A Randomized, Open-label Study to Evaluate the Immunogenicity of Anthrax Vaccine Adsorbed Alone or Concomitantly With Raxibacumab (GSK3068483)
Phase: PHASE4
Conditions: Infections, Bacterial
Sponsor: Emergent BioSolutions

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The GlaxoSmithKline group of companies
201436
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A Randomized, Open-label Study to Evaluate the 
Immunogenicity of Anthrax Vaccine Adsorbed Alone or 
Concomitantly with Raxibacumab (GSK3068483)
Compound Number:
GSK3068483
Development Phase:
IV
Effective Date:
25-APR-2016
Protocol Amendment Number:  1
Author (s):
 
Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2014N194186_00
2014-OCT-21
Original
2014N194186_01
2016-APR-25
Amendment No. 1
This amendment serves to update contraception requirements for study participation to be 
consistent with updated GSK guidance on reproductive issues in clinical studies.  The 
amendment also updates the secondary medical monitor information.
Copyright 2016 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD

33'
33'

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MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information: 
Role
Name
Day Time Phone 
Number and email 
address
After-hours 
Phone/Cell/
Pager 
Number
Fax 
Number
Site Address
Primary 
Medical 
Monitor 
 
M.D.
(Quintiles)
 
1801 Rockville 
Pike, Suite 300, 
Rockville, MD 
20852
Secondary 
Medical 
Monitor
 
 M.D.
(GSK)
 
N/A
Stockley Park 
West, 
1-3 Ironbridge 
Road, 
Uxbridge, 
Middlesex, 
UB11 1BT, 
United Kingdom
SAE 
contact  
information 
 
(Quintiles)
5927 S. Miami 
Blvd Morrisville, 
NC 27560
Sponsor Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Regulatory Agency Identifying Number(s):  IND BB011069
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PP
DPPD
PPD
PPD
PPD
PPD
PPD
PPD

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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 201436.
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date

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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS..........................................................................................8
2.
INTRODUCTION....................................................................................................10
2.1.
Brief Background ........................................................................................10
2.2.
Study Rationale ..........................................................................................11
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................11
4.
STUDY DESIGN ....................................................................................................12
4.1.
Overall Design ............................................................................................12
4.2.
Treatment Arms and Duration.....................................................................13
4.3.
Type and Number of Subjects.....................................................................13
4.4.
Design Justification.....................................................................................14
4.5.
Dose Justification........................................................................................15
4.6.
Benefit:Risk Assessment ............................................................................15
4.6.1.
Benefit Assessment.....................................................................17
4.6.2.
Overall Benefit:Risk Conclusion...................................................17
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............17
5.1.
Inclusion Criteria.........................................................................................17
5.2.
Exclusion Criteria........................................................................................18
5.3.
Screening/Baseline/Run-in Failures............................................................20
5.4.
Withdrawal/Stopping Criteria.......................................................................20
5.4.1.
Liver Chemistry Stopping Criteria ................................................21
5.4.1.1.
Study Treatment Restart or Rechallenge....................22
5.5.
Subject and Study Completion....................................................................22
5.6.
Definition of an Analyzable Subject.............................................................22
6.
STUDY TREATMENT ............................................................................................22
6.1.
Investigational Product and Other Study Treatment....................................22
6.2.
Treatment Assignment................................................................................24
6.3.
Blinding.......................................................................................................25
6.4.
Packaging and Labeling..............................................................................26
6.5.
Preparation/Handling/Storage/Accountability..............................................26
6.6.
Compliance with Study Treatment Administration.......................................26
6.7.
Treatment of Study Treatment Overdose....................................................27
6.8.
Treatment after the End of the Study ..........................................................27
6.9.
Lifestyle and/or Dietary Restrictions............................................................28
6.10.
Concomitant Medications and Non-Drug Therapies....................................28
6.10.1.
Permitted Medications and Non-Drug Therapies..........................28
6.10.2.
Prohibited Medications and Non-Drug Therapies.........................28
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................28
7.1.
Time and Events Table...............................................................................30
7.2.
Screening and Critical Baseline Assessments ............................................33
7.3.
PA, TNA and Anti-raxibacumab Antibodies.................................................34
7.4.
Safety .........................................................................................................34
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........34

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7.4.1.1.
Time Period and Frequency for Collecting AE 
and SAE Information ..................................................35
7.4.1.2.
Method of Detecting AEs and SAEs ...........................35
7.4.1.3.
Follow-up of AEs and SAEs........................................35
7.4.1.4.
Regulatory Reporting Requirements for SAEs............36
7.4.2.
Pregnancy ...................................................................................36
7.4.3.
Physical Exams ...........................................................................36
7.4.4.
Vital Signs....................................................................................36
7.4.5.
Clinical Safety Laboratory Assessments ......................................37
7.5.
Pharmacokinetics .......................................................................................38
7.5.1.
Pharmacokinetic Analyses...........................................................38
7.5.1.1.
Pharmacokinetic Parameters......................................38
8.
DATA MANAGEMENT ...........................................................................................39
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................39
9.1.
Hypotheses.................................................................................................39
9.2.
Sample Size Considerations.......................................................................40
9.2.1.
Sample Size Assumptions ...........................................................40
9.2.2.
Sample Size Sensitivity................................................................40
9.2.3.
Sample Size Re-estimation or Adjustment...................................42
9.3.
Data Analysis Considerations .....................................................................42
9.3.1.
Analysis Populations....................................................................42
9.3.2.
Interim Analysis ...........................................................................43
9.4.
Key Elements of Analysis Plan ...................................................................45
9.4.1.
Primary Analyses.........................................................................45
9.4.2.
Secondary Analyses ....................................................................45
9.4.2.1.
Anti-PA Antibodies......................................................45
9.4.2.2.
Toxin Neutralizing Activity (TNA) ................................45
9.4.2.3.
Safety Analyses..........................................................46
9.4.2.4.
Statistical Analysis of Pharmacokinetic Data ..............46
10. STUDY GOVERNANCE CONSIDERATIONS........................................................46
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............46
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................46
10.3.
Quality Control (Study Monitoring) ..............................................................47
10.4.
Quality Assurance.......................................................................................47
10.5.
Study and Site Closure ...............................................................................48
10.6.
Records Retention......................................................................................48
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................49
11. REFERENCES.......................................................................................................50
12. APPENDICES........................................................................................................52
12.1.
Appendix 1  Abbreviations and Trademarks................................................52
12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................54
12.3.
Appendix 3: GSK Modified List of Highly Effective Methods for 
Avoiding Pregnancy in Females of Reproductive Potential (FRP)...............56

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12.4.
Appendix 4: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................57
12.4.1.
Definition of Adverse Events........................................................57
12.4.2.
Definition of Serious Adverse Events...........................................58
12.4.3.
Recording of AEs and SAEs ........................................................59
12.4.4.
Evaluating AEs and SAEs............................................................60
12.4.5.
Reporting of SAEs to GSK...........................................................61
12.5.
Appendix 5: Collection of Pregnancy Information........................................62
12.6.
Appendix 6: Modified Division of Microbiology and Infectious 
Diseases (DMID) Toxicity Tables................................................................63
12.7.
Appendix 7:  Protocol Changes...................................................................74

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1.
PROTOCOL SYNOPSIS
Rationale
Raxibacumab was approved for the treatment of inhalation anthrax by the United States 
(US) Food and Drug Administration (FDA) on December 14, 2012 under the Animal 
Efficacy Rule per the U.S. Code of Federal Regulations (CFR) (21 CFR § 314.610). 
Raxibacumab is a fully human monoclonal IgG1λ antibody (Ab) which binds the 
protective antigen (PA) component of the tripartite anthrax toxin, thus blocking the 
deleterious effects of lethal toxin and edema toxin. Raxibacumab may be administered 
for prophylaxis of inhalation anthrax when alternative therapies are not available or are 
not appropriate. Anthrax Vaccine Adsorbed (AVA, BioThrax) which is mainly composed 
of adsorbed PA, may also be administered as part of a prophylaxis regimen. Published 
results indicate that a polyclonal anti-PA antitoxin administered to rabbits with AVA 
resulted in essentially complete abrogation of the immune response to AVA [Malkevich, 
2013].  Since the primary antigen in AVA is PA, it is possible that concurrent 
administration of AVA and raxibacumab would result in raxibacumab binding the PA 
from AVA, leading to a reduced immune response to the vaccine and decreased anti-PA 
Ab concentrations and toxin neutralizing activity (TNA) titers.  This study, as a post-
marketing commitment to the FDA, is designed to detect the effect of raxibacumab on 
AVA immunogenicity in a healthy volunteer population.  
Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary

To compare the immunogenicity of AVA at 4 
weeks after the first AVA dose, when AVA 
is administered alone or concomitantly with 
raxibacumab.

Ratio of geometric mean concentrations 
(GMC) of anti-PA Ab at 4 weeks after the 
first AVA dose (prior to the third AVA dose), 
between the AVA alone and the AVA with 
raxibacumab treatment groups. 
Secondary

To compare the immunogenicity of AVA at 
Weeks 8 and 26 after the first AVA dose, 
when AVA is administered alone or 
concomitantly with raxibacumab. 

Ratio of GMC of anti-PA Ab at Weeks 8 
and 26 after the first AVA dose, between 
the AVA alone and the AVA with 
raxibacumab treatment groups.

To estimate and compare seroconversion, 
defined as a 4-fold increase in TNA titer 
from baseline, at Weeks 4, 8 and 26 after 
the first AVA dose, when AVA is 
administered alone or concomitantly with 
raxibacumab.

Percentage of subjects who seroconvert, at 
Weeks 4, 8 and 26 after the first AVA dose, 
between the AVA alone and the AVA with 
raxibacumab treatment groups.

To describe the safety of AVA when co-
administered with raxibacumab versus 
AVA alone.

Rates of reported adverse events (AE) as 
well as review of vital signs, urinalysis and 
clinical laboratory data in the AVA alone 
and the AVA with raxibacumab treatment 
groups.

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Overall Design
This is a randomized, open-label, parallel group, two arm study in healthy subjects who 
have not previously been immunized against PA.   Although this is an open-label study, 
measures have been introduced to minimize bias. 
Treatment Arms and Duration
Subjects will be randomized into one of the following treatment groups:

Treatment Group1 - subjects will be administered subcutaneous (SC) 0.5 mL AVA 
doses on Days 1, 15, and 29 (0, 2, and 4 weeks),

Treatment Group 2- subjects will be administered SC 0.5 mL AVA doses on Days 1, 
15, and 29 (0, 2, and 4 weeks), with the first AVA dose administered immediately 
after completion of a single 40 mg/kg intravenous (IV) infusion of raxibacumab. 
Subjects will be premedicated with diphenhydramine (25-50 mg) up to 1 hour prior to 
the raxibacumab infusion to reduce the risk of infusion reactions. 
Beginning with the screening visit, the total duration of study for each subject may be 
approximately 28 to 31 weeks.  This study duration was selected because it allows for 
assessment of the durable immune response to AVA.  
Type and Number of Subjects
This study will be conducted in healthy adult subjects who have not been previously 
immunized against PA.
A total of at least 534  subjects (267  analyzable subjects per treatment group) may be 
enrolled in the study, in 3 cohorts separated by interim analyses. The trial will continue to 
subsequent cohorts only if the prospective criteria for discontinuing the trial are not met 
at the interim analysis.  If the outcome of this trial shows a large impact on 
immunogenicity, then the trial will likely be stopped at one of the two interim analyses.
Subjects will be enrolled in the study in up to 3 cohorts separated by 2 interim analyses. 
The trial will continue to subsequent cohorts only if the prospective criteria for 
discontinuing the trial are not met at the interim analysis.

at least 30 subjects will be enrolled in Cohort 1, 

at least an additional 70 subjects will be enrolled in Cohort 2 if the study 
progresses beyond interim 1.

and at least an additional 434  subjects will be enrolled in Cohort 3 if the study 
progresses beyond interim 2.  

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Analysis
At the final analysis, the non-inferiority test will be based on a comparison of the 
confidence interval (CI) for the ratio of anti-PA Ab (attributable to AVA) GMCs between 
the AVA and the AVA + raxibacumab groups at week 4. This analysis will be performed 
in the per protocol population.  If the upper bound of the 90% CI is less than 1.5, non-
inferiority will be established.  This analysis will be repeated in the subset of the intent-
to-treat population with available week 4 results and in the full ITT population with 
imputed results for those with missing data, as sensitivity analyses .
The GMC ratio and GMCs within each treatment group and corresponding CIs will be 
calculated by first log transforming all of the data by a log base 10.  CIs will be 
calculated about the mean logs and the difference of the mean logs assuming these values 
follow a t-distribution.  The results will be translated back to the original scale by 
exponentiation them, again using a base 10.  The exponentiating differences of the 
sample mean logs will be the ratio of the sample geometric means of the untransformed 
results.
Two interim analyses are scheduled during this study.  A two sample t-test for the log 
transformed data will be performed and used as the basis of determining whether the 
futility threshold has been crossed at the respective interim analyses.  The futility 
thresholds for the interim analyses will be based on a rho (0.5) Type II error spending 
function.
As a secondary endpoint, ratios of the anti-PA Ab GMC for each treatment group at 
Weeks 8 and 26 will be calculated as described above. 
TNA geometric mean titers (GMTs) along with 95% CI will be summarized for each 
treatment group at each timepoint. The percentage of subjects, along with 95% CI, who 
seroconvert, defined as a >4-fold increase in TNA titer will be summarized, at Weeks 4, 8 
and 26 after the first AVA dose for both arms separately.  
Clinical safety observations will include AEs, urinalysis, vital sign measurements, and 
clinical laboratory assessments. Safety data will be tabulated and, where appropriate, 
analyzed by the use of descriptive statistics. Safety data will be tabulated for the safety 
population.
2.
INTRODUCTION
2.1.
Brief Background
Anthrax is a bacterial zoonosis caused by the gram-positive, aerobic, spore-forming 
Bacillus anthracis.  Depending on the route of transmission, anthrax presents in different 
forms: cutaneous, gastrointestinal, injectional and inhalational [Booth, 2010].  
Inhalational anthrax is the most severe form of anthrax because of the rapid progression 
of the disease to hemorrhagic mediastinitis, toxemia, and massive pulmonary edema, and 
because of the difficulty in establishing the diagnosis quickly [Dixon, 1999].  The 
incubation period for inhalational anthrax in humans ranges from 1 to 43 days [Meselson, 
1994]. 

