A Global, Open-Label, Multicenter, Phase 1/2 Study of the Safety and Dose Escalation of BAX 888, an Adeno-Associated Virus Serotype 8 (AAV8) Vector Expressing B-Domain Deleted Factor VIII (BDD-FVIII) in Severe Hemophilia A Subjects Administered a Single Intravenous Infusion
Phase: PHASE1
Conditions: Hemophilia A
Sponsor: Baxalta now part of Shire

For non-commercial use only.

PROTOCOL: 201501
TITLE:
A Global, Open-Label, Multicenter, Phase 1/2 Study of the Safety and 
Dose Escalation of BAX 888, an Adeno-Associated Virus Serotype 8 
(AAV8) Vector Expressing B-Domain Deleted Factor VIII 
(BDD-FVIII) in Severe Hemophilia A Subjects Administered a Single 
Intravenous Infusion
SHORT TITLE:
Safety and Dose Escalation Study of an Adeno-Associated Viral 
Vector for Gene Transfer in Hemophilia A Subjects
STUDY PHASE:
Phase 1/2
DRUG:
BAX 888
IND NUMBER:
017523
EUDRACT 
NUMBER:
2015-005576-22
NCT NUMBER:
NCT03370172
SPONSOR:
Takeda Development Center Americas, Inc.*
95 Hayden Ave, Lexington, MA 02421 
USA
AND 
Baxalta Innovations GmbH**
Industriestrasse 67, A-1221 Vienna
AUSTRIA
*Formerly Baxalta and later Shire
**Baxalta is now part of Takeda
PROTOCOL 
HISTORY:
Amendment 9: 2021 NOV 10
Replaces: Amendment 8: 2021 MAR 22
Amendment 7:2020 MAR 12
Amendment 6: 2019 MAY 03
Amendment 5: 2018 AUG 16
Amendment 4: 2018 JAN 24
Amendment 3 (USA): 2017 SEP 01
Amendment 2 (USA): 2017 AUG 03 
Amendment 1: 2017 MAR 15
Original: 2016 FEB 01
For
ustrie
For 
ustrie
F
USTR
Fo
USTR
non-commercial 
Center 
rcia
Center 
xington
merc
xington
a Inno
no
Inno
n
use only.

For non-commercial use only.

Takeda
CONFIDENTIAL
Page 3
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
1. STUDY PERSONNEL
1.1 Authorized Representative (Signatory) / Responsible Party
, PhD
 GT/Hematology
1.2 Study Organization
The name and contact information of the responsible party and individuals involved with the 
study (eg, investigator[s], sponsor’s medical expert and study monitor, sponsor’s 
representative[s], laboratories, steering committees, and oversight committees (including ethics 
committees [ECs], as applicable) will be maintained by the sponsor and provided to the 
investigator.
For non-commercial use only.

Takeda
CONFIDENTIAL
Page 4
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
2. SERIOUS ADVERSE EVENT REPORTING
The investigator will comply with applicable laws/requirements for reporting serious adverse 
events (SAEs) to the ECs.
ALL SAEs, INCLUDING SUSARs, ARE TO BE REPORTED ON THE 
SERIOUS ADVERSE EVENT REPORT (SAER) FORM AND 
TRANSMITTED TO THE SPONSOR 
WITHIN 24 HOURS AFTER BECOMING AWARE OF THE EVENT
Drug Safety contact information: see SAE Report form.
Refer to SAE Protocol Sections and the study team roster for further information.
For definitions and information on the assessment of these events, refer to the following:
1.
Adverse events (AEs), Section 11.1
2.
SAE, Section 11.1.1.1
3.
SUSARs, Section 11.1.1.2
4.
Assessment of AEs, Section 11.1.2.
For non-commercial use only.
ts, ref
ly.
ts, ref

Takeda
CONFIDENTIAL
Page 5
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
3. SYNOPSIS
INVESTIGATIONAL PRODUCT
Name of Investigational Product (IP)
BAX 888
Name(s) of Active Ingredient(s)
AAV8.BDD-FVIIIopt
CLINICAL CONDITION(S)/INDICATION(S)

Severe hemophilia A (≤1% Factor VIII [FVIII] activity)
PROTOCOL ID
201501
PROTOCOL TITLE
A Global, Open-Label, Multicenter, Phase 1/2 Study of the Safety 
and Dose Escalation of BAX 888, an Adeno-Associated Virus 
Serotype 8 (AAV8) Vector Expressing B-Domain Deleted Factor 
VIII (BDD-FVIII) in Severe Hemophilia A Subjects Administered a 
Single Intravenous Infusion
Short Title
Safety and Dose Escalation Study of an Adeno-Associated Viral 
Vector for Gene Transfer in Hemophilia A Subjects
STUDY PHASE
Ph1/2
PLANNED STUDY PERIOD
Initiation
Q1 2018 (First subject first visit)
Primary Completion
Q3 2021 (Last subject in)
Study Completion
Q3 2026 (Last subject out)
Duration
Approximately 8 years
STUDY OBJECTIVES AND PURPOSE
Study Purpose
1. To evaluate the safety and determine the dose of BAX 888 required to achieve FVIII activity levels ≥20% of 
normal in severe hemophilia A subjects.
Primary Objective
1. To evaluate the safety of a single intravenous (IV) infusion of BAX 888 in up to 3 dose cohorts.
Secondary Objectives
1. To evaluate plasma FVIII activity levels pre- and post-BAX 888 infusion and investigate the relationship 
between FVIII activity levels and BAX 888 dose.
2. To determine the BAX 888 dose needed to achieve FVIII activity level of ≥20% of normal in ≥60% of the 
subjects.
3. To collect bleeding rate and consumption of exogenous FVIII after gene transfer.
4. To assess humoral and cellular immune responses to FVIII and the AAV8 viral capsid.
5. To determine the duration of BAX 888 genome presence in blood, saliva, semen, urine and stool.
For
determin
For 
determin
a A s
F
a A s
on-commercial
subjec
ial 
subjec
Last sub
erci
Last sub
cia
26
m
26 (Las
mme
(Las
e
Approxim
com
Approxim
m
E
co
non
on
use 
e
u
only.
y o
Hemoph
nly.
Hemoph
n y

Takeda
CONFIDENTIAL
Page 6
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
STUDY DESIGN
Study Type/ Classification/ 
Discipline
Safety, Efficacy, Pharmacodynamics
Control Type
No control
Study Indication Type
Treatment
Intervention model 
Single-administration, up to 3 cohorts
Blinding/Masking
Open-label
Study Design
This is a global, Phase 1/2 multicenter, open-label, safety and dose escalation study 
of BAX 888 in adult subjects with severe hemophilia A. Up to 12 subjects may be 
administered BAX 888 in up to 3 dose cohorts.
Study Procedures
Before any study-related procedures are followed, subjects will provide signed 
informed consenti. During the course of the study, FVIII activity levels will be 
assessed by a central laboratory (both one-stage and chromogenic assays) and by 
the local laboratory (either one-stage or chromogenic assay) as specified in 
Table 3. However, only central laboratory FVIII activity levels derived from the 
one-stage assay will be utilized for the primary analysis. FVIII activity levels 
obtained from the central laboratory chromogenic assay will be utilized to support 
the one-stage assay results. Baseline FVIII activity levels will be assessed by the 
central laboratory one-stage clotting assay at the Screen 1 visit. Upon completion 
of screening activities, on the day of BAX 888 dosing (Day 0)ii, subjects will be 
admitted to the infusion centeriii. 
BAX 888 will be administered as a single peripheral IV infusion on Day 0. 
Subjects will be evaluated at the infusion center for the first 8 hours post-BAX 888 
infusion (and up to 24 hours at the discretion of the investigator), and for the Day 1 
visit. The subject will then be evaluated at the hemophilia treatment center at 
Weeks 1 and 2 (once weekly), Weeks 3 to 14 (twice weekly, with separate clinic 
visit and laboratory visit each week), Weeks 15 to 18 (once weekly), and at 
Months 5, 6, 9, 12, 16, 20, 24, 28, 32, 36, 48, and 60. To assess long-term safety 
(adverse events [AEs]) and efficacy (FVIII activity levels, bleeding episodes, 
FVIII consumption) subjects will continue to be followed every 4 months through 
Years 2 and 3, and annually on Years 4 and 5.
Blood samples and urine for clinical safety evaluations will be collected and FVIII 
activity will be collected as an efficacy-related parameter to support future clinical 
i Subjects will initially provide consent for the Screen 1 visit. Subjects who pass Screen 1 will then provide consent 
for the second screening visit and all subsequent study visits at the Screen 2 visit.
ii If the infusion center is not the subject’s Hemophilia Treatment Center/local investigator’s institution, a second 
separate consent will be obtained from the subject for the Day 0 visit and for all procedures surrounding the 
infusion period.
iii At the discretion of the investigator, subjects may remain in the infusion center for 24 hours following infusion, or 
return to the center for follow-up at 24 hours post-infusion.
For
usion (
For 
usion (
F
sit. Th
Fo
sit. Th
mercial
ratory
ial 
ratory
. Baselin
rcia
. Baselin
stage clo
merc
stage clo
on-comm
ies, on th
mm
ies, on th
nfusion
om
nfusion
w
o
will be 
on-
ill be 
n
s will b
no
will b
n
use
tory 
se 
tory 
the pr
use
the pr
c
u
c
only.
dy
tage and
ly.
tage and
chromoge
only
hromoge
FV
o
FV

Takeda
CONFIDENTIAL
Page 7
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
development. Electrocardiograms will be obtained, and vital signs will be 
monitored frequently over the first 8 hours following BAX 888 infusion. Blood and 
bodily secretions (saliva, semen, urine, and stool) will be obtained to assess 
BAX 888 genomes until 2 consecutive measurements are negative.
In addition to a safety data review by the Data Monitoring Committee (DMC), 
further analyses on efficacy and safety data may be performed at study milestones 
(eg, when the initial two subjects in the first cohort finish the Week 18 visit), or 
otherwise up to twice a year for the duration of the study. Analyses due to different 
trigger points may be waived or combined for efficiency.
Clinical bleeding episodes will be managed with infusion of exogenous FVIII. 
Usage of exogenous FVIII for prevention (prophylactic treatment) or episodic 
management (on-demand treatment) of hemorrhages will be at the discretion of the 
investigator and/or local hemophilia physician, and in consultation with the study 
subject. However, in order to measure FVIII activity that is derived from the BAX 
888 transgene and not exogenous FVIII products, subjects will be asked to refrain 
from prophylactic FVIII usage between Weeks 3 to 18 after BAX 888 
administration and during the 3 weeks prior to the Month 9 visit. During these 
periods which are critical for the assessment of sustained FVIII activity levels from 
the vector (as both an efficacy and safety evaluation), on-demand treatment that is 
required for clinical bleeding should, if possible, be performed using a standard 
half-life FVIII product (rather than an extended half-life FVIII concentrate). 
Whenever possible, a 3- to 5-day wash-out period should be observed prior to any 
study visit with a FVIII activity level assessment, however, scheduled visits (except 
for Screen 1) should not be missed in the case of a wash-out of less than 3 days. 
Dose Escalation
At study initiation, subjects will be assigned to a dose cohort, with a minimum of 
24 hours between dosing of each subject. Initially, 2 subjects will be dosed in a 
cohort, with up to a total of 5 subjects if the cohort is expanded. Safety and FVIII 
activity level data from subjects dosed with BAX 888 will be utilized to make 
decisions on dose escalation and cohort expansion. Rules for cohort expansion and 
dose escalation are provided below. However, if any subject in a given cohort 
achieves >50% FVIII activity levels at Week 14, the DMC will provide a 
recommendation on further dose escalations after review of all safety and FVIII 
activity level dataiv. If any subject in any cohort achieves ≥150% FVIII activity 
levels at any time while on the study, further dosing will be paused until DMC 
review. Baseline FVIII activity level is defined as the value obtained based on the 
central laboratory one-stage FVIII assay.
iv DMC recommendations will be based on, but not limited to, the following considerations: (1) mean, median, and 
range of FVIII activity levels (central lab, one-stage clotting assay) observed within the dosing cohort, (2) 
variability in response between subjects, (3) liver function tests, and (4) other product-related adverse events 
(AEs) 
For 
udy i
or
udy i
4
F
4 hours 
For
hours 
or
F
or
non-commercial
nd
l
nd
g should
cial 
g should
ather tha
erci
ather tha
3
m
3-
m
- to 5
me
to 5
FVIII 
mm
FVIII ac
m
ac
hould no
com
hould no
alation
on
alation
no
init
n
init
use
essmen
se 
essmen
safet
us
safet
only.
ucts, 
y
ucts, 
eeks
nly
eeks 3 to
ly
3 to
ior to th
on
ior to th

