MTB 
Mycobacterium Tuberculosis 
N 
Number (typically refers to subjects) 
NIAID 
National Institute of Allergy and Infectious Diseases, NIH, DHHS 
NIH 
National Institutes of Health 
NK 
Natural Killer 
OCRA 
Office of Clinical Research Affairs, DMID, NIAID, NIH, DHHS 
OHRP 
Office for Human Research Protections 
ORA 
Office of Regulatory Affairs, DMID, NIAID, NIH, DHHS 
OTC 
Over the Counter 
PBMC 
Peripheral Blood Mononuclear Cell 
PoD 
Prevention of Disease 
PoI  
Prevention of Infection 
PoR 
Prevention of Relapse 
PPD  
Purified Protein Derivative  
PI 
Principal Investigator 
rRNA 
Ribosomal Ribonucleic Acid 
RT – PCR 
Reverse-Transcription Polymerase Chain Reaction 
SAE 
Serious Adverse Event 
Seattle MCTC 
Seattle Malaria Clinical Trials Center 
SMC 
Safety Monitoring Committee 
SRC 
Scientific Review Committee  


 
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TB 
Tuberculosis 
WBC 
Whole Blood Cell 
WHO 
World Health Organization 
 
 
5.0 BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
 
5.1 
Background Information 
 
5.1.1 
The Challenge of Achieving TB Control 
Tuberculosis (TB) can be diagnosed, treated and prevented, yet TB is the leading cause of death 
from an infectious agent globally, accounting for ~1.6 million deaths in 2016 - 20171.  It is also 
the leading cause of death among people living with HIV, totaling 300,000 deaths in 2016 - 2017.  
The World Health Organization (WHO) estimated that in 2017, 10 million people developed 
active tuberculosis (36% in women; 9% in people living with HIV; 72% living in Africa), causing 
substantial global morbidity and renewing the source of transmission2.  Multidrug and 
rifampicin-resistant tuberculosis (MDR/RR-TB) remains a global health threat with an estimated 
558,000 MDR/RR-TB cases in 20173.  There are an estimated 1.7 billion people (23% of the 
world’s population) that are latently infected with Mycobacterium tuberculosis (MTB), from 
which cases of active TB disease arise.  While the WHO has set a target for ending the TB 
epidemic by 2030, progress has been inadequate, with TB rates declining at a rate of 2% per 
year4.  Although effective TB therapies are available, the impact on the global TB epidemic has 
been limited.  TB treatment, particularly for multidrug resistant TB, is long, toxic, has drug-drug 
interactions with antiretroviral drugs and suboptimal adherence.  Effective TB vaccines that 
prevent TB infection, disease, and recurrence are essential to eliminate TB globally, and may 
prove to be effective against drug susceptible and resistant forms of TB, as the genetic 
mutations that confer resistance are not likely to alter susceptibility to immunological activity.  
 
5.1.2 
Evaluating New Vaccines for TB 
Although BCG (Mycobacterium bovis Bacillus Calmette-Guerin) vaccination offers some 
protection against TB in some populations, its efficacy is suboptimal, variable, and not adequate 
for disease control5.  The correlates of protective immunity and the reason for BCG’s variable 
and partial efficacy are unknown.  Very few studies have examined the immune correlates of 
risk associated with BCG vaccination.  Development of a more effective TB vaccine is a high 
priority in global health.   
 
The complexity of TB pathogenesis and immunology has led to the identification of several 
different populations that could be targeted for evaluations of TB vaccines.  Ultimately, the 
objective of a TB vaccine is prevention of microbiologically confirmed TB disease (PoD).  
Recently a Phase 2b study showed that M72/AS01E conferred an estimated 54% efficacy against 
disease among latently infected individuals6.  This is an exciting result for the field, though with 
only 32 primary cases, a Phase 3 PoD study and immunological correlates analyses will be 
needed for validation.  Prior to this study, the low incidence of TB disease spurred HVTN and TB 
collaborators to advocate for screening vaccine candidates based on efficacy in the prevention 
of infection (PoI)7.  Due to the higher incidence of infection compared to disease, such a trial can 
efficiently move forward promising vaccines that elicit functional immunological responses 
against the pathogen, mitigating risk of a large future PoD trials.  In 2018 results of the first PoI 
study showed that BCG re-vaccination can prevent sustained MTB infection8, generating 


 
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renewed interest in BCG and other recombinant BCG or MTB vaccine candidates for use both in 
adolescent and infant populations.  BCG has also been considered as a challenge agent for the 
purposes of evaluating TB vaccines, primarily for POD.  
 
Patients undergoing standard treatment for active TB disease are at a much higher risk of 
relapse or reinfection9.  Modeling suggests that therapeutic TB vaccines (PoR) may not only 
reduce recurrence, shorten treatment and decrease post treatment morbidity via immune-
mediated mechanisms, but may also serve as a unique setting to discover immune correlates of 
protection that could be applied generally to preventive vaccines.  Thus, there are several 
promising avenues for TB vaccine development, but stage-gating strategies for down-selecting 
the most promising candidates are still lacking. 
 
5.1.3 
Evaluating New Drugs for TB 
The development of new drugs for TB falls far short of the pressing need.  The current frontline 
regimen of TB drugs is fifty years old, treatment requires a minimum of six months and four 
different agents, involves notable risks of toxicity, and drug resistance is rising. In response, 
experts have called for entirely new regimens to combat the TB pandemic10.  Despite some 
notable and welcome recent success with the approval by the FDA of Pretomanid Tablets in 
combination with bedaquiline and linezolid for the treatment of a specific type of highly 
treatment-resistant TB of the lungs, TB drug discovery remains severely impeded by insufficient 
resources and outdated approaches. 
 
Almost universally, the first test of a new agent in TB patients involves the early bactericidal 
activity (EBA).  In this test, a patient receives a new agent as monotherapy for 2, 7, or 14 days, 
and the decrease in bacterial colony forming units (CFU) in sputum is determined.  While the 
original purpose of the assay was dose finding11, the EBA is now employed as a gating tool to 
predict drug efficacy in humans.  Unfortunately, the predictive power of this test is notably 
poor12.  For but one example, the recently approved new TB drug bedaquiline was nearly 
shelved prematurely due to disappointing results in the EBA13.  In response, field experts have 
called for development of “novel, more efficient screening trial designs” to expand the 
throughput and accuracy of phase 2 studies of anti-TB agents11. 
 
5.1.4 
The Need for a Human Challenge Model 
Human challenge studies have aided the development of drugs and vaccines for malaria, 
typhoid, and influenza.  A study design with a defined time point for challenge creates 
opportunities to rigorously test the efficacy of drugs and vaccines with smaller sample sizes and 
controlled time points for more informative data from immunologic and biologic assays.  
Although human challenge infections with live fully virulent MTB have not been done and have 
significant health risks that would not be ethical, auxotrophic strains of MTB are being 
developed with properties that may solve these ethical hurdles.  Preparation for these future 
trials will create opportunities for leading efforts of future challenge studies.  In addition to 
testing of drugs and vaccines, human challenge models provide opportunities to intensively 
interrogate the host immune response.  Almost all in vivo human TB studies are hampered by 
the limitations of an observational study design with many important unknowns including the 
time and extent of exposure.  A human challenge model, even with a less virulent Mycobacteria 
would address these problems. 
 
Previous human challenge work in the TB field employs BCG.  Dr. Helen McShane at the Jenner 
Institute, Oxford University has already created a precedent of BCG challenge studies in animals 


 
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and humans (see below). We propose a phase 1 trial to analyze the local and systemic immune 
response to intradermal BCG and the effects of approved drugs with known microbicidal 
activity.  This study design will demonstrate the capabilities of our local infrastructure and 
expertise in TB immunology and microbiology.  The trial will illuminate the nature of local and 
systemic immune responses to BCG and treatment response, as well as demonstrate our local 
capacity for newer, more innovative study designs.   
5.2 
Rationale 
 
We propose to develop a BCG challenge model for use in short term Phase I human trials capable of 
assessing the ability of TB drugs and/or vaccine-induced immune responses to impact in vivo 
mycobacterial replication as a method of assessing antimycobacterial agents and/or protective 
immunity elicited by vaccines or host-directed therapy.   We are well equipped to implement efficient 
and successful TB drug and vaccine trials, leveraging our extensive experience with the Seattle Malaria 
Clinical Trials Center and our collaborations with colleagues at the University of Washington, Seattle 
Children’s Research Institute, the Infectious Disease Research Institute, as well as TB investigators 
globally.  This demonstration of BCG as a candidate TB challenge agent will provide our respective 
investigators and institutions experience and data for future work. 
 
5.3 
Preclinical Data  
 
5.3.1 
BCG  
Preclinical work by Dr. Helen McShane at the Jenner Institute, Oxford University has served to 
validate the BCG challenge model in animals.  They used the mouse ear as a surrogate of human 
skin and showed that intradermal BCG vaccination protects against subsequent intradermal BCG 
challenge14.  In a separate study, they also validated this strategy in rhesus and cynomolgus 
macaques15.  They were able to demonstrate a detectable vaccine effect, which was similar in 
magnitude to that seen in an aerosol MTB infection model.  Together, these data provide 
support the further development of a human BCG infection model to evaluate new drugs and 
vaccines. 
 
5.3.2 
Isoniazid (INH)  
Since its introduction in 1954, isoniazid has been a cornerstone of frontline TB treatment in 
humans.  It has also been tested in numerous animal models of TB infection including mice16, 
guinea pig17, zebrafish18, and nonhuman primates19.  BCG vaccination is both safe and efficacious 
in conjunction with INH treatment in animal models20, 21.  In culture, BCG is as sensitive to INH as 
is M. tuberculosis22.  These data suggest that INH provides an excellent opportunity to test novel 
approaches to measuring anti-TB drug efficacy in humans. 
 
5.3.3 
Novel Pre-ribosomal RNA Assay to Assess the Viable BCG Bacterial Burden in Skin Biopsies  
Mycobacterial 16S ribosomal RNA (rRNA) is a sensitive indicator of the presence of BCG but does 
not completely discriminate between viable and non-viable organisms.  To obtain more 
discriminating data for this viable/non-viable distinction, testing for labile pre-rRNA was 
explored. Like other bacteria, M. tuberculosis was known to transiently express pre-rRNAs that 
could be measured by comparing the reverse transcription PCR (RT-PCR) vs. PCR-only assay for a 
pre-rRNA region of the 16S rRNA23,24.  In vitro studies have been performed in-house (Murphy 
Laboratory) to hold 2x106 cfu BCG in nutrient-depleted conditions (PBS), nutrient-limited 
conditions (human serum) or nutrient-rich conditions (7H9 broth media) for four days with or 


 
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without isoniazid.  After four days, 1% of the material (intended to mimic the biopsy recovery of 
BCG at the administration site), was diluted into drug-free 7H9 media and monitored by pre-
rRNA molecular viability testing and by OD600 measurements of growth. BCG held in 7H9 for the 
first four days and then diluted into 7H9 showed high pre-rRNA levels at the time of dilution, 
followed by rising OD600 measurements and high pre-rRNA levels indicating robust growth.  BCG 
held in serum showed no appreciable OD600 change during the first four days of incubation, but 
did show a small, but statistically significant increase in pre-rRNA compared to static cultures or 
drug-killed cultures.  Upon dilution, the serum-held BCG showed rising pre-rRNA levels followed 
by rising OD600 levels, indicating that the pre-rRNA molecular viability assay highlighted the 
viable nature of these BCG, despite no appreciable change in OD600 during the early time points.  
Thus, this data suggests that pre-rRNA molecular viability testing may shorten the time needed 
to identify viable bacteria in a clinical sample.  Additional in vitro and pre-clinical animal studies 
are underway to better understand whether the serum-held BCG is an appropriate surrogate for 
skin-inoculated BCG and to understand the ability of pre-rRNA molecular viability testing to 
detect viable BCG exposed to sub-therapeutic concentrations of isoniazid or other drugs. 
 
5.4 
Clinical Data to Date 
 
In their first human study, Dr. McShane recruited 40 healthy volunteers and performed intradermal 
challenge with BCG in the upper arm followed by central punch biopsies after two weeks25.  They 
quantified BCG using solid culture as well as quantitative PCR.  They also measured local immune changes 
by collecting blister fluid and performing flow cytometry.  In a subsequent study, they measured the effect 
of pre-existing BCG immunity or MVA85A-induced immunity on BCG challenge.  They found a reduction 
in bacterial burden among participants who previously received BCG compared to those who were BCG-
naive, but did not see an effect due to MVA85A26.  In a third study, they tested variations in the source of 
BCG and challenge dose27.  Since intradermal challenge may not be physiologically relevant for a 
pulmonary infection, they are now testing aerosol BCG challenge in humans (ClinicalTrials.gov 
NCT02709278).   
 
 Another group that has published in this area is led by Dr. Dan Hoft at St. Louis University, though the 
focus of their efforts has been bacterial persistence and shedding.  In their first study, they performed 
serial punch biopsies adjacent to the site of BCG vaccination (rather than in the center of the lesion) in 
order to quantify mycobacterial shedding using PCR and solid culture28.  More recently, they repeated this 
study using swabs to measure shedding non-invasively by three different methods (solid culture, liquid 
culture, and quantitative PCR)29. 
 
Together, these studies validate the feasibility and safety of our proposed study. 
 
5.5 
Protocol Agents  
 
• 
BCG vaccine (Bacillus of Calmette and Guerin (BCG) strain of Mycobacterium bovis): one 
intradermal injection of on-label dose of 2x106 cfu Tice® BCG 
• 
Isoniazid (INH): oral tablets of on-label standard dose of either three 100mg tablets (300mg) or 
one 300mg tablet for 3 days post BCG injection. 
5.6 
Handling, Storage and Accountability and Preparation 
 


 
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Handling, storage and preparation will be conducted according to the instructions per the drug package 
inserts. The pharmacy and research team will adhere to their internal MOPs that determine 
accountability procedures. 
5.7 
Study Compliance 
 
Upon enrollment, participants will be trained on the protocol procedures and receive ongoing education 
by study staff to encourage adherence to the protocol.  There is some flexibility in the timing of clinic 
visits to increase protocol adherence and maximize chance of retention. 
 