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Anthrax Vaccine Adsorbed (AVA) is a current United Sates (U.S.) Food and Drug 
Administration (FDA)-approved form of anthrax vaccine.  The vaccine requires multiple 
injections over several weeks before immunity is initially established, so it may not be 
effective in the event of acute exposure to B. anthracis [Bartlett, 2002]
Raxibacumab is indicated for the treatment of adult and pediatric patients with inhalation 
anthrax due to B. anthracis in combination with appropriate antibacterial drugs.  
Raxibacumab is also indicated for prophylaxis of inhalation anthrax when alternative 
therapies are not available or are not appropriate [Raxibacumab Package Insert, 2012].  In 
contrast to the anthrax vaccine, a single intravenous (IV) dose of raxibacumab provides 
immediate protection.  Section 6 of the raxibacumab Investigator’s Brochure (IB, 2013, 
Version 8) provides a summary of the non-clinical data, including efficacy and the safety 
profile of raxibacumab in human volunteer studies to date.
2.2.
Study Rationale
Raxibacumab was approved for the treatment of inhalation anthrax by the FDA on 
December 14, 2012 under the Animal Efficacy Rule per the U.S. Code of Federal 
Regulations (CFR) (21 CFR § 314.610). Raxibacumab is a fully human monoclonal 
IgG1λ antibody (Ab) which binds the protective antigen (PA) component of the tripartite 
anthrax toxin, thus blocking the deleterious effects of lethal toxin and edema toxin. 
Raxibacumab may be administered for prophylaxis of inhalation anthrax when alternative 
therapies are not available or are not appropriate. Anthrax Vaccine Adsorbed (AVA, 
BioThrax) which is mainly composed of adsorbed PA, may also be administered as part 
of a prophylaxis regimen. Published results indicate that a polyclonal anti-PA antitoxin 
administered to rabbits with AVA resulted in essentially complete abrogation of the 
immune response to AVA [Malkevich, 2013].  Since the primary antigen in AVA is PA, 
it is possible that concurrent administration of AVA and raxibacumab would result in 
raxibacumab binding the PA from AVA, leading to a reduced immune response to the 
vaccine and decreased anti-PA Ab concentrations and toxin neutralizing activity (TNA) 
titers.  This study, as a post-marketing commitment to the FDA, is designed to detect the 
effect of raxibacumab on AVA immunogenicity in a healthy volunteer population.
3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary

To compare the immunogenicity of AVA 
at 4 weeks after the first AVA dose, when 
AVA is administered alone or 
concomitantly with raxibacumab.

Ratio of geometric mean concentrations 
(GMC) of anti-PA Ab at 4 weeks after the 
first AVA dose (prior to the third AVA 
dose), between the AVA alone and the 
AVA with raxibacumab treatment groups.
Secondary

To compare the immunogenicity of AVA 
at Weeks 8 and 26 after the first AVA 
dose, when AVA is administered alone 

Ratio of GMC of anti-PA Ab at Weeks 8 
and 26 after the first AVA dose, between 
the AVA alone and the AVA with 

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Objectives
Endpoints
or concomitantly with raxibacumab. 
raxibacumab treatment groups.

To estimate and compare 
seroconversion, defined as a 4-fold 
increase in toxin neutralizing activity 
(TNA) titer from baseline, at Weeks 4, 8 
and 26 after the first AVA dose, when 
AVA is administered alone or 
concomitantly with raxibacumab.

Percentage of subjects who seroconvert, 
at Weeks 4, 8 and 26 after the first AVA 
dose, between the AVA alone and the 
AVA with raxibacumab treatment groups.

To describe the safety of AVA when co-
administered with raxibacumab versus 
AVA alone.

Rate of reported adverse events (AE) as 
well as review of vital signs, urinalysis 
and clinical laboratory data in the AVA 
alone and the AVA with raxibacumab 
treatment groups.
4.
STUDY DESIGN
4.1.
Overall Design
This is a randomized, open-label, parallel-group, two-arm study in healthy adult subjects 
who have not previously been immunized against PA.  The schematic diagram below 
illustrates the study design:
Screening 
Visit 
Study Visit
Days
-36 to -15 
Sign 
ICF
First  AVA Dose
Raxibacumab Dose
Day 
1
Day
15
Day
29
Day
57
Day
183
(Week 26)
Follow Up Visit 
AVA Dose
Day
-1
Randomization (1:1)

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4.2.
Treatment Arms and Duration
Subjects will be randomized into one of the following two treatment groups:

Treatment Group 1- subjects will be administered subcutaneous (SC) 0.5 mL AVA 
doses on Days 1, 15, and 29 (0, 2, and 4 weeks).

Treatment Group 2- subjects will be administered SC 0.5 mL AVA doses on Days 
1, 15, and 29 (0, 2, and 4 weeks), with the first AVA dose administered immediately 
after completion of a single IV infusion 40 mg/kg raxibacumab dose.  Subjects will 
be premedicated with 25-50 mg of diphenhydramine up to 1 hour prior to the 
raxibacumab infusion to reduce the risk of infusion reactions.
Subjects will begin the study with a screening visit up to 35 days before the start of study 
treatment on Day 1.  Results of the screening test for the anti-PA Ab levels must be 
available prior to randomization on Day -1.  Study visits will occur at Days -1, 1, 15, 29, 
57, and 183 (Week 26).  The total study duration for each subject may be approximately 
28 to 31 weeks.
4.3.
Type and Number of Subjects
A total of at least 534 subjects (267 analyzable subjects per treatment group) may be 
enrolled in the study.  Enrollment will occur in 3 cohorts separated by interim analyses. 
The trial will continue to subsequent cohorts only if the prospective criteria for 
discontinuing the trial are not met at the interim analysis:

at least thirty subjects will be enrolled in Cohort 1, 

at least an additional 70 subjects will be enrolled in Cohort 2 if the study 
progresses beyond interim 1.

and at least an additional 434 subjects will be enrolled in Cohort 3 if the study 
progresses beyond interim 2.  
If a subject prematurely discontinues the study prior to the Day 29 primary endpoint 
measurement, additional subjects will  be randomized to reach the required number of 
analyzable subjects for a given analysis (please refer to Section 9.3.1 for definition of an 
analyzable  subject). The goal will be to only enroll the minimum number of subjects to 
reach the target number of analyzable subjects.  Although the number of randomized 
subjects who will not be analyzable is unknown, based on expectations of study 
withdrawal and data from previous trials with AVA, it is estimated that no more than 620 
subjects will be randomized to reach the target of 534 analyzable.   The decision to 
randomize additional subjects will be made without knowledge of the ongoing 
comparative results; if ongoing comparative results are known to the Sponsor, no 
additional subjects may be enrolled.

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4.4.
Design Justification
This is a Phase 4 study to evaluate the immunogenicity of SC-administered AVA when 
administered alone or concomitantly with a single IV raxibacumab dose, in healthy adult 
volunteers who have not previously been immunized against the PA of B. anthracis. 
Subjects will receive the first AVA dose immediately after completion of a single 40 
mg/kg raxibacumab IV infusion. Although this is an open-label study, measures have 
been introduced to minimize bias (refer to Section 6.3). 
As a passive anti-toxin antibody, raxibacumab is expected to provide protection against 
PA for up to 28 days post dose [Migone, 2009]. The expected, but currently unapproved, 
use of AVA in combination with raxibacumab would be in the post-exposure prophylaxis 
setting. In that setting, raxibacumab would provide the initial toxin neutralizing activity 
while AVA immunization would generate a durable, toxin neutralizing anti-PA Ab 
response that maintains protection beyond 28 days, since raxibacumab levels may not be 
adequate for protection for more than 28 days post-infusion.  Relative to this, 93% of 
subjects administered SC AVA doses at Weeks 0, 2, and 4 had at least a 4-fold increase 
in TNA titer by Week 4, with higher titers than for intramuscular (IM) doses 
administered according to the same schedule [Marano, 2008].  Based on these findings, 
this study will utilize SC-administered AVA rather than IM-administered AVA because 
the immunogenicity of SC-administered AVA early in the immunization series (at week 
4) is of primary interest. Because of a lack of assay specificity for TNA response due to 
AVA when raxibacumab is present, it is not possible to specifically evaluate a 4 fold 
increase in the TNA titer due to AVA in this study. However, GSK developed analytical 
techniques which allow specific determination of anti-PA Ab concentrations in response 
to AVA vaccination, even in the presence of raxibacumab. Therefore, anti-PA Ab 
concentration will be assessed as the primary endpoint in this study, instead of >4-fold 
increase in TNA titers.  Relative to this, a high correlation between anti-PA Ab levels and 
TNA has been reported [Crowe, 2010; Pittman, 2002; Pittman, 2005; Pittman, 2006; 
Quinn, 2004].  Thus, it is reasonable to expect that measurement of anti-PA Ab is 
reflective of a functional immune response.
Since an immune response to AVA requires some time to develop, it is anticipated that in 
the post-exposure prophylaxis setting the initial AVA dose would be in close temporal 
proximity to the raxibacumab dose. For this study, the first AVA dose will be 
administered immediately after completion of the raxibacumab IV infusion, so that 
raxibacumab levels are as high as possible when AVA administration starts. This should 
maximize the potential for raxibacumab to interfere with AVA immunogenicity. A 
finding of no effect of raxibacumab on AVA immunogenicity in this study can be 
extrapolated to other timings between raxibacumab and AVA administration since it 
represents the worst case scenario for a potential interaction between raxibacumab and 
AVA.
Based on published results, polyclonal anti-PA antitoxin administered to rabbits in 
combination with AVA resulted in essentially complete abrogation of the immune 
response to AVA [Malkevich, 2013].  Thus, it is possible that co-administration of 
raxibacumab with AVA will essentially eliminate any immunogenic response to AVA.  
Given that expectation, this study will enroll subjects in 3 cohorts, with two interim 

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analyses to allow early termination of the study if a large effect of raxibacumab on AVA 
immunogenicity is confirmed at the interim. 
Additional description of the interim analyses, including justification for the timing and 
how they impact the operating characteristics of the study, can be found in Section 9.3.2.
The study duration of 26 weeks was chosen to allow evaluation of the secondary endpoint 
of AVA immunogenicity, including TNA titer, after raxibacumab is essentially 
completely eliminated as an assessment of the durable immune response to AVA. Week 
26 is of interest since it represents the nadir response at the time when an AVA dose 
would be administered to boost response.  In addition, that study duration allows 
collection of safety and tolerability data throughout the period of raxibacumab exposure.  
This is based on data from healthy volunteer studies indicating that >99% of subjects can 
be expected to attain raxibacumab wash-out (i.e., less than 5% of the administered dose 
remaining in the body) by week 24.
4.5.
Dose Justification
Raxibacumab will be administered in accordance with approved product label dosing 
recommendations [Raxibacumab Package Insert, 2012]. Per the package insert, subjects 
will be premedicated with diphenhydramine (25-50 mg) up to 1 hour prior to the 
raxibacumab infusion to reduce the risk of infusion reactions.
AVA will be administered in accordance with the approved product label dosing 
recommendations [Anthrax Vaccine Adsorbed Package Insert, 2012].  This study will 
utilize the SC-administered AVA dosing schedule rather than the IM-administered AVA 
dosing schedule because the immunogenicity of AVA early in the immunization series (at 
Week 4) is of primary interest.  Findings from Marano et al., 2008  indicate that the SC 
regimen affords superior geometric mean serum anti-PA Ab concentrations and >4-fold 
responder percentages at 4 weeks post-vaccination, relative to IM administration given on 
the same schedule.  Hence, the SC regimen could be preferable in a post-exposure 
prophylaxis setting [Centers for Disease Control and Prevention, 2010].
4.6.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
raxibacumab (GSK3068483) can be found in the IB.  Summaries of findings from both 
clinical and non-clinical studies conducted with AVA can be found in the prescribing 
information [Anthrax Vaccine Adsorbed Package Insert, 2012].  The following section 
outlines the risk assessment and mitigation strategy for this protocol
Clinical parameters will be monitored throughout the study in order to assess the safety 
and tolerability of AVA when administered alone or concomitantly with raxibacumab.  
The study design in place will allow in-stream blinded review of the aggregated safety 
and tolerability data during the study. Refer to protocol Section 7.1 for the timing of all 
clinical assessments.

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Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Drug 
Infusion Site Reactions (ISRs)
Infusion-related reactions were reported 
during administration of raxibacumab in 
clinical trials in healthy volunteers including 
reports of rash, urticaria, and pruritus.
Subjects will be premedicated with 25-50 
mg of diphenhydramine up to 1 hour prior 
to the raxibacumab infusion, as 
recommended in the product label.
Close monitoring of clinical parameters and 
adverse events will be conducted to assess 
effects of infusion site reactions.
Other
Injection-site reactions
The most common (≥10%) local (injection-
site) adverse reactions observed in clinical 
studies with AVA were tenderness, pain, 
erythema, edema, and arm motion 
limitation.
Close monitoring of clinical parameters and 
adverse events will be conducted to assess 
effects of injection-site reactions.

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4.6.1.
Benefit Assessment
An individual may benefit from participation in this study due to the following:

Physical exam and hematology and clinical chemistry assessments conducted as 
part of the study procedures.

Participation in this study could contribute valuable information on the 
immunogenicity of AVA administered alone or concomitantly with raxibacumab.
Since no subject will receive the full AVA immunization series as part of this study, no 
subject should be considered to have a durable anti-PA Ab response at completion of the 
study.  Hence, the subject should be considered to be at risk if exposed to anthrax.
4.6.2.
Overall Benefit:Risk Conclusion
Taking into account the measures taken to minimize risk to subjects participating in this 
study, the potential risks identified in association with this study are justified by the 
anticipated benefits that may be afforded to subjects.
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GlaxoSmithKline (GSK) investigational product or 
other study treatment that may impact subject eligibility is provided in the raxibacumab, 
diphenhydramine, and AVA package inserts.
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
1. Healthy as determined by the Investigator or medically qualified designee based 
on a medical evaluation including medical history, physical examination and 
laboratory tests
2. Men and women between 18 to 65 years of age
3. Willing and able to adhere to the procedures stated in the protocol.
4. Female subject is eligible to participate if she is not pregnant (as confirmed by a 
negative serum or urine human chorionic gonadotrophin (hCG) test), not 
lactating, and at least one of the following conditions applies:

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A. Non-reproductive potential defined as:

Pre-menopausal females with one of the following:

Documented tubal ligation

Documented hysteroscopic tubal occlusion procedure with follow-
up confirmation of bilateral tubal occlusion 

Hysterectomy

Documented Bilateral Oophorectomy

Postmenopausal defined as 12 months of spontaneous amenorrhea [in 
questionable cases a blood sample with simultaneous follicle stimulating 
hormone (FSH) and estradiol levels consistent with menopause (refer to 
laboratory reference ranges for confirmatory levels)].  Females on 
hormone replacement therapy (HRT) and whose menopausal status is in 
doubt will be required to use one of the highly effective contraception 
methods if they wish to continue their HRT during the study.  
Otherwise, they must discontinue HRT to allow confirmation of post-
menopausal status prior to study enrollment.
B. Reproductive potential and agrees to follow one of the options listed in 
Appendix 3 requirements, the GSK Modified List of Highly Effective 
Methods for Avoiding Pregnancy in Females of Reproductive Potential 
(FRP), from 30 days prior to the first dose of study medication and until after 
the last dose of study medication and completion of the follow-up visit at 
Day 183 (at least five terminal half-lives for raxibacumab).
5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
1. Concurrently participating in another clinical study, at any time during the study 
period, in which the subject has been or will be exposed to an investigational or 
non-investigational study vaccine/product (pharmaceutical product or device).
2. Be a member of the military, a laboratory worker, first responder, health care 
worker, or otherwise be at higher risk of exposure to anthrax
3. History of regular alcohol consumption within 1 month of the study defined as: 

An average weekly intake of >14 drinks for males or >7 drinks for 
females. One drink is equivalent to 12 g of alcohol: 12 ounces (360 ml) of 
beer, 5 ounces (150 ml) of wine or 1.5 ounces (45 ml) of 80 proof distilled 
spirits.
4. Female planning to become pregnant or planning to discontinue contraceptive 
precautions before the Day 183 study visit.