Takeda
CONFIDENTIAL
Page 8
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
Only central laboratory one-stage FVIII activity levels will be considered for dose 
escalation or cohort expansion decisions.
Subjects within the same dose cohort will be infused with BAX 888 no less than 
24 hours apart to ensure sufficient time is given to observe for infusion-related 
hypersensitivity reactions prior to dosing the next subject. Since asymptomatic 
liver inflammation has not been observed in any individuals who have not 
expressed FIX or FVIII in the AAV hemophilia gene therapy trials, hence dosing 
of subjects after dose escalation can occur as early as 4 weeks in the absence of 
FVIII expression in the lower dose subjects. 
Cohort 1 (2.0 × 1012 cp/kg):
After dosing of the first 2 subjects in Cohort 1: 

If Week 4 FVIII activity levels of both subjects are <2%, then dose escalation 
to Cohort 2 will be triggered with no further dosing in Cohort 1. 
Alternatively, if FVIII activity levels (≥2%) are observed in at least 1 subject, 
the decision to escalate dose or expand the cohort will be based on all data 
available through Week 14.

If sustained Week 14 FVIII activity levels of ≥30%v are not achieved in both 
subjects, then escalation to Cohort 2 will be triggered after DMC review of 
all available safety and FVIII activity level data inclusive of Week 14.

If sustained Week 14 FVIII activity levels of ≥30%v are achieved in at least 
1 of the 2 subjects, then expansion of Cohort 1 will be initiated with dosing 
of 3 additional subjects.
For an expanded Cohort 1 with 5 subjects dosed with BAX 888:

If sustained Week 14 FVIII activity levels of ≥30%v are not achieved in at 
least 3 of the 5 subjects, then escalation to Cohort 2 will be triggered after 
DMC review of all available safety and FVIII activity level data inclusive of 
Week 14.

If sustained Week 14 FVIII activity levels of ≥30%v are achieved in at least 
3 of the 5 subjects, one of the following would be pursued based on the 
safety, FVIII activity levels, and the variability in response that is observed 
among the 5 dosed subjects: 

Completion of study enrollment with no further dosing of additional 
subjects since the secondary objective to determine a BAX 888 dose 
needed to attain FVIII activity levels ≥20% in at least 60% of the 
subjects would have been achieved.
v
Sustained Week 14 FVIII level ≥30% is defined as 3 or more FVIII activity level measurements ≥30% between 
Week 12 and Week 18. If applicable per protocol, a DMC meeting will be held when either 3 or more FVIII 
activity level measurements ≥30% between Weeks 12 and Week 18 are obtained or after Week 18, whichever 
comes first. 
For 
ea
r
ea
DMC
For
DMC
W
F
W
n-commercial
 C
l
 C
FVIII 
cial
FVIII a
l 
a
14 FVII
erc
14 FVII
cts, then
mme
cts, then
nal subj
omm
nal subj
xpanded
co
xpanded
c
non
ustained
on
ustained
st 3 o
no
st 3 o
use
ivity
se
ivity le
e 
le
ohort
us
ohort
only.
%)
d the coh
nly.
d the co

Takeda
CONFIDENTIAL
Page 9
BAX 888
201501 Protocol Amendment 9
10 Nov 2021

Expansion of Cohort 1 to include dosing of additional subjects at the 
same dose level.

Escalation to a higher dose (eg, subsequent patients will be enrolled in 
Cohort 2).
Cohort 2 (6.0 × 1012 cp/kg):
After dose escalation and administration of BAX 888 to the first 2 subjects in 
Cohort 2:

If sustained Week 14 FVIII activity levels of ≥30%v are not achieved in both 
subjects, then expansion of Cohort 2 or escalation to Cohort 3 will be 
triggered after DMC review of all data inclusive of Week 14iv.

If sustained Week 14 FVIII activity levels of ≥30%v are achieved in at least 
1 of the 2 subjects, then, after review of all the available data the DMC will 
make a recommendation to continue with expansion of Cohort 2 up to 
5 subjects, or escalate dosing to Cohort 3 (1.2 x 1013 cp/kg).
For an expanded Cohort 2 with up to 5 subjects dosed with BAX 888: 

If sustained Week 14 FVIII activity levels of ≥30%v are not achieved in at 
least 3 subjects, then one of the following would be pursued after DMC 
review of all available safety and FVIII activity level data inclusive of Week 
14:

Escalation to Cohort 3 (1.2 × 1013 cp/kg)

Completion of study enrollment with no further dosing

If sustained Week 14 FVIII activity levels of ≥30%v are achieved in at least 
1 of the subjects, one of the following would be pursued after DMC review 
and based on the safety, FVIII activity levels, and the variability in response, 
and other clinical data that is observed among all the dosed subjects in the 
study:
Continue to expand Cohort 2 up to 5 subjects
Escalation to Cohort 3 (1.2 × 1013 cp/kg) 
Completion of study enrollment with no further dosing
Preliminary evaluation following 2 subjects dosed with 2.0 × 1012 cp/kg (lowest 
dose level) showed minimal impact on FVIII activity levels. Preliminary 
evaluation following 2 subjects dosed 6.0 × 1012 cp/kg (middle dose level; 3-fold 
higher than lowest dose level) suggests that the peak FVIII activity was as 
expected but increased more than proportional to the increase in dose. A mouse 
model suggested a potential non-linear dose-FVIII activity relationship (doubling 
of the dose might produce more than a doubling of the FVIII activity). To ensure 
informed dose escalation in subjects with Hemophilia A, instead of a 3-fold 
increase in dose, the next proposed dose is 1.2 × 1013 cp/kg which is 2-fold the 
middle dose level originally proposed.
For 
and 
r
and 
study
For
study
non-commercial
fety an
ial 
fety an
n to Coh
mer
n to Coh
pletion o
mm
pletion o
d Week 
com
d Week 
e subject
n-c
e subject
based o
non
based o
othe
n
othe
use 
ty
se
ty le
e
le
e follo
use
e follo
d
u
d
only.
(
ubjects do
only
ubjects do
on
vels
o
vels

Takeda
CONFIDENTIAL
Page 10
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
Cohort 3 (1.2 × 1013 cp/kg)
After dose escalation and administration of BAX 888 to the first 2 subjects in 
Cohort 3

If sustained Week 14 FVIII activity levels of ≥30%v are not achieved in both 
subjects, then dosing of additional subjects will be paused until further review 
of all available data. 

If sustained Week 14 FVIII activity levels of ≥30%v are achieved in at least 1 
of the 2 subjects, then expansion of Cohort 3 will be initiated with dosing of 
up to 3 additional subjects.

Study could be completed with no further dosing.
Immunosuppression
Vector-derived factor expression followed by a decrease in factor levels has been 
observed in previous hemophilia gene therapy trials and has been attributed to an 
immune response directed against the successfully transduced cells. To address 
this issue and to ensure sustained factor levels are achieved, BAX 888 has been 
engineered to have a reduced prospect of eliciting an immune response.
Nevertheless, a prophylactic course of glucocorticosteroid treatment 
with prednisolone (as shown in the table below) will be employed starting at Day 8 
post-BAX 888 infusion. 
The following dosing schedule will be followed as a guideline. The corticosteroid 
regimen may be adjusted at the discretion of the Investigator in consultation with 
the Sponsor Medical Monitor depending on the subject’s tolerance of the 
regimen and the observed hepatic transaminase response. 
Subjects receiving corticosteroids may require additional unscheduled visits to 
evaluate potential side effects of corticosteroid therapy and for corticosteroid dose 
adjustments, FVIII activity levels and liver function tests (LFTs) will be measured 
at these unscheduled visits by local laboratories.
Prednisolone Dosing Regimen
Prednisolone Dose (mg/day)
Duration
60
4 weeks
40
2 weeks
30
2 weeks
25
2 weeks
20
2 weeks
15
1 week
10
1 week
5
1 week
Determine alanine aminotransferase (ALT) and FVIII activity level 
weekly or twice weekly (as per study protocol).
For 
uate p
or
uate p
djustme
For
djustme
he
F
he
non-commercial 
n the t
al 
n the t
schedul
mer
schedul
djusted
mm
djusted
m
edical
com
edical M
m
M
d the ob
n-c
the ob
 receivi
non
receivi
pote
n
pote
use 
e of glu
use
e of glu
tab
u
tab
only.
ull
els are a
nly.
els are a
f eliciting
on
eliciting