5.8 
Potential Risks and Benefits 
 
5.8.1 
Known Potential Risks 
 
Risks of BCG 
The BCG vaccine continues to be the most widely distributed vaccine worldwide, generally 
provided to infants immediately after birth, so it is safe and well tolerated.  Typically, most 
people will develop a small swelling (nodule) at the injection site that break open, release pus or 
blood-tinged discharge, and form an ulcer the size of a dime.  The ulcer will heal over a period of 
weeks and forms a scar that remains for life.  Occasionally, lymph nodes around the vaccination 
site can become tender to touch.  “Flu-like” symptoms that are common to many vaccines 
includes fevers, chills, loss of appetite, muscle aches, and generally not feeling well can last 1-2 
days. 
 
A very small number of people (1 in 4 million) have an immediate allergic reaction to BCG.  
Symptoms include rash, swelling around the mouth, difficulty breathing.  These can be treated 
with emergency medications.  If severe, they can cause death. 
 
There is a risk that by receiving the BCG vaccine, participants may develop a false positive 
tuberculin skin test (PPD) that will complicate the early diagnosis and treatment of latent 
(inactive) TB.  However, a diagnosis of latent TB can be confirmed by other methods, including a 
clinical examination, chest x-ray, and blood test (IFN-g release assay).  
 
Risks of Isoniazid (INH) 
Participants who are administered Isoniazid may experience some side effects that include: 
numbness and tingling in the extremities, hepatitis (symptoms include loss of appetite, nausea, 
vomiting, fatigue, malaise, and weakness), nausea, vomiting, upset stomach, fever, and rash. 
 
Participants will be closely monitored by study staff and necessary treatment will be 
administered to alleviate symptoms that may occur. 
 
Risks of Intradermal Injection 
Participants may experience: pain, swelling, redness, itching caused by the ID injection. There is 
potential for an infection at the ID challenge site. 
 
Risks of Skin Biopsy 
Participants may experience: pain, swelling, redness, bleeding and bruising at the biopsy site 
during and a day or two after, damage to the skin such as artery or nerve and possible scarring.  
There is potential for an infection at biopsy site or allergic reaction to the anesthetic or gel foam 


 
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used to close the biopsy site. Participants cannot swim in a chlorinated water until the gel foam 
has sufficiently closed the biopsy area. 
 
Risks of Blood Draws 
Participants may experience: pain, swelling, redness, caused by the insertion of the needle, 
nausea, light headedness and there is a slight chance of fainting. There is potential for an 
infection at the needle insertion site  
 
Risks of PPD Skin Test 
Participants may experience: pain, swelling, redness, itching caused by the insertion of the 
needle and/or PPD agent. There is potential for an allergic reaction to the agent and/or infection 
at the PPD test site. 
 
Risk of the loss of confidentiality 
There is a potential for the loss of confidentiality. Each member of the research team has 
completed human subjects protections, and HIPAA and confidentiality training.  Trainings inform 
the research team members to follow confidentiality policies and best practices when handling 
identifiable information. 
 
5.8.2 
Known Potential Benefits 
 
There will be no direct benefit to participants in this study.  Others in the future may benefit 
from the information gained from this research, which will help scientists develop a better TB 
vaccine. 
 
 
6.0 OVERVIEW OF CLINICAL TRIAL 
6.1 
Study Objectives 
 
6.1.1 
Primary Objectives 
• 
Evaluate the safety and tolerability of Intradermal Tice® BCG followed by a short course (3 
days) of isoniazid (INH). 
• 
Assess the BCG bacterial burden in skin biopsies as measured by culture. 
6.1.2 
Secondary Objectives 
• 
Assess the BCG bacterial burden in skin biopsies as measured by a novel qPCR assay. 
• 
Evaluate peripheral blood cellular frequencies (Trucount) after intradermal BCG.  
• 
Evaluate adaptive immune response after intradermal BCG (validated intracellular cytokine 
staining after stimulation). 
6.1.3 
Exploratory Objectives 
• To conduct analyses related to furthering the understanding of TB, immunology, 
vaccines, and clinical trial conduct. 
6.2 
Study Design 
 


 
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This Phase I single site open-label clinical trial will evaluate the use of Tice® BCG in healthy adult 
participants as a challenge model for future assessment of TB drugs. Subjects (N=10) will be divided into 
two groups, where group 1 will receive INH in the dose of 300 mg for three days post BCG injection and 
group 2 (control arm) will not receive any treatment. All groups will receive a dose titration of 2x106 cfu 
of Tice® BCG intradermally as noted in the following table: 
 
 
Group 1 
Group 2 
N 
5 
5 
Tice® BCG Dose 2x106 cfu 
2x106 cfu 
INH Dose 
300 mg/3 days Control 
 
Participants will have follow-up clinic visits that will include: clinical assessments, AE/SAE review, ID 
challenge assessments, blood draws for immunogenicity and mycobacteria assays, skin biopsies, general 
exams and PPD skin testing.  
 
 
7.0 STUDY POPULATION 
 
Ten healthy, HIV and TB uninfected, male and non-pregnant female subjects, 18 to 45 years old, inclusive, will be 
enrolled from a single study site in Seattle, Washington.  The target population should reflect the Seattle King 
County community.  Recruitment materials may be dispersed in the community and participants from other 
research registries may be contacted.    Enrollment will occur over a 2-month period.  Consent will be required 
for enrollment. 
 
 
8.0 SUBJECT ELIGIBLITY 
 
Inclusion and Exclusion Criteria must be assessed by a medically licensed study clinician to make medical 
diagnoses. 
8.1 
Inclusion Criteria  
 
Participants must meet all of the following criteria to participate in this study. 
 
1. 
Provide written informed consent prior to initiation of any study procedures, 
2. 
Are males or non-pregnant females between the ages of 18 and 45 years, inclusive, 
3. 
Women of childbearing potential* in sexual relationships with men must use an acceptable 
method of preventing conception** from 30 days prior to 3 months after Tice® BCG 
administration, 
*Not sterilized via tubal ligation, bilateral oophorectomy, hysterectomy or successful Essure® 
placement (permanent, non-surgical, non-hormonal sterilization) with documented radiological 
confirmation test at least 90 days after the procedure, and still menstruating or < 1 year of the 
last menses if menopausal). 
**Includes, but is not limited to, sexual abstinence, monogamous relationship with vasectomized 
partner who has been vasectomized for 6 months or more prior to the subject receiving Tice® 
BCG, barrier methods such as condoms or diaphragms with spermicide or foam, effective 
intrauterine devices, NuvaRing ®, and licensed hormonal methods such as implants, injectables 
or oral contraceptives (“the pill”). 


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4.
For women of childbearing potential, negative serum pregnancy test at screening and negative
urine pregnancy test within 24 hours prior to enrollment and Tice® BCG administration,
5.
Are in good health, as judged by the investigator and determined by vital signs (oral
temperature, pulse, and blood pressure), medical history and physical examination,
6.
Have a negative HIV-1 ELISA test,
7.
Have negative serology tests for hepatitis B surface antigen and hepatitis C virus antibody,
8.
Have a negative QuantiFERON-TB Gold test,
9.
Negative is defined as Nil response < 0.8 IU/ml and TB Antigen response minus Nil response
<0.35 IU/mL or TB Antigen response minus Nil response > 0.35 IU/mL and < 25% of Nil response
and Mitogen response minus Nil response > 0.5 IU/ml,
10.
Have a urine dipstick for protein less than 1,
11.
Have a urine dipstick negative for glucose,
12.
Ability to understand and complete all study visits as required per protocol and be reachable by
telephone.
8.2 
Exclusion Criteria 
Participant cannot meet any of the following criteria and must be excluded from participating in this 
study. 
1.
Have a history of suspected, confirmed, treated or have other evidence of active tuberculosis, 
Symptoms may include recurrent fever, fatigue, night sweats, weight loss, oral ulcers, diarrhea, 
nausea, vomiting, or bleeding,
2.
Have any systemic symptoms* within 72 hours before Tice BCG administration or signs of 
lymphadenopathy, hepatosplenomegaly, or pulmonary disease by physical examination on day 
of Tice BCG administration,
*Includes fever, chills, malaise, fatigue, headache, night sweats, weight loss, nausea, vomiting, 
bleeding, diarrhea, abdominal pain, rhinorrhea, cough, wheezing, or shortness of breath.
3.
Have history of any significant acute or chronic medical conditions* or need for chronic 
medications that, in the opinion of the investigator, will interfere with immunity or affect safety,
*Includes, but is not limited to, disorders of the liver, kidney, lung, heart, or nervous system, or 
other metabolic or autoimmune/inflammatory conditions. Have any history of excessive scarring 
or keloid formation.
4.
Have household contact or occupation involving significant contact with someone who is 
immunocompromised,
*Includes persons with HIV, AIDs, or active cancer; infants (children < 1 year); pregnant women; 
or persons who are immunosuppressed for approximately 6 weeks (during the time of active ID 
lesion drainage).
5.
Have a history of epilepsy (does not include febrile seizures as a child),
6.
Have a pacemaker, prosthetic valve, or implantable cardiac devices,
7.
Have a history of bleeding disorder,
8.
Have a known allergy to any Tice BCG components (glycerin, asparagine, citric acid, potassium 
phosphate, magnesium sulfate, iron ammonium citrate, and lactose),
9.
Received blood products or immunoglobulin within 6 months prior to Tice BCG administration,
10.
Received immunotherapy within one year prior to Tice BCG administration,
11.
Received or plan to receive live attenuated vaccines 4 weeks before or after Tice BCG 
administration,
12.
Received or plan to receive inactivated or killed vaccines 2 weeks before or after Tice BCG 
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13.
Plans to enroll in another clinical trial* that could interfere with safety assessment of the 
investigational product at any time during the study period,
*Includes trials that have a study intervention such as a drug, biologic, or device.
14.
Received an experimental agent* within 30 days prior to Tice BCG administration or planned 
receipt of an experimental agent within 90 days after Tice BCG administration,
*Includes vaccine, drug, biologic, device, blood product, or medication.
15.
Have a history of use of a systemic antibiotic within 14 days prior to Tice BCG administration or 
planned use of a systemic antibiotic for 3 months after Tice BCG administration,
16.
Have any medical, psychiatric, occupational, or behavioral problems that make it unlikely for the 
subject to comply with the protocol as determined by the investigator,
17.
Are health care providers at the highest risk of acquiring MTB infection, such as pulmonologists 
performing bronchoscopies on TB patients,
18.
Are breastfeeding or plan to breastfeed at any given time throughout the study,
19.
Have long term use* of high dose oral or parenteral glucocorticoids**, or high-dose inhaled 
steroids***.
*Defined as taken for 2 weeks or more in total at any time during the past 2 months.
**High dose defined as prednisone ≥ 20 mg total daily dose, or equivalent dose of other 
glucocorticoids.
***High dose defined as > 800 mcg/day of beclomethasone dipropionate or equivalent. If short 
term corticosteroids are given, then the subject should not receive Tice® BCG or have blood 
collected for immunogenicity studies within 1 week of steroid administration.
20.
Have immunosuppression or are taking systemic immunosuppressants as a result of an 
underlying illness or treatment,
21.
Use of anticancer chemotherapy or radiation therapy (cytotoxic) within 36 months prior to Tice® 
BCG administration,
22.
Any active neoplastic disease,
23.
Have a pulse rate less than 50 bpm or greater than 100 bpm,
24.
Have a systolic blood pressure less than 90 mm Hg or greater than 140 mm Hg,
25.
Have a diastolic blood pressure less than 50 mm Hg or greater than 90 mmHg,
26.
Have a WBC less than 4.0x103/uL or greater than 10.5x103/uL,
27.
Have hemoglobin less than 11.5x103/uL (female) or less than 12.5x103/uL (male),
28.
Have a platelet count less than 140x103/UL,
29.
Have a creatinine greater than 1.30 mg/dL,
30.
Have an ALT (SGPT) greater than 40 IU/L (female) or greater than 55 IU/L (male),
31.
Have known HIV, Hepatitis B, or Hepatitis C infection,
32.
Have a history of alcohol or drug abuse in the last 5 years,
33.
Have had a positive PPD skin test in the past or received BCG vaccine (BCG vaccination history 
will be determined by self-report, country of birth, and/or evidence of BCG scar),
34.
Have a BMI >35,
35.
PPD skin test within 2 months prior to Tice BCG administration or planned receipt during the 
study other than from participation in this study,
36.
Oral temperature ≥ 100.4°F (≥ 38.0°C) or other symptoms of an acute illness within 3 days 
before Tice BCG administration. (Subject may be rescheduled),
37.
Any medical disease or condition that, in the opinion of the investigator, is a contraindication to 
study participation*,
*Includes medical disease or condition that would place the subject at an unacceptable risk of 
injury, render them unable to meet the requirements of the protocol, or may interfere with the 
evaluation of responses or their successful completion of the study.


 
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38. 
Have any condition that would, in the opinion of the site investigator, place the subject at an 
unacceptable risk of injury or render the subject unable to meet the requirements of the 
protocol or compromise the interpretation of data or the scientific integrity of the protocol.  
 
 
9.0 RECRUITMENT 
 
Participants will be recruited from the Seattle King County area.  Recruitment materials may be posted in 
community areas such as, but not limited to: the campuses of Fred Hutchinson and University of Washington, 
and community businesses that allow the posting of flyers.  Enrollment may also come from participants of 
other research studies and registries.   
 
All recruitment methods and will be reviewed and approved by the IRB prior to approaching participants.  The 
participants from other studies or repositories must have granted consent to allow being contacted and given 
information about other research studies.  The method of contact is determined by the IRB’s approval per the 
other research studies protocols and registries as they may have certain limitations.  
 
The gender and ethnic and racial demographics will reflect the Seattle King County community at large. 
10.0 STUDY PROCEDURES AND EVALUATIONS 
 
10.1 
Consent 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continuing throughout their study participation.  The consent process will include the 
explanation of the research study to the participant and answer any questions that may arise.  The study 
team member who conducts the consent process will be medically qualified to answer any health 
concerns, risks and possible benefits of participation in this study.  The consent form will be provided to 
the subject which they may share with their families. The consent form describes in detail the study 
procedures and risks.  The participant will be given an adequate amount of time to review the consent 
form prior to giving consent by signing the form.  Consent forms are IRB reviewed and approved prior to 
being distributed to participants. They are written documentation of informed consent and the 
participant is required to sign it prior to enrolling in the study.  The subjects may withdraw consent at 
any time throughout the course of the study.  A copy of the informed consent document will be given to 
the participants for their records. 
 