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5. Pregnant (confirmed by a serum or urine hCG test) or lactating female.
6. ALT and bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if 
bilirubin is fractionated and direct bilirubin <35%).
7. Current or chronic history of liver disease, or known hepatic or biliary 
abnormalities (with the exception of Gilbert's syndrome or asymptomatic 
gallstones).
8. Any confirmed or suspected immunosuppressive or immunodeficient condition 
resulting from disease (e.g., malignancy, human immunodeficiency virus [HIV] 
infection) or immunosuppressive/cytotoxic therapy (e.g., medications used during 
cancer chemotherapy, organ transplantation or to treat autoimmune disorders).
9. Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody 
test results at screening or within 3 months prior to first dose of study treatment.
10. A positive pre-study drug/alcohol screen.  
11. A positive test for HIV antibody.
12. History of sensitivity to any of the study medications, or components thereof 
(especially latex and aluminium) or a history of other known drug allergies that, 
in the opinion of the Investigator or GSK Medical Monitor, contraindicates their 
participation.  Refer to raxibacumab, diphenhydramine and AVA package inserts 
for product specific information [Anthrax Vaccine Adsorbed Package Insert, 
2012; Raxibacumab Package Insert, 2012; Diphenhydramine Package Insert].
13. Have previously been vaccinated against PA.
14. Have an anti-PA Ab concentration >2 times the lower limit of quantitation at 
screening.
15. Administration of immunoglobulins not included in this trial and/or any blood 
products within the 3 months preceding the first dose of study vaccine or planned 
administration during the study period.
16. Administration of long-acting immune-modifying drugs (e.g. infliximab) within 
six months prior to the first vaccine dose or expected administration at any time 
during the study period.
17. Chronic administration (defined as more than 14 consecutive days) of systemic 
immunosupressants or other immune-modifying drugs within six months prior to 
the first vaccine dose. Inhaled, topical and intra-articular corticosteroids are 
allowed.
18. Administration or planned administration of a vaccine not foreseen by the study 
protocol within the period starting 35 days before the first dose of study 
vaccine(s) and ending 30 days after the last dose of study vaccine.  This includes 

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any type of vaccine such as (but not limited to) live, inactivated, and subunit 
vaccines. Influenza vaccines are permitted after Week 8. 
19. Subjects must abstain from taking prescription or non-prescription drugs 
(including vitamins and dietary or herbal supplements), within 7 days (or 14 days 
if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) 
prior to the first dose of study medication until completion of the follow-up visit, 
unless in the opinion of the Investigator and sponsor the medication will not 
interfere with the study.  Refer to Section 6.10.1 for permitted medications.
20. Exposure to more than four new chemical entities within 12 months prior to the 
first dosing day.
21. Any condition which, in the opinion of the investigator, prevents the subject from 
participating in the study.
5.3.
Screening/Baseline/Run-in Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized. In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria, and any Serious Adverse Events (SAE).
Subjects who initially do not meet eligibility criteria may be re-screened one time if their 
potential eligibility status has changed.  Eligible subjects may then be enrolled in this 
study.
5.4.
Withdrawal/Stopping Criteria
Criteria for study treatment withdrawal may include:

Sponsor terminates the study

Subject lost to follow-up

Subject withdraws consent

Protocol deviation

Investigator discretion

Subject experiences an adverse event(s) that is considered to be related to study drug 
or study procedures and is severe enough in nature to warrant treatment 
discontinuation.

Pregnancy (confirmed by a serum or urine hCG test)

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Subjects withdrawn from study treatment will be permitted to continue on the study. 
Subjects withdrawn from the study due to safety reasons or pregnancy will continue to be 
followed for safety data until resolution of the safety event and for pregnancy outcomes 
(please refer to Appendix 5 and Section 7.4.1 for additional information).
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as soon 
as possible. 

The site must counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the study. 

In cases where the subject is deemed ‘lost to follow up’, the investigator or designee 
must make every effort to regain contact with the subject (where possible, 3 
telephone calls and if necessary a certified letter to the subject’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the subject’s medical record. 

Should the subject continue to be unreachable, only then will he/she be considered to 
have withdrawn from the study with a primary reason of “Lost to Follow-up”. 
A subject may withdraw from study treatment at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioural or 
administrative reasons. If a subject withdraws from the study, he/she may request 
destruction of any samples taken, and the investigator must document this in the site 
study records. 
The reason(s) for a subject not completing the study will be recorded in the Case Report 
Form (CRF), and the investigator must document, if applicable, the reason (if specified 
by the subject) for withdrawal of consent.
5.4.1.
Liver Chemistry Stopping Criteria
As experience in humans is limited, it is standard GSK practice to collect information on 
liver events if they occur.
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
If liver chemistry abnormalities are seen (e.g., ALT ≥ 3xULN and bilirubin ≥ 2xULN; 
ALT ≥ 5xULN; ALT ≥ 3xULN if associated with symptoms believed to be related to 
hepatitis or hypersensitivity), it is recommended that the physician obtains follow-up 
liver chemistries until resolved, stabilized or returned to baseline.

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It is recommended that additional follow-up assessments (e.g., viral hepatitis serology, 
serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH), liver imaging) 
are performed as clinically indicated to further evaluate other potential causes of the 
abnormalities and to assess the severity of the injury.
Refer to Appendix 2 for liver safety required actions and follow-up assessments. 
5.4.1.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any subject participating in this study is not allowed.
5.5.
Subject and Study Completion
A completed subject is one who has completed all study visits including the follow-up 
visit. 
The end of the study is defined as the last subject’s last visit.
5.6.
Definition of an Analyzable Subject
A subject will be considered to be analyzable if they meet all of the following criteria:
1. Receive at least the Day 1 and Day 15 AVA doses,
2. Receive the raxibacumab dose, if randomized to that treatment, and
3. Complete the primary study endpoint assessment (anti-PA Ab concentration at 
Week 4).
Any subject who meets these criteria will be included in data analysis for the primary 
endpoint.
6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design. Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments.

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Study Treatmenta
Product name:
GSK3068483 
raxibacumab
BioThrax
Diphenydramine
Formulation 
description:
Raxibacumab drug 
product comprises 50 
mg/mL protein in 
0.13 mg/mL citric 
acid, 2.8 mg/mL 
sodium citrate, 10 
mg/mL sucrose, 18 
mg/mL glycine, and 
0.2 mg/mL 
polysorbate 80, 
pH 6.5
34 mL and 1700 mg 
deliverable per vial
BioThrax is made from cell-free 
filtrates of microaerophilic 
cultures of an avirulent, 
nonencapsulated strain of B. 
anthracis. The production 
cultures are grown in a 
chemically defined protein-free 
medium consisting of a mixture 
of amino acids, vitamins, 
inorganic salts, and sugars. The 
final product, prepared from the 
sterile filtrate culture fluid 
contains proteins, including the 
83kDa protective antigen (PA) 
protein, released during the 
growth period and contains no 
dead or live bacteria. The final 
product is formulated to contain 
1.2 mg/mL aluminum, added as 
aluminum hydroxide in 0.85% 
sodium chloride. The final 
product is formulated to contain 
25 mcg/mL benzethonium 
chloride and 100 mcg/mL 
formaldehyde, added as 
preservatives.
Diphenhydramine route of 
administration (oral or IV) 
should be based on the 
temporal proximity to the 
start of raxibacumab 
infusion.
For formulation information, 
refer to the labelling of the 
specific product chosen for 
administration
Dosage form:
sterile, liquid 
formulation in single-
use vials
Sterile, milky-white suspension, 
in multi-use vials. 
Refer to the labelling of the 
specific product chosen for 
administration
Unit dose 
strength(s)/
Dosage 
level(s):
40 mg/ kg
0.5 mL dose
Diphenhydramine should 
be administered at 25 – 50 
mg.  Refer to the labelling 
of the specific product
chosen for administration 
for unit dose strength.
Route of 
Administration
IV
SC
Route of administration 
(oral or IV) should be based 
on the temporal proximity to 
the start of raxibacumab 
infusion.

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Study Treatmenta
Product name:
GSK3068483 
raxibacumab
BioThrax
Diphenydramine
Dosing 
instructions:
For the combination 
treatment group, the 
raxibacumab dose 
will be administered 
just prior to the first 
AVA dose.The 
calculated 
raxibacumab dose to 
be administered to 
the subject will be 
diluted in normal 
saline with a final 
volume of 250 mL. 
The rate of 
raxibacumab infusion 
should be set for 
15 mL/hour for the 
first 20 minutes and 
then adjusted to 125 
mL/hour for the 
remainder of the 
infusion period. With 
this schedule, 
approximately 250 
mL should be infused 
over the course of 2 
hours and 15 
minutes.
For the combination treatment 
group, the first Biothrax dose will 
be administered immediately 
after completion of the 
raxibacumab IV infusion, in the 
opposite arm.  Refer to Section 2
of the Biothrax product label for 
dosing instructions.
Key points to consider are:
Shake the vial thoroughly;
inspect visually for 
particulate matter and 
discoloration prior to 
administration. Do not 
administer if present;
administer by SC route 
using a ⅝-inch, 25- to 27-
gauge sterile needle and 
syringe;
use a different injection site 
(e.g. alternating arms) for 
each sequential injection;
For the combination 
treatment group, 
premedicate with 
diphenhydramine within 1 
hour prior to raxibacumab 
infusion. Refer to the 
labelling of the specific 
product chosen for 
administration for dosing 
instructions
Physical 
description:
The drug product is 
filled into 50 mL USP 
Type I borosilicate 
glass vials, sealed 
with a 20 mm 
chlorobutyl rubber 
stopper and 20 mm 
flip-off aluminum seal, 
and stored at 2-8ºC 
protected from light
BioThrax is supplied in 5 mL 
multidose vials containing ten 0.5 
mL doses, and stored at 2-8ºC 
(36F to 46F).  Do not freeze. 
Refer to the labelling of the 
specific product chosen for 
administration
Method for 
individualizing 
dosage:
Weight-based dosing.
None
None
a.
Listed study products are commercially sourced
6.2.
Treatment Assignment
Subjects will be assigned to Treatment Group 1 or Treatment Group 2 in accordance with 
a balanced independent randomization schedule generated prior to the start of the study.  
A corresponding set of randomization envelopes (one per subject) will be generated. A 

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randomization envelope for each subject will be opened prior to dosing (on day -1) to 
reveal the subject’s treatment assignment.  This process will ensure that study personnel 
and the volunteers will have no knowledge of the next treatment to be assigned.
Once a randomization number has been assigned to a subject, it will not be re-assigned to 
another subject.  Randomization numbers will be assigned sequentially as subjects 
become eligible for dosing.
6.3.
Blinding
This will be an open-label study.  However, measures will be taken to reduce introduction 
of bias and the following will apply. 

Investigators, site staff and the subject have direct access to each subject’s individual 
study treatment only with the opening of the randomization envelope.

The following measures will be incorporated to blind specific aspects of the study in 
order to minimize bias and maintain study integrity:

Within the clinic, only the pharmacy will have access to the full randomization 
schedule.

The Sponsor team will be blinded except for the laboratory personnel, who must 
meet the following criteria:
1. All analysts will be trained to Good Laboratory Practice (GLP) and follow 
Standard Operating Procedure (SOP) on the analysis of samples, inclusive 
of having Quality Control (QC) checks of all their work throughout the 
entire analysis. 
2. The final data will be peer-reviewed, minimizing the opportunity for any 
bias to affect the results. All samples will be analyzed and reported in a 
validated computer system with documented audit trails.
An external statistician and clinician (ie. not involved in conduct of the trial) will 
be responsible for performing the interim analyses, and will be instructed to only 
communicate to the team whether or not the futility boundary has been crossed, 
and will not share any subject-specific or summary-level information with the 
Sponsor team.   
Monitoring will be completed by unblinded GSK monitors who will not share 
blinded information with the Sponsor team.  An unblinded Clinical Research 
Associate independent from the study team will review monitoring reports and 
specific protocol deviations outlined in the Protocol Deviation Management Plan. 
Throughout the course of study, the raxibacumab Safety Review Team (SRT) will 
evaluate accumulating aggregate blinded clinical trial safety data to monitor for 
potential treatment related effects (such as the identification of new safety issues, 
as well as the identification of clinically relevant changes in known safety issues).

GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff or delegates may 
unblind the treatment assignment for any subject with an SAE. If the SAE requires 
that an expedited regulatory report be sent to one or more regulatory agencies, a copy 
of the report, identifying the subject’s treatment assignment, may be sent to 
investigators in accordance with local regulations and/or GSK policy.