Takeda
CONFIDENTIAL
Page 11
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
NOTE: In geographies where prednisolone cannot be sourced at the strengths 
required for the specified dosing regimen (eg USA), prednisone will be provided. 
Prednisone is converted to the active metabolite prednisolone and is recommended 
by the American Association for the Study of Liver Disease (AASLD) and the 
European Association for the Study of the Liver (EASL) for the treatment of 
autoimmune hepatitis.
Assessment of possible reactions to corticosteroids will be performed by the 
Investigator and modification of treatment will be done as necessary after 
consultation with the Sponsor’s Medical Monitor. In such instances, consideration 
should be given to combination therapy with azathioprine/corticosteroid per 
AASLD guidelines or other drug as per standard of practice, in consultation with a 
hepatologist, so that the care can be individualized to the subject’s needs.
Further Management of Presumptive Vector-Related Hepatitis
Any subject who develops an ALT and/or or aspartate aminotransferase (AST) 
level >3 × upper limit of normal (ULN) during the study will continue to be treated 
with prednisolonevi as outlined in the Prednisolone Dosing Regimen Table above 
in the Immunosuppression Section. Additionally, the subject must have 
the test repeated and confirmed within 72 hours. If the level remains >3 × ULN, a 
diagnostic workup of potential infectious and toxic/metabolic causes of hepatitis 
will be pursued, including consultation with a hepatologist. If no other cause of the 
elevated ALT and/or AST is identified, consideration should be given to 
combination therapy with azathioprine/corticosteroid per AASLD guidelines or 
other drug regimens as per standard of practice, in consultation with a hepatologist.
Recurrent elevations in transaminases after Year 1 should be evaluated and treated 
at the discretion of the investigator. Abdominal ultrasound examination will be 
performed locally to assess liver health. In addition, and at the discretion of the 
Investigator serum alpha fetoprotein level, an exploratory biomarker for 
hepatocellular carcinoma, will be measured at local laboratories.
Study Stopping Rules
Each subject will receive only 1 dose of BAX 888 during the course of the study; 
hence study stopping rules apply only to subjects during the screening period. 
Subjects who have been dosed with BAX 888 will be followed to the end of the 
study as per protocol.
If any one of the following criteria are met, dosing will be paused and further 
enrollment will be halted until an independent DMC evaluates all available study 
data and makes a recommendation:
vi
In geographies where prednisolone cannot be sourced at the strengths required for the specified dosing regimen 
(eg, USA), prednisone will be provided. Prednisone is converted to the active metabolite prednisolone, and is 
recommended by the AASLD and the EASL for the treatment of autoimmune hepatitis.
For
ormed
or 
ormed
nvestiga
Fo
nvestiga
F
non-commercial
w
l
wi
l
i
ial infec
cial 
ial infec
g consu
erc
g consu
AST
me
AST is 
me
is 
apy with
mm
apy with
imens as
com
imens as
levation
n-c
levation
scretion
non
scretion
d l
n
d l
use
Additio
se 
Additio
thin 7
us
thin 7
only.
aspar
y.
aspar
uring the 
nly
uring the 
dnisolo
on
dnisolo

Takeda
CONFIDENTIAL
Page 12
BAX 888
201501 Protocol Amendment 9
10 Nov 2021

More than 3 × ULN increase in ALT, aspartate aminotransferase (AST), or 
both in any subject after BAX 888 administration that is not responsive after 
12 weeks of corticosteroid rescue treatment implemented according to 
AASLD guidelines.

A serious adverse event (SAE) that may or may not be potentially related to 
BAX 888 and which poses either an immediate risk to the subject’s health or 
is likely to adversely affect the subject’s health long term. This includes 
events classified as AEs qualifying for special notification (Brussels, 
03/12/2009, ENTR/F/2/SF/dn D (2009) 35810; 
EMEA/CHMP/GTWP/60436/2007) if these are judged as potentially related 
to the investigational product (IP). 

The development, after having received BAX 888, of an inhibitor towards 
FVIII in any subject will lead to pausing of dosing and further investigations 
of the characteristics and potential contributing factors and causal 
relationships of the observed FVIII inhibitor.

Death of a subject, after having received BAX 888, that is judged as 
definitely, probably or possibly attributed to BAX 888. The study will be 
temporarily stopped in order to undergo review by the institutional review 
board (IRB), DMC and the FDA.

The occurrence of a malignancy at any point after gene transfer that is judged 
as probably or possibly related to BAX 888.
Enrollment in the study may be terminated if one or more of the following criteria 
are met:

The sponsor decides to stop enrollment into the study based upon its 
assessment of safety.

The sponsor decides to stop enrollment into the study for administrative 
reasons.
If enrollment on the study is terminated, the study will remain open for clinical 
safety evaluations and FVIII activity level assessments as an efficacy-related 
parameter that will be recorded for approximately the first five years post subject 
dosing. 
Planned Duration of 
Subject Participation
The overall duration of the study is approximately 8 years from study initiation (ie, 
first subject enrolled) to study completion (ie, last subject last visit, 5 years 
post-gene transfer). The recruitment period is expected to be about 40 months.
Each subject participation period is expected to be up to 5.5 years. Every effort 
will be made to follow subjects for approximately 5-years post-gene transfer 
period.
Primary Outcome Measure
1. Incidence of BAX 888-related AEs (serious or non-serious) including development of FVIII inhibitory 
antibodies, clinically significant changes in standard laboratory parameters, physical exam, and vital signs 
that are reported as AEs.
For
reaso
or 
reaso
F
n-commercial
nan
l
nan
y related
cial 
y related
dy may b
me
dy may b
nsor dec
co
nsor dec
non
sment o
on-c
sment o
e spon
no
e spon
use 
A.
s
A.
ncy at
us
ncy at
only.
BAX
y
BAX
uted to B
nly
uted to B
ergo rev
on
ergo rev

Takeda
CONFIDENTIAL
Page 13
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
Secondary Outcome Measures
Efficacy
1. Circulating plasma FVIII activity and antigen levels.
2. Annualized bleed rate (ABR) in comparison to before gene transfer.
3. Consumption of exogenous FVIII in comparison to before gene transfer.
Safety 
1. Development of inhibitory and total binding antibodies to FVIII.
2. Humoral and cell-mediated immune response to AAV8 and FVIII proteins.
3. Surveillance of AAV8 genome shedding in blood, saliva, semen, urine and stool.
Tertiary Outcome Measures
1. Hemophilia Joint Health Score at screening and Months 12, 24, 36, 48, and 60 post-gene transfer.
2. Changes in the following assessments:

Health-related quality of life (HRQoL) (post-gene transfer vs. baseline) measured by:
Generic: 36-item Short Form survey (SF-36v2), EuroQol-5D (EQ-5D).
Disease-specific: Hemophilia-Specific Quality of Life Index (Haemo-QoL-A).

Patient experience (baseline):
Adherence: Validated Hemophilia Regimen Treatment Adherence Scale-Prophylaxis 
(VERITAS-Pro).
Disease-specific patient experience: Patients' preference for hemophilia treatment questionnaire 
(HaemoPREF).
INVESTIGATIONAL PRODUCT(S), DOSE AND MODE OF ADMINISTRATION
Active Product
BAX 888 (AAV8.BDD-FVIIIopt)
Dosage form: Injection, solution.
Dosage frequency: Once. No repeat dose will be given to same subject.
Mode of Administration: IV infusion.
SUBJECT SELECTION 
Targeted Accrual
Up to 12 evaluable subjects.
Number of Groups/ 
Arms/ Cohorts
Up to three dose cohorts.
Inclusion Criteria
Subjects must meet all of the following criteria prior to enrollment into the study:
1. Male, aged 18 to 75 years at the time of screening.
2. Established severe hemophilia A (FVIII:C <1%, measured following ≥5 days without FVIII treatment) 
and/or documented intron 1 inversion or intron 22 inversion mutation in the F8 gene, consistent with severe 
hemophilia A AND documented evidence of ≥3 hemorrhages over the previous 12 months requiring 
treatment with exogenous FVIII or use of FVIII prophylaxis because of history of frequent bleeding 
episodes
3. History of >150 exposure days to exogenously administered FVIII concentrates or cryoprecipitate.
For 
e fre
r
e fre
de of A
Fo
de of A
F
non-commercial 
s' prefer
rcia
s' prefer
AND M
mm
AND M
me
V8.BDD
co
V8.BDD
m
o
m: I
on
: Injec
on
njec
eque
n
eque
om
use 
ent Ad
use
ent Ad
only.
(EQ
y
(EQ
y.
ex
on
ex (Haem
only
(Haem

Takeda
CONFIDENTIAL
Page 14
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
4. Sexually active men must agree to use barrier contraception (combination of a condom and spermicide) or 
limit sexual intercourse to post-menopausal, surgically sterilized, or contraception-practicing partners for a 
minimum of 6 months after administration of BAX 888, or until BAX 888 genomes are no longer detected 
in the semen, whichever is sooner.
5. Subject is willing and able to comply with the requirements of the protocol, including provision of semen 
samples, maintenance of a diary of bleeding episodes and FVIII protein use.
6.
Signed informed consent.
Exclusion Criteria
Subjects meeting any one of the following criteria will be deemed ineligible for participation in the study:
1. Bleeding disorder(s) other than hemophilia A.
2. Personal laboratory evidence of having developed inhibitors to FVIII protein at any time (≥0.6 Bethesda 
Units on any single test).
3. Documented prior allergic reaction to any FVIII product.
4.
Anti-AAV8 neutralizing antibody titer ≥1:5. Subjects whose laboratory assessments are ≤1:10 may be 
re-tested within the same Screening window and, if eligibility criterion is met on retest, may be enrolled 
after confirmation by the Sponsor Medical Monitor. 
5. Known hypersensitivity to prednisolone or prednisone, or to any of the excipients.
6. Having a disease in which treatment with prednisolone or prednisone is not tolerated (including but not 
limited to osteoporosis with vertebral fractures, difficult to control hypertension and difficult to control 
diabetes).
7. Evidence of markers of potential underlying risk for autoimmune mediated hepatic disease:
a. Anti-smooth muscle antibody assay results ≥40 (Inova QUANTA LiteTM Actin IgG enzyme-linked 
immunosorbent assay); values of 31 to 39 will be flagged as possibly abnormal and the Investigator and 
Medical Monitor will evaluate the subject for eligibility.
b. Elevated anti-liver-kidney microsomal antibody type 1 (LKM1) titers.
c. Total immunoglobulin G (IgG) >1.5 × ULN.
d. Antinuclear antibody (ANA) titer >1:320; OR ANA titer >1:80 if demonstrated concurrently with ALT 
that is >ULN.
8. Active Hepatitis C virus (Hepatitis C): As indicated by detectable HCV ribonucleic acid by polymerase 
chain reaction.
9. Hepatitis B: If surface antigen is positive.
10.Seropositive for Human Immunodeficiency Virus (HIV)
11.Receiving systemic antiviral and/or interferon therapy within 4 weeks prior to enrollment.
12.Clinically significant infections (eg, systemic fungal infections) requiring systemic treatment.
13.Known immune disorder (including myeloma and lymphoma).
14.Concurrent chemotherapy or biological therapy for treatment of neoplastic disease or other disorders.
15.An absolute neutrophil count <1000 cells/mm3.
16.Markers of hepatic inflammation or cirrhosis as evidenced by 1 or more of the following:
a. Platelet count of <150,000/µL.
b. Serum albumin level is below the central laboratory’s lower limit of normal and FibroSURE is ≥0.48 
(ie, Metavir staging of F2 or greater). Of note, in subjects with a known history of Gilbert’s syndrome, a 
Fibrotest cannot be used for fibrosis testing.
For 
IgG
r
IgG
ANA) ti
For
ANA) ti
non-commercial 
to c
al
to c
for auto
erc
for auto
ts
m
ts ≥40 (I
mme
≥40 (I
o 39 w
om
o 39 will
m
ill
subject 
-co
subject 
rosomal
on
rosomal
)
n
) >1
no
>1
use 
e
dnison
use
dnison
contr
us
contr
only.
is m
y
of t
o
f the ex
on
he ex