10.2 
Screening 
 
Those who consent will be considered for eligibility and will undergo evaluations and assessments 
(screening process).  Screening procedures include review of the participant’s medical history and 
concomitant medications, and collecting their vital signs (oral temperature, pulse, blood pressure) and 
height and weight (to calculate BMI).  The Participant will undergo a physical examination within 42 days 
prior to receiving Tice® BCG.  Female participants of childbearing potential must have a negative serum 
pregnancy test at screening and a negative urine pregnancy test within 24 hours prior to enrollment and 
receipt of Tice® BCG.  Participants must have a urine dipstick for protein < 1 and negative for glucose at 


 
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screening.  Participants will have their blood drawn via venipuncture to be screened for HIV, hepatitis B 
surface antigen, antibody to hepatitis C virus, and QuantiFERON®-TB Gold Test.  Results of these 
screening tests must be negative. 
 
 
10.3 
Group Assignment 
 
After the participant meets enrollment criteria, they are randomly assigned by a computer program to 1 
of the 2 groups.  In both groups, participants will be immunized intradermally with a single dose of 2x106 
cfu Tice® BCG. 
 
• 
Group 1 subjects will receive INH dosages on Days 4, 5, and 6. 
• 
Group 2 (control arm) will not receive INH. 
10.4 
Study Drug Administration 
 
Tice® BCG and INH preparations will be performed by the participating clinical study site pharmacist and 
administration will be performed by a study clinician licensed to administer study product. 
10.4.1 BCG injection (all participants) 
One intradermal injection of Administration of BCG 2x106 cfu Tice® BCG in the deltoid region, 
Following administration of Tice® BCG, intradermal (ID) site reactions will be assessed for at 
least 30 minutes.  
10.4.2 INH (Group 1 only) 
For the 5 participants assigned to Group 1, they will take INH: oral tablets of either three 100mg 
tablets (300mg) or one 300mg tablet on days 4, 5, and 6 post BCG dosing. 
10.5 
Study Duration 
 
The participants will come to the study clinic 17 times to undergo study procedures.  Additional visits 
may be required if they experience an abnormal ID challenge site.  The maximum study duration will be 
22 weeks (about 6 months).  A screening visit, BCG dosing visit and 15 follow up visits within 4 months 
will occur after skin biopsy.  
 
10.6 
Evaluations 
 
10.6.1 Physical Examination and Clinical Assessments 
A physical examination will be performed within 42 days prior to getting BCG and at the final 
study visit.  Participants medical history, concomitant medications, their vital signs (oral 
temperature, pulse, blood pressure), and height and weight (to calculate Body Mass Index 
(BMI)) will be collected.  Participants will be assessed for lymphadenopathy if indicated based on 
review of interim medical history and clinical assessment.  A medically licensed research team 
member will review the participants health status and eligibility at the clinic visits.   
   
10.6.2 Participant Self-monitoring AEs/SAEs and Health Status Records 
Participants will be asked to record their solicited local and systemic reactions, any unsolicited 
AEs/SAEs (pain, tenderness and drainage) and concomitant medications throughout the study. 


 
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They can optionally record their oral temperature as well.  They will be sent a redcap survey to 
record this information.  They will be instructed on how to measure and record AEs/SAEs. 
 
10.6.3 Concomitant Medication and Supportive Care Guidelines 
At each study visit/contact, the investigator will ask the participants about any medication 
taken, including herbals, vitamins and holistic/naturopathic medications, concomitant 
medication, including vaccines, and any other medication relevant to the protocol, including any 
specifically contraindicated will be recorded in the eCRF device with trade name and/or generic 
name of the medication, medical indication, start and end dates of treatment.  Concomitant 
medications will include but are not limited to: 
 
• 
Antibiotics, 
• 
Over the counter (OTC) 
• 
Prescription meds. 
10.6.4 Laboratory Evaluations/Assays 
Whole blood samples will be collected via venipuncture for clinical safety laboratory evaluations 
and BCG response assays.  A total of ~730mls (~3 cups) will be drawn for the entire study.  At 
the screening visit (visit 1)and Days 0 (visit 2), 1 (visit 3), 2 (visit 4), 3 (visit 5), 4 (visit 6), 8±1 (visit 
7), 15±1 (visit 8) , 28±1 (visit 9), 56±2 (visit 10), 84+3 (visit 11), 98+1 (visit 12), 112+1 (visit 14), 
and 114+1 (visit 15), these standard blood draws will be collected from each participant to 
perform immunogenicity and humoral assays.   
 
Clinical safety assessments 
Blood samples for clinical safety laboratory evaluations (WBC, hemoglobin, platelet count, ALT 
(SGPT), creatinine) will be collected from each subject prior to administration of Tice® BCG at 
the screening visit (visit 1).  These parameters must meet protocol-defined eligibility criteria to 
be enrolled and receive Tice® BCG. Additional clinical safety laboratory evaluations may be 
deemed necessary during the study. 
 
Measuring BCG response 
 
Skin biopsy (via XX) 
Skin biopsies will be taken to quantify BCG bacteria. The ID challenge site will be biopsied on 
Days 3, 8, 15 and 56 (visits 5, 9, 10, and 12) after Tice® BCG administration.  A 4mm skin 
biopsy using the punch method will be taken at the ID challenge site. A local anesthetic 
injection will be given to numb the site. Gel foam will be used to close the biopsy area. A 
medically licensed research team member will perform the biopsy. 
 
The number of viable BCG bacteria will be measured on Day 3 from the skin biopsy by 1) 
quantitative CFU plating, 2) the numbers of genomes of BCG by quantitative real time PCR,  
and if sufficient material is available, by 3) additional assays may be performed to assess the 
integrity of the immune system. 
 
Blood samples (via venipuncture) 
• 
Serum will be collected on Days: 0, 1, 2, 3, 4, 8±1, 15±1, 28±1 56±2, and 84±3, scheduled 
visits will be collected for inflammatory markers (IL-2, IL-4, IL-5, IL-8, IL-10, INFγ, 1l-
12p70, 1l-17A, IL-1, IL-6 and TNF-α levels) using Cytokine BeadArray, and clinical testing 
for acute phase reactants (ESR and CRP). 


 
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• 
Blood will be collected for ELISPOT/ICS and additional assays to assess the integrity of 
the immune system on Days: 0, 8±1, 28±1, 56±2, 84±3, and 114±1.  Whole blood will be 
collected for RNA seq studies on Days: 0, 1, 2, 3, 4, 8±1, 15±1, 28±1, 56±2, and 84±3.  
Plasma obtained from the density gradients used to purify PBMCs will be collected and 
frozen on Days: 0, 1, 8±1, 15±1, 28±1, 56±2, 84±3, and 114±1.  Anticoagulated whole 
blood will be collected for dendritic cell (DC), monocyte and natural killer (NK) cell 
assays on Days: 1, 4, 8±1, 15±1, 28±1, 56±2, and 114±1.  
10.7 
Photographs 
 
Photographs of the ID challenge site will be taken at each follow-up visit after Tice® BCG administration 
starting on Day 4 through Day 56±2.  If the participant has any abnormality and does not have a well-
healed scar, or the site is open and/or draining, photographs will continue once/week from the day the 
abnormality was identified until it has resolved.  All subjects will have a final photograph of the ID 
challenge site on Day 114±1 or upon early termination. 
 
10.8 
PPD Skin Test 
 
2-Step PPD skin test will be performed and/or accessed on Days: 98±1, 100±1, 112±1 and 114±1.  If the 
first PPD skin test result is negative, then the second PPD skin test will be performed 2-4 weeks later. If 
either of the 2-Step PPD skin test results is positive, defined as ≥ 10 mm of induration, then the subject 
will have a QuantiFERON®-TB Gold Test performed to determine TB infection or BCG immunity. 
 
10.9 
Memory Aid eCRF Device and AE/SAE Recording Training 
 
Participants will be instructed on how to use the initial and on-going subject memory aids eCRF device 
and how to measure and record AEs/SAEs, concomitant medication and other health status information. 
11.0 STUDY SCHEDULE 
 
11.1 
Participant Procedures Schedule 
See Appendix B 
 
11.2 
Clinic Visit Schedule 
 
Screening visit: A single visit between Days -42 and -1 (visit 1) 
• 
Informed Consent 
• 
Review medical history,  
• 
Review concomitant medications, 
• 
Collect vital signs (oral temperature, pulse, blood pressure),  
• 
Collect height and weight (to calculate BMI), 
• 
General examination, 
• 
Collect urine for dipstick for protein < 1 and negative for glucose and chlamydia/gonorrhea test, 


 
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• 
Blood draw (29mls (6 teaspoons (tsp)) for testing HIV, hepatitis B surface antigen, antibody to 
hepatitis C virus, syphilis and QuantiFERON®-TB Gold Test.  Results of these screening tests must be 
negative, 
• 
Pregnancy tests for females of childbearing potential (must be negative for eligibility). 
o Serum pregnancy test at screening, 
o Urine pregnancy test within 24 hours prior to enrollment and receipt of Tice® BCG and INH. 
Day 0 (clinic visit 2) 
• 
Administration of BCG 2x106 cfu Tice® BCG: one intradermal injection in the deltoid region, 
* Following administration of Tice® BCG, intradermal (ID) site reactions will be assessed for at least 
30 minutes.  
• 
Blood draw via venipuncture for immunogenicity and mycobacteria assays: 114.5mls (8 tbs), 
• 
Participants will be instructed on how to use the initial and on-going subject memory aids eCRF 
device and how to measure and record AEs/SAEs prior to discharge from the clinic,  
• 
In addition, subjects will be instructed to keep the ID challenge site covered with a dressing (sterile 
gauze, etc.) and all dressings that have been used to cover the ID challenge site will be collected in 
sealable clear plastic bags. These materials will be collected from subjects at follow-up visits and 
properly disposed of as biohazard waste. Subjects will also be counseled to avoid any direct contact 
of drainage with an immunosuppressed person. 
Day 1 (clinic visit 3), Day 2 (clinic visit 4), and Day 3 (clinic visit 5) 
• 
Assess ID challenge site, 
• 
Day 3 (clinic visit 5) only: skin biopsy, 
• 
Review health status and AEs/SAEs that were recorded on the memory aid eCRF device,  
• 
Blood draws via venipuncture for immunogenicity and mycobacteria assays:  
o Day 1: 6.5mls (1.5 tsp),  
o Day 2: 6.5mls (1.5 tsp),  
o Day 3: 6.5mls (1.5 tsp), 
• 
Subjects will be reminded to record self-assessments on their redcap survey: 
o Oral temperature (optional)  
o Solicited local and systemic reactions recorded Days 1-114,  
o Unsolicited AEs/SAEs recorded Days 1-114, 
o Concomitant medications recorded Days 1-114. 
• 
Collection of used dressing/gauze. 
Days 4 (clinic visit 6), 5 (clinic visit 7), 6 (clinic visit 8), 8±1 (clinic visit 9), 15±1 (clinic visit 10), and 28 ± 1 
(clinic visit 11) 
• 
INH dosing days 4, 5, and 6 only: For the 5 participants assigned to Group 1, they will take INH: oral 
tablets of either three 100mg tablets (total 300mg) or one 300mg tablet for 3 days post BCG dosing, 
• 
Days 8±1 (clinic visit 9) and 15±1 (clinic visit 10) only: Repeat skin biopsy, 
• 
Assess ID challenge site,  
• 
Review health status and AEs/SAEs that were recorded on the memory aid eCRF device,  
• 
Review concomitant medications,  
• 
Assess for lymphadenopathy if indicated based on review of interim medical history and clinical 
assessment,  


 
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• 
Targeted physical exam and clinical assessment may be performed if indicated based on review of 
interim medical history, reactogenicity (as applicable), 
• 
Blood draws via venipuncture for immunogenicity and mycobacteria assays:  
o Day 4: 6.5mls (1.5 tsp), 
o Day 8±1: 74.5mls (5 tablespoons (tbs)), 
o Day 15±1: 56.5mls (4 tbs), 
Day 28±1: 94.5mls (6 tbs),  
• 
Collect used dressing/gauze,  
• 
Photograph of ID challenge site. 
Days 16-114±1  
• 
On-going participant self-evaluations that will be recorded on their memory aid eCRF device for 
pain, tenderness and drainage. Participants can record their temperature if taken.  
 
Days 56±2 (clinic visit 12) and 84±3 (clinic visit 13) 
• 
Day 56±2 (clinic visit 12) only: Repeat skin biopsy 
• 
Assess ID challenge site (if an abnormal BCG injection site is identified see Abnormal BCG Injection 
Site Procedures in section 11.3), 
• 
Review health status and AEs/SAEs that were recorded on the memory aid eCRF device,  
• 
Review concomitant medications,  
• 
Assessments for lymphadenopathy if indicated based on review of interim medical history and 
clinical assessment,  
• 
Targeted general exam and clinical assessment may be performed if indicated based on review of 
interim medical history, reactogenicity (as applicable), 
• 
Blood draws via venipuncture for immunogenicity and mycobacteria assays: 
o Day 56±2: 94.5mls (6 tbs) 
o Day 84±3: 94.5mls (6 tbs) 
• 
Collect used dressing/gauze, 
• 
Photograph of ID challenge site. 
Day 98±1 (clinic visit 14) 
• 
Assess ID challenge site, 
• 
Review health status and AEs/SAEs that were recorded on the memory aid eCRF device,  
• 
Review concomitant medications,  
• 
Blood draw via venipuncture for diagnostic assays: 4mls (1 tsp), 
• 
PPD skin test. 
Day 100±1 (clinic visit 15) 
• 
Assess ID challenge site, 
• 
Review health status and AEs/SAEs that were recorded on the memory aid eCRF device,  
• 
Review concomitant medications, 
• 
PPD skin test assessment. 
*Day 120/134: If the first PPD skin test result is negative, then the second PPD skin test will be 
performed 2-4 weeks later.  If either of the 2-Step PPD skin test results is positive, defined as ≥ 10 


 
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mm of induration, then the participant will have a QuantiFERON®-TB Gold Test performed to 
determine TB infection or BCG immunity. 
Days 112±1 (clinic visit 16) 
• 
Assess ID challenge site, 
• 
Review health status and AEs/SAEs that were recorded on the memory aid eCRF device,  
• 
Review concomitant medications, 
• 
Blood draw via venipuncture for diagnostic assays: 4mls (1 tsp), 
• 
PPD skin test. 
Day 114±1 (clinic visit 17) End of Study 
• 
General exam, 
• 
Assess ID challenge site, 
• 
Review health status and AEs/SAEs that were recorded on the memory aid eCRF device,  
• 
Review concomitant medications, 
• 
Blood draw via venipuncture for immunogenicity and humoral assays: 138mls (9.5 tbs),  
• 
Photograph of ID challenge site, 
• 
PPD skin test assessment, 
• 
Participants returns memory aid eCRF devices. 
 