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6.4.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
6.5.
Preparation/Handling/Storage/Accountability
Diphenhydramine, raxibacumab and AVA will be prepared, stored and administered 
according to current product label requirements [Anthrax Vaccine Adsorbed Package 
Insert, 2012; Raxibacumab Package Insert, 2012; Diphenhydramine Package Insert].  A 
description of the methods and materials required for preparation of raxibacumab and 
AVA will be detailed in a Study Specific Technical Agreement/Memo (TTS) or 
Pharmacy Manual which will be accompanied by a Quality Agreement.
When the individual dose of study treatments are prepared for a subject, the preparation 
of the dose will be confirmed by a second member of the study site staff.  
Only subjects enrolled in the study may receive study treatment and only authorized site 
staff may supply or administer study treatment.  All study treatments must be stored in a 
secure environmentally controlled and monitored (manual or automated) area in 
accordance with the labelled storage conditions with access limited to the investigator 
and authorized site staff. 
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance 
(i.e. receipt, reconciliation and final disposition records).  
Further guidance and information for final disposition of unused study treatment are 
provided in the Study Reference Manual (SRM). 
Under normal conditions of handling and administration, study treatment is not expected 
to pose significant safety risks to site staff.  Take adequate precautions to avoid direct eye 
or skin contact and the generation of aerosols or mists. In the case of unintentional 
occupational exposure notify the monitor, Medical Monitor and/or GSK study contact.
A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from GSK.
6.6.
Compliance with Study Treatment Administration
Subjects will receive raxibacumab intravenously in accordance with the approved dosing 
recommendations for adults [Raxibacumab Package Insert, 2012] and/or AVA 
subcutaneously in accordance with the approved dosing recommendations for adults 
[Anthrax Vaccine Adsorbed Package Insert, 2012].  Raxibacumab and AVA will be 
administered in opposite limbs.  Each sequential AVA injection will be administered in a 
different injection site (e.g. alternating arms). Diphenhydramine, 25 to 50 mg, should be 
administered within 1 hour prior to raxibacumab infusion to reduce the risk of infusion 
reactions.  Diphenhydramine route of administration (oral or IV) should be based on the 

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temporal proximity to the start of raxibacumab infusion.  Administration will be recorded 
in the source documents and reported in the CRF.  
Subjects will receive study treatment directly from the investigator or designee, under 
medical supervision.  The date and time of each dose administered in the clinic will be 
recorded in the source documents.  The dose of study treatment and study subject 
identification will be confirmed at the time of dosing by a member of the study site staff 
other than the person administering the study treatment.
Mild infusion site reactions have been observed in subjects dosed with raxibacumab, 
which have been successfully prevented using an anti-histamine prior to dosing.  
Hypersensitivity reactions have been reported with AVA. Should symptoms of acute 
hypersensitivity occur, an extended period of monitoring may be appropriate, based on 
clinical judgement.  Subjects should be made aware of the potential risk, the signs and 
symptoms of such reactions, and the importance of immediately seeking medical 
attention.
The schedule for the administration of study treatment is outlined in the Time and Events 
Tables (Section 7.1).  The site staff should monitor any subject who may experience a 
hypersensitivity reaction following the administration of study treatment.  Refer to 
Section 7.4.1 and Appendix 4 for information on the procedures for recording and 
evaluating AEs/SAEs.  The decision regarding the administration of the vaccine 
following a hypersensitivity reaction will be made by the investigator in consultation with 
the Medical Monitor based on the clinical evaluation of the subject.
6.7.
Treatment of Study Treatment Overdose
For this study, any dose of study treatment greater than that described in the product label 
will be considered an overdose [Anthrax Vaccine Adsorbed Package Insert, 2012; 
Raxibacumab Package Insert, 2012; Diphenhydramine Package Insert].
GSK does not recommend specific treatment for a raxibacumab overdose
In the event of an overdose, the investigator should:
1.
contact the Medical Monitor immediately
2.
closely monitor the subject for AEs/serious adverse events (SAEs) and laboratory 
abnormalities until drug can no longer be detected
3.
document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF.
Since only AVA is dosed on more than one occasion, the decision regarding the 
administration of the second dose of vaccine will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the subject.
6.8.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study because only healthy volunteers are eligible for study participation.

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6.9.
Lifestyle and/or Dietary Restrictions
Subjects who have a history of regular alcohol consumption as defined in Section 5.2 will 
be excluded from the study.
During each dosing session, subjects will abstain from alcohol for 24 hours prior to the 
study visit. 
6.10.
Concomitant Medications and Non-Drug Therapies
6.10.1.
Permitted Medications and Non-Drug Therapies
Concomitant medication may be considered on a case by case basis by the investigator in 
consultation with the Medical Monitor if required.  Any concurrent medication 
administered to the subject during the study should be recorded in CRF.  Tylenol, 
effective methods of contraception (detailed in Appendix 3), and the influenza vaccine 
will be permitted. 
6.10.2.
Prohibited Medications and Non-Drug Therapies
Subjects must abstain from taking prescription or non-prescription drugs (including 
vitamins and dietary or herbal supplements), within 7 days (or 14 days if the drug is a 
potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of 
study medication until completion of the follow-up visit, unless in the opinion of the 
Investigator and sponsor the medication will not interfere with the study.
Medication prohibited during the course of this study include:

immunoglobulins not included in this trial 

any blood products 

long-acting immune-modifying drugs (e.g. infliximab)

chronic administration (defined as more than 14 consecutive days) of 
immunosupressants or other immune-modifying drugs (such as corticosteroids).  
Inhaled, topical and intra-articular corticosteroids are allowed.

administration of a vaccine not foreseen by the study protocol.  This includes any 
type of vaccine such as (but not limited to) live, inactivated, and subunit vaccines.  
Influenza vaccine is permitted after Week 8. 

Administration of an investigational or non-investigational study vaccine/product 
(pharmaceutical product or device).
7.
STUDY ASSESSMENTS AND PROCEDURES
Informed consent must be obtained prior to enrollment in the study and conduct of any 
study procedures.  
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 

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specified in the Time and Events Tables (Section 7.1), are essential and required for study 
conduct.
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table (Section 7.1).  All 
data collected for this study will be recorded in the subjects’ CRF.
The timing and number of planned study assessments, including safety assessments may 
be altered during the course of the study based on newly available data to ensure 
appropriate monitoring.
The change in timing or addition of time points for any planned study assessments must 
be documented in a Note to File which is approved by the relevant GSK study team 
member and then archived in the study sponsor and site study files, but this will not 
constitute a protocol amendment. 
The IRB/IEC will be informed of any safety issues that require alteration of the safety 
monitoring scheme or amendment of the Informed Consent Form (ICF). 
No more than 500 mL of blood will be collected over the duration of the study, including 
any extra assessments that may be required. The Time and Events Tables (Section 7.1) 
detail the timings for study assessment.

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7.1.
Time and Events Table
Table 1
Screening assessments for subjects administered AVA or co-administered raxibacumab and AVA
Screening Assessments 
Days -36 to -15a
Notes
Informed consent process
X
Demographic information
X
Inclusion/Exclusion criteria
X
Medical history (includes substance usage and 
Family history of premature CV disease)
X
Physical exam including height and weight 
X
Alcohol and Drug Screening
X
Urinalysis
X
Vital signs
X
Hematology and clinical chemistry
X
Refer to Table 4 for specific laboratory tests.
HIV, Hep B and Hep C screen
X
Review concomitant medications
X
Serum or urine pregnancy test
X
AE/SAE assessment  
X
Will capture SAEs reported between Screening visit and 
Day -1.
Toxin Neutralizing Ab (TNA)
X
Anti-PA Ab
X
a.
The screening window closes at Day -15 to allow all analyses to be completed to confirm subject eligibility.

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Table 2
Treatment Group 1: Time and Events for subjects administered AVA
Protocol Activity
Study Visit
Notes
Assessments
Day -1a
Day 1
Day 15
(2 days)
Day 29
(2 days)
Day 57
(2 days)
Day 183
(4 days)
Inpatient visit
X
Outpatient visit
------X------
Urinalysis
X
Admit to unit
X
Randomization
X
Discharge from unit
X
The subject will be discharged from the unit after all assessments are completed.
Vital signs
X
X
X
X
X
Hematology and clinical chemistry
X
X
X
Refer to Table 4 for specific laboratory tests. On Day 29 the specimen will be collected 
prior to AVA injection.
Review concomitant medications
X
X
X
X
X
Serum or urine pregnancy test
X
X
X
X
X
AVA administration
X
X
X
Each sequential AVA injection will be administered in a different injection site (e.g. 
alternating arms).
AE/SAE assessment  
X
X
X
X
X
X
Toxin Neutralizing Ab (TNA)
X
X
X
X
On Days 1 and 29 the specimen will be collected prior to AVA injection.
Anti-PA Ab
X
X
X
X
On Days 1 and 29 the specimen will be collected prior to AVA injection.
a.
Day -1 is the calendar day preceding Day 1; the designation “Day 0” is not used in this study.

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Table 3
Treatment Group 2: Time and Events Table for subjects co-administered raxibacumab and AVA
Protocol Activity
Study Visit
Notes
Assessments
Day -1a
Day 1
Day 15
(2 days)
Day 29
(2 days)
Day 57
(2 days)
Day183
(4 days)
pre-raxi 
infusion
0 hr
0.5 hr
(5 min)
2-6 hrs
Inpatient visit
----------X----------
Outpatient visit
----------X----------
Urinalysis
X
Admit to unit
X
Randomization
X
Discharged from unit
X
The subject will be discharged from the unit after all assessments are completed.
Vital signs
X
X
X
X
X
Hematology and clinical 
chemistry
X
X
X
Refer to Table 4 for specific laboratory test.  On Day 29 the specimen will be 
collected prior to treatment administration.
Review concomitant medications
X
X
X
X
X
Serum or urine pregnancy test
X
X
X
X
X
Diphenhydramine administration
X
Diphenhydramine (25-50 mg) must be administered within 60 minutes prior to the 
raxibacumab infusion.
Raxibacumab administration 
X
Raxibacumab infusion must be completely administered prior to first AVA dose 
on Day 1 and administered in opposite limb from AVA injection.
AVA administration
X
X
X
Each sequential AVA injection will be administered in a different injection site (eg. 
alternating arms).
AE/SAE assessment
X
X
X
X
X
X
X
X
PK sampling
X
X
X
X
X
X
X
A blood specimen will be collected prior to raxibacumab infusion, 30 minutes post 
raxibacumab infusion (5 min), 2-6 hours post infusion on Day 1, and at Days 
15, 29, and 57 (14, 28, and 56 days post raxibacumab administration). An 
additional sample will be collected at the Day 183 visit.
Anti-raxibacumab Ab
X
X
X
Toxin Neutralizing Ab (TNA)
X
X
X
X
The Day 29 specimens will be collected prior to AVA administration.
Anti-PA Ab
X
X
X
X
The Day 29 specimens will be collected prior to AVA administration.
a.
Day -1 is the calendar day preceding Day 1; the designation “Day 0” is not used in this study.

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7.2.
Screening and Critical Baseline Assessments
After written informed consent is provided, the following data will be collected at the 
screening visit for all subjects:

Demographic parameters: year of birth, gender, race, and ethnicity.

Medical/medication/family history will be assessed as related to the 
inclusion/exclusion criteria listed in Section 5.

Physical assessment data including vital signs (temperature, heart rate, systolic 
and diastolic blood pressure, respiratory rate), height and weight.

Laboratory assessments (hematology, clinical chemistry)

Urinalysis 

Alcohol, Drug, HIV, Hepatitis B and Hepatitis C screenings 

A serum or urine pregnancy test on women of childbearing potential

Blood specimen for anti-PA Ab levels and TNA titers.

Record of concomitant medications

Monitoring and reporting of SAEs
The following will be collected as baseline data on Day -1:

A serum or urine pregnancy test on women of childbearing potential

Record of concomitant medications

Vital signs

Results from clinical chemistry and hematology laboratory evaluations (refer to 
Table 4 for specific assessments)

Monitoring and reporting of AEs including SAEs
The following will be collected as baseline data on Day 1 prior to study treatment 
administration:

Blood specimen for anti-PA Ab levels and TNA titers
Additionally, for subjects randomized to Treatment Group 2, the following will be 
collected as baseline data on Day 1 prior to study treatment administration:

Blood specimen for anti-raxibacumab Ab level

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
Blood specimen for serum raxibacumab concentrations
7.3.
PA, TNA and Anti-raxibacumab Antibodies
Serum anti-PA Ab concentrations and raxibacumab will be determined by GSK PTS-
DMPK.  Serum AVA derived anti-PA Ab concentrations will be determined using an 
approved immunoassay. Additionally, serum raxibacumab concentrations will be 
determined using an approved method based on immunocapture and  trypsin digest, 
followed by UHPLC/MS/MS analysis. All data will be held under the control of US 
(UM) GSK  R&D GLP archive.
Serum TNA titers will be determined using a cell-based assay, under the auspices of 
Clinical Immunology, GSK.
Serum anti-raxibacumab Ab analysis will be performed under the control of Clinical 
Immunology, GSK.  The presence of anti-raxibacumab Ab will be determined using 
validated ECL bridging assay.
Details of the anti-PA Ab concentration, TNA titer, and anti-raxibacumab Ab analyses 
and the archiving of raw data will be included in the SRM.    
7.4.
Safety
Clinical safety observations will include AEs, urinalysis, vital sign measurements, and 
clinical laboratory assessments.  Planned time points for all safety assessments are listed 
in the Time and Events Table (Section 7.1).  Additional time points for safety tests (such 
as vital signs, physical exams and laboratory safety tests) may be added during the course 
of the study based on newly available data to ensure appropriate safety monitoring.
Safety evaluations of data from clinical laboratory tests and spontaneous adverse event 
reporting will be performed for all subjects who receive study treatment.  Details on 
specific safety assessments are provided below.
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 4.  
AEs will be assessed for severity based on the modified Division of Microbiology and 
Infectious Diseases (DMID) toxicity tables in Appendix 6. For AEs not included in these 
toxicity tables, the following guidelines apply:
Mild 
An event causing no limitation of usual activities
Moderate
An event causing some limitation of usual activities
Severe
An event causing inability to carry out usual activities
Life threatening*
An event that is potentially life threatening or disabling 

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The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
7.4.1.1.
Time Period and Frequency for Collecting AE and SAE Information
AEs and SAEs will be collected from the start of study treatment until the follow-up 
contact (see Section 7.4.1.3), at the timepoints specified in the Time and Events Table 
(Section 7.1).
Medical occurrences that begin prior to the start of study treatment but after obtaining 
informed consent may be recorded on the Medical History/Current Medical Conditions 
section of the CRF.
Any SAEs assessed as related to study participation (e.g., protocol-mandated procedures, 
invasive tests, or change in existing therapy) or related to a GSK product will be recorded 
from the time a subject consents to participate in the study up to and including any 
follow-up contact. 
All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Appendix 4.
Investigators are not obligated to actively seek AEs or SAEs in former study subjects. 
However, if the investigator learns of any SAE, including a death, at any time after a 
subject has been discharged from the study, and he/she considers the event reasonably 
related to the study treatment or study participation, the investigator must promptly notify 
GSK.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 4.
7.4.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:

“How are you feeling?”

“Have you had any (other) medical problems since your last visit/contact?”