Takeda
CONFIDENTIAL
Page 15
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
c. Total bilirubin >1.5 × ULN and direct bilirubin ≥0.5 mg/dL.
d. ALT or AST >1.0 × ULN.
e. Alkaline phosphatase >2.0 × ULN.
f.
History of liver biopsy indicating moderate or severe fibrosis (Metavir staging of F2 or greater).
g. History of ascites, varices, variceal hemorrhage, or hepatic encephalopathy.
h. Any findings on screening ultrasound that would preclude the safe use of AAV gene therapy.
17.Prothrombin time (PT) international normalized ratio (INR) ≥1.4.
18.Serum creatinine >1.5 mg/dL.
19.Urine protein >30 mg/dL OR >0.5 g/day.
20.Body mass index >38.
21.Orthopedic surgery or other major surgery planned within 6 months after enrollment.
22.Acute or chronic disease that, in the opinion of the investigator, would adversely affect subject safety or 
compliance or interpretation of study results.
23.Received an AAV vector previously or any other gene transfer agent in the previous 12 months prior to 
Study Day 0.
24.Received an investigational intervention or participated in another clinical trial within 4 weeks prior to 
enrollment or within 5 half-lives of the investigational drug administration, whichever is longer.
25.Significant cardiovascular disease (such as New York Heart Association Class III or IV cardiac disease, 
congestive heart failure, myocardial infarction within the previous 6 months, unstable arrhythmias, or 
unstable angina) or significant pulmonary disease (including obstructive pulmonary disease).
26.Recent history of psychiatric illness or cognitive dysfunction (including drug or alcohol abuse) that, in the 
opinion of the investigator, is likely to impair subject’s ability to comply with protocol mandated 
procedures.
27.Subject is a family member or employee of the investigator.
STATISTICAL ANALYSIS
Sample Size Calculation
The sample size is expected to range from 2 to 12 evaluable subjects depending on the actual number of cohorts 
and the actual number of subjects in each cohort. This sample size was chosen to provide sufficient evidence of 
safety and exploration of signs of efficacy for this indication and is not based on formal statistical considerations.
Planned Statistical Analysis
In general, descriptive summaries will be presented for the primary, secondary, and tertiary outcome measures. 
Continuous variables will be summarized using mean, standard deviation, maximum, minimum, median, and 
other percentiles as appropriate. Categorical variables will be summarized using frequency counts and 
percentages. Analyses will be performed within each cohort separately and overall. The primary outcome of the 
incidence of BAX 888-related AEs will be analyzed as a categorical variable. An exploratory, descriptive 
analysis will also be performed for events categorized as development of inhibitory antibodies to FVIII and total 
binding antibodies to FVIII, severe allergic reactions, and thrombosis-associated events. More detailed 
information about summarization of data, graphical representations, and analysis conventions will be provided in 
the Statistical Analysis Plan.
For 
nge
F
nge
r
on-commercial
he pre
ial 
he pre
ncludin
rcia
ncludin
e dysfun
mer
e dysfun
ir subjec
mm
ir subjec
yee of th
n-c
yee of th
non
on
n
use 
minis
e
minis
Assoc
use
Assoc
vi
u
vi
only.
clinical t
only
clinical t
strati
o
strati

Takeda
CONFIDENTIAL
Page 16
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
4. TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE..............................................................................................2
1. STUDY PERSONNEL ..............................................................................................................3
1.1 Authorized Representative (Signatory) / Responsible Party ..........................................3
1.2 Study Organization.............................................................................................................3
2. SERIOUS ADVERSE EVENT REPORTING........................................................................4
3. SYNOPSIS..................................................................................................................................5
4. TABLE OF CONTENTS ........................................................................................................16
LIST OF IN-TEXT TABLES .....................................................................................................20
LIST OF IN-TEXT FIGURES ...................................................................................................20
LIST OF ABBREVIATIONS .....................................................................................................21
5. BACKGROUND INFORMATION .......................................................................................24
5.1 Description of Investigational Product ...........................................................................24
5.2 Clinical Condition/Indication...........................................................................................25
5.3 Population to be Studied...................................................................................................25
5.4 Findings from Nonclinical and Clinical Studies.............................................................26
5.4.1 Nonclinical Studies .....................................................................................................26
5.4.2 Clinical Studies ...........................................................................................................26
5.5 Evaluation of the Unmet Medical Need in the Treatment of Severe Hemophilia A...26
5.5.1 Evaluation of Anticipated Benefits and Risks of AAV-FVIII Gene Therapy.......26
5.5.1.1 Prednisolone .........................................................................................................30
5.5.1.2 Evaluation of Anticipated Benefits and Risks of Co-administration of 
Prednisolone and AAV ........................................................................................30
5.6 Compliance Statement......................................................................................................32
6. STUDY PURPOSE AND OBJECTIVES ..............................................................................33
6.1 Study Purpose....................................................................................................................33
6.2 Primary Objective.............................................................................................................33
6.3 Secondary Objectives........................................................................................................33
7. STUDY DESIGN......................................................................................................................34
7.1 Brief Summary ..................................................................................................................34
7.2 Overall Study Design ........................................................................................................34
7.2.1 Screen 1........................................................................................................................38
7.2.2 Screen 2........................................................................................................................39
7.2.3 Day 0 ............................................................................................................................40
For
ticipa
For 
ticipa
e
F
e
F
....
F
....
n-commercial 
....
...........
cia
...........
........
er
........
........
m
........
Clinica
omm
Clinica
.........
co
.........
non
........
on
........
Medi
no
Medi
t
n
t
use 
.....
u
.....
only.
......
y
......
..........
on
.........

Takeda
CONFIDENTIAL
Page 17
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
7.2.4 Day 1 ............................................................................................................................41
7.2.5 Weeks 1-2 ....................................................................................................................41
7.2.6 Weeks 3-14 ..................................................................................................................42
7.2.7 Week 15-18..................................................................................................................43
7.2.8 Months 5, 6, 9, 12........................................................................................................44
7.2.9 Years 2-5 (Months 16, 20, 24, 28, 32, 36, 48, 60)......................................................45
7.2.10 Early Termination Visit...........................................................................................46
7.2.11 Further Management of Presumptive Vector-Related Hepatitis.........................47
7.3 Duration of Study Period(s) and Subject Participation ................................................48
7.4 Outcome Measures............................................................................................................48
7.4.1 Primary Outcome Measure .......................................................................................48
7.4.2 Secondary Outcome Measures ..................................................................................48
7.4.2.1 Efficacy..................................................................................................................48
7.4.2.2 Safety.....................................................................................................................49
7.4.3 Tertiary Outcome Measures......................................................................................49
7.5 Randomization and Blinding ...........................................................................................49
7.6 Study Stopping Rules........................................................................................................49
7.7 Investigational Product(s) ................................................................................................50
7.7.1 Packaging, Labeling, and Storage.............................................................................50
7.7.2 Administration............................................................................................................51
7.7.2.1 Monitoring and Treatment of Allergic Reaction to BAX 888..........................52
7.7.3 Description of the Investigational Product...............................................................52
7.7.4 Investigational Product Accountability....................................................................52
7.8 Source Data........................................................................................................................53
8. SUBJECT SELECTION, WITHDRAWAL, AND DISCONTINUATION .......................54
8.1 Inclusion Criteria ..............................................................................................................54
8.2 Exclusion Criteria .............................................................................................................54
8.3 Withdrawal and Discontinuation ....................................................................................56
9. STUDY PROCEDURES .........................................................................................................58
9.1 Informed Consent .............................................................................................................58
9.2 Subject Identification Code..............................................................................................58
9.3 Screening and Study Visits...............................................................................................58
9.4 Medications and Non-Drug Therapies............................................................................59
9.4.1 Use of Exogenous FVIII Throughout the Study......................................................60
9.5 Subject Diary and Patient Reported Outcomes .............................................................60
9.5.1 Subject Diary ..............................................................................................................60
9.5.2 Patient Reported Outcomes.......................................................................................61
9.6 Subject Completion/Discontinuation...............................................................................62
9.7 Procedures for Monitoring Subject Compliance ...........................................................63
9.8 Communication with Sites................................................................................................63
10. ASSESSMENT OF EFFICACY...........................................................................................64
10.1 Circulating Plasma FVIII Activity and Antigen Levels ..............................................64
or 
......
r
......
Fo
contin
For
contin
mmercial
rgic R
ial 
rgic R
roduct
rcia
roduct
ability
merc
ability
non-comm
........
mm
........
DRAW
-co
DRAW
..........
non
..........
.
use
.......
se 
.......
.......
us
.......
R
u
R
only.
..
...........
ly
..........
............
only
...........
.....
o

Takeda
CONFIDENTIAL
Page 18
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
10.2 Number of Bleeding Episodes Post-BAX 888 Infusion................................................64
10.3 Consumption of Exogenous FVIII Compared to before Gene Transfer ...................64
11. ASSESSMENT OF SAFETY................................................................................................66
11.1 Adverse Events ................................................................................................................66
11.1.1 Definitions .................................................................................................................66
11.1.1.1 Serious Adverse Event.......................................................................................66
11.1.1.2 Suspected Unexpected Serious Adverse Reaction (SUSAR)..........................67
11.1.1.3 Non-Serious Adverse Event ..............................................................................67
11.1.1.4 Unexpected Adverse Events..............................................................................67
11.1.1.5 Preexisting Diseases ...........................................................................................68
11.1.2 Assessment of Adverse Events.................................................................................68
11.1.2.1 Severity................................................................................................................69
11.1.2.2 Causality .............................................................................................................70
11.2 Urgent Safety Measures..................................................................................................70
11.3 Untoward Medical Occurrences....................................................................................71
11.3.1 Pregnancies in Female Partners of Male Subjects ................................................72
11.4 Non-Medical Complaints................................................................................................72
11.5 Medical, Medication, and Non-Drug Therapy History ...............................................73
11.6 Physical Examinations....................................................................................................73
11.7 Clinical Laboratory Parameters....................................................................................74
11.7.1 Additional Sample Collection..................................................................................74
11.7.2 Hematology, Coagulation, Clinical Chemistry, and Markers of Autoimmune 
Response......................................................................................................................74
11.7.3 Viral Serology ...........................................................................................................75
11.7.4 Gene Mutation and HLA.........................................................................................75
11.7.5 Immunogenicity ........................................................................................................76
11.7.6 Vector Genomes........................................................................................................76
11.7.7 Assessment of Laboratory Values...........................................................................77
11.8 Vital Signs and 12-Lead Electrocardiogram ................................................................77
11.9 Hemophilia Joint Health Score......................................................................................78
11.10 Patient Reported Outcomes .........................................................................................78
11.11 Evaluation of Liver Health...........................................................................................78
11.12 Exploratory Assays .......................................................................................................78
11.13 Assessment of Pharmacodynamics..............................................................................79
12. STATISTICS..........................................................................................................................80
12.1 Sample Size and Power Calculations.............................................................................80
12.2 Analysis Sets ....................................................................................................................80
12.3 Handling of Missing, Unused, and Spurious Data .......................................................80
12.4 Methods of Analysis........................................................................................................80
12.4.1 Primary Outcome Measure .....................................................................................81
12.4.2 Secondary Outcome Measures ................................................................................81
12.4.2.1 Efficacy................................................................................................................81
12.4.2.2 Safety...................................................................................................................81
For 
......
r
......
Labor
For
Labor
ea
F
ea
non-commercial 
..
l
..
........
ia
........
........
rc
........
nical Ch
mer
nical Ch
........
mm
........
........
co
........
LA
n
LA....
n-
....
........
no
........
.
use
Histo
se 
Histo
....
u
....
only.
....
....
cts ........
nly.
cts .......
........
o
........
r