11.3 
Abnormal BCG Injection Site Procedures 
 
The BCG injection site evaluations are scheduled from Day 0 to 84±3. However, signs of an abnormal 
injection site may present around Day 28. If an injection site does not have a well healed scar, or has an 
open and draining ulcer, then the subject will be asked to return to the clinic twice per/week from the 
time the abnormality is identified until it has resolved.  At each of these visits the following evaluations 
will be completed: assessments of the ID challenge site, assessments for lymphadenopathy if indicated 
based on review of interim medical history and clinical assessment, as well as review AEs/SAEs, 
concomitant medications, and health status, and collect and dispose of returned biohazard materials. 
Photographs will be taken once per/week from the day of the abnormal assessment until it has resolved.  
 
11.4 
Withdrawal Procedures 
 
Participants who discontinue from the study will be asked to complete visits 14-17. Visits 14-17 will 
occur using the same chronology as in the procedures schedule. If a female becomes pregnant, PBMC 
will not be collected on visit 17. However, PBMC will be collected from all other participants. If the 
participant refuses to complete visits 14-17, they will be asked to complete visit 17 which should occur 
at least 7 days, but < 30 days, after the dose of BCG. 
Procedures to be performed on visits 14-17: see above in section 11.2 Clinic Visit Schedule. 
12.0 LABORATORY TESTING AND ASSAY SCHEDULE 
 
See Appendix A for Laboratory Procedures Table. 


 
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13.0 SAFETY MONITORING COMMITTEE 
 
A Safety Monitoring Committee (SMC) will be convened periodically by Fred Hutch to review participant safety 
data, which may include solicited and unsolicited AEs/SAEs, concomitant medications, clinical laboratory values 
and any physical examinations. Interim statistical reports may be generated as deemed necessary. The SMC may 
receive data in aggregate and presented by group. As an outcome of each review, the SMC will make a 
recommendation at that time as to the advisability of proceeding with Tice® BCG administration, and to 
continue, modify or terminate the study. 
13.1 
Primary Endpoint 
• 
The rate of AE’s/SAE’s related to Tice® BCG administration reported at any point during the 
study, 
• 
Summary of the distribution of viable BCG bacteria from intradermal challenge sites at 4 
time points (approximately 3 days and 1, 2, and 4 weeks following Tice® BCG 
administration), as detected by quantitative CFU plating. The distribution will be 
summarized in terms of its central tendency (mean or GM) and its precision represented by 
the appropriate 95% confidence interval. 
13.2 
Secondary Endpoint  
• 
Quantitative bacterial 16S ribosomal DNA PCR, 
• 
Microbial viability testing pre-ribosomal RNA RT-PCR, 
• 
Humoral and cellular immune responses after BCG immunization. 
 
 
14.0 SUBJECT DISCONTINUATION OF ACTIVE TREATMENT 
 
Subjects may voluntarily withdraw their consent for study participation at any time and for any reason, without 
penalty. 
A subject may be withdrawn from the study for the following reasons:  
• 
The subject withdraws consent,  
• 
The subject develops a medical disease or condition, or any new clinical findings for which 
continued participation, in the opinion of the site principal investigator or appropriate sub-
investigator, would compromise the safety of the subject, would interfere with the subject's 
successful completion of this study, or would interfere with the evaluation of responses, 
• 
The subject fails to comply with the scheduled study visits,  
• 
The study is terminated, 
• 
Any reason that, in the opinion of the investigator, precludes the subject's continued 
participation in the study,  
• 
The subject becomes pregnant. 


 
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15.0 ASSESSMENT OF SAFETY 
15.1 
Specification of Safety Parameters 
 
Safety will be assessed by the frequency and severity of: 
1. Tice® BCG-related serious adverse events occurring throughout the course of the study, 
2. Solicited Adverse Events – reactogenicity events following Tice® BCG administration: 
a) Local reactions including pain, tenderness, erythema/redness, and induration/swelling at 
the injection site. 
b) Systemic reactions including fever, chills, malaise/fatigue, headache, night sweats, nausea, 
vomiting, diarrhea, rhinorrhea, cough, and wheezing or shortness of breath. 
3. Lesion characterized as erythematous macule, non-erythematous papule, erythematous papule, 
vesicle, pustule, ulcer, eschar/crust, healed, scar, or keloid, 
4. Lymphadenopathy,  
5. Clinical safety laboratory adverse events to include WBC, hemoglobin, and platelet count, creatinine 
and ALT (SGPT), 
6. Unsolicited Adverse Events. 
a) Non-serious adverse events occurring in the 56 days following Tice® BCG administration. 
15.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters 
 
15.2.1 Adverse Events 
Adverse Event (AE): 
International Conference on Harmonisation (ICH) E6 defines an AE as any untoward medical 
occurrence in a patient or clinical investigation subject administered a pharmaceutical product 
regardless of its causal relationship to the study treatment. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product. The 
occurrence of an AE may come to the attention of study personnel during study visits and 
interviews of a study treatment recipient presenting for medical care, or upon review by a study 
monitor. 
 
All AEs, including local and systemic reactions, not meeting the protocol-defined criteria for 
serious adverse events (SAEs) should be captured on the appropriate data collection form and 
eCRF. Information to be collected for unsolicited AEs includes event description, date of onset, 
study clinician’s assessment of severity and relationship to study product and alternate etiology 
(if not related to study product) (assessed only by those with the training and authority to make 
a diagnosis), date of resolution/stabilization of the event, seriousness and 
outcome. All AEs occurring while on study will be documented appropriately regardless of 
relationship. All AEs will be followed to adequate resolution. 
 
Any medical condition that is present at the time that the subject is screened should be 
considered as baseline and not reported as an AE. However, if the severity of any pre-existing 
medical condition increases at any time during the study, it should be recorded as an AE. 
 


 
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All AEs must be graded for severity and assessed for relationship to study product (see 
definitions below). Adverse events characterized as intermittent require documentation of 
onset and duration of each episode. The start and stop date of each reported AE will be 
recorded on the appropriate data collection form and eCRF. 
 
Severity of Event:  
All AEs will be assessed by the site principal investigator or appropriate sub-investigator using 
the protocol-defined grading system (Section 15.2.2-15.2.3). For events not included in the 
protocol defined grading system, the following guidelines will be used to quantify severity: 
• 
Mild (Grade 1): events require minimal or no treatment and do not interfere 
with the patient’s daily activities. 
• 
Moderate (Grade 2): events result in a low level of inconvenience or concern 
with the therapeutic measures. Moderate events may cause some interference 
with functioning and daily activities. 
• 
Severe (Grade 3): events interrupt a patient’s usual daily activity and may 
require systemic drug therapy or other treatment. Severe events are usually 
incapacitating. 
Relationship to Study Products:  
The study clinician’s assessment of the relationship of an AE’s relationship to study product is 
part of the documentation process, but it is not a factor in determining what is or is not 
reported in the study. If there is any doubt as to whether a clinical observation is an AE, the 
event should be reported. All AEs must have their relationship to study product assessed using 
the following terms: related or not related. In a clinical trial, the study product must always be 
suspect. To help assess, the following guidelines are used: 
• 
Related: There is a reasonable possibility that the study product caused the 
adverse event. Reasonable possibility means that there is evidence to suggest a 
causal relationship between the study product and the adverse event. 
• 
Not Related: There is not a reasonable possibility that the administration of the 
study product caused the event. 
15.2.2 Reactogenicity 
 
Reactogenicity events are AEs that are known to occur with Tice® BCG. Reactogenicity events 
will be analyzed according to the following grading scales: 
 
Table 1: Reactogenicity Events Grading Scales 
 
Local Reaction 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Pain – experienced 
without touching 
the injection site 
Subject is aware of pain 
but it does not interfere 
with daily activity and no 
pain medication is taken 
Subject is aware of pain; 
there is interference 
with daily activity or it 
requires use of pain 
medication 
Subject is aware of pain 
and it prevents daily 
activity 
Tenderness – hurts 
only when injection 
site is touched 
The area immediately 
surrounding the 
injection site hurts only 
when touched and it 
does not 
The area immediately 
surrounding the 
injection site hurts when 
touched and it interferes 
with daily activity 
The area immediately 
surrounding the 
injection site hurts when 
touched and it prevents 
daily activity 


 
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interfere with daily 
activity 
Erythema/Redness* Does not interfere with 
activity 
Interferes with activity 
Prevents daily activity 
Induration/ 
Swelling* 
Does not interfere with 
activity 
Interferes with activity 
Prevents daily activity 
Drainage 
Continuous use of 
bandage cover or less 
than 2, 2x2 gauze 
pads/day 
Needs 2-4, 2x2 gauze 
pads/day 
Needs more than 4, 2x2 
gauze pads/day 
* Will be also measured in mm but size will not be used as halting criteria. 
 
Erythema/redness, induration/swelling and lesion as analyzed by measurement will be graded as 
follows: 
 
Table 2: Erythema/Redness, Induration/Swelling and Lesion Measurement Grading Scales 
 
 
Small 
Medium 
Large 
Total 
Erythema/Redness* 
<20 mm 
20-50 mm 
>50 mm 
Maximum Diameter 
of 
Induration/Swelling* 
<20 mm 
20-50 mm 
>50 mm 
Central Lesion 
<10 mm 
10-30 mm 
>30 mm 
* Measurement will not be used as halting criteria 
 
 
Table 3: Reactogenicity Events Grading Scales (Continued) 
 
Systemic 
(Subjective) 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Chills 
No interference with 
activity 
Some interference with 
activity 
Significant interference, 
prevents daily activity 
Malaise/Fatigue 
No interference with 
activity 
Some interference with 
activity 
Significant interference, 
prevents daily activity 
Headache 
No interference with 
activity 
Some interference with 
activity 
Significant interference, 
prevents daily activity 
Night Sweats 
No interference with 
activity 
Some interference with 
activity 
Significant interference, 
prevents daily activity 
Nausea 
No interference with 
activity 
Some interference with 
activity 
Significant interference, 
prevents daily activity 
Vomiting 
No interference with 
activity 
Some interference with 
activity 
Significant interference, 
prevents daily activity 
Diarrhea 
No interference with 
activity 
Some interference with 
activity 
Significant interference, 
prevents daily activity 
Rhinorrhea 
No interference with 
activity 
Some interference with 
activity 
Significant interference, 
prevents daily activity 
Cough 
No interference with 
activity 
Some interference with 
activity 
Significant interference, 
prevents daily activity 


 
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Wheezing/Shortness 
of Breath 
No interference with 
activity 
Some interference with 
activity 
Significant interference, 
prevents daily activity 
 
Vital signs# (oral temperature, pulse and blood pressure) will be analyzed according to the following 
grading scales: 
 
 
Table 4: Vital Signs Grading Scales 
 
Systemic (Quantitative) 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Fever* 
38.0-38.4°C 
100.4-101.1°F 
38.5-38.9°C 
101.2-102°F 
≥39°C 
≥102.1°F 
Tachycardia - beats per 
minute† 
101-115 
116-130 
>130 
Bradycardia - beats per 
minute 
45-49 
40-44 
<40 
Hypertension (systolic) 
mm Hg 
141-150 
151-155 
>155 
Hypertension (diastolic) 
mm Hg 
91-95 
96-100 
>100 
Hypotension (systolic) 
mm Hg 
85-89 
80-84 
<80 
Hypotension (diastolic) 
mm Hg 
45-49 
40-44 
<40 
# Vital Signs assessed at Day 1 will be considered as baseline. 
* Oral temperature, no recent hot or cold beverages or smoking. Note: A fever can be considered not 
related to the study product if an alternative etiology can be documented and it is confirmed to be not 
related to the study product by the Independent Safety Monitor at the site. 
† Subject at rest. 
 
15.2.3 Additional Adverse Event Characterization and Severity Grading 
 
Lesions at the ID challenge site will be characterized by the study site staff as follows: 
1. Erythematous Macule: flat red spot. 
2. Non-Erythematous Papule: a small, circumscribed, non-erythematous, palpable elevation in 
the skin. 
3. Erythematous Papule: a small, circumscribed, erythematous, palpable elevation in the skin. 
4. Vesicle: clear fluid filled papule. 
5. Pustule: cloudy, purulent fluid filled papule. 
6. Ulcer: an open lesion on the surface of the skin caused by superficial loss of tissue, often 
attended by the formation of pus. 
7. Eschar/Crust: a lesion with an erythematous base and a central scab (a coagulation product 
of blood, serum, pus, or a combination of two or more of these). 
8. Healed: previously observed lesion that has dried up without any persistent induration, 
ulcer, or eschar. Redness under an area of previous eschar formation seen after the eschar 


 
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has fallen off during the healing process would not be considered active erythema, but 
instead would be considered evidence of a healed lesion. 
9. Scar: replacement of normal skin with fibrous tissue (other than keloid formation). 
10. Keloid: nodular scar. 
Severity Grading for Lymphadenopathy 
The site principal investigator or appropriate sub-investigator licensed to make medical 
diagnoses will assess the severity of axillary, cervical, and epitrochlear lymphadenopathy 
bilaterally by applying the grading scale in the following table: 
 
Table 5: Severity Grading for Lymphadenopathy 
 
Grade 
Definition 
Grade 0 (none) 
No palpable nodes, or all nodes < 1 cm (pea-sized), 
mobile, and nontender. 
Grade 1 (mild) 
At least one node ≥ 1 cm (pea-sized) but < 2.5 cm 
(cherry-sized), but mobile and non- tender or 
tender only with firm pressure. 
Grade 2 (moderate) 
At least one node ≥ 2.5 cm (cherry-sized) or tender 
to light touch or spontaneously reported as 
painful, but not causing significant limitation of 
normal everyday activities. 
 