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?”
7.4.1.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All SAEs, and non-serious AEs of special interest 
(as defined in Appendix 4) will be followed until resolution, until the condition stabilizes, 

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until the event is otherwise explained, or until the subject is lost to follow-up (as defined 
in Section 5.4). Further information on follow-up procedures is given in Appendix 4.
7.4.1.4.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK or designee of SAEs and non-serious AEs 
related to study treatment (even for non- interventional post-marketing studies) is 
essential so that legal obligations and ethical responsibilities towards the safety of 
subjects and the safety of a product under clinical investigation are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRB/IEC and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
7.4.2.
Pregnancy
Details of all pregnancies in female subjects will be collected after the start of dosing and 
until Day 183.
If a pregnancy is reported then the investigator should inform GSK within 2 weeks of
learning of the pregnancy and should follow the procedures outlined in Appendix 5.
7.4.3.
Physical Exams
A complete physical examination will include, at a minimum, assessment of the 
cardiovascular, respiratory, gastrointestinal and neurological systems. Height and weight 
will also be measured and recorded. 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
7.4.4.
Vital Signs
Vital signs will be measured in semi-supine position after 5 minutes rest and will include 
temperature, systolic and diastolic blood pressure and pulse rate and respiratory rate. 
For the Screening visit, three readings of blood pressure and pulse rate will be taken

First reading should be rejected

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
Second and third readings should be averaged to give the measurement to be 
recorded in the CRF. 
At all other study visits where vital signs will be assessed (refer to Section 7.1), single 
measurements are permitted.  If an abnormal reading occurs then repeat measurements 
should be taken as described above.
7.4.5.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 4, must be conducted in 
accordance with the Laboratory Manual, and Protocol Time and Events Schedule.
Laboratory requisition forms must be completed and samples must be clearly labelled 
with the subject number, protocol number, site/centre number, and visit date. Details for 
the preparation and shipment of samples will be provided by the laboratory and are 
detailed in the SRM or the laboratory manual. Reference ranges for all safety parameters
will be provided to the site by the laboratory responsible for the assessments.
Hematology, clinical chemistry and additional parameters to be tested are listed in Table 
4. 
Table 4
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
Automated WBC Differential:
RBC Count
MCV
Neutrophils
WBC Count (absolute)
MCH
Lymphocytes
Reticulocyte Count
MCHC
Monocytes
Hemoglobin
Eosinophils
Hematocrit
Basophils
Clinical 
Chemistry 1
BUN
Potassium
AST (SGOT)
Total and direct 
bilirubin
Creatinine
Chloride
ALT (SGPT)
Uric Acid
Glucose 
Total CO2
GGT
Albumin
Magnesium
Sodium
Calcium
Alkaline phosphatase
Total Protein
Calculated Creatinine clearance – Cockcroft-Gault 
Calculation
Other Screening 
Tests

Urinalysis (routine dipstick)

HIV

Hepatitis B (HBsAg)

Hepatitis C (Hep C antibody)

FSH and estradiol (as needed in women of non-child bearing potential only)

Alcohol and drug screen  (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines)

Urine or serum hCG Pregnancy test (as needed for women of child bearing 
potential) 

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NOTES :
Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up Assessments after liver stopping or 
monitoring event are given in Section 5.4.1 and Appendix 2. 
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE) the results must be 
recorded in the CRF.
Refer to the SRM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws.
All laboratory tests with values that are considered clinically significantly abnormal 
during participation in the study should be repeated until the values return to normal or 
baseline.  If such values do not return to normal within a period judged reasonable by the 
investigator, the etiology should be identified and the sponsor notified.
7.5.
Pharmacokinetics
Blood samples for pharmacokinetic (PK) analysis of raxibacumab will be collected from 
all the subjects in the AVA/raxibacumab treatment group at the time points indicated in 
Section 7.1, Time and Events Table.  The actual date and time of each blood sample 
collection will be recorded.  The timing of PK samples may be altered and/or PK samples 
may be obtained at additional time points to ensure thorough PK monitoring.  
Detailed processing, storage and shipping procedures are provided in the SRM.
7.5.1.
Pharmacokinetic Analyses
Serum raxibacumab concentrations will be determined using a LC-MS/MS assay by
DMPK, GSK.  All pharmacokinetic data will be stored in the Archives, GSK R&D.
7.5.1.1.
Pharmacokinetic Parameters
PK analysis will be the responsibility of the CPMS Department, Quantitative Sciences, 
GSK.  PK analysis of serum raxibacumab concentration-time data will be conducted 
using non-compartmental methods.
The following PK parameters will be determined if data permit:

maximum observed serum raxibacumab concentration (Cmax)

time of occurrence for Cmax (tmax)

area under the serum raxibacumab concentration-time curve to the time of the last 
measurable concentration (AUC0-t)

area under the serum raxibacumab concentration-time curve to infinite time 
(AUC0-∞)

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
percentage of AUC0-∞that is extrapolated

terminal elimination rate constant (λz)

half-life of drug elimination in the terminal phase (t1/2,z)

mean residence time (MRT)

clearance (CL)

volume of distribution in the terminal phase (Vz)

volume of distribution at steady-state (Vss)
8.
DATA MANAGEMENT
For this study subject data will be entered into GSK defined eCRFs, transmitted 
electronically to GSK or designee and combined with data provided from other sources in 
a validated data system.  
Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., removing 
errors and inconsistencies in the data.
Adverse events and concomitant medications terms will be coded using MedDRA 
(Medical Dictionary for Regulatory Activities) and an internal validated medication 
dictionary, GSKDrug.  
CRFs (including queries and audit trails) will be retained by GSK, and copies will be sent 
to the investigator to maintain as the investigator copy.  Subject initials will not be 
collected or transmitted to GSK according to GSK policy.
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1.
Hypotheses
Given concentrations are often approximately log normally distributed, they are 
customarily analyzed on a logarithmic (log) scale; a difference in arithmetic means on a 
log scale becomes a ratio of geometric means when the results of analysis are converted 
back to the original data scale. Thus, each hypothesis is a statement regarding a ratio of 
geometric mean concentrations of the anti-PA Ab attributable to AVA.
The null and alternative hypotheses are as follows: 
H0: θ = μAVA / μAVA+Raxibacumab ≥ 1.5 
HA: θ = μAVA / μAVA+Raxibacumab < 1.5 

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Where θ is the ratio of the geometric mean concentrations (GMCs); μAVA and 
μAVA+Raxibacumab are the population GMCs of the anti-PA Ab attributable to AVA 
for the two arms.
The null hypothesis is that the ratio of the GMC of anti-PA Ab attributable to AVA in the 
AVA arm to the GMC of anti-PA Ab in the AVA+ raxibacumab arm is greater than or 
equal to 1.5. The alternative hypothesis is that the ratio is less than 1.5. 
As described above, the non-inferiority margin for the ratio of the geometric means was 
selected to be 1.5. This is the same margin selected in Marano et al. (2008) based on 
guidances from the FDA and ICH (International Conference on Harmonisation of 
Technical Requirements for Registration of Pharmaceuticals for Human Use) and 
literature precedent.
9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
The sample size calculation is based on the assumption that the individual values will be 
analyzed after being transformed by log10 resulting in data that is approximately normal. 
In the transformed data the analysis of the ratio of the means is equivalent to a difference 
of mean values with a margin of log10 (1.5)= 0.176. 
The standard deviation of the log10 transformed data is assumed to be 0.75. This is 
selected based on the fact that the sample size in Marano et al. (2008) was based on a 
standard deviation of 0.45 based on the data from [Pittman, 2002], but the results from
the Marano et al. (2008) study had higher standard deviations suggesting an estimate 
closer to 0.85. 
The sample size is calculated assuming 1:1 randomization and two interim analyses for 
futility after 30 and 100 analyzable subjects. The boundaries for the futility analysis are 
based on Rho family error spending function with a rho of 0.5. For the purposes of the 
sample size calculation, the power will be calculated under the alternative hypothesis 
setting, where the ratio is 1, or equivalence between the two arms with respect to 
concentrations of anti-PA antibody. With a type 1 error of 5% one-sided a sample size of 
534  subjects will allow for 80% power to make a claim of non-inferiority (margin of 
1.5), if the true ratio between the geometric means is 1. In a trial of 534  patients, the 
largest observed GMC ratio between the AVA and the combination that results in a 
statistically significant non-inferiority result is an estimated ratio of 1.173. This can 
alternatively be viewed as a minimum observed anti-PA concentration due to the addition 
of AVA in the combination of ~85% of the concentration when AVA is administered 
alone.   This is under the assumption that the observed variability in the study population 
is similar to the study design assumption.
9.2.2.
Sample Size Sensitivity
Simulations were performed to estimate the chances of the study crossing the futility 
boundaries or ending in a result of non-inferiority under various true population ratios of 
geometric means. The inverse of the ratios, shown in the second column, represent the 

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percentage of the monotherapy AVA effect that is retained when given in combination 
with raxibacumab.  The percentages shown in the table are based on 10,000 simulated 
trials for each scenario.  Simulations were performed in East 5.4, assuming the log 
transformed data has a common standard deviation of 0.75 in each arm. The results are 
displayed in Table 5.
This table indicates that if the addition of raxibacumab has a very strong, almost 
nullifying, effect on the vaccine at week 4 (GMC ratio of 10 or higher), that the study 
will almost always end with a futility result after only 30 analyzable subjects. If the effect 
is a little less strong, but still below the non-inferiority margin, there will be a large 
probability that the study will end early for futility by the second interim analysis (100 
analyzable subjects). 
Given the study design, the probability of a non-inferiority result is 80% if the true GMC 
ratio is 1, i.e., if raxibacumab does not inhibit the immunogenicity of AVA at all.  The 
trial is not designed to have sufficient power to detect non-inferiority in all instances 
where there is a small effect (that may not be clinically meaningful) on the 
immunogenicity.  The chance of finding a non-inferiority result drops off fairly rapidly as 
the effect on the immunogenicity increases.  Nearly twice as many subjects would be 
required to have an 80% chance of declaring non-inferiority (with a margin of 1.5) when 
the GMC of AVA in the combination arm is 90% of the AVA in the AVA alone arm.
Table 5
Simulated Operating Characteristics of the Trial Under Different True 
GMC Ratios (SD=0.75; 10,000 simulations each)
Ratio of 
Geometric 
Means
Percent Effect in 
combination 
Probability of 
stopping at the 
First Interim
Probability of 
stopping at the 
Second Interim
Probability of 
stopping at either 
interim
Probability of 
Non-
inferiority
20
5%
99.9%
0.1%
100%
0%
10
10%
97.5%
2.5%
100%
0%
4
25%
70.1%
29.3%
100%
0%
2
50%
29.2%
39.0%
68.2%
0.01%
1.5
67%
15.8%
22.5%
38.3%
4.5% (5%*)
1.25
80%
9.4%
12.0%
21.4%
29.6%
1.11
90%
6.7%
6.8%
13.5%
59.0%
1
100%
4.9%
3.8%
8.7%
80%*
* These values are not simulated, but are instead the theoretical true values based on the trial design of 5% one-sided 
type 1 error and 80% power.
A second set of simulations was performed to estimate the sensitivity of the results in 
Table 5 to the assumption regarding the standard deviation (SD).  These simulations 

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assume that the standard deviation of the data after the log transformation is 0.90, higher 
than the originally assumed 0.75.
The increased variability leads to a lower probability of finding non-inferiority.  The 
power for the study would be reduced to 65-70% with the higher standard deviation of 
0.9.  The chances of stopping at the interim would be fairly close to under the original 
assumptions.  The chances of stopping at one of the interims is still over 95% if the true 
GMC ratio is greater than 4, indicating the addition of raxibacumab has a large effect on 
the vaccine immunogenicity.
Table 6
Simulated Operating Characteristics of the Trial Under Different True 
GMC Ratios (SD=0.9; 10,000 simulations)
Ratio of 
Geometric 
Means
Percent Effect in 
combination 
Probability of 
stopping at the 
First Interim
Probability of 
stopping at the 
Second Interim
Probability of 
stopping at either 
interim
Probability of 
Non-
inferiority
20
5%
99.2%
0.8%
100%
0%
10
10%
92.8%
7.2%
100%
0%
4
25%
61.3%
36.5%
100%
0%
2
50%
26.6%
36.6%
63.2%
0.1%
1.5
67%
15.1%
22.0%
37.1%
5.0%
1.25
80%
10.5%
13.6%
24.0%
23.7%
1.11
90%
8.2%
9.0%
17.0%
46.5%
1
100%
6.3%
5.7%
12.0%
67.6%
9.2.3.
Sample Size Re-estimation or Adjustment
Sample size re-estimation is not planned.
9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
The Intent-to-Treat (ITT) population will comprise all randomized subjects.
The Per Protocol (PP) population will comprise all analyzable subjects and will be used 
for the primary analysis.   
A subject will be considered to be analyzable if they meet all of the following criteria: 
1.
Receive at least the Week 0 and 2 AVA doses, 

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2.
Receive the raxibacumab dose, if randomized to that treatment 
3.
Complete the primary study endpoint assessment (anti-PA Ab concentration at Week 
4). 
The Safety population will comprise all randomized subjects receiving at least one dose 
of study treatment and will be based on the actual treatment received if this differs from 
that to which the subjects were randomized.   The Safety population will be the primary 
dataset used for the analysis of safety data. For analyses using the safety population only, 
subjects will be analyzed based on the treatment they received if this differs from the 
treatment to which they were randomized.  That is, subjects randomized to receive both 
raxibacumab and AVA, who only receive AVA will be summarized with the other 
subjects who only received AVA.  Subjects who only receive raxibacumab will not be 
included in the Safety population summaries and their data will be listed separately.
9.3.2.
Interim Analysis
Based on published results, polyclonal anti-PA antitoxin administered to rabbits in 
combination with AVA resulted in essentially complete abrogation of the immune 
response to AVA (Malkevich, 2013).  Thus, it is possible that co-administration of 
raxibacumab with AVA will essentially eliminate any immunogenic response to AVA.  
Given that expectation, this study will consist of 3 cohorts, with two interim analyses to 
allow early termination of the study if a large effect of raxibacumab on AVA 
immunogenicity is confirmed at the interim. 
The first interim analysis will be performed after the first 30 analyzable subjects have 
reached the week 4 endpoint. The second interim will be performed after the first 
analyzable 100 subjects have reached the week 4 endpoint. 
These sample sizes for the interim analyses were selected based on the goal to minimize 
exposure to subjects if the anti-PA antibody levels attributable to AVA in the 
combination treatment group were truly inferior to the AVA alone treatment group.  The 
boundary for the first interim was selected such that it would nearly guarantee that the 
trial would end after only 30 subjects if the true GMC ratio was very large (>10), while 
simultaneously having a low probability that the trial would be ended prematurely (true 
GMC ratio near 1); see Table 5 for actual probabilities.  If the results of this combination 
in humans taking a monoclonal antibody are similar to the results in rabbits receiving a 
polyclonal antibody in the Malkevich, 2013 paper, the GMC ratio could be considerably 
larger than 10.
A second interim was included to end the trial early for scenarios that fell in between the 
non-inferiority margin and the very large effects the first interim was designed to capture.  
This interim is designed to capture the case where there is still a fair impact due to the 
addition of raxibacumab, but there is a variation from the results seen in rabbits with the 
polyclonal antibody.  As can be seen in Table 5 the addition of this second interim will 
result in a futility result at either interim with a 99% chance if the true GMC ratio is >4 
and with high likelihood (>67%) if the true GMC ratio is >2. 