Takeda
CONFIDENTIAL
Page 19
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
12.4.3 Tertiary Outcome Measures....................................................................................82
12.5 Planned Interim Analysis of the Study .........................................................................82
13. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .................................................83
14. QUALITY CONTROL AND QUALITY ASSURANCE...................................................84
14.1 Investigator’s Responsibility..........................................................................................84
14.1.1 Final Clinical Study Report.....................................................................................84
14.2 Training............................................................................................................................84
14.3 Monitoring .......................................................................................................................84
14.4 Auditing............................................................................................................................84
14.5 Safety Monitoring ...........................................................................................................85
14.6 Non-Compliance with the Protocol ...............................................................................85
14.7 Laboratory and Reader Standardization......................................................................85
15. ETHICS ..................................................................................................................................86
15.1 Subject Privacy................................................................................................................86
15.2 Ethics Committee and Regulatory Authorities ............................................................86
15.3 Informed Consent ...........................................................................................................86
15.4 Data Monitoring Committee..........................................................................................87
16. DATA HANDLING AND RECORD KEEPING................................................................88
16.1 Confidentiality Policy......................................................................................................88
16.2 Study Documentation and Case Report Forms............................................................88
16.3 Document and Data Retention.......................................................................................88
17. FINANCING AND INSURANCE........................................................................................89
18. PUBLICATION POLICY.....................................................................................................90
19. SUPPLEMENTS....................................................................................................................91
19.1 Study Design Flow Chart and Dose Escalation Scheme..............................................91
19.2 Schedule of Study Procedures and Assessments ..........................................................93
19.3 Clinical Laboratory Assessments ..................................................................................98
19.4 Definitions......................................................................................................................103
19.4.1 Joint Bleeds .............................................................................................................103
19.4.2 Muscle Bleeds..........................................................................................................103
20. REFERENCES.....................................................................................................................104
21. SUMMARY OF CHANGES...............................................................................................106
For 
CY
Fo
CY.
Fo
.
mercial 
.....
l
.....
EPING
erci
EPING
on-comm
........
mm
........
e Repo
om
e Repo
on
c
on....
c
....
n
ANCE
no
ANCE
use 
..
e
..
......
se
......
.....
us
.....
s
only.
..
.....
nl
............
nly
.......
..........
on
.........

Takeda
CONFIDENTIAL
Page 20
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
LIST OF IN-TEXT TABLES
Table 1. Prednisolone Dosing Regimen......................................................................................37
Table 2. Schedule of Study Procedures and Assessments ........................................................93
Table 3. Clinical Laboratory Assessments ................................................................................98
LIST OF IN-TEXT FIGURES
Figure 1. Vector DNA Structure.................................................................................................51
Figure 2. Study Design for Takeda Clinical Study 201501 ......................................................91
Figure 3. Dose Escalation Schema for Takeda Clinical Study 201501 ...................................92
For non-commercial use only.

Takeda
CONFIDENTIAL
Page 21
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
LIST OF ABBREVIATIONS
Abbreviation
Definition
AASLD
American Association for the Study of Liver Diseases
AAV
adeno-associated virus 
ABR
annualized bleed rate
AE
adverse event
ALT
alanine aminotransferase
ANA
antinuclear antibody
AMA
antimitochondrial antibody
AST
aspartate aminotransferase
BDD
B-domain deleted
BU
Bethesda units
BUN
blood urea nitrogen
CK
creatine kinase
CMI
cell-mediated immune
CNS
central nervous system
CRF
case report form
CTCAE
Common Terminology Criteria for Adverse Events
CTL
cytotoxic lymphocyte
DMC
Data Monitoring Committee
EASL
European Association for the Study of the Liver
EC
ethics committee
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
ELISA
enzyme-linked immunosorbent assay
EQ-5D
EuroQol-5D
FIX
factor IX
FVIII
factor VIII
GCP
Good Clinical Practice
GGT
gamma-glutamyl transpeptidase
Haemo-QoL-A
Hemophilia-Specific Quality of Life Index
HaemoPREF
Patients' Preference for Hemophilia Treatment Questionnaire
HAV
Hepatitis A virus
For 
cs com
For
cs com
r
F
non-commercial l
cia
gy Criter
mme
gy Criter
me
ocyte
com
ocyte
m
oring Co
on-c
oring Co
co
n Asso
no
Asso
on
n
use 
e
u
only.y
on

Takeda
CONFIDENTIAL
Page 22
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
Abbreviation
Definition
HBc
hepatitis B core 
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HEV
Hepatitis E virus
HIV
human immunodeficiency virus 
HJHS
Hemophilia Joint Health Score
HLA
human leukocyte antigen
HRQoL
health-related quality of life
IB
investigator's brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IFN-γ
interferon-γ
IgG/IgM
immunoglobulin G/immunoglobulin M
IP
investigational product
IRB
Investigational Review Board
IV
intravenous
ITR
inverted terminal repeats 
LDH
lactate dehydrogenase
LC 1
liver cytosol type 1
LFT
liver function test
LKM1
liver-kidney microsomal antibody type 1
NAbs
Neutralizing antibodies
NMC 
non-medical complaint
PAMPs
pathogen-associated molecular patterns 
PBMC
peripheral blood mononuclear cell
PCR
polymerase chain reaction
polyA
short polyadenylation sequence 
PRO
patient reported outcome
PT
prothrombin time
rAAV
recombinant adeno-associated virus
RBC
red blood cell
RNA
ribonucleic acid
RSI
Reference Safety Information
For 
functi
or
functi
Fo
er
F
er
F
-
F
-kid
Fo
kid
Fo non-commercial 
rd
r
rd
ial
erc
epeats
omm
epeats
m
ogenase
-co
ogenase
om
sol type
non
sol type
n
on
n
on
no
use 
M
s
M
us
only.
nly
o

Takeda
CONFIDENTIAL
Page 23
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
Abbreviation
Definition
SAE
serious adverse event
SAER
serious adverse event report
SAP
statistical analysis plan
SD
standard deviation
SF-36v2
36-item Short Form survey version 2
SIC
subject identification code
SMA
smooth muscle antibody
SUSAR
suspected unexpected serious adverse reaction 
TTR
transthyretin
ULN
upper limit of normal
UPR
unfolded protein response
VERITAS-Pro
Validated Hemophilia Regimen Treatment Adherence Scale-Prophylaxis
vWF
Von Willebrand factor 
WT
wild-type
For non-commercial use 
us
only.
dherenc
ly.
dherenc
nly
o

Takeda
CONFIDENTIAL
Page 24
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
5. BACKGROUND INFORMATION
5.1 Description of Investigational Product
The investigational product (IP), BAX 888, is a gene therapy product engineered to induce the 
production of human factor VIII (FVIII) protein in the liver cells of individuals with severe 
congenital FVIII deficiency. The BAX 888 drug product is based on an adeno-associated virus, 
serotype 8 (AAV8) vector expressing a functional human B-domain deleted, codon-optimized
FVIII protein. The wild type AAV upon which the recombinant AAV vector is based is a 
non-pathogenic, replication defective dependoparvovirus, which is not associated with human 
disease. During the manufacture of recombinant AAV gene delivery vectors, all viral genes are 
removed such that the only protein-coding DNA sequence that is delivered in the BAX 888 
vector is the FVIII gene along with DNA elements required for expression of the potentially 
therapeutic F8 gene. The rationale for the choice of the serotype of 8 for the BAX 888 capsid is 
that, among the naturally occurring AAV serotypes, AAV8 is particularly efficient at infecting 
and directing gene expression in the human liver, with minimal “off-target” gene expression in 
other tissues (eg, in antigen presenting cells). In addition, BAX 888 incorporates a hepatocyte 
specific promoter to further restrict FVIII expression to the target liver tissue.
BAX 888 is intended to be given as a single, one-time intravenous (IV) infusion by a health care 
provider, at a qualified Center. If successful transduction of hepatocytes is achieved, long-term 
hepatic expression and secretion of endogenous FVIII into the blood stream may support 
hemostasis and in turn eliminate or reduce the prophylactic and/or on-demand use of exogenous 
FVIII concentrate therapy in hemophilia A patients. For the initial Phase 1/2 clinical study, 
BAX 888 will be supplied as a 5 mL or 10 mL frozen, sterile, non-pyrogenic solution intended 
for IV infusion, and dosing will be based on the subject’s body weight. The current safety study
will include investigation of the proposed doses of 2.0 × 1012 cp/kg (lowest BAX 888 dose 
predicted to provide FVIII expression), 6.0 × 1012 cp/kg and a further dose of 1.2 × 1013 cp/kg 
(see proposed dose escalation scheme in Figure 3). A single dose based on observed therapeutic 
durability is to be determined from this Phase 1/2 study for further evaluation in future clinical 
studies.
See Section 5.4 for further information on BAX 888 and its usage in this study. A detailed 
description of BAX 888 is also provided in the BAX 888 Investigator’s Brochure (IB).
The study design is in compliance with the EMA/CHMP/BPWP/144533/2009 guidelines for the 
study of FVIII in hemophilia A (Committee for Medicinal Products for Human Use, 2009).
For 
a 5
o
a 5 m
or
m
F
will b
Fo
will b
commercial 
to
l
to
ne-
e
ne-time 
erci
time 
transdu
mme
transdu
genous
om
genous
non-
educe th
n-co
educe th
ophilia
non
ophilia
mL
n
mL
n
use
BAX
se 
BAX
the t
us
the t
only.
articul
ly.
articu
mal “off
only
mal “off
X 8
o
X 8

Takeda
CONFIDENTIAL
Page 25
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
5.2 Clinical Condition/Indication
Hemophilia A is a rare congenital disease characterized by reduced or absent levels of the 
coagulation FVIII. It occurs in approximately 1 in 5,000 live male births. FVIII is encoded by 
F8, a large gene (186 kb) that is found in the most distal band (Xq28) of the long arm of the 
X chromosome. Thus, females are carriers of the disease, which almost exclusively affects males 
through inheritance from the maternal side. Mutations of the FVIII gene result in a congenital 
deficiency or defect in FVIII, a crucial factor in blood coagulation. In the absence of functional 
FVIII, the coagulation cascade is severely impaired resulting in a bleeding disorder, the severity 
of which is dependent on the residual endogenous levels of FVIII.
Severity of hemophilia is typically categorized as follows:

Severe hemophilia: FVIII activity levels <1% of normal FVIII activity.

Moderate hemophilia: FVIII activity levels ≥1 to 5% of normal FVIII activity.