Grade 3 (severe) 
At least one node that is tender to light touch or 
spontaneously reported as painful AND causing 
significant limitation of normal everyday activities. 
Any one of palpable fluctuance or heat, fixation to 
underlying tissues, or visible erythema. 
 
 
Severity Grading for Clinical Safety Laboratory Adverse Events 
 
Table 6: Severity Grading for Clinical Safety Laboratory Adverse Events - Hematology 
Hematology 
Mild  
(Grade 1) 
Moderate 
 (Grade 2) 
Severe  
(Grade 3) 
WBC (Increase) 103/UL 
10.6 – 15.0 
15.1 – 20.0 
>20.0 
WBC (Decrease) 103/UL 
2.5 – 3.9 
1.5 – 2.4 
<1.5 
HgB (Female) g/dL 
10.1 – 11.4 
8.5 – 10 
<8.5 
HgB (Male) g/dL 
11.0 – 12.4 
9.5 – 10.9 
<9.5 
Platelets (Decrease) 103/UL 
125 – 139 
100 – 124 
<100 
 
Table 7: Severity Grading for Clinical Safety Laboratory Adverse Events - Chemistries 
 
Chemistries 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Creatinine mg/dL 
1.31 – 1.70 
1.71 – 2.00 
>2.00 
ALT (SGPT) (Female) IU/L 
41 – 100 
101 – 200 
>200 


 
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ALT (SGPT) (Male) IU/L 
56 – 138 
139 – 275 
>275 
 
15.2.4 Serious Adverse Events 
 
Serious Adverse Event (SAE):  
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the site principal investigator or sponsor, it results in any of the following outcomes: 
 
• 
Death. 
• 
A life-threatening adverse event*. 
• 
Inpatient hospitalization or prolongation of existing hospitalization. 
• 
A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions, or 
• 
A congenital anomaly or birth defect. 
• 
Important medical events that may not result in death, be life threatening, or 
require hospitalization, may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this 
definition. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
 
* Life-threatening adverse event. An adverse event is considered “life-
threatening” if, in the view of either the investigator or sponsor, its occurrence 
places the patient or subject at immediate risk of death. It does not include an 
adverse event that, had it occurred in a more severe form, might have caused 
death. 
 
All SAEs will be: 
• 
Assessed for severity and relationship to study product and alternate etiology (if not 
related to study product) by a licensed study physician. 
• 
Recorded on the appropriate SAE form and eCRF. 
• 
Followed through resolution or stabilization by a study clinician licensed to make 
medical diagnoses. 
• 
Reviewed and evaluated by the SMC periodically. Related and unexpected SAEs will 
also be reviewed by the IRB. 
 
15.2.5 Procedures to be Followed in the Event of Abnormal Laboratory Test Values or Abnormal Clinical 
Findings 
 
The site principal investigator is responsible for reporting all AEs/SAEs that are observed or 
reported during the study, regardless of their relationship to study product. AEs/SAEs, abnormal 
laboratory test values or abnormal clinical findings will be documented, reported and followed 
appropriately. Adverse events will be assessed through approximately 8 weeks following Tice® 
BCG administration. Serious adverse events will be assessed for the study duration. 
 
15.3 
Reporting Procedures 
 


 
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• 
Document AEs from Visit 02 (Day 0) through Visit 10 (Day 56±2). 
• 
Document SAEs from Visit 02 (Day 0) through Visit 15 (Day 114±1). 
 
16.0 DATA AND SAFETY MONITORING PLAN 
 
The Data Safety Monitoring Plan for this study includes the Safety Monitoring Committee (SMC) noted in Section 
13.0 above and the safety assessments noted in Section 15.0.  As this is an observational study using licensed 
products consistent with product labeling, external monitoring and a chartered committee with independent 
representation is not required.  
 
The protocol will be reviewed at least annually and as needed by the Institutional Review Board (IRB). The IRB 
reviews the study progress and safety information to assess continued acceptability of the risk-benefit ratio for 
human subjects.  Approval of committees as applicable is necessary to continue the study. The study 
investigators will monitor for adverse events and will refer participants for local medical care if necessary. 
 
 
17.0 DATA MANAGEMENT/CONFIDENTIALITY 
 
The site principal investigator is responsible to ensure the accuracy, completeness, legibility, and timeliness of 
the data reported. 
 
Data collection forms will be derived from the eCRF and provided by the Seattle MCTC to record and maintain 
data for each subject enrolled in the study.  All data collection forms should be completed in a neat, legible 
manner to ensure accurate interpretation of data.  Black or blue ink is required to ensure clarity of reproduced 
copies.  When making a change or correction, cross out the original entry with a single line and initial and date 
the change.  Do not erase, overwrite, or use correction fluid or tape on the original.   
 
Data reported in the eCRF should be consistent with all source documents or the discrepancies should be 
explained. 
 
17.1 
Data Management Responsibilities 
 
All data collection forms must be reviewed by the clinical team and data entry staff, who will ensure that 
they are accurate and complete.  Adverse events must be graded, assessed for severity and causality, 
and reviewed by the site principal investigator or designee.  Data collection is the responsibility of the 
clinical trial staff at the site under the supervision of the site principal investigator.  During the study, the 
investigator must maintain complete and accurate documentation for the study. 
 
The Seattle MCTC will be responsible for data management, quality review, analysis, and reporting of 
the study data.   
17.2 
Data Capture Methods 
 
Clinical data (including AE/SAEs, concomitant medications, physical assessments, and reactogenicity 
data) will be entered into the Seattle MCTC’s Clinical Conductor® web-based 21 CFR Part 11-compliant 
Clinical Trial Management System. Clinical data will primarily be entered directly from the data 
collection forms.    
 


 
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17.3 
Types of Data 
 
Data for this study will include safety, laboratory (clinical and research), and outcome measures (e.g., 
reactogenicity and immunogenicity). 
17.4 
Study Records Retention 
 
Records and documents pertaining to the conduct of this study, including eCRFs, data collection forms, 
consent forms, laboratory test results, and medication inventory records, must be retained by the 
investigator indefinitely that is the policy of Fred Hutch.  
 
The principal investigators will ensure that this trial is conducted in full conformity with principles of the 
Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research 
(National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research [April 
18, 1979]) and codified in 45 CFR 46, 21 CFR 50 and 21 CFR 56, as applicable. The PI will also ensure 
conformity with ICH E6 Good Clinical Practice, and applicable federal regulations, guidance, and 
guidelines for Good Clinical Practice and Clinical Trials with humans. 
 
 
 
17.5 
Quality Control 
 
The Principal Investigator will provide direct access to all protocol-related source data/source documents, 
and reports for the purpose of monitoring and auditing and inspection by local and regulatory 
authorities. The Principal Investigator will ensure all study personnel are appropriately trained and 
current documentations are maintained on site. All personnel involved in the conduct of this study have 
completed Human Subjects Protection and ICH GCP Training. The study staff will implement quality 
control procedures beginning with the data entry system; database quality control checks will be 
implemented. Any missing data or data anomalies will be updated for clarification and resolution. 
 
 
18.0 STATISTICAL CONSIDERATIONS  
 
18.1 Sample Size and Power for Outcome Measures 
 
The study is designed to demonstrate the safety, tolerability and feasibility of using intradermal BCG as a model 
for the evaluation of TB drugs. With 5 participants in each arm and a low number of AE/SAEs expected, the study 
is not powered for direct comparison of the two study groups. Instead, reactogenicity, AEs and SAEs will be 
presented with descriptive statistics summarizing each group. Interpretation of differences will rely heavily upon 
clinical judgment. In the rare event that there is a high frequency safety event of at least 25% in one of the 
groups there will be a 76% chance of observing at least one event and a 37% chance of observing 2 events in the 
relevant group. All participants are expected to provide safety data. 
 
True event 
rate (%) 
Pr(0/5) 
Pr(≥1/5) 
Pr(≥2/5) 
5 
0.77 
0.23 
0.02 


 
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10 
0.59 
0.41 
0.08 
15 
0.44 
0.56 
0.16 
20 
0.33 
0.67 
0.26 
25 
0.24 
0.76 
0.37 
 
It is expected that BCG will be detectable in all skin biopsies provided 4 days after BCG immunization and that 
the 3 day INH treatment will eliminate detectable BCG in all participants. Therefore, even with only 5 
participants per group there will be power to detect a difference in the number of participants with detectable 
BCG either by qPCR or culture. The plot below shows that a low rate of BCG detection in the treatment arm 
(<0.05) and a high rate of detection in the control arm (>0.95) there will be >90% power to detect a difference 
between the groups (Fisher’s exact test, two-sided α=0.05). Power will be diminished if the actual detection 
rates are shifted toward 0.5 for either group. It is assumed all participants will contribute data for this objective. 
 
 
 
Descriptive statistical analyses will be conducted with the data generated from the Secondary Endpoints. The 
analyses will generate hypotheses to be tested in future studies. 
 
18.2 Randomization 
The participants assignment to either Group 1 and 2 will be computer generated. 
18.3 
Ethnic and Gender Distribution Chart 
The target population reflects the Seattle King County community. Projected Target Accrual 
 
ETHNIC AND GENDER DISTRIBUTION CHART 
 
TARGETED / PLANNED ENROLLMENT: Number of Subjects 
Ethnic Category 
 
Sex / Gender 
 
Females 
Males 
Total 
Hispanic or Latino 
0 
0 
0 


 
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Not Hispanic or Latino 
5 
5 
10 
Ethnic Category Total of All Subjects* 
5 
5 
10 
 
Racial Categories 
 
 
American Indian / Alaska Native 
0 
0 
0 
Asian 
1 
1 
2 
Native Hawaiian or Other Pacific Islander 
0 
0 
0 
Black or African American 
0 
0 
0 
White 
4 
4 
8 
More Than One Race 
0 
0 
0 
Racial Categories: Total of All Subjects* 
5 
5 
10 
19.0 ETHICS/PROTECTION OF HUMAN SUBJECTS 
 
19.1 
Institutional Review Board 
 
The participating institution will provide for the review and approval of this protocol and the associated 
informed consent documents and recruitment material to the Fred Hutch IRB, registered with OHRP.  
Any amendments to the protocol or consent materials will also be IRB approved before they are placed 
into use. 
 
19.2 
Informed Consent Process 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continuing throughout the individual’s study participation.  Extensive discussion of risks and 
possible benefits of participation in this study will be provided to the subjects and their families.  
Consent forms describing in detail the study procedures and risks are given to the subject and written 
documentation of informed consent is required prior to enrolling in the study.  Consent forms will be IRB 
approved and the subject will be asked to read and review the document. Upon reviewing the 
document, the investigator will explain the research study to the subject and answer any questions that 
may arise.  The subjects will sign the informed consent document prior to being enrolled in the study.  
The subjects should have the opportunity to discuss the study with their surrogates or think about it 
prior to agreeing to participate.  The subjects may withdraw consent at any time throughout the course 
of the study.  A copy of the informed consent document will be given to the subjects for their records.  
The rights and welfare of the subjects will be protected by emphasizing to them that their medical care 
will not be adversely affected if they decline to participate in this study. 
 
19.3 
Exclusion of Minors 
 
Minors under the age of 18 are excluded from this study as there are no benefits for participation in the 
study.  
 


 
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19.4 
Subject Confidentiality 
 
Each subject will be assigned a unique subject number to protect subject confidentiality. Data collected 
for this protocol will be stored in a password-protected a database stored on secured servers or on 
coded paper documents in locked filing cabinets at the sponsor site. All non-clinical specimens, 
evaluation forms, reports, and other records that leave the site will be identified only by a coded 
number. Only trained study staff approved by the principal investigator will have access to subject data. 
In the even that a staff member leaves the center, subject data access will be revoked.   
 
19.5 
Future Use of Stored Specimens and Data 
Data collected for this study will be analyzed and stored on secured, password-protected servers at 
sponsor site. After the study is completed, the coded data may be used by other researchers including 
those outside of the study. Permission for use of coded, deidentified data collected for the study for 
future research will be included in the informed consent.  
 
With the participant’s approval and as approved by Fred Hutch IRB, de-identified biological samples will 
be stored as part of a repository so it can later could be used to research the role of BCG in human 
challenge models and other inflammatory processes. The repository will also be provided with a code-
link that will allow linking the biological specimens with the phenotypic data from each participant, 
maintaining the blinding of the identity of the participant. 
 
During the conduct of the study, an individual participant can choose to withdraw consent to have 
biological specimens stored for future research. However, withdrawal of consent with regard to 
biological sample storage may not be possible after the study is completed. 
20.0 PUBLICATION POLICY 
 
All investigators funded by the NIH must submit or have submitted for them to the National Library of 
Medicine’s PubMed Central (http://www.ncbi.nlm.nih.gov/pmc/) an electronic version of their final, peer-
reviewed manuscripts upon acceptance for publication, to be made publicly available no later than 12 months 
after the official date of publication. The NIH Public Access Policy ensures the public has access to the published 
results of NIH funded research. It requires investigators to submit final peer-reviewed journal manuscripts that 
arise from NIH funds to the digital archive PubMed Central upon acceptance for publication. Further, the policy 
stipulates that these papers must be accessible to the public on PubMed Central no later than 12 months after 
publication. 
 