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The t-statistics for the boundaries, as calculated in East 5.4, are 1.0274 for interim 1, 
0.4437 for interim 2 and -1.645 for the final analysis.  These correspond to p-values for 
the t-test of p=.848 at interim 1, p=.671 at interim 2, and p=.05 for the final analysis.  
The clinical interpretation of these thresholds is easier to evaluate if they are converted to 
thresholds for the GMC ratio.  The challenge with this conversion is that the thresholds 
for the GMC ratios that will lead to a futility result or a result of non-inferiority will be 
dependent on the variability in the estimates observed in the trial.  However, a conversion 
can be made assuming the standard deviation will match the one used in the sample size 
calculation of 0.75.  Under this assumption, the log transformed scale the boundaries 
correspond approximately to an observed difference in the means of >.4575 at interim 1 
and >.242 at interim 2, or observed GMC ratios of > 2.87 and >1.75 respectively.  The 
threshold for success at the final analysis would be an observed GMC ratio of 1.173 or 
less.
Given the high level of variance of anti-PA antibody levels at week 4 with AVA (as 
observed in  Marano, 2008), it is challenging to estimate either the GMC or the GMC 
ratios with precision without a very large sample size. The total sample size was 
determined based on how many subjects were required to have an 80% chance of ruling 
out that the GMC ratio was >1.5 when it was truly 1.  Many more subjects would be 
required to estimate the actual ratio with considerable precision.
Similarly the interim analyses will not result in precise estimates of the GMC ratio.  
There will be sufficient data collected to determine whether it is futile to expect that the 
trial would result in a non-inferiority conclusion.  The beta error spending boundary was 
chosen such that approximately 25% of the Type II error is spent in the first interim.  
There was a willingness to allow for this much error in the first interim after only 30 
subjects, because it is assumed that there is a high likelihood the anti-PA antibody levels 
will be inferior when raxibacumab is given with AVA, based on the results of the 
Malkevich (2013) paper.  
At the first interim the confidence interval for the ratio will be based on a t statistic with 
28 degrees of freedom (for instance for a 90% CI the relevant t value is t.05,28=1.701).  
The exact precision of the estimate will be dependent on the observed sample estimate of 
the standard deviations.  Assuming both treatment groups have a sample standard 
deviation equivalent to the assumed 0.75, the assumed standard error would be 0.274.  
The 90% confidence interval will vary by .466.  Translated back to the original scale, 
the GMC ratio will be scaled by .342 or 2.92.
For the second interim, the assumed standard error in the log transformed data would be 
.15.  The 90% confidence interval would vary by .249 in the log transformed data and 
scaled 0.564 or 1.775 in the original scale GMC ratio.
At the final analysis, the assumed standard error in the log transformed data would be 
.065.  The 90% confidence interval would vary by .107 in the log transformed data and 
scaled by 0.782 or 1.28 in the original scale GMC ratio.

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9.4.
Key Elements of Analysis Plan
9.4.1.
Primary Analyses
At the final analysis, the non-inferiority test will be based on a comparison of the CI for 
the ratio of anti-PA Ab (attributable to AVA) GMCs between the AVA and the AVA + 
raxibacumab groups at week 4. This analysis will be performed in the per protocol 
population.  If the upper bound of the 90% CI is less than 1.5, non-inferiority will be 
established. 
This analysis will be repeated in the subset of the intent-to-treat population with available 
week 4 results, as a sensitivity analysis.  Another set of sensitivity analyses will use the 
full ITT population with imputation for subjects without week 4 anti-PA Ab 
concentration results.  The first imputation will be as follows: In the AVA + raxibacumab 
arm, missing data will be imputed with the first quartile from the non-missing data in this 
arm. In the AVA arm, missing data will be imputed with the third quartile from the non-
missing data in this arm.  The second imputation will be as follows: In the AVA + 
raxibacumab arm, missing data will be imputed with the lower limit of quantitation 
(LLQ). In the AVA arm, missing data will be imputed with the maximum from the non-
missing data.  
The GMCs for each treatment group will be summarized along with the 95% confidence 
intervals for the week 4 timepoint as well as weeks 8 and 26.
The GMC ratio and GMCs within each cohort and corresponding CIs will be calculated 
by first log transforming all of the data by a log base 10.  A t-test will be performed and 
CIs will be calculated about the mean logs and the difference of the mean logs.  The 
results will be translated back to the original scale by exponentiating them, again using a 
base 10.  The exponentiated differences of the sample mean logs will be the ratio of the 
sample geometric means of the untransformed results.
Sensitivity analyses will be performed to assess the sensitivity of the results to the 
assumption of equality of variances between the anti-PA Ab concentrations in the two 
treatment groups.  Details will be described in the analysis plan. 
9.4.2.
Secondary Analyses
9.4.2.1.
Anti-PA Antibodies
Anti-PA antibody concentrations will also be collected at weeks 8 and 26 after the first 
AVA dose.  The GMCs along with 95% CI will be summarized for each treatment group 
at each timepoint.  There will be no imputation for subjects with missing data at a given 
timepoint.
9.4.2.2.
Toxin Neutralizing Activity (TNA)
TNA titers will be collected at weeks 4, 8 and 26 after the first AVA dose.  The GMTs 
along with 95% CI will be summarized for each treatment group at each timepoint.  
There will be no imputation for subjects with missing data at a given timepoint.

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The percentage of subjects, along with 95% CI, who seroconvert, defined as a >4-fold 
increase in toxin neutralizing activity (TNA) titer will be summarized, at Weeks 4, 8 and 
26 after the first AVA dose for both arms separately.
9.4.2.3.
Safety Analyses
Clinical safety observations will include AEs, urinalysis, vital sign measurements, and 
clinical laboratory assessments. Safety data will be tabulated and, where appropriate, 
analyzed by the use of descriptive statistics. Safety data will be tabulated for the Safety
Population.
The number (%) of subjects withdrawing from the study will be summarized for each 
treatment group and the number (%) subjects withdrawing for each individual reason will 
be summarized by treatment group.
Reported AEs will be coded using MedDRA. The number (%) of subjects in each 
treatment group with treatment-emergent AEs will be compared for overall incidence and 
by system organ class and preferred term. Similar summaries will also be presented for 
deaths, all SAEs, AEs leading to withdrawal, and drug-related AEs. Severity of 
treatment-emergent AEs will also be summarized by system organ class, preferred term, 
and treatment group.
Additionally, the frequency of laboratory abnormality events along with shifts from 
baseline will be summarized, as well as changes over time in laboratory parameters, 
urinalysis and vital signs.
9.4.2.4.
Statistical Analysis of Pharmacokinetic Data
Drug concentration-time data will be listed for each subject and summarized by 
descriptive statistics at each nominal collection time. PK parameters will be listed for 
each subject and summarized by descriptive statistics.
Specimens will also be analyzed for the presence of anti-raxibacumab antibodies.  Those 
results will be descriptively and/or graphically summarized as appropriate to the data.
10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.

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The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH GCP, all applicable subject 
privacy requirements, and the guiding principles of the current version of the Declaration 
of Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable

Signed informed consent  to be obtained for each subject before participation in the 
study (and for amendments as applicable)

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviations 
to IRB/IEC)

GSK will provide full details of the above procedures, either verbally, in writing, or 
both.
10.3.
Quality Control (Study Monitoring)
In accordance with applicable regulations including GCP, and GSK procedures, GSK or 
delegated monitors will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy regulatory, 
ethical, and GSK requirements.  
When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the CRF will serve 
as the source document.
GSK will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any other 
study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents
10.4.
Quality Assurance
To ensure compliance with GCP and all applicable regulatory requirements, GSK may 
conduct a quality assurance assessment and/or audit of the site records, and the regulatory 
agencies may conduct a regulatory inspection at any time during or after completion of 
the study. 
In the event of an assessment, audit or inspection, the investigator (and institution) must 
agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all relevant 

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documents and to allocate their time and the time of their staff to discuss the conduct of 
the study, any findings/relevant issues and to implement any corrective and/or 
preventative actions to address any findings/issues identified.
10.5.
Study and Site Closure
Upon completion or premature discontinuation of the study, the GSK monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and GSK Standard Operating 
Procedures.
GSK reserves the right to temporarily suspend or prematurely discontinue this study at 
any time for reasons including, but not limited to, safety or ethical issues or severe non-
compliance. For multicenter studies, this can occur at one or more or at all sites.  
If GSK determines such action is needed, GSK will discuss the reasons for taking such 
action with the investigator or the head of the medical institution (where applicable).  
When feasible, GSK will provide advance notification to the investigator or the head of
the medical institution, where applicable, of the impending action.
If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform all investigators, heads of the medical institutions (where applicable) 
and/or institution(s) conducting the study. GSK will also promptly inform the relevant 
regulatory authorities of the suspension or premature discontinuation of the study and the 
reason(s) for the action.  
If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the reason 
for the suspension or premature discontinuation.
10.6.
Records Retention
Following closure of the study, the investigator or the head of the medical institution 
(where applicable) must maintain all site study records (except for those required by local 
regulations to be maintained elsewhere), in a safe and secure location.  
The records must be maintained to allow easy and timely retrieval, when needed (e.g., for 
a GSK audit or regulatory inspection) and must be available for review in conjunction 
with assessment of the facility, supporting systems, and relevant site staff.  
Where permitted by local laws/regulations or institutional policy, some or all of these
records can be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution needs to be exercised before such action is taken.  
The investigator must ensure that all reproductions are legible and are a true and accurate 
copy of the original and meet accessibility and retrieval standards, including re-
generating a hard copy, if required.  Furthermore, the investigator must ensure there is an 
acceptable back-up of these reproductions and that an acceptable quality control process 
exists for making these reproductions.

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GSK will inform the investigator of the time period for retaining these records to comply 
with all applicable regulatory requirements.  The minimum retention time will meet the 
strictest standard applicable to that site for the study, as dictated by any institutional 
requirements or local laws or regulations, GSK standards/procedures, and/or institutional 
requirements.  
The investigator must notify GSK of any changes in the archival arrangements, including, 
but not limited to, archival at an off-site facility or transfer of ownership of the records in 
the event the investigator is no longer associated with the site.
10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy.

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11.
REFERENCES
Anthrax Vaccine Adsorbed [US Package Insert](USP).  Lansing, MI, US: Emergent 
BioDefense Operations Lansing LLC; May 2012.
Bartlett JG, Inglesby TV, Borio L. Management of Anthrax. Clinical Infectious Diseases. 
2002: Oct:35 (7):851-858.
Booth MG, Hood J, Brooks TJ, Hart A. Health Protection Scotland Anthrax Clinical N. 
Anthrax Infection in Drug Users. Lancet. 2010;375(9723):1345-1346. 
Centers for Disease Control and Prevention. Vaccine Information Statement, Anthrax 
Vaccine.  U.S. Department of Health and Human Services; 2010. 
http://www.cdc.gov/vaccines/hcp/vis/vis-statements/anthrax.html
Crowe SR, Ash LL, Engler RJ, Ballard JD, Harley JB, Farris AD, et al. Select Human 
anthrax protective antigen (PA) epitope-specific antibodies provide protection from lethal 
toxin challenge. J Infect Dis. 2010;202:251-260. 
Diphenhydramine US Package Insert (USP)
Dixon TC, Meselson M, Guillemin J, Hanna PC. Anthrax. New England Journal of 
Medicine. 1999;341(11):815-826. 
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, Policar MS, editors. 
Contraceptive Technology. 20th edition. Atlanta, Georgia: Ardent Media, 2011: 50. 
Table 3-2.
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
Malkevich NV, Basu S, Rudge TL, Clement KH, Chakrabarti AC, Aimes RT, et al. 
Effect of anthrax immune globulin on response to BioThrax (anthrax vaccine adsorbed) 
in New Zealand white rabbits. Antimicrob Agents Chemother. 2013;57:5693-5696. 
Marano N, Plikaytis BD, Martin SW, Rose C, Semenova VA, Martin SK, et al. Effects of 
a reduced dose schedule and intramuscular administration of anthrax vaccine adsorbed on 
immunogenicity and safety at 7 months: a randomized trial. JAMA. 2008;300:1532-1543. 
Meselson M, Guillemin J, Hugh-Jones M, et al. The Sverdlovsk Anthrax Outbreak of 
1979. Science. 1994;266 (5188):1202-1208. 
Migone TS, Subramanian GM, Zhong J, Healey LM, Corey A, Devalaraja M, et al. 
Raxibacumab for the treatment of inhalation anthrax. N Engl J Med. 2009;361:135-144. 
Pittman PR, Kim-Ahn G, Pifat DY, Coonan K, Gibbs P, Little S, et al. Anthrax vaccine: 
immunogenicity and safety of a dose-reduction, route-change comparison study in 
humans. Vaccine. 2002;20:1412-1420. 