Mild hemophilia: FVIII activity levels >5 to <40% of normal FVIII activity.
Hemophilia A is characterized by easy bruising in early childhood, spontaneous bleeding 
(particularly into joints, musculoskeletal tissues, and other soft tissues causing significant pain, 
and permanent damage if left untreated), and excessive bleeding following trauma or surgery.
Current standard of care management of hemophilia A is to treat mainly by replacement of FVIII 
using prophylactic or on-demand regimens to control bleeding episodes, and ultimately to 
prevent joint damage and death in severe cases. For long-term prophylaxis against bleeding in 
patients with severe hemophilia A, the usual replacement doses are 30 to 40 IU of FVIII per kg 
body weight at intervals of 2 to 3 days. In patients under the age of 6, doses of 20 to 50 IU of 
FVIII per kg body weight 3 to 4 times weekly are recommended.
In comparison to the current treatment modalities, gene transfer in hemophilia A holds 
substantial promise in that it is considered to be a one-time intervention that is potentially
curative. This intervention may lead to complete avoidance of the need for IV infusions and their 
side effects and, ultimately, would be life-changing for patients affected with this condition.
5.3 Population to be Studied
The target population for this Phase 1/2 first-in-human study is male subjects, aged 18 to 
75 years inclusive, with severe hemophilia A, as evidenced by a FVIII:C level <1% following 
≥5 days without FVIII treatment, and documented evidence of ≥3 hemorrhages over the previous 
12 months requiring treatment with exogenous FVIII or use of FVIII prophylaxis due to a history
of frequent bleeding episodes. All subjects will have previously been treated with exogenously 
administered FVIII concentrates or cryoprecipitate for >150 documented exposure days.
For
to 3 d
For 
to 3 d
o 4
F
o 4
on-commercial
d othe
al 
d othe
cessive
rcia
cessive
emophi
mm
emophi
mens to 
com
mens to 
evere c
on-c
evere c
n
A, the 
no
A, the 
use 
childh
use
childh
er
u
er
only.
rma
y
rma
normal F
only
ormal F

Takeda
CONFIDENTIAL
Page 26
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
Subjects with a detectable FVIII inhibitor with a titer ≥0.6 Bethesda units (BU) at the time of 
screening or well documented personal laboratory evidence of a FVIII inhibitor with a titer 
≥0.6 BU will not be eligible. Similarly, subjects with an inherited or acquired hemostatic defect 
other than hemophilia A and subjects with chronic hepatic dysfunction or severe renal 
impairment will not be eligible to participate. See Section 8.2.
5.4 Findings from Nonclinical and Clinical Studies
5.4.1 Nonclinical Studies
Nonclinical dose response and toxicology studies have been completed. Data from these and 
additional nonclinical studies can be found in the BAX 888 IB.
5.4.2 Clinical Studies
No prior studies of BAX 888 in humans have been performed.
5.5 Evaluation of the Unmet Medical Need in the Treatment of Severe Hemophilia A
Current standard of care therapy for severe hemophilia A consisting of continuous repeated 
prophylactic infusions of FVIII concentrates is effective in controlling most hemorrhages and 
slowing or preventing the development of hemophilic arthropathy and other chronic 
complications of bleeding. Major limitations to continuous prophylactic FVIII therapy include 
the painful and time-consuming nature of repeated IV therapy and the continuous need for access 
to clotting factor concentrate and infusion supplies, which are associated with poor adherence. A 
recent analysis of 4899 adult men with severe hemophilia in the United States multidisciplinary
Hemophilia Treatment Center Network demonstrated that regular prophylactic clotting factor 
infusion was performed by less than 30% of participants (including less than 50% of men with 
severe hemophilia less than 30 years of age) (Mazepa et al., 2016). Despite relatively good 
access to clotting factor concentrates in the United States and other resource-rich countries 
(~75% of men across all age groups in this analysis practiced home infusion of factor 
concentrates) 39% reported having very frequent joint bleeding (≥5 joint bleeds per six month 
period) and 36% reported limitations of school/work and activities of daily living as a result of 
joint bleeding (Mazepa et al., 2016).
5.5.1 Evaluation of Anticipated Benefits and Risks of AAV-FVIII Gene Therapy
Rigorous efforts to decrease the burden and improve the care of the disease by prolonging the 
circulating half-life of infused FVIII concentrate have resulted in only modest improvements 
(<1.5 times prolongation of FVIII half-life). Since even a modest increase in the level of missing 
FVIII can ameliorate the severe bleeding phenotype, it is anticipated that the successful 
development of a hemophilia A gene therapy product would lead to continuous endogenous 
expression of FVIII and would address many of the current treatment limitations by achieving 
greater than 1% of circulating FVIII activity at all times. 
For
ss tha
or 
ss tha
30 y
Fo
30 y
o
on-commercial
ilic art
cial 
ilic art
 contin
erc
 contin
epeated
mme
epeated
on supp
om
on supp
th seve
n-co
th seve
no
twork 
non
twork 
n
n
n
use
cons
se 
cons
e in co
use
e in co
only.
nt of Se
nly.
nt of Se
sisti
o
sisti

Takeda
CONFIDENTIAL
Page 27
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
Such an endpoint, if achievable, could convert the severe bleeding phenotype to that of moderate 
or mild hemophilia (which is the goal of FVIII prophylaxis).
Adherence to repeated venipuncture and infusions would not be needed to achieve this clinical 
goal if gene transfer is successful, wherein the goal is for the disease to be cured with a single 
intervention that effects durable gene expression.
The IP BAX 888 has not been tested in humans previously. The primary objective of the current 
study is to evaluate safety and to determine a dose of BAX 888 that may lead to levels of FVIII 
expression that have been associated with freedom from spontaneous joint hemorrhage. As with 
all Phase 1 trials, there is not an expectation that study subjects will receive benefit, although 
participation is expected to provide benefit in further directing the development of BAX 888 
hemophilia gene therapy. BAX 888 doses for the current Phase 1/2 trial have been chosen based 
upon preclinical research suggesting that all of the chosen doses may lead to FVIII expression; 
however, there is no prior experience with BAX 888 in humans. For this same reason, if a single 
injection of BAX 888 directs FVIII expression in humans, the anticipated length of persistence 
of expression following a single injection of BAX 888 in humans is currently not known. The 
AAV8 vector is predominantly a non-integrating virus, and so there is a potential for the loss of 
the episomally maintained AAV vector genomes with division of the transduced cells, which 
would result in a loss of expression of the therapeutic transgene over time. Targeting clotting 
factor expression to post-mitotic hepatocytes with a low cellular turnover rate may minimize 
dilutional effects resulting from new hepatocyte generation (Kattenhorn et al., 2016). AAV8 
vectors expressing clotting factors have led to expression for greater than 10 years (and counting) 
in large animals and greater than 6 years (and counting) in one human trial 
(Nienhuis et al., 2016).
The long-term safety of recombinant AAV (rAAV) vectors in humans is unknown; however, 
AAV vectors have been delivered to several hundred human subjects to date, in trials for cystic 
fibrosis, α1-antitrypsin deficiency, rheumatoid arthritis, congestive heart failure, lipoprotein 
lipase deficiency, as well as hemophilia, and have been remarkably free of vector-related adverse 
events (AE). 
Several clinical trials have used naturally occurring or engineered AAV serotype vectors to 
achieve expression of FVIII or Factor IX (FIX). The chief risk that has been observed in human 
clinical trials using systemic delivery of AAV vectors is that the subject’s immune system 
recognizes the AAV as an infectious agent and raises humoral (antibody-mediated) and 
potentially cell-mediated immune responses against the vector.
For 
n 6
r
n 6
mercial 
us, a
al
us, a
with d
rcia
with d
rapeuti
mer
rapeuti
om
y
non-c
tes wit
mm
tes wit
epatocy
com
epatocy
have le
on-c
have le
6
n
6
n
yea
no
yea
use
n hum
use 
n hum
and
u
and
only.
ma
s. For t
nly.
s. For t
e antic
on
e antic

Takeda
CONFIDENTIAL
Page 28
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
Wild-type AAV (WT AAV), the parent virus upon which rAAV vectors are based, is 
non-pathogenic, resulting in a milder immune response than would be expected for a pathogenic 
virus. In addition, WT AAV is replication-defective and cannot produce an active infection 
without the coincident infection of a helper virus. Recombinant AAVs are further rendered 
non-pathogenic by having all of the gene sequences of WT AAV removed, resulting in 
extremely low environmental risk related to rAAV viral shedding (Baldo et al., 2013). 
Nevertheless, at doses of rAAV gene therapy vectors used clinically, it is anticipated that all 
subjects will develop neutralizing antibodies (NAbs) against the capsid serotype. Although 
development of AAV-specific NAbs is not associated with any symptoms or AEs, these 
antibodies would persist for years and prevent the repeat treatment with the same AAV vector 
until they are naturally cleared. Furthermore, the AAV serotype-specific NAbs may or may not 
also cross-neutralize rAAV made using alternative AAV serotypes and diminish their efficiency. 
This consideration is relevant since the expected persistence of expression from a single injection 
of BAX 888 is currently unknown.
In addition to the humoral response described above, a clinical laboratory
complication of asymptomatic liver transaminase elevation (in particular the relatively 
liver-specific alanine aminotransferase – ALT) has been documented in some subjects on
multiple hemophilia gene therapy and other AAV liver-directed gene therapy trials 
(Manno et al., 2006; Nathwani et al., 2014)vii. The systemic delivery of rAAV has been 
associated with a T lymphocyte response directed against the rAAV capsid that in many but not 
all cases has occurred coincident with the ALT elevations. This response has been ascribed to 
recall AAV-specific memory T cells previously generated following WT AAV natural infection 
in combination with a helper virus. Specifically, partial or complete loss of FIX expression 
following initial successful gene transfer has been observed in previous human clinical studies 
(Manno et al., 2006; Nathwani et al., 2014);vii utilizing liver-directed AAV vectors to correct 
hemophilia B.
The loss of FIX expression could be demonstrated in some subjects to be associated with the 
expansion of AAV capsid-specific T effector lymphocytes in the peripheral blood, resulting in 
inflammatory signaling targeting the AAV transduced hepatocytes. This has been further noted 
clinically by observations of vector dose-dependent elevations of liver transaminase (serum 
ALT), which in all cases were within normal range and were asymptomatic. 
                                                
vii NCT00076557 (https://clinicaltrials.gov/ct2/show/NCT00076557); 
NCT00979238 (https://clinicaltrials.gov/ct2/show/NCT00979238); 
NCT01620801 (https://clinicaltrials.gov/ct2/show/NCT01620801); 
NCT01687608 (https://clinicaltrials.gov/ct2/show/NCT01687608); 
NCT02484092 (https://clinicaltrials.gov/ct2/show/NCT02484092); 
NCT02971969 (https://clinicaltrials.gov/ct2/show/NCT02971969)
For 
irus.
or
irus.
F
gene tr
Fo
gene tr
n-commercial
been 
ial 
been 
V liver
ercia
V liver
. The s
me
. The s
directe
omm
directe
the
c
the AL
co
AL
no
lls prev
non
lls prev
. Sp
n
. Sp
use 
ica
e
ica
ion (in
use
ion (in
d
u
d
only.
al lab
on
al lab