As of January 2018, all clinical trials supported by the NIH must be registered on ClinicalTrials.gov, no later than 
21 days after the enrollment of the first subject. Results of all clinical trials supported by the NIH, generally, need 
to be submitted no later than 12 months following the primary completion date. A delay of up to 2 years is 
available for trials that meet certain criteria and have applied for certification of delayed posting. 
21.0  REFERENCES 
 
1. World Health Organization (WHO). (2019 Oct 17). Global tuberculosis report 2019. Retrieved from 
https://www.who.int/tb/publications/global_report/en 


 
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2. Kyu HH, Maddison ER, Henry NJ, Ledesma JR, Wiens KE,… Murray CJL. Global, regional, and national 
burden of tuberculosis, 1990-2016: results from the Global Burden of Diseases, Injuries, and Risk Factors 
2016 Study. Lancet Infect Dis. 2018 Dec;18(12):1329-1349. PMID 30507459. 
3. MacNeil A, Glaziou P, Sismanidis C, Maloney S, Floyd K. Global Epidemiology of Tuberculosis and 
Progress Toward Achieving Global Targets - 2017. MMWR Morb Mortal Wkly Rep. 2019 Mar 
22;68(11):263-266. PMID 30897077. 
4. Floyd K, Glaziou P, Houben RMGJ, Sumner T, White RG, Raviglione M. Global tuberculosis targets and 
milestones set for 2016-2035: definition and rationale. Int J Tuberc Lung Dis. 2018 Jul 1;22(7):723-730. 
PMID 29914597. 
5. Sable SB, Posey JE, Scriba TJ. Tuberculosis Vaccine Development: Progress in Clinical Evaluation. Clin 
Microbiol Rev. 2019 Oct 30;33, Print 2019 Dec 18. PMID 31666281. 
6.  Van Der Meeren O, Hatherill M, Nduba V, Wilkinson RJ, Muyoyeta M,…Tait DR. Phase 2b Controlled 
Trial of M72/AS01E Vaccine to Prevent Tuberculosis. N Engl J Med. 2018 Oct 25;379(17):1621-1634. 
PMID 30280651. 
7. Hawn TR, Day TA, Scriba TJ, Hatherill M, Hanekom WA,… Self SG. Tuberculosis vaccines and prevention 
of infection. Microbiol Mol Biol Rev. 2014 Dec;78(4):650-71. PMID 25428938. 
8. Nemes E, Geldenhuys H, Rozot V, Rutkowski KT, Ratangee F,… C-040-404 Study Team. Prevention of M. 
tuberculosis Infection with H4:IC31 Vaccine or BCG Revaccination. N Engl J Med. 2018 Jul 12;379(2):138-
149. PMID 29996082. 
9. Imperial MZ, Nahid P, Phillips PPJ, Davies GR, Fielding K,…Savic RM. Publisher Correction: A patient-level 
pooled analysis of treatment-shortening regimens for drug-susceptible pulmonary tuberculosis. Nat 
Med. 2019 Jan;25(1):190. PMID 30429542. 
10. Mdluli K, Kaneko T, Upton A. The tuberculosis drug discovery and development pipeline and emerging 
drug targets. Cold Spring Harb Perspect Med. 2015 Jan 29;5(6). PMC 4448709. 
11. Jindani A, Aber VR, Edwards EA. The early bactericidal activity of drugs in patients with pulmonary 
tuberculosis. Am Rev Respir Dis. 1980 Jun;121(6):939-49. PMID 6774638. 
12. Bonnett LJ, Ken-Dror G, Koh GCKW, Davies GR. Comparing the Efficacy of Drug Regimens for Pulmonary 
Tuberculosis: Meta-analysis of Endpoints in Early-Phase Clinical Trials. Clin Infect Dis. 2017 Jul 
1;65(1):46-54. PMID 28402396. 
13. Field SK. Bedaquiline for the treatment of multidrug-resistant tuberculosis: great promise or 
disappointment? Ther Adv Chronic Dis. 2015 Jul;6(4):170-84. PMID 26137207. 
14. Minassian AM1, Ronan EO, Poyntz H, McShane H. Preclinical development of an in vivo BCG challenge 
model for testing candidate TB vaccine efficacy. PLoS One. 2011;6(5): Epub 2011 May 24. PMID 
21629699. 
15. Harris SA, White A, Stockdale L, Tanner R, Sibley L,…,Sharpe S. Development of a non-human primate 
BCG infection model for the evaluation of candidate tuberculosis vaccines. Tuberculosis (Edinb). 2018 
Jan;108:99-105. PMID 29523335. 
16. Tyagi S, Ammerman NC, Li SY, Adamson J, Converse PJ,… Grosset JH. Clofazimine shortens the duration 
of the first-line treatment regimen for experimental chemotherapy of tuberculosis. Proc Natl Acad Sci U 
S A. 2015 Jan 20;112(3):869-74. PMID 25561537. 
17. Ahmad Z, Klinkenberg LG, Pinn ML, Fraig MM, Peloquin CA... Karakousis PC. Biphasic kill curve of 
isoniazid reveals the presence of drug-tolerant, not drug-resistant, Mycobacterium tuberculosis in the 
guinea pig. J Infect Dis. 2009 Oct 1;200(7):1136-43. PMID 19686043. 


 
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18. Sridevi JP, Anantaraju HS, Kulkarni P, Yogeeswari P, Sriram D. Optimization and validation of 
Mycobacterium marinum-induced adult zebrafish model for evaluation of oral anti-tuberculosis drugs. 
Int J Mycobacteriol. 2014 Dec;3(4):259-67. PMID 26786625. 
19. Lin PL1, Coleman T2, Carney JP, Lopresti BJ, Tomko J,…Flynn JL. Radiologic Responses in Cynomolgus 
Macaques for Assessing Tuberculosis Chemotherapy Regimens. Antimicrob Agents Chemother. 2013 
Sep;57(9):4237-4244. PMID 23796926. 
20. Dhillon J, Mitchison DA. Influence of BCG-induced immunity on the bactericidal activity of isoniazid and 
rifampicin in experimental tuberculosis of the mouse and guinea-pig. Br J Exp Pathol. 1989 
Feb;70(1):103-10. PMID 2493801. 
21. Shang S, Shanley CA, Caraway ML, Orme EA, Henao-Tamayo M,…Basaraba RJ. Drug treatment combined 
with BCG vaccination reduces disease reactivation in guinea pigs infected with Mycobacterium 
tuberculosis. Vaccine. 2012 Feb 21;30(9):1572-82. PMID 22244979. 
22. Akselband Y, Cabral C, Shapiro DS, McGrath P. Rapid mycobacteria drug susceptibility testing using Gel 
Microdrop (GMD) Growth Assay and flow cytometry. J Microbiol Methods. 2005 Aug;62(2):181-97. 
PMID 16009276. 
23. Weigel KM, Jones KL, Do JS, Melton Witt J, Chung JH, Valcke C, Cangelosi GA. Molecular viability testing 
of bacterial pathogens from a complex human sample matrix. PLoS One. 2013;8(1). PMID 23365682. 
24. Do JS, Weigel KM, Meschke JS, Cangelosi GA. Biosynthetic enhancement of the detection of bacteria by 
the polymerase chain reaction. PLoS One. 2014 Jan 17;9(1): eCollection 2014. PMID 24466092. 
25. Minassian AM, Satti I, Poulton ID, Meyer J, Hill AV, McShane H. A human challenge model for 
Mycobacterium tuberculosis using Mycobacterium bovis bacille Calmette-Guerin. J Infect Dis. 2012 Apr 
1;205(7):1035-42. PMID 22396610. 
26. Harris SA, Meyer J, Satti I, Marsay L, Poulton ID,… McShane H. Evaluation of a human BCG challenge 
model to assess antimycobacterial immunity induced by BCG and a candidate tuberculosis vaccine, 
MVA85A, alone and in combination. J Infect Dis. 2014 Apr 15;209(8):1259-68. PMID 24273174. 
27. Minhinnick A, Harris S, Wilkie M, Peter J, Stockdale L, … McShane H. Optimization of a Human Bacille 
Calmette-Guérin Challenge Model: A Tool to Evaluate Antimycobacterial Immunity. J Infect Dis. 2016 
Mar 1;213(5):824-30. PMID 26450421. 
28. Hoft DF, Leonardi C, Milligan T, Nahass GT, Kemp B, … Carey M. Clinical reactogenicity of intradermal 
bacille Calmette-Guérin vaccination. Clin Infect Dis. 1999 Apr;28(4):785-90. PMID 10825039. 
29. Blazevic A, Xia M, Turan A, Tennant J, Hoft DF. Pilot studies of a human BCG challenge model. 
Tuberculosis (Edinb). 2017 Jul;105:108-112. PMID 28610781. 
 
 
 


 
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22.0 APPENDICES 
 


 
Kublin_Phase I human BCG challenge trial         
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Version: 03/29/2022 
 
 
Appendix A: Lab Procedures Table 
 
 
 
Visit:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Day:
D0
D1
D2
D3
D4
D5
D6
D8
D15
D28
D56
D84
D98
D100
D112
D114
Week:
W0
W0
W0
W0
W0
W0
W0
W1
W2
W4
W8
W12
W14
W14
W16
W16
BCG
—
—
Biopsy
INH
INH
INH
—
—
—
—
—
—
—
—
—
Procedure
Ship to
Tube
Tube size 
(vol. 
capacity)
BLOOD COLLECTION
Screening or diagnostic assays
     IGRA
Local Lab Local Lab
EDTA
5mL
4
—
—
—
—
—
—
—
—
—
—
—
—
4
—
4
—
12
     Screening HIV test
Local Lab Local Lab
EDTA
5mL
5
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
5
     HBsAg/anti-HCV
Local Lab Local Lab
SST
5mL
5
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
5
     PPD
?
?
—
Injection
—
—
—
—
—
—
—
—
—
—
—
—
—
X
X
X
X
0
Safety labs
     CBC/ Diff/ platelets
Local lab
Local lab
EDTA
5mL
5
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
5
     Chemistry panel5
Local lab
Local lab
SST
5mL
5
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
5
STI Serology
     Syphilis
Local Lab Local Lab
SST
5mL
5
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
5
Immunogenicity & Mycobacteria assays
     HLA host genetics
CSR
FHCRC
ACD
8.5mL
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
0
     Cellular assays
—
—
—
—
          ICS/ELISPOT / additional tests
CSR
FHCRC
ACD
8.5mL
—
51
—
—
—
—
—
—
51
—
51
51
51
—
—
—
51
306
     Humoral assays
           Ab Assays / additional tests
CSR
?
SST
8.5mL
—
17
—
—
—
—
—
—
17
—
17
17
17
—
—
—
17
102
     Mycobacteria assays
          BCG PCR
CSR
UW
—
—
—
—
—
—
X
—
—
X
X
X
—
—
—
—
—
—
0
          BCG Invitro Culture
CSR
CIDR
—
Biopsy
—
—
—
—
—
X
—
—
X
X
X
—
—
—
—
—
—
0
     Innate Immunity 
          Serum Cytokines 
CSR
?
SST
3.5mL
—
3.5
3.5
3.5
3.5
3.5
—
—
3.5
3.5
3.5
3.5
3.5
—
—
—
—
35
          Whole Blood Gene Expression
CSR
?
Tempus
3mL
—
3
3
3
3
3
—
—
3
3
3
3
3
—
—
—
—
30
STORAGE
     PBMC
CSR
FHCRC
ACD
8.5mL
—
40
—
—
—
—
—
—
—
50
20
20
20
—
—
—
70
220
Visit total
29
114.5
6.5
6.5
6.5
6.5
74.5
56.5
94.5
94.5
94.5
4
0
4
138
730
56-Day total
29
143.5
150
156.5
163
169.5
244
300.5
395
489.5
283.5
193
193
197
240.5
URINE COLLECTION
      Urinalysis
Local lab
Local lab
X
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
      Pregnancy test
Local lab
Local lab
X
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
      Chlamydia/Gonorrhea
Local lab
Local lab
X
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
Tube volume (mL)
Total
Screening 
visit


 
 
Kublin_Phase I human BCG challenge trial         
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Version: 03/29/2022 
 
Appendix B: Participant Procedures Table
 
 * Only if applicable due to medical history and clinical assessment 
 
 
O = microbiology 
 
 
X = immunology 
 
 
S = swab 
Clinic Visit
1 
(Screening 
Visit)
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Day
-42 to -1
0
1
2
3
4
5
6
8+1
15+1
28+1
56+2
84+3
98+1
100+1
112+1
114+1
Week
1
2
4
8
12
Agents
BCG
INH
INH
INH
Informed consent
X
Medical history
X
Height, weight: BMI
X
Vitals (pulse, blood 
pressure)
X
Urine collection
X
Pregnancy test (blood)
X
Pregnancy test (urine)
24 hr before 
to BCG dose
General exam and 
Clinical assessment
X
X*
X*
X*
X*
X*
X*
X
Lymphadenopathy 
assessment
X*
X*
X*
X*
X*
X*
BCG injection site 
evaluation
X
X
X
X
X
X
X
X
X
X
X
X
Abnormal BCG injection site 
Abnormal BCG injection site 
clinic visits
Abnormal BCG injection site 
photos
Health status and 
AE/SAE review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant med review
X
X
X
X
X
X
X
X
X
X
X
X
X
Oral temperature 
reporting
X
AE/SAE reporting 
Concomitant medication 
reporting
ID site pain, tenderness, 
drainage reporting
Blood draw
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Skin biopsy
O/S
X/S
O/S
X/S
Photographs of ID site
X
X
X
X
X
X
X
PPD skin test
X 
X
X 
X
Dressing/guaze 
collection
X
X
X
X
X
X
X
X
X
* Only if applicable due to medical history and clinical assessment
O = microbiology
X = immunology
S = swab
Days 1 - 112 (recorded on Memory Aid eCRF device)
Days 1 - 114 (recorded on Memory Aid eCRF device)
Days 1 - 114 (recorded on Memory Aid eCRF device)
Days 1- 114 (recorded on Memory Aid eCRF device)
0
14
16
See section 11.3 for procedures
Clinic visits 2x/week from Day 28 +1   until resolved
Once/week from Days 28 + 1 until resolved

ICF_000.pdf: 
 
 
Official Title: 
A Phase I Single Site Open Label Clinical Trial for the 
Development of a Human BCG Challenge Model to Assess 
TB Drugs and Vaccines.   
NCT Number: 
NCT05592223 
Document Type:  
Informed Consent Form 
Date of the 
Document: 
November 10, 2022 
 
 


IR File: 10903 
        
 IRB Approved:  
 