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Pittman PR, Leitman SF, Barrera Oro JG, Norris SL, Marano NM, Ranadive MV, et al. 
Protective antigen and toxin neutralization antibody patterns in anthrax vaccines 
undergoing serial plasmapheresis. Clin Diagn Lab Immunol. 2005;12:713-721. 
Pittman PR, Norris SL, Barrera Oro JG, Bedwell D, Cannon TL, McKee KT. Patterns of 
antibody response to the anthrax vaccine adsorbed (AVA) primary (six-dose) series. 
Vaccine. 2006;24:3654-3660. 
Quinn CP, Dull PM, Semenova V, Han L, Crotty S, Taylor TH, et al. Immune responses 
to Bacillus anthracis protective antigen in patients with bioterrorism-related cutaneous or 
inhalation anthrax. J Infect Dis. 2004;190:1228-1236. 
Raxibacumab [Package Insert]. 2012; 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/125349s000lbl.pdf.  Accessed 
May 28, 2014
Raxibacumab Investigator’s Brochure, GlaxoSmithKline Document Number 
2013N162863_00: Version 08, 07 June 2013

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12.
APPENDICES
12.1.
Appendix 1  Abbreviations and Trademarks
Abbreviations
Ab
Antibody
AE
Adverse event
ALT
Alanine amino transferase
AST
Aspartate amino transferase
AUC0-t
Area under the serum raxibacumab concentration-time 
curve to the time of the last measureable concentration 
AUC0-
Area under the raxibacumab concentration-time curve to the 
time of the last measurable concentration
AVA
Anthrax vaccine absorbed
B. anthracis
Bacillus anthracis
BUN
Blood urea nitrogen
Cmax
Maximum observed serum raxibacumab concentration 
CFR
U.S. Code of Federal Regulations
CI
Confidence interval
CL
Clearance
CO2
Carbon dioxide
CONSORT
Consolidated standards of reporting trials
CPK
Creatine phosphokinase
CPMS
Clinical Pharmacology Modeling and Simulation
CRF
Case report form
DMID
Division of Microbiology and Infectious Diseases
DMPK
Drug Metabolism and Pharmacokinetics
FDA
Food and Drug Administration
FRP
Female of reproductive potential
FSH
Follicle stimulating hormone
GCP
Good Clinical Practice
GCSP
Global clinical safety and pharmacovigilance
GLP
Good Laboratory Practices
GMC
Geometric mean concentration
GMT
Geometric mean titer
GSK
GlaxoSmithKline
HBsAg
Hepatitis B surface antigen
hCG
Human chorionic gonadotrophin
HIV
Human immunodeficiency virus
HRT
Hormone replacement therapy
IB
Investigator’s brochure
ICH
International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for 
Human Use
ICF
Informed consent form
IEC
Independent ethics committee

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IM
Intramuscular
IND
Investigational new drug
IRB
Institutional review board
ITT
Intent-to-treat
IV
Intravenous
LDH
Lactate dehydrogenase
MedDRA
Medical dictionary for regulatory activities
MRT
Mean residence time
MSDS
Medical Safety Data Sheet
PA
Protective antigen
PI
Package insert
PK
Pharmacokinetics
PP
Per protocol
QC
Quality control
RBC
Red blood cell
R&D
Research & Development
SAE
Serious adverse event
SC
Subcutaneous
SD
Standard deviation
SOP
Standard operating procedure
SRM
Study reference manual
SRT
Safety review team
tmax
Time of occurrence for Cmax
t½, z
Half-life of drug elimination in the terminal phase
TNA
Toxin neutralizing activity
TTS
Study specific technical agreement
UHPLC/MS
Ultra high performance liquid chromatography – mass 
spectrometry
ULN
Upper limit of normal
UM
Upper Merion
US
United States
Vss
Volume of distribution in the terminal phase
Vz
Volume of distribution at steady-state
WBC
White blood cell
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
BioThrax

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12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT-absolute
ALT≥3xULN
If  ALT≥3xULN  AND bilirubin1,2 2xULN (>35% direct bilirubin) or  INR >1.5, Report as an 
SAE.
See additional Actions and Follow Up Assessments listed below
Required Actions and Follow up Assessments following Liver Stopping Event
Actions
Follow Up Assessments

Discontinue study treatment

Report the event to GSK within 24 hours

Complete the liver event CRF, and complete an SAE 
data collection tool if the event also meets the criteria 
for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries resolve, 
stabilise, or return to within baseline (see 
MONITORING below)
MONITORING:
If ALT≥3xULN AND bilirubin 2xULN  or INR >1.5

Repeat liver chemistries (include ALT, AST, alkaline 
phosphatase, bilirubin) and perform liver event follow 
up assessments within  24 hrs

Monitor subjects twice weekly until liver chemistries 
resolve, stabilise or return to within baseline

A specialist or hepatology consultation is 
recommended
If ALT≥3xULN AND bilirubin < 2xULN  and INR ≤1.5:

Repeat liver chemistries (include ALT, AST, alkaline 
phosphatase, bilirubin) and perform liver event follow 
up assessments within 24-72 hrs

Monitor subjects weekly until liver chemistries 
resolve, stabilize or return to within baseline

Viral hepatitis serology3

Serum creatine phosphokinase (CPK) and lactate 
dehydrogenase (LDH).

Fractionate bilirubin, if total bilirubin2xULN

A pharmacokinetic (PK) sample to be collected up 
to 7 days following the liver event.

Obtain complete blood count with differential to 
assess eosinophilia

Record the appearance or worsening of clinical 
symptoms of liver injury, or hypersensitivity, on the 
AE report form

Record use of concomitant medications on the 
concomitant medications report form including 
acetaminophen, herbal remedies, other over the 
counter medications.

Record alcohol use on the liver event alcohol intake 
case report form
If ALT≥3xULN AND bilirubin 2xULN  or INR >1.5:

Anti-nuclear antibody, anti-smooth muscle antibody, 
Type 1 anti-liver kidney microsomal antibodies, and 
quantitative total immunoglobulin G (IgG or gamma 
globulins).

Serum acetaminophen adduct HPLC assay 
(quantifies potential acetaminophen contribution to 
liver injury in subjects with definite or likely 
acetaminophen use in the preceding week [James, 
2009]. 

Liver imaging (ultrasound, magnetic resonance, or 
computerised tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver Imaging 
and/or Liver Biopsy CRF forms.

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1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured, which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to subjects receiving anticoagulants
3.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 

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12.3.
Appendix 3: GSK Modified List of Highly Effective Methods 
for Avoiding Pregnancy in Females of Reproductive 
Potential (FRP)
This list does not apply to FRP with same sex partners, when this is their preferred and 
usual lifestyle or for subjects who are and will continue to be abstinent from penile-
vaginal intercourse on a long term and persistent basis.
A. Contraceptive subdermal implant that meets the SOP effectiveness criteria 
including a <1% rate of failure per year, as stated in the product label
B. Intrauterine device or intrauterine system that meets the SOP effectiveness criteria 
including a <1% rate of failure per year, as stated in the product label 
C. Oral Contraceptive, combined estrogen and progestogen [Hatcher, 2011] 
D. Injectable progestogen [Hatcher, 2011]
E. Contraceptive vaginal ring [Hatcher, 2011]
F. Percutaneous contraceptive patches [Hatcher, 2011]
G. Male partner sterilization with documentation of azoospermia prior to the female 
subject's entry into the study, and this male is the sole partner for that subject.  
The documentation on male sterility can come from the site personnel’s: review 
of subject’s medical records, medical examination and/or semen analysis, or 
medical history interview provided by her or her partner.
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label.  The investigator is responsible 
for ensuring that subjects understand how to properly use these methods of 
contraception.

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12.4.
Appendix 4: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.4.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae).
Events NOT meeting definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.

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12.4.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
Results in disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday 
life functions but do not constitute a substantial disruption
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 

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Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
other outcomes listed in the above definition.  These should also be considered 
serious.

Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse
g.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick.  If fractionation is unavailable and ALT 3xULN 
and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.
12.4.3.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the CRF

It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to GSK in lieu of completion of the GSK, AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK.  In this instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 
submission of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.

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12.4.4.
Evaluating AEs and SAEs
Assessment of Intensity
AEs will be assessed for severity based on the modified Division of Microbiology and 
Infectious Diseases (DMID) toxicity tables in Appendix 6.   
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event causing no limitation of usual activities

Moderate:  An event causing some limitation of usual activities

Severe:  An event causing inability to carry out usual activities.

Life-threatening:  An event that is potentially life threatening or disabling.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of his/her assessment.

For each AE/SAE the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK.  However, it is very important 
that the investigator always make an assessment of causality for every event 
prior to the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.

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Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.

The investigator is obligated to assist.  This may include additional laboratory tests 
or investigations, histopathological examinations or consultation with other health 
care professionals.

If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide GSK with a copy of any post-mortem findings, 
including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
12.4.5.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool

If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the Medical Monitor or the SAE 
coordinator

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes to 
existing data

If a site receives a report of a new SAE from a study subject or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, the site can report this information on a paper SAE form or to the Medical 
Monitor or the SAE coordinator by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.

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12.5.
Appendix 5: Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study

Information will be recorded on the appropriate form and submitted to GSK within 2 
weeks of learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on mother and infant, which will be 
forwarded to GSK.  Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date. 

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK 
as described in Appendix 4. While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.
Any female subject who becomes pregnant while participating will discontinue study 
medication and will continue to be followed for pregnancy outcome.

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12.6.
Appendix 6: Modified Division of Microbiology and Infectious Diseases (DMID) Toxicity Tables
HEMATOLOGIC
Grade 1
Grade 2
Grade 3
Grade 4
Hemoglobin
9.5-10.9 g/dL
8.0-9.4 g/dL
6.5-7.9 g/dL
< 6.5 g/dL
Leukocytes
3000/mm3 to < LLN OR
> ULN to 13,000/mm3
2000 to < 3000/mm3 OR
> 13,000 to 15,000/mm3
1000 to < 2000/mm3 OR
> 15,000 to 30,000/mm3
< 1000/mm3 OR
> 30,000/mm3
Absolute neutrophil count (ANC)
1000 to 1500/mm3
750 to < 1000/mm3
500 to < 750/mm3
< 500/mm3
Platelets
75,000 to 
< 100,000/mm3
50,000 to < 75,000/mm3
20,000 to < 50,000/mm3
< 20,000/mm3
Lymphocyte count
800/mm3 to < LLN
500 to < 800/mm3
200 to < 500/mm3
< 200/mm3
% Polymorphonuclear leukocytes + band 
cells
80-90%
> 90-95%
> 95%
---
Abnormal fibrinogen
Low: 100-200 mg/dL
High: 400-600 mg/dL
Low: 50 to < 100 mg/dL
High: > 600 mg/dL
Low: < 50 mg/dL
---
Fibrinogen associated with 
gross bleeding or with 
disseminated coagulation
Fibrin split product
20-40 mcg/mL
41-50 mcg/mL
51-60 mcg/mL
> 60 mcg/mL
Prothrombin time (PT)
> 1.0-1.25 x ULN
> 1.25-1.5 x ULN
> 1.5-3.0 x ULN
> 3.0 x ULN
Activated partial thromboplastin time 
(APPT)
> 1.0-1.66 x ULN
> 1.66-2.33 x ULN
> 2.33-3.0 x ULN
> 3.0 x ULN
Methemoglobin
5.0-9.9%
10.0-14.9%
15.0-19.9%
≥ 20%
LLN = lower limit of normal; ULN = upper limit of normal.
Modified DMID Adult Toxicity Tables (Version 2.0, Aug 2004)
(continued)

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CHEMISTRIES
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia 
130-135 mEq/L
123-129 mEq/L
116-122 mEq/L
< 116 mEq/L OR
Abnormal sodium with mental status changes or seizures
Hypernatremia 
146-150 mEq/L
151-157 mEq/L
158-165 mEq/L
> 165 mEq/L OR
Abnormal sodium with mental status changes or seizures
Hypokalemia 
3.0-3.4 mEq/L
2.5-2.9 mEq/L
2.0-2.4 mEq/L OR
Intensive replacement therapy 
or hospitalization required
< 2.0 mEq/L OR
Abnormal potassium with paresis, ileus, or 
life-threatening arrhythmia
Hyperkalemia 
5.6-6.0 mEq/L
6.1-6.5 mEq/L
6.6-7.0 mEq/L
> 7.0 mEq/L OR
Abnormal potassium with life-threatening arrhythmia
Hypoglycemia 
55-64 mg/dL
40-54 mg/dL
30-39 mg/dL
< 30 mg/dL OR
Abnormal glucose with mental status changes or coma
Hyperglycemia (nonfasting 
and no prior diabetes)
116-160 mg/dL
161-250 mg/dL
251-500 mg/dL
> 500 mg/dL OR
Abnormal glucose with ketoacidosis or seizures
Hypocalcemia 
(corrected for albumin) 
7.8-8.4 mg/dL
7.0-7.7 mg/dL
6.1-6.9 mg/dL
< 6.1 mg/dL OR
Abnormal calcium with life-threatening arrhythmia or 
tetany
Hypercalcemia 
(corrected for albumin) 
10.6-11.5 mg/dL
11.6-12.5 mg/dL
12.6-13.5 mg/dL
> 13.5 mg/dL OR
Abnormal calcium with life-threatening arrhythmia
Hypomagnesemia 
1.2-1.4 mEq/L
0.9-1.1 mEq/L
0.6-0.8 mEq/L
< 0.6 mEq/L OR
Abnormal magnesium with life-threatening arrhythmia
Hypophosphatemia 
2.0-2.4 mg/dL
1.5-1.9 mg/dL OR
Replacement 
therapy required
1.0-1.4 mg/dL OR
Intensive therapy or 
hospitalization required
< 1.0 mg/dL OR
Abnormal phosphate with life-threatening arrhythmia
Hypoalbuminemia
3.00-3.49 g/dL
2.50-2.99 g/dL
2.00-2.49 g/dL
< 2.00 g/dL

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CHEMISTRIES
Grade 1
Grade 2
Grade 3
Grade 4
Hyperbilirubinemia
> 1.25-2.5 x 
ULN
> 2.5-5.0 x ULN
> 5.0-10 x ULN
> 10 x ULN
Hypothyroid
Asymptomatic, 
no treatment 
required
Symptomatic, not 
interfering with 
ADLs; thyroid 
replacement 
indicated
Symptoms interfering with 
ADLs; hospitalization required
Life-threatening myxedema coma
ADLs = activities of daily living; LLN = lower limit of normal; ULN = upper limit of normal.
Modified DMID Adult Toxicity Tables (Version 2.0, Aug 2004)
(continued)

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CHEMISTRIES 
(continued)
Grade 1
Grade 2
Grade 3
Grade 4
Hyperthyroid
Asymptomatic, 
no treatment 
required
Symptomatic, not 
interfering with 
ADLs; thyroid 
suppression 
therapy indicated
Symptoms interfering with 
ADLs; hospitalization required
Life-threatening consequences (eg, thyroid storm)
Blood urea nitrogen (BUN)
1.25-2.5 x ULN
> 2.5-5.0 x ULN
> 5.0-10 x ULN
> 10 x ULN
Hyperuricemia (uric acid)
7.5-10.0 mg/dL
10.1-12.0 mg/dL
12.1-15.0 mg/dL
> 15.0 mg/dL
Creatinine
1.1-1.5 x ULN
> 1.5-3.0 x ULN
> 3.0-6.0 x ULN
> 6.0 x ULN OR
Dialysis required
ADLs = activities of daily living; LLN = lower limit of normal; ULN = upper limit of 
normal.
Modified DMID Adult Toxicity Tables (Version 2.0, Aug 2004)
ENZYMES
Grade 1
Grade 2
Grade 3
Grade 4
AST (SGOT) 
1.25-2.5 x ULN
> 2.5-5.0 x ULN
> 5.0-10 x ULN
> 10 x ULN
ALT (SGPT) 
1.25-2.5 x ULN
> 2.5-5.0 x ULN
> 5.0-10 x ULN
> 10 x ULN
Gamma glutamyl transpeptidase (GGT)
1.25-2.5 x ULN
> 2.5-5.0 x ULN
> 5.0-10 x ULN
> 10 x ULN
Alkaline phosphatase 
1.25-2.5 x ULN
> 2.5-5.0 x ULN
> 5.0-10 x ULN
> 10 x ULN
Amylase 
1.1-1.5 x ULN
> 1.5-2.0 x ULN
> 2.0-5.0 x ULN
> 5.0 x ULN
Lipase 
1.1-1.5 x ULN
> 1.5-2.0 x ULN
> 2.0-5.0 x ULN
< 5.0 x ULN
ULN = upper limit of normal.
Modified DMID Adult Toxicity Tables (Version 2.0, Aug 2004)
(continued)