Takeda
CONFIDENTIAL
Page 29
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
It remains unknown whether the capsid-directed immune response is the initiating phenomenon 
that leads to the loss of gene expression or whether other mechanisms are primary with the T cell 
signaling being a secondary phenomenon. In several of the clinical studies, the observed 
transaminitis and/or decrease in FIX levels was treated with weeks to months of high, tapering 
dose corticosteroids (prednisone / prednisolone), which have a broad but not T cell specific 
immunosuppressive action. Corticosteroid therapy has in general been associated with 
normalizing liver transaminase levels, and in some (although not all) trials, with maintenance of 
some level of clotting factor activity.
Besides the primary T-cell mediated immune responses, innate immune responses to rAAV 
infection have been described in the preclinical setting. However, such responses have rarely 
been detected systemically in human clinical studies.
Preliminary results from an ongoing clinical study using the AAV5 vector to deliver the 
B-domain deleted (BDD) FVIII gene were recently published (Rangarajan et al., 2017). Six of 
seven subjects treated with high doses of rAAV5 BDD FVIII were reported to be expressing 
FVIII at normal or supernormal levels with at least 34 weeks of follow-up, with a seventh subject 
expressing FVIII at 15%. Although chronic expression of FVIII at >150% activity carries an 
increased relative risk of thrombosis, no thromboses have been reported in this or any other trial 
of AAV-directed gene therapy for hemophilia. Following elevation of ALT in the first high dose 
subject in the hemophilia A trial, all subsequent subjects were treated with prophylactic 
corticosteroids. The utility of prophylactic corticosteroids was not demonstrated in this trial, 
however, as all subjects developed mild transaminitis in the 1-2X normal range (ie, in the same 
range as the high dose individual who did not receive prophylactic corticosteroids, but instead 
received corticosteroid dosing only after developing transaminase elevation). Following 
prolonged taper of corticosteroids, the ALT levels of the seven subjects are reportedly at or near 
normal levels. The sponsors of this single study of AAV gene therapy for hemophilia A have 
concluded that prophylactic corticosteroids will not be used with future dosing.
Neutralizing antibodies (“inhibitors”) to FIX or FVIII have not developed in any AAV-directed 
trial of gene therapy for hemophilia. The specific concern that expression of FVIII after AAV 
gene transfer to hepatocytes might promote cellular stress via activation of the unfolded protein 
response (UPR) has recently been examined in a preclinical model, and a dose-dependent UPR 
could not be demonstrated, nor any negative effect upon liver pathology or FVIII 
immunogenicity (Zolotukhin et al., 2016). Moreover, data from large and small animal disease 
models suggests that liver-mediated expression of potentially immunogenic antigens, in the 
context of gene transfer, can mitigate the immune response to the transgenic protein, mediated in 
part by the induction of CD4+CD25+FoxP3+ regulatory T cells (Crudele et al., 2015; Perrin et 
al., 2016).
For 
al w
r
al w
Fo
ng onl
For
ng only
r
y
oi
F
oi
mercial 
on o
al
on o
oses hav
rcia
oses hav
a. Follo
mer
a. Follo
non-com
equent s
mm
equent s
ctic co
com
ctic co
mild tr
on-c
mild tr
who 
no
who 
use
eeks o
use 
eeks o
of F
u
of F
only.
5 
(Rangar
nly.
Ranga
I were 
on
were 

Takeda
CONFIDENTIAL
Page 30
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
5.5.1.1 Prednisolone
Prednisolone is a highly potent glucocorticoid steroid having anti-inflammatory and 
immunosuppressive activity, as well as anti-proliferative, vasoactive, hormonal and metabolic 
effects qualitatively similar to those of hydrocortisone (Czaja and Manns, 2010; Liu et al., 2013). 
The anti-inflammatory and immunosuppressive properties of glucocorticosteroids result from 
upregulating the transcription of anti-inflammatory genes or by downregulating the 
transcription of inflammatory genes, leading to changes in downstream production of 
cytokine/chemokine proteins that initiate or maintain inflammation. Prednisolone, which is the 
active metabolite of prednisone, modifies the body's immune responses to diverse stimuli 
including autoimmune processes. Taking this into consideration, the American Association for 
the Study of Liver Disease (AASLD) recommendations for the treatment of autoimmune 
hepatitis, for example, specify a starting dose and tapering approach using the corticosteroid 
prednisone as a single agent (Manns et al., 2010; Soloway et al., 1972), while the European 
Association for the Study of the Liver (EASL) guidelines allow initiation of therapy with either 
prednisone or prednisolone (given at identical total dose) (European Association for the Study of 
the Liver, 2015).
Prednisolone toxicity is related to both the dose and cumulative duration of its use. For most 
prednisolone-related AEs, a precise threshold dose or duration of treatment is not established. 
Despite the beneficial effects of glucocorticoids, and the very common clinical use of 
prednisolone in a variety of disorders, the use of these agents (in particular long-term systemic 
use) is associated with a great variety of well-recognized adverse events, including: low bone 
mineral density; osteonecrosis; adrenal suppression; hyperglycemia and diabetes; cardiovascular 
disease and lipid dysregulation; sleep and psychiatric disturbances; and immune suppression 
(Liu et al., 2013).
NOTE: In geographies where prednisolone cannot be sourced at the strengths required for the 
specified dosing regimen (eg, USA), prednisone will be utilized. Prednisone is converted to the 
active metabolite prednisolone in the liver and is recommended by the AASLD and the EASL 
for the treatment of autoimmune hepatitis.
5.5.1.2 Evaluation of Anticipated Benefits and Risks of Co-administration of Prednisolone 
and AAV
The BAX 888 vector design incorporates a single-stranded genome structure and an efficient 
codon optimization which greatly reduces the content of CpG repeats. These features minimize 
the appearance of pathogen-associated molecular patterns (PAMPs) so as to minimize potential 
innate immune signaling via Toll-like Receptors.
For
n; sle
or 
n; sle
non-commercial
d cum
ial 
d cum
ose or 
erci
ose or 
oids, an
mme
oids, an
e use o
om
e use o
y of we
n-co
y of we
drenal s
non
renal s
ep
n
ep
use only.
initiat
ly.
initia
uropean
only
ropean

Takeda
CONFIDENTIAL
Page 31
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
The protocol includes a prophylactic course of corticosteroids. As seen in prior AAV hemophilia 
gene therapy trials, subjects may demonstrate clotting factor expression followed by an apparent 
cytotoxic lymphocyte (CTL) response against transduced hepatocytes. The rationale to use 
corticosteroids in an attempt to prevent the course of the apparent CTL response includes 1) to 
maintain the health of the gene-transduced liver and 2) to rescue transgenic clotting factor 
expression, with the understanding that rescue (if possible) of even modest amounts of sustained 
circulating factor activity is expected to improve the severe bleeding phenotype and that repeat 
administration of the same gene therapy vector will not be possible due to expected development 
of high titer and long-lived AAV NAb. The rAAV-associated liver inflammation has in most 
individuals resolved rapidly (ie, within 2 weeks) (Nathwani et al., 2014) with the institution of 
high dose corticosteroid therapy, followed by taper over 8-12 weeks. What has varied between 
individuals enrolled in three different AAV hemophilia B gene therapy trials is that the degree to 
which the supportive institution of corticosteroids has been associated with sustained clotting 
factor expression has varied from 0% to 100%.
Utilization of supportive corticosteroid treatment to interrupt ongoing transaminitis/loss of factor 
activity involves an initial systemic high dose of prednisolone followed by a conservative taper 
over 5 to 8 weeks, patterned after the guidelines of the AASLD and the EASL for the treatment 
of autoimmune hepatitis (Nathwani et al., 2014; Manns et al., 2010; Soloway et al., 1972). 
Chronic use of systemic steroids at doses of ≥5 mg daily is associated with a wide variety of 
AEs, although the risk for many of these AEs increases particularly with continuous use for 
greater than 3-6 months. Should subjects receive a course of prednisolone therapy of <3 months 
(per protocol) the most important risks include: low bone mineral density (osteoporosis), 
osteonecrosis, adrenal suppression, hyperglycemia and diabetes; sleep and psychiatric 
disturbances. Loss of bone mineral density may occur with the planned doses, although in a 
meta-analysis of adult patients, the fracture risk rose with duration of therapy of 3 to 6 months or 
longer (Liu et al., 2013; van Staa et al., 2002). Nevertheless, low bone mineral density and 
osteoporosis at baseline are prevalent in the hemophilia population, and understanding this risk is 
important. Osteonecrosis (most commonly at the femoral head) is greatest with courses longer 
than proposed in this protocol but has occurred with short-term glucocorticoid exposure. Adrenal 
suppression is expected after two weeks of prednisolone therapy (Liu et al., 2013). The 
protocol’s empiric prednisolone taper minimizes this risk, and screening for this outcome will be 
performed following tapering of prednisolone to a physiologic dose (Liu et al., 2013;
Ahmet et al., 2011). Subjects will be monitored for the development of Cushingoid features, as it 
is common within 2 months of start of therapy (Fardet et al., 2007). Hyperglycemia may occur 
and glucose will be assayed regularly in all study subjects. Glucocorticoids used for even short 
periods of time may lead to psychiatric and cognitive disturbances including memory
impairment, irritability, mood lability and sleep disturbance. 
For 
sion
or
sion
F
minera
Fo
minera
n-commercial
the A
ial 
the A
Manns
ercia
Manns
≥5 mg 
me
≥5 mg 
AEs in
omm
AEs in
ects rec
-co
ects rec
no
risks in
non
risks in
n, hy
n
n, hy
use 
pt o
e
pt o
solone
use
solone
A
u
A
only.
ongo
on
ongo

Takeda
CONFIDENTIAL
Page 32
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
The BAX 888 protocol specifies for subjects who are at increased risk from corticosteroid 
therapy, including individuals with osteoporosis and vertebral fractures, hard to control diabetes 
and hard to control hypertension, emotional instability, and obesity combination therapy with 
azathioprine/prednisone per AASLD guidelines which allows lower cumulative glucocorticoid 
dose and risk.
5.6 Compliance Statement
This study will be conducted in accordance with this protocol, the International Council for 
Harmonisation Guideline for Good Clinical Practice E6 (ICH GCP, April 1996), Title 21 of the 
US Code of Federal Regulations, the EU Directives 2001/20/EC and 2005/28/EC, and applicable 
national and local regulatory requirements.
This study will be conducted in a manner that assures that the rights, safety and well-being of the 
participating study subjects are protected consistent with the ethical principles that have their 
origin in the Declaration of Helsinki.
For non-commercial use only.
ical p
ly.
ical p

Takeda
CONFIDENTIAL
Page 33
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
6. STUDY PURPOSE AND OBJECTIVES
6.1 Study Purpose
The purpose of the study is to evaluate the safety and determine the dose of BAX 888 required to 
achieve FVIII activity levels ≥20% of normal in severe hemophilia A subjects.
6.2 Primary Objective
The primary objective of the study is to evaluate the safety of a single IV infusion of BAX 888 in 
up to 3 dose cohorts.
6.3 Secondary Objectives
1.
To evaluate plasma FVIII activity levels pre- and post-BAX 888 infusion and investigate 
the relationship between FVIII activity levels and BAX 888 dose.
2.
To determine the BAX 888 dose needed to achieve FVIII activity level of ≥20% of normal 
in ≥60% of the subjects.
3.
To collect bleeding rate and consumption of exogenous FVIII after gene transfer.
4.
To assess humoral and cellular immune responses to FVIII and the AAV8 viral capsid.
5.
To determine the duration of BAX 888 genome presence in blood, saliva, semen, urine and 
stool.
For 
ial 
nses 
al
nses 
non-commerc
nome pr
rcia
nome pr
use
nous F
se 
nous F
to F
us
to F
only.
d
I activi
nly.
I activi
V

Takeda
CONFIDENTIAL
Page 34
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
7. STUDY DESIGN
7.1 Brief Summary
This is a global, Phase 1/2 multicenter, open-label, safety, and dose escalation study of BAX 888 
in adult subjects with severe hemophilia A. Up to 12 subjects may be administered BAX 888 in 
up to 3 dose cohorts. 
Before any study-related procedures are followed, subjects will provide signed informed consent. 
During the course of the study, FVIII activity levels will be assessed by a central laboratory
(both the one-stage and chromogenic assays) and by the local laboratory (either one-stage or 
chromogenic assay) as specified in Table 3. However, only central laboratory FVIII activity
levels derived from the one-stage clotting assay will be utilized for the primary analysis. FVIII 
activity levels obtained from the central laboratory chromogenic assay will be utilized to support 
the one-stage assay results. BAX 888 will be administered as a single peripheral IV infusion. On 
the day of dosing with BAX 888 (Day 0), subjects will be admitted to the infusion center and 
will be observed for at least 8 hours following dosing. If the infusion center is not the subject’s 
Hemophilia Treatment Center/local investigator’s institution, a second separate consent will be 
obtained from the subject for the Day 0 visit and for all procedures surrounding the infusion 
period. Subjects will be monitored for the first 8 hours and may remain in the infusion center for 
24 hours following the BAX 888 infusion at the discretion of the investigator or return to the 
center for the 24-hour post-infusion follow-up. All subsequent follow-up visits will take place at 
the subject’s own Hemophilia Treatment Center/local investigator’s institution at: Week 1 and 
Week 2 (once weekly), Weeks 3 to 14 (twice weekly, with separate clinic visit and laboratory 
visit each week), Week 15-18 (once weekly), and then Months 5, 6, 9, 12, 16, 20, 24, 28, 32, 36, 
48, and 60.
Safety, efficacy, and health-related quality of life (HRQoL) data will be collected throughout the 
5-year post-gene transfer period.
7.2 Overall Study Design
This is an open-label, Phase 1/2 study designed to evaluate the safety, efficacy, and 
pharmacodynamics of up to 3 doses of BAX 888. The overall study design is illustrated in 
Figure 2.
The target population is up to 12 evaluable adult male subjects with severe hemophilia A 
(FVIII:C level <1%). This sample size was chosen to provide sufficient evidence of safety and 
exploration of signs of efficacy for this indication and is not based on formal statistical 
considerations.
For
(onc
or 
(onc
mmercial
or all p
ial 
or all p
e
hours
erci
hours
t the dis
mme
t the dis
non-com
ow-up. 
om
ow-up. 
ment Ce
n-co
ment Ce
to 14 (tw
non
o 14 (tw
ce w
n
ce w
use 
e in
e
e in
ution,
use
ution,
u
only.
ingle
y.
ingle
mitted to
only
mitted to
nfusi
o
nfusi

Takeda
CONFIDENTIAL
Page 35
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
Subjects will be assigned to 1 of 3 dose cohorts (Figure 3), with a minimum of 24 hours between 
dosing of each subject. Initially, 2 subjects will be dosed in a cohort, with up to a total of 
5 subjects if the cohort is expanded. Safety and FVIII activity level data from subjects dosed 
with BAX 888 will be utilized to make decisions on dose escalation and cohort expansion. If any
subject in a given cohort achieves >50% FVIII activity levels at Week 14, the Data Monitoring 
Committee (DMC) will provide a recommendation on further dose escalations after review of all 
safety and FVIII activity level data. If any subject in any cohort achieves ≥150% FVIII activity
levels at any time while on the study, further dosing will be paused until DMC review. Only 
central laboratory FVIII activity levels will be utilized for dose escalations. DMC 
recommendations will be based on, but not limited to, the following considerations: (1) mean, 
median, and range of FVIII activity levels (central lab, one-stage clotting assay) observed within 
the dosing cohort, (2) variability in response between subjects, (3) liver function tests, and (4) 
other product-related adverse events (AEs).
Cohort 1 (2.0 × 1012 cp/kg):
After dosing the first 2 subjects in Cohort 1:

If Week 4 FVIII activity levels of both subjects are <2%, then dose escalation to Cohort 2 
will be triggered with no further dosing in Cohort 1. Alternatively, if FVIII activity levels
(≥2%) are observed in at least 1 subject, the decision to escalate dose or expand the cohort 
with dosing of additional subjects will be based on all available data through Week 14. 

If sustained Week 14 FVIII activity levels of ≥30%viii are not achieved in both subjects, 
then escalation to Cohort 2 will be triggered after DMC review of all safety and FVIII 
activity level data inclusive of Week 14.

If sustained Week 14 FVIII activity levels of ≥30%viii are achieved in at least 1 of the 
2 subjects, then expansion of Cohort 1 will be initiated with dosing of 3 additional subjects.
For an expanded Cohort 1 with 5 subjects dosed with BAX 888:

If sustained Week 14 FVIII activity levels of ≥30%viii are not achieved in at least 3 of the 
5 subjects, then escalation to Cohort 2 will be triggered after DMC review of all available 
safety and FVIII activity level data inclusive of Week 14.

If sustained Week 14 FVIII activity levels of ≥30%viii are achieved in at least 3 of the 
5 subjects, one of the following would be pursued based on safety, FVIII activity levels, 
and the variability in response that is observed among the 5 dosed subjects:
viii Sustained Week 14 FVIII activity level ≥30% is defined as 3 or more FVIII activity level measurements ≥30% 
between Week 12 and Week 18. If applicable per protocol, a DMC meeting will be held when either 3 or more 
FVIII activity level measurements ≥30% between Weeks 12 and Week 18 are obtained or after Week 18, 
whichever comes first.
For
VIII 
For
VIII a
r 
a
ion
F
ion
non-commercial
ts are
ial 
ts are
Cohort
rcia
Cohort
, the de
merc
, the de
ll be ba
mm
ll be ba
vity
co
vity lev
com
lev
ill be tr
on-c
ill be tr
of We
non
of We
use 
<
u
<
only.

Takeda
CONFIDENTIAL
Page 36
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
1.
Completion of study enrollment with no further dosing since the secondary objective 
to determine a BAX 888 dose needed to attain FVIII activity levels ≥20% in at least 
60% of the subjects would have been achieved.
2.
Expansion of Cohort 1 to include dosing of additional subjects at the same dose 
level.
3.
Escalation to a higher dose (eg, subsequent patients will be enrolled in Cohort 2). 
Cohort 2 (6.0 × 1012 cp/kg): 
After dose escalation and administration of BAX 888 to the first 2 subjects in Cohort 2:

If sustained Week 14 FVIII activity levels of ≥30%viii are not achieved in both subjects, 
then expansion of Cohort 2 or escalation to Cohort 3 will be triggered after DMC review of 
all available safety and FVIII activity level data inclusive of Week 14.

If sustained Week 14 FVIII activity levels of ≥30%viii are achieved in at least 1 of the 
2 subjects, then, after review of all the available safety and FVIII activity level data, the 
DMC will make a recommendation to continue with expansion of Cohort 2 up to 
5 subjects, or escalate dosing to Cohort 3 (1.2 × 1013 cp/kg).
For an expanded Cohort 2 with up to 5 subjects dosed with BAX 888: 

If sustained Week 14 FVIII activity levels of ≥30%v are not achieved in at least 3 subjects, 
then one of the following would be pursued after DMC review of all available safety and 
FVIII activity level data inclusive of Week 14:
Escalation to Cohort 3 (1.2 × 1013 cp/kg)
Completion of study enrollment with no further dosing

If sustained Week 14 FVIII activity levels of ≥30%v are achieved in at least 1 of the subjects, 
one of the following would be pursued after DMC review and based on the safety, FVIII 
activity levels, and the variability in response, and other clinical data that is observed among 
all the dosed subjects in the study: 
Continue to expand Cohort 2 up to 5 subjects
Escalation to Cohort 3 (1.2 × 1013 cp/kg) 
Completion of study enrollment with no further dosing
-
Preliminary evaluation following 2 subjects dosed with 2.0 × 1012 cp/kg (lowest dose level) 
showed minimal impact on FVIII activity. Preliminary evaluation following 2 subjects dosed 
6.0 × 1012 cp/kg (middle dose level; 3-fold higher than lowest dose level) suggests that the 
peak FVIII activity was as expected but increased more than proportional to the increase in 
dose. A mouse model suggested a potential non-linear dose-FVIII activity relationship 
(doubling of the dose might produce more than a doubling of the FVIII activity). To ensure 
informed dose escalation in subjects with hemophilia A, instead of a 3-fold increase in dose, 
the next proposed dose is 1.2 × 1013 cp/kg which is 2-fold the middle dose level originally
proposed.
For
II 
Fo
II act
For 
act
uld be
Fo
uld be
non-commercial 
d w
l
d w
l
f 
e
f ≥30%
erci
≥30%
ued afte
mer
ued afte
Week 1
mm
Week 1
× 10
co
× 1013
o
13
nrollme
non
nrollme
n
use 
cp/
e
cp/
with B
us
with B
u
only.
d FVI
ly.
d FVI
xpansion
only
pansion
/kg)
o
/kg)

Takeda
CONFIDENTIAL
Page 37
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
Cohort 3 (1.2 x 1013 cp/kg):
After dose escalation and administration of BAX 888 to the first 2 subjects in Cohort 3:

If sustained Week 14 FVIII activity levels of ≥30%viii are not achieved in in both subjects, 
then dosing of additional subjects will be paused until further review of all available data.

If sustained Week 14 FVIII levels of ≥30%viii are achieved in at least 1 of the 2 subjects, 
then expansion of Cohort 3 will be initiated with dosing of up to 3 additional subjects. 
Study could be completed with no further dosing.
Immunosuppression
Vector-derived factor expression followed by a decrease in factor levels has been observed in 
previous hemophilia gene therapy trials and has been attributed to an immune response directed 
against the successfully transduced cells. To address this issue and to ensure factor activity is 
achieved and sustained, BAX 888 has been engineered to have a reduced prospect of eliciting an 
immune response.
Nevertheless, a prophylactic course of glucocorticosteroid treatment with prednisolone as shown 
in Table 1 will be employed starting at Day 8 post-BAX 888 infusion. The following dosing 
schedule will be followed as a guideline. The corticosteroid regimen may be adjusted at the 
discretion of the Investigator in consultation with the Sponsor Medical Monitor depending on the 
subject’s tolerance of the regimen and the observed hepatic transaminase response. Subjects 
receiving corticosteroids may require unscheduled additional visits to evaluate potential side 
effects of corticosteroid therapy and for corticosteroid dose adjustments. FVIII activity levels 
and liver function tests (LFTs) will be measured at these unscheduled visits by local laboratories.
Table 1. Prednisolone Dosing Regimen
Prednisolone Dose (mg/day)
Duration