BCG Main Consent 
Page 1 of 14 
Consent Version: 09/12/2022 
Fred Hutchinson Cancer Center 
University of Washington 
Consent to Participate in a Research Study Called: 
A phase 1, single site, open label clinical trial for the development of a human BCG challenge model 
to assess TB drugs and vaccines 
MAIN CONSENT FORM 
Principal Investigator:  
James Kublin, MD, MPH. 
Executive Director, CoVPN/HVTN, Fred Hutch  
 206-667-1970 
 
Investigators: 
Chetan Seshadri, MD 
 
Associate Professor, UW Medicine  
 206-543-6709 
E. Chandler Church, MD, MSc       Senior Fellow, HVTN/CoVPN  Fred Hutch      206-667-6982 
Thomas R. Hawn, MD, PhD 
Professor, UW Medicine 
 
 
 206-616-4124 
Jay Vary, MD, PhD 
 
Associate Professor, UW Medicine  
 206-598-5065 
David Sherman, PhD 
 
Professor and Chair, UW Medicine  
 206-543-4547 
M. Juliana  McElrath, MD, PhD 
Sr. VP, Fred Hutch/Professor, UW Medicine   206-667-6704  
Emergency number (24 hours): Dr. Chetan Seshadri pager:  
 
 (206)-559-0431 
 Important things to know about this study 
You are invited to participate in a research study. These are some of the things you should know about the 
study:  
• 
Being in this research study is voluntary. Whether you join or not is your choice.  
• 
The purpose of this study is to develop a challenge model using Tice® Bacillus Calmette-Guerin 
(BCG) which is a tuberculosis (TB) vaccine. A challenge model is a scientific method of 
measuring the immune responses in a person’s body that protect them from a specific infection. 
We are developing this challenge model to evaluate the use of BCG for future studies of TB 
drugs and vaccines. 
• 
In this study we are using the FDA approved TB vaccine, Bacillus Calmette-Guerin (BCG)  
• 
In this study we are using the FDA approved antibacterial treatment Isoniazid (INH) 
• 
You will have about 17 visits over about 6 months.  
• 
We will collect blood at about 14 visits. You will receive study vaccine at one visit. If you are in 
group 1 you will receive an antibacterial drug at 3 visits. We will do a skin test at 4 visits, and a 
skin biopsy at 4 visits.  
We will give you details about why we are conducting this study, the study procedures, and the risks and 
possible benefits of participating in this study. We will also give you any other information that you need 
in order to make an informed decision about joining this study.  
Below is a more complete description of this study. Please read this description carefully.  
 What is the purpose of this consent form?  
Thank you for your interest in our research study. Please read this consent form or ask someone to read it 
to you. If you decide to join the study, we will ask you to sign or make your mark on this form. We will 
offer you a copy to keep.  
IRO REC'D NOV 09 2022
FHCRC IRB Approval  
NOV 10 2022 
Document Released Date


IR File: 10903 
        
 IRB Approved:  
 
BCG Main Consent 
Page 2 of 14 
Consent Version: 09/12/2022 
It is completely up to you whether or not to join the study. Take your time in deciding. If it helps, talk to 
people you trust, such as your doctor, friends, or family. If you decide not to join this study, or if you 
leave it after you have joined, your other care at this clinic and the benefits or rights you would normally 
have will not be affected. 
 Why have I been asked to take part in this research study, and who is in charge of it? 
We invite you to join this research study because you are generally healthy and do not have human 
immunodeficiency virus (HIV) or TB, are 18 to 45 years old, and do not live or work with someone who 
is immunocompromised, including infants or pregnant people. 
The researcher in charge of this study is Dr. James Kublin, (206) 667-1970.  
Merck Sharpe & Dohme LLC is supplying the BCG vaccine for this study.  
Research is not the same as treatment or medical care. The purpose of a research study is to answer 
scientific questions.  
 Why is this research study being done? 
We are doing this study to develop a scientific method that will measure the body’s immune response 
before, during and after an injection of  the BCG TB vaccine taken with or without the treatment of  
Isoniazid (INH) which is an antibacterial drug that treats TB infection. We want to better understand the 
effects the BCG vaccine has on people’s immune system. 
 How many people will take part in this study? 
About 10 people will take part in this study.  
 What is the vaccine being used in this study? 
The vaccine being used in this study is called Bacillus Calmette-Guerin (BCG). BCG is an FDA approved 
vaccine used to provide immunity, or protection against TB.   
 What is the antibacterial treatment drug being used in this study? 
In this study, we are using the FDA approved antibacterial drug Isoniazid (INH). INH is an FDA 
approved antibiotic that fights bacteria. INH is used to treat and to prevent TB.  
 What will I have to do if I am in this study? 
Before Entering the Study 
To see if you can take part in this study, you will have a screening visit. The study staff will use 
information from the screening procedures to decide whether you can take part in the study.  
Screening Procedures 
If you want to join this study, we will screen you to see if you are eligible to join. You will be able to ask 
questions before deciding if you want to participate in this study. Screening involves a physical exam, and  
review of your health history. The study team will ask you about any medications you are currently taking  
including herbals, vitamins, and holistic/naturopathic medications. If you were born female and could 
become pregnant, we will test you for pregnancy.   
FHCRC IRB Approval  
NOV 10 2022 
Document Released Date


IR File: 10903 
        
 IRB Approved:  
 
BCG Main Consent 
Page 3 of 14 
Consent Version: 09/12/2022 
A physical exam may include but is not limited to:  
• 
Checking your height, weight, temperature, pulse and blood pressure 
• 
Looking in your mouth and throat 
• 
Examining your lymph nodes  
• 
Listening to your heart and lungs 
• 
Feeling your abdomen (stomach and liver) 
• 
Asking about any vaccines you have gotten recently 
We will do blood tests to screen for Pregnancy, HIV, Hepatitis B surface antigen, antibody to hepatitis C, 
Syphilis, and latent Tuberculosis (TB). Results of these screening tests must be negative in order for you 
to participate in the study.  
We will also collect urine to test for pregnancy, Chlamydia, and Gonorrhea.  
If you test positive for active hepatitis B, hepatitis C, Chlamydia, Gonorrhea, active or untreated Syphilis,  
we are required by law to report your name and your positive test results to the Seattle-King County 
Health Department. This will be done in a private manner.  
If you test positive for HIV, the study staff will counsel you on your HIV infection and notifying your 
partner(s). As researchers, we are not required to report positive HIV tests to the health department. We 
are required to notify your primary care provider if we find you are infected with HIV. Your primary care 
provider would be required to report your name to the local health department when you seek his or her 
care.  
If you were born female and are sexually active in a way that could lead you to get pregnant, you must 
agree to use birth control from 30 days prior to your BCG vaccination until 4 months after your BCG 
vaccination. You should not become pregnant during the study because we do not know how the study 
procedures could affect a developing baby. We will talk to you about effective birth control methods. If 
you join the study, we will test you for pregnancy before the BCG vaccination. 
During the Study:  
Clinic visits 
If you meet the study requirements, want to join the study and your study clinician agrees, here is what 
will happen:  
You will  come to the clinic for scheduled visits about 17 times over about 6 months. The length of the 
visits will vary. Visits can last from 30 minutes to 2 hours.  
During the study, or even after your last scheduled visit, we may ask you to return to the clinic for extra 
visits and/or laboratory tests and medical exams. We would do this, for instance if your laboratory results 
are not normal, if your BCG vaccination site does not have a well healed scar, or if you have a health 
issue.  
We would ask you to return so that we may follow-up on the results of your original tests and/or medical 
exams and repeat these procedures as necessary for your health and safety. If we confirm you have a 
health problem, you will be referred to a local provider for appropriate care.  
Being Assigned to a Group 
There are 2 groups of participants in this study. We will give one group INH and the other group will not 
be given INH in order to measure the effect of INH on the immune response to BCG vaccine as well as 
the effect of INH on BCG itself.  In this study, we use a computer program to decide which group you 
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will be in. If you join this study, you will not be allowed to choose the group you are in. You will have a 
1-in-2 chance of being in either group. 
The two groups are: 
• Group 1 (INH): This group will take INH in either three 100mg tablets or one 300mg tablet for 
three days (Study Days 4, 5, and 6) after the BCG vaccination.  
•  Group 2 (Control): No INH will be taken. 
Procedures: 
In addition to giving you the BCG vaccine and NIH treatment, we will:  
• 
Ask questions about your medical history, and medications you are taking.   
• 
Do pregnancy testing if you were born female and can become pregnant 
• 
 Do physical exams, and vital signs  
• 
Assess BCG vaccination site 
• 
Collection of BCG vaccination site gauze/dressing 
• 
Collect urine and blood samples.   
Receiving the BCG Vaccination:  
One intradermal (under the skin) injection of BCG  will be given to all participants in the upper 
arm/shoulder or forearm region. Following the injection, we will ask you to remain at the clinic for about 
30 minutes to monitor any injection site reactions or problems.  Intradermal administration of BCG is an 
off-label use of the FDA approved BCG. The FDA approved application of BCG is via the percutaneous 
route that requires a special pronged device. BCG is administered most frequently outside of the U.S. via 
the intradermal route or subcutaneous routes.   
If your BCG vaccination site does not have a well healed scar, then you will be asked to return to the 
clinic twice per/week from the day it is identified as abnormal until it has resolved. 
Receiving INH (only for Group 1) 
If you have been assigned to Group 1, you will take INH: oral tablets of either three 100mg tablets (total 
300mg) or one 300mg tablet for three days after receiving BCG (Study Days 4, 5, and 6).  
Self-monitoring and health status recorded on Memory Aid device 
You will be asked to complete a daily electronic questionnaire called a memory aid,  to help record any 
reactions you may experience during the study. The study team will send you a link daily to access the 
memory aid. You will be instructed on how to use the initial and on-going memory aids and how to 
measure and record any symptoms. It will be optional to record your oral temperature as well as the 
medications you are taking throughout the study.  You will also be asked to record side effects and 
reactions to BCG such as: pain, tenderness and drainage, fevers, nausea, and vomiting. You will be asked 
to record your health status information using the memory aid from Day 1 until the end of the study at 
Day 114.  
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Blood draws 
You will have blood draws for screening laboratory tests, clinical safety tests, and measurement of 
immune response to BCG throughout the study.   
When we take blood, the amount will depend on the lab tests we need to do. It will be some amount 
between 6.5mL and 138mL (a little more than 1 teaspoon to about a half cup) depending on the visit.  
Your body will make new blood to replace the blood we take out. To compare, people who donate blood 
in the US can give a total of about 500mL in an 8-week period.  
Skin biopsy 
A 4 mm (about the size of a grain of rice) skin biopsy will be taken at the BCG vaccination site 4 times 
during the study to measure the level of BCG in the skin. A study clinician will perform the procedure 
known as punch biopsy of the skin. A punch biopsy is a surgical procedure performed following the 
administration of local anesthesia (lidocaine). A small piece of skin at the BCG vaccination site will be 
removed. The area of the biopsy will be closed using gel foam. We will ask you not to swim in 
chlorinated water until the gel foam has sufficiently closed the biopsy area. 
If you do not agree to this skin biopsy, you will not be able to participate in the study.  
Photographs 
We will take photographs of the BCG vaccination site after the BCG vaccination at 7 different clinic 
visits. If there are any abnormalities or the vaccination site does not have a well-healed scar, we will 
continue to take photographs once per week until it has resolved. We will take a final photograph of the 
BCG vaccination site for all participants at Visit 17 or if you leave the study early. We will not 
photograph your face or other identifiable markings. These photographs will be stored confidentially in 
the research record.  
 
PPD Skin Test 
Purified Protein Derivative (PPD) is a skin test to determine if you have TB. A small shot that contains 
PPD is given under the top layer of your skin. You may feel a slight sting. A bump or small welt will 
form, which usually goes away in a few hours. After 2-3 days you must return to the clinic to have the 
area checked to see if you have had any reaction to the PPD.  
The test will be performed up to two times during the study. The first test will be at Visit 14 and checked 
by the clinician at Visit 15. If the first PPD skin test is negative, then the second PPD skin test will be 
done 2 weeks later at Visit 16 and checked by the clinician at Visit 17.  If either test is positive, we will 
draw your blood to distinguish between a true TB infection or false positive result due to BCG 
vaccination. 
Abnormal BCG Vaccination Site Procedures 
If an abnormal vaccination site is identified as not having a healed scar, or has an open and draining ulcer, 
then you will be asked to return to the clinic twice per/week until it has resolved.   
Withdrawal Procedures 
If you decide to withdraw from the study early, we will ask you to complete visits 14-17. These visits will 
be scheduled according to when your dose of BCG was given. If you cannot complete visits 14-17, you 
will be asked to complete the end of study visit 17 procedures.  
 
The table below shows the schedule of clinic visits during the study.  
 
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Clinic Visit  
1 
(Screening 
Visit) 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
Day 
-42 to -1 
0 
1 
2 
3 
4 
5 
6 
8 
15 
28 
56 
84 
98 
100 
112 
114 
Week 
0 
 
 
1 
2 
4 
8 
12 
14 
16 
Study Drugs  
 
BCG 
 
 
 
INH** 
INH** 
INH** 
 
 
 
 
 
 
 
 
 
Informed Consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height, weight: BMI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Draw 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
Urine Collection  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test (blood) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test (urine) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam & Clinical 
Assessment 
X 
 
 
 
 
X* 
 
 
X* 
X* 
X* 
X* 
X* 
 
 
 
X 
Injection  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
INH Administration  
 
 
 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Skin Biopsy 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
 
 
 
 
Injection Site Evaluation 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Health Status & AE / SAE 
Review 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medication Review  
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Memory Aid eCRF 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Photographs of Injection 
site 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
X 
PPD skin test / Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Dressing / gauze 
Collection  
 
 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
 
Compensation  
$50*** 
$75 
$50 
$50 
$100 
$50 
$25 
$25 
$100 
$100 
$50 
$100 
$50 
$50 
$25 
$50 
$50 
 
* Only if applicable if indicated based on review of interim medical history and previous clinical assessments 
** Only if you are in Group 1  
*** $50 for the completion of the screening visit, this visit could occur over multiple days. 
 