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URINALYSIS
Grade 1
Grade 2
Grade 3
Grade 4
Proteinuria
1+ OR
< 0.3 g/dL
2+ to 3+ OR
0.3 to 1.0 g/dL
4+ OR
> 1.0 g/dL
Nephrotic syndrome
Hematuria 
Microscopic only OR
< 10 RBCs/hpf
Gross, no clots OR
≥ 10 RBCs/hpf
Gross with clots OR
RBC casts
Obstructive uropathy OR
Transfusion required
RBC = red blood cell; hpf = high power field.
Modified DMID Adult Toxicity Tables (Version 2.0, Aug 2004)

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CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Cardiac rhythm 
---
Asymptomatic, transient signs; 
no treatment required
Recurrent/persistent 
dysrhythmia; symptomatic 
treatment required
Unstable dysrhythmia; 
hospitalization and treatment 
required
Hypertension 
Transient increase > 20 mmHg; 
no treatment required
Recurrent; chronic increase 
> 20 mmHg; treatment required
Acute treatment required 
(outpatient or hospitalized)
End organ damage OR
Hospitalization required
Hypotension 
Transient orthostatic 
hypotension, with heart rate 
increased by < 20 bpm or SBP 
decreased by < 10 mmHg; no 
treatment required
Symptoms due to orthostatic 
hypotension or SBP decreased 
by < 20 mmHg; correctable with 
oral fluid treatment
IV fluids required; no 
hospitalization required
Mean arterial pressure 
< 60 mmHg or end organ 
damage or shock OR
Hospitalization and 
vasopressor treatment 
required
Pericarditis 
Minimal effusion
Mild/moderate asymptomatic 
effusion; no treatment required
Symptomatic effusion, pain, 
ECG changes
Tamponade OR
Pericardiocentesis OR
Surgery required
Hemorrhage, Blood loss
Microscopic/occult
Mild, no transfusion required
Gross blood loss or 1 to 2 units 
transfused
Massive blood loss or
> 2 units transfused
bpm = beats per minute; ECG = electrocardiogram; SBP = systolic blood pressure.
Modified DMID Adult Toxicity Tables (Version 2.0, Aug 2004)
(continued)

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RESPIRATORY
Grade 1
Grade 2
Grade 3
Grade 4
Cough 
Transient; no treatment
Persistent cough; treatment 
responsive
Paroxysmal cough; uncontrolled 
with treatment
---
Bronchospasm, acute 
Transient; no treatment 
required; FEV1 70% to 
< 80% of peak flow
Treatment required; 
normalizes with 
bronchodilator; FEV1 50% to 
< 70% of peak flow
No normalization with 
bronchodilator; FEV1 25% to
< 50% of peak flow OR
Retractions
Cyanosis; FEV1 < 25% of 
peak flow OR
Intubation required
Dyspnea 
Dyspnea on exertion
Dyspnea with normal activity
Dyspnea at rest
Dyspnea requiring O2
treatment
FEV1 = forced expiratory volume in 1 second.
Modified DMID Adult Toxicity Tables (Version 2.0, Aug 2004)

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GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Constipation
Stool softener or dietary 
modification required
Laxatives required
Obstipation requiring manual 
evacuation or enema
Obstruction or toxic 
megacolon
Diarrhea
Mild or transient;
3 to 4 loose stools per day 
OR
Mild diarrhea lasting < 1 wk
Moderate or persistent;
5 to 7 loose stools per day OR
Diarrhea lasting ≥1 wk
Bloody diarrhea OR
Diarrhea accompanied by 
orthostatic hypotension or 
electrolyte imbalance OR
> 7 loose stools per day OR
> 2 L IV fluids required
Hypotensive shock OR
Physiologic consequences 
requiring hospitalization
Oral discomfort/Dysphagia
Mild discomfort or mild 
soreness with erythema; no 
difficulty swallowing
Erythema with ulcers; some 
limits on eating & drinking
Ulcers and/or very limited eating 
& talking; unable to swallow solid 
foods
Unable to drink fluids; 
IV fluids required
See “Flu-like Symptoms” for nausea and vomiting.
Modified DMID Adult Toxicity Tables (Version 2.0, Aug 2004)
(continued)

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NEUROLOGIC
Grade 1
Grade 2
Grade 3
Grade 4
Mood alteration (specify)
-Anxiety
-Agitation
-Depression
Mild mood alteration, but not 
interfering with function
Moderate mood alteration 
interfering with function but not 
with ADLs; treatment indicated
Severe mood alteration interfering 
with ADLs
Suicidal ideation; 
danger to self or others
Insomnia
Occasional difficulty sleeping, but 
not interfering with function
Difficulty sleeping, interfering 
with function but not with ADLs
Frequent difficulty sleeping, 
interfering with ADLs
Disabling
Neuro - cerebellar 
Slight incoordination OR
Dysdiadochokinesia
Intention tremor OR
Dysmetria OR
Slurred speech OR
Nystagmus
Locomotor ataxia
Incapacitated
Neuro - muscular
Subjective weakness; no objective 
signs/symptoms
Mild, objective signs/symptoms; 
no decrease in function
Objective weakness; limited 
function
Paralysis
Neuro - sensory 
Mild impairment of sensations 
(eg, vibratory, pinprick, hot/cold to 
great toes) in focal area or 
symmetrical distribution OR
Change in taste, smell, vision, 
and/or hearing
Moderate impairment of 
sensations (eg, vibratory, 
pinprick, hot/cold to ankles) 
and/or joint position OR
Mild impairment that is not 
symmetrical
Severe impairment (decreased or 
loss of sensation to knees or 
wrists) OR
Loss of sensation of at least 
moderate degree in multiple 
different body areas (ie, upper & 
lower extremities)
Sensory loss involving 
limbs & trunk OR
Paralysis OR
Seizures
Paresthesia 
(burning, tingling, etc) 
Mild discomfort; no treatment 
required
Moderate discomfort; 
non-narcotic analgesic required
Severe discomfort; narcotic 
analgesic required, with 
symptomatic improvement
Incapacitating; not 
responsive to narcotic 
analgesic
ADLs = activities of daily living.
Modified DMID Adult Toxicity Tables (Version 2.0, Aug 
2004)
(continued)

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SKIN/DERMATOLOGIC
Grade 1
Grade 2
Grade 3
Grade 4
Alopecia
Minimal hair loss
Moderate, patchy hair loss
Complete hair loss; reversible
Nonreversible hair loss
Mucocutaneous
Erythema or pruritus
Diffuse maculopapular rash or 
dry desquamation
Vesiculation, moist 
desquamation, or ulceration
Exfoliative dermatitis, mucous 
membrane involvement, 
erythema multiforme,
Stevens-Johnson 
syndrome/TEN, or necrosis 
requiring surgery
Induration
< 15 mm
15 to 30 mm
> 30 mm
---
Erythema
< 15 mm
15 to 30 mm
> 30 mm
---
Edema
< 15 mm
15 to 30 mm
> 30 mm
---
Rash at injection site
< 15 mm
15 to 30 mm
> 30 mm
---
Pruritus
Slight itching at injection site
Moderate itching at
injection extremity
Itching over entire body
---
TEN = toxic epidermal necrolysis.
Modified DMID Adult Toxicity Tables (Version 2.0, Aug 2004)
MUSCULOSKELETAL
Grade 1
Grade 2
Grade 3
Grade 4
Arthritis
Mild pain with inflammation, 
erythema or joint swelling, but 
not interfering with function
Moderate pain with 
inflammation, erythema or 
joint swelling, interfering with 
function but not with ADLs
Severe pain with inflammation, 
erythema or joint swelling, 
interfering with ADLs
Permanent and/or disabling 
joint destruction
ADLs = activities of daily living.
See “Flu-like Symptoms” for arthralgia and myalgia.
Modified DMID Adult Toxicity Tables (Version 2.0, Aug 2004)
(continued)

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SYSTEMIC
Grade 1
Grade 2
Grade 3
Grade 4
Allergic reaction 
Pruritus without rash
Localized urticaria
Generalized urticaria; 
angioedema
Anaphylaxis
Weight gain/loss
5.0-9.9%
10.0-19.9%
≥ 20.0%
---
See “Flu-like Symptoms” for headache, chills, fever, fatigue, and malaise.
Modified DMID Adult Toxicity Tables (Version 2.0, Aug 2004)
FLU-LIKE 
SYMPTOMS
Grade 1
Grade 2
Grade 3
Grade 4
Arthralgia
Joint pain, but no effect on 
daily function
Joint pain, moderate decrease 
in daily function
Joint pain, incapacitating to daily 
function
---
Chills
Mild to moderate shaking
Severe shaking
Rigors, incapacitating to daily function
---
Fatigue
Fatigue, but no effect on 
daily function
Fatigue, moderate decrease in 
daily function
Fatigue, incapacitating to daily 
function
---
Fever
38.0-38.6ºC
(100.4-101.5ºF)
> 38.6-40ºC
(> 101.5-104ºF)
> 40ºC
(> 104ºF)
Fever with hypotension
Headache
< 2 hr, no analgesic required
2 to 24 hr, non-narcotic 
analgesic required
> 24 hr, multiple doses of 
non-narcotic analgesic required
Intractable; repeated narcotic 
analgesic treatment required
Malaise
< 24 hr duration
24 to 48 hr duration
Persistent, > 48 hr duration
---
Myalgia
Muscle pain, but no effect 
on daily function
Muscle pain, moderate 
decrease in daily function
Muscle pain, incapacitating to daily 
function
---
Nausea
Occasional and transient
Persistent, > 24 hr
Persistent, > 24 hr, with daily vomiting
---
Vomiting
Sporadic emesis, not 
occurring daily
Daily emesis
Daily emesis, intolerable;
treatment required
Intractable vomiting
Modified DMID Adult Toxicity Tables (Version 2.0, Aug 2004)
(concluded)

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12.7.
Appendix 7:  Protocol Changes
The following changes were made, where text in strikethrough is deleted and text in bold 
is added.
Medical Monitor/SAE Contact Information: 
Role
Name
Day Time Phone 
Number and email 
address
After-hours 
Phone/Cell/
Pager 
Number
Fax 
Number
Site Address
Primary 
Medical 
Monitor 
 
M.D.
(Quintiles)
 
1801 Rockville 
Pike, Suite 300, 
Rockville, MD 
20852
Secondary 
Medical 
Monitor
 
 
M.D.
(GSK)
1250 S. 
Collegeville Road, 
Collegeville, 
Pennsylvania, 
19426
Secondary 
Medical 
Monitor
 
 M.D.
(GSK)
 
N/A
Stockley Park 
West, 
1-3 Ironbridge 
Road, 
Uxbridge, 
Middlesex, 
UB11 1BT, 
United Kingdom
SAE 
contact  
information 
 
(Quintiles)
5927 S. Miami 
Blvd Morrisville, 
NC 27560
Section 6.2 Treatment Assignment 
Aligned the text with the Time and Events Table that states that randomization is 
occurring on day -1 of the study.
A randomization envelope for each subject will be opened just prior to dosing (on day     
-1) to reveal the subject’s treatment assignment.
Appendix 2: Liver Safety Required Actions and Follow up Assessments
Added PK assessments to Follow up Assessments.
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PP
DPPD
PPD
PPD
PPD
PPD
PPD
PPD

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Required Actions and Follow up Assessments following Liver Stopping Event
Actions
Follow Up Assessments

Discontinue study treatment

Report the event to GSK within 24 hours

Complete the liver event CRF, and complete an SAE 
data collection tool if the event also meets the criteria 
for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries resolve, 
stabilise, or return to within baseline (see 
MONITORING below)
MONITORING:
If ALT≥3xULN AND bilirubin 2xULN  or INR >1.5

Repeat liver chemistries (include ALT, AST, alkaline 
phosphatase, bilirubin) and perform liver event follow 
up assessments within  24 hrs

Monitor subjects twice weekly until liver chemistries 
resolve, stabilise or return to within baseline

A specialist or hepatology consultation is 
recommended
If ALT≥3xULN AND bilirubin < 2xULN  and INR ≤1.5:

Repeat liver chemistries (include ALT, AST, alkaline 
phosphatase, bilirubin) and perform liver event follow 
up assessments within 24-72 hrs

Monitor subjects weekly until liver chemistries 
resolve, stabilize or return to within baseline

Viral hepatitis serology3

Serum creatine phosphokinase (CPK) and lactate 
dehydrogenase (LDH).

Fractionate bilirubin, if total bilirubin2xULN

A pharmacokinetic (PK) sample to be collected 
up to 7 days following the liver event.

Obtain complete blood count with differential to 
assess eosinophilia

Record the appearance or worsening of clinical 
symptoms of liver injury, or hypersensitivity, on the 
AE report form

Record use of concomitant medications on the 
concomitant medications report form including 
acetaminophen, herbal remedies, other over the 
counter medications.

Record alcohol use on the liver event alcohol intake 
case report form
If ALT≥3xULN AND bilirubin 2xULN  or INR >1.5:

Anti-nuclear antibody, anti-smooth muscle antibody, 
Type 1 anti-liver kidney microsomal antibodies, and 
quantitative total immunoglobulin G (IgG or gamma 
globulins).

Serum acetaminophen adduct HPLC assay 
(quantifies potential acetaminophen contribution to 
liver injury in subjects with definite or likely 
acetaminophen use in the preceding week [James, 
2009]. 

Liver imaging (ultrasound, magnetic resonance, or 
computerised tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver Imaging 
and/or Liver Biopsy CRF forms.
Appendix 3: GSK Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP):
A. Contraceptive subdermal implant that meets the SOP effectiveness criteria 
including a <1% rate of failure per year, as stated in the product label
B. Intrauterine device or intrauterine system that meets the SOP effectiveness criteria 
including a <1% rate of failure per year, as stated in the product label [Hatcher, 
2007(a)]
C. Oral Contraceptive, either combined or estrogen and progestogen alone [Hatcher,
201107(a)] 

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D. Injectable progestogen [Hatcher, 201107(a)]
E. Contraceptive vaginal ring [Hatcher, 201107(a)]
F. Percutaneous contraceptive patches [Hatcher, 201107(a)]
G. Male partner sterilization with documentation of azoospermia prior to the female 
subject's entry into the study, and this male is the sole partner for that subject 
[Hatcher, 2007(a)].  The documentation on male sterility can come from the 
site personnel’s: review of subject’s medical records, medical examination 
and/or semen analysis, or medical history interview provided by her or her 
partner.
H. Male condom combined with a vaginal spermicide (foam, gel, film, cream, or 
suppository) [Hatcher, 2007(b)] 
Section 11, References:  
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, editors. 
Contraceptive Technology. 19th edition. New York: Ardent Media, 2007(a): 24. Table 3-
2.
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, editors. 
Contraceptive Technology. 19th edition. New York: Ardent Media, 2007(b): 28.
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, Policar MS, 
editors. Contraceptive Technology. 20th edition. Atlanta, Georgia: Ardent Media, 
2011: 50. Table 3-2.