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 What if I choose to leave this study? 
You  are free to leave the study at any time and for any reason. Your care at this clinic and your 
legal rights will not be affected, but it is important for you to let us know.  
If you withdraw from the study during the follow up stage, we will ask you to come back to the 
clinic for the End of Study visit procedures within 7 days, but ≤ 30 days, after the dose of BCG. 
 Can the researchers take me out of this study? 
The researchers could take you out of this study at any time. This would happen if: 
• 
They think it is in your best interest not to continue in the study. 
• 
If you are a female who becomes pregnant. 
• 
You are not able or willing to follow study procedures. 
• 
The whole study is stopped.   
If you withdraw from the study for any reason, previously collected information will remain in 
the study records and will be included in the analysis of results. This information could not be 
removed from the study records.  
 What are the risks and inconveniences of this study? 
In this part of the consent form, we describe the side effects we expect from the tests, procedures, 
and treatments in this study. BCG TB vaccine and/or INH could cause side effects we do not 
know about yet. We carefully watch everyone in the study for side effects.   
If you join this study, we will tell you if we discover new side effects that could affect you.  
This form lists side effects of individual drugs. Other side effects could occur when we use these 
drugs together. 
Side effects may be mild or very serious. Medicines could be given to help lessen side effects. In 
some cases, side effects can last a long time or never go away.  
 
Risks of the BCG Vaccine  
The BCG vaccine continues to be the most widely distributed vaccine worldwide, generally 
provided to infants immediately after birth, so it is safe and well tolerated.   
Typically, most people will develop a small swelling (nodule) at the vaccination site that can 
break open, release pus or blood-tinged discharge, and form an ulcer the size of a dime.  The 
ulcer will heal over a period of weeks and forms a scar that remains for life.  Occasionally, lymph 
nodes around the vaccination site can become tender to touch.  “Flu-like” symptoms that are 
common to many vaccines includes fevers, chills, loss of appetite, muscle aches, and generally 
not feeling, which can last 1-2 days. 
A very small number of people (1 in 4 million) have an immediate allergic reaction to BCG.  
Symptoms include rash, swelling around the mouth, and difficulty breathing.  These can be 
treated with emergency medications.  If severe, they can cause death. 
A very small number of people (1.56 to 4.29 cases per million) may have a disseminated BCG 
infection. These occur most frequently in people who are immunosuppressed, which is why 
people with immunosuppression should not participate in this study. This infection can be treated 
with medications. 
You may develop a false positive tuberculin skin test (PPD) that will complicate the early 
diagnosis and treatment of latent (inactive) TB.  However, a diagnosis of latent TB can be 
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confirmed by other methods, including a clinical examination, chest x-ray, and blood test 
(QuantiFERON®-TB Gold Test).  
You may experience:  
• 
Pain, swelling, redness, and/or itching caused by the intradermal injection,  
• 
There is a slight chance of getting an infection at the intradermal challenge site. 
 
Risks of Isoniazid (INH) 
You may experience some side effects that include:  
• 
Numbness and tingling in the arms and legs,  
• 
Inflammation of the Liver / Hepatitis (symptoms include loss of appetite, nausea, vomiting, 
fatigue, malaise, and weakness),  
• 
Nausea with or without vomiting  
• 
Upset stomach 
• 
Rash. 
You will be closely monitored by study staff and necessary treatment will be administered to 
alleviate symptoms that may occur. 
 
Risks of Skin Biopsy 
This procedure generally is safe, but certain risks accompany any surgical procedure.  
Risks associated with punch biopsy of the skin include: 
• Local bleeding and bruising in the surrounding tissues,  
• Pain associated with the surgery or the healing process,  
• Excessive scarring at the surgery site, 
• Allergic reaction to the numbing medicine (lidocaine), gel foam or the surgical instruments,  
• Local infection in the surrounding tissues, 
• Damage to structures beneath the skin such as an artery or nerve. 
 
Risks of PPD Skin Test 
You may experience:  
• Pain, swelling, redness, and/or itching caused by the PPD injection,  
• Allergic reaction to the agent, 
• There is a slight chance of getting an infection at the site. 
 
Risk of Blood Draw 
• Pain, swelling, or redness, caused by the insertion of the needle,  
• Nausea/light headedness and there is a slight chance of fainting, 
• There is potential for an infection at the needle insertion site. 
 
Risks of Lidocaine 
May cause mild discomfort when injected, skin discoloration or an allergic reaction.  
 
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Possible Risks Related to Allergic Reactions  
As with all vaccines or drugs, you could have an allergic reaction, like a rash, hives, or even 
difficulty breathing. Allergic reactions can be life threatening. When they occur, it is usually soon 
after the vaccination or study drug dose. Therefore, the study staff will give you treatment if you 
need it. 
Risk of the Loss of Confidentiality 
There is a chance of the loss of your confidentiality. Each member of the research team has 
completed human subjects protections, and HIPAA and confidentiality training. Your information 
will be stored in secure buildings under password protected computers to protect your identifiable 
information. 
Reproductive Risks 
Taking the BCG vaccine and INH may involve unknown risks to an embryo, fetus (unborn baby) 
or nursing infant. Therefore, you should not join this study if you are pregnant, if you are planning 
to become pregnant, or if you are breast-feeding.   
If you join this study, you will have to use an effective method of birth control from the time this 
form is signed until at least 4 months after the last dose of BCG vaccine and INH. If you are 
already using a method of birth control, you will have to check with the study team to make sure it 
is acceptable.  
If you became pregnant after joining this study, you would have to notify the study team 
immediately. You will be asked to complete the visits 12-15. 
The effects of the BCG vaccine and INH on fathering a child are also unknown.  
 Are there benefits to taking part in this study? 
We do not expect a direct  health benefit to you for participating in this study. Even though you 
are TB negative, we hope to see if INH is an effective treatment for those who have TB. We hope 
the information from this study will give us insight on the TB drugs and vaccines given to 
individuals who have TB. This will help us in the development of better drugs and vaccines to 
help other people with TB in the future. 
 What other choices do I have besides this study? 
You may choose not to participate in this study. Other services you receive at this institution will 
not be affected. If you choose not to join this study, you could join another study if one is 
available and you are eligible. You could also choose not to join any study.  
 Will I receive any payment? 
You will receive compensation per study visit based on which procedure(s) are being done. The 
compensation is as follows:  
o $50 for the completion of the screening process  
o $25 for scheduled visits without blood collection  
o $50 for scheduled visits with blood collection  
o $75 for completion of the BCG vaccination visit  
o $100 for completion of visits with skin biopsy procedure 
o $25 for any unscheduled visit without blood collection  
o $50 for any unscheduled visit with blood collection  
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The compensation you receive for being in this study may be considered taxable income. This 
happens if we pay you more than $600 between January 1 and December 31 of the same year. 
The study staff may collect your name, address, and social security or tax ID number for tax 
purposes. This information may be shared with the accounting department at Fred Hutchinson 
Cancer Center and the US Internal Revenue Service (IRS). We will not share the name of this 
study or nature of the research with these groups.  
 Protecting Your Privacy / Who has access to my research records? 
If you join this study, some people or organizations might need to look at your medical records 
and research records for quality assurance or data analysis. They include: 
• 
Researchers involved with this study. 
• 
Fred Hutchinson Cancer Center Institutional Review Board (IRB). An IRB is a group that 
reviews the study to protect the rights and welfare of research participants. 
• 
Fred Hutchinson Cancer Center. 
• 
Office for Human Research Protections, and other regulatory agencies as required. 
• 
Merck Sharpe & Dohme LLC and the people who work for them  
All reviewers will keep your records private. We cannot guarantee absolute privacy. If you have a 
medical condition that we are required to report by law, then some of your information may be 
shared. At this clinic, we have to report the following information:  
• 
Hepatitis B and Hepatitis C, and sexually transmitted diseases 
• 
We suspect you may be harming yourself or others or planning to do so 
If your confidential information is released, you will be told.  
We will not use personal information in any reports about this study, such as journal articles or 
presentations at scientific meetings. 
 How is my genetic information protected? 
A federal law called the Genetic Information Nondiscrimination Act (GINA) helps protect 
genetic information about people who join research studies.  
GINA restricts access to genetic information so that it cannot be used for health insurance 
coverage decisions. GINA prevents health insurance companies or group health plans from:  
• 
Asking for genetic information obtained in research studies, or 
• 
Using genetic information when making decisions regarding your eligibility or premiums  
GINA does not help or protect against genetic discrimination by companies that sell life, 
disability or long-term care insurance.  
 What are the costs to me? 
You do not have to pay anything to be in this study. 
 What happens if I am injured? 
For a life threatening problem, call 911 right away or seek help immediately.  Contact the study 
team when the medical emergency is over or as soon as you can.    
For all other medical problems or illness related to this research, immediately contact Dr. Chetan 
Seshadri (UW Pager 206-559-0431 or cellphone 206-660-0118).  They will treat you or refer you 
for treatment.  You or your health insurance will have to pay for the treatment. There are no funds 
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to pay you for a research-related injury, added medical costs, loss of a job, or other costs to you or 
your family.  State or national law may give you rights to seek payment for some of these 
expenses.  You do not waive any right to seek payment by signing this consent form. 
You or your insurer will be billed for treatment of problems or complications that result from 
your condition or from standard clinical care. 
You will not lose any legal right to seek payment for treatment if you sign this form. 
 What will my information and samples be used for? 
Your information and tissue samples (such as blood) will be used for the purposes of this study. 
Your tissue samples might help researchers develop new products. This research could be done 
by for-profit companies. There is no plan to share with you any revenue generated from products 
developed using your tissue samples. 
Test results would not affect your care, so we do not plan to return results to you. 
In addition, be aware that by agreeing to participate in this study, your information or tissue 
samples could be used for future research studies or sent to other investigators for future research 
studies without additional consent from you. These future research studies will be reviewed by an 
oversight group known as an institutional review board if required by law. The information that 
identifies you will first be removed from your information or tissue samples. If you do not want 
your information or tissue samples to be used for future research studies without your consent, 
you should not participate in this study. 
 We invite you to donate tissue and blood samples for other research. 
After we do tests on samples in this study, some samples may be left over. We invite you to 
donate these leftover samples for future research. This may include genetic research. 
If you join this study, you will not have to donate samples for future research. You would be free 
to say “yes” or “no.” Regular medical care would not change if you say “no.”  
If you donate samples, they would be stored in a secure location. If we want to use your samples 
for other research or share it with other scientists for research, an ethics review committee (IRB) 
would review the request. The IRB would decide if we need to ask you for permission to do the 
research.  
Your donated samples will be used only for research. This research could be done by for-profit 
companies. Researchers would not report their results to you or your doctors. The research results 
would not be included in medical records. The results would not affect your medical care.  
Research with these samples might help develop new products. If these products make money, 
there is no plan to share the money with the participants who donate their samples.  
If your samples are released, your identity remains confidential. Your personal information stays 
with the study site that collected the sample from you. Each sample contains only 4 pieces of 
information:  
• 
A participant ID number 
• 
The type of specimen inside the tube 
• 
A visit number 
• 
A specimen collection date 
If you donate samples for research, you could withdraw the donation at any time by calling Dr. 
Chetan Seshadri at 206-543-6709 (seshadri@uw.edu). You would have no penalty for 
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withdrawing the donation, and regular medical care would not change. We could not return 
donated samples, but we might be able to destroy them. We could not destroy samples if they are 
stored or shared without any label saying who donated them. In this case, it could still be used for 
research.   
 What are my rights as a research subject? 
• 
You do not have to join this study. You are free to say “yes” or “no”.  
• 
If you get sick or hurt in this study, you do not lose any of your legal rights to seek payment 
by signing this form. 
• 
During the study, we might learn new information that you need to know. For example, 
some information may affect your health or well-being. Other information might make you 
change your mind about being in this study. If we learn these kinds of information, we will 
tell you. 
• 
If you join this study, you will not have to stay in it. You could stop at any time (even before 
you start). Your regular medical care would not change. You would have no penalty for 
stopping, but it would be better not to join the study if you think that you would change your 
mind later.   
• 
If you decide to drop out, we would want you to tell the study team. You and the study team 
could talk about the follow-up care and testing that would help the most.  
• 
Before you leave the study, the study team would ask you to complete the End of Study 
procedures. 
 
What are my responsibilities as a research subject?If you join this study, you will have some 
responsibilities.  
• 
Follow the schedule of study visits and procedures. 
• 
Take study medications as directed.  
• 
Prevent pregnancy. 
• 
Tell us about side effects.    
 
 
 
 
 
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 
Who should I call if I have questions or research study problems? 
Earlier in this consent form, we told you about possible other uses of your extra samples and 
information outside this study.  Please choose only one of the options below and INITIAL next 
to the option you choose. Whatever you choose, the research team will keep track of your 
decision about how your samples and information can be used. You can change your mind after 
signing this form.  
 
Yes, I agree to allow my extra samples and information to be used for other studies related to TB, 
vaccines, the immune system, and other diseases. This may include genetic testing and keeping my 
cells growing over time.  
OR 
 
 
 
  Yes, I agree to the option above and also agree to allow my extra samples and information to be 
used in genome wide studies. 
OR 
 
 
No, I do not agree to allow my extra samples to be used in any other studies.  This includes not 
allowing genetic testing, growing more of my cells, or genome wide studies.   
 
 
I also give permission to the people and organizations connected with this research study to 
review and copy my research records, both during and after the study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For Questions About 
Please Contact 
This study (including complaints and 
requests for information) 
Dr. Chetan Seshadri 
206-543-6709 
Your rights as a participant in a 
research study 
Director of Institutional Review Office of the Fred 
Hutchinson Cancer Center: (206) 667-5900 or 
irodirector@fredhutch.org 
 
A research related symptom or injury 
Dr. Chetan Seshadri 
206-543-6709 
What if I need emergency care? 
Emergency (24 hour) phone: (206) 540-9680 
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Please sign below if you:  
• have read this form (or had it read to you); 
• had the opportunity to ask any questions you have; 
• had the opportunity to discuss the research with the person obtaining consent; and  
• agree to participate in this study. 
 
 
Participant: 
 
 
 
 
 
Printed Name 
 
Signature 
 
Date/Time 
Researcher’s statement 
I have discussed the research study, including procedures and risks, with the person 
signing above. A copy of the signed consent form will be given to the participant. 
 
Person obtaining consent signature: 
 
 
 
 
 
Printed Name 
 
Signature 
 
Date/Time 
 
 
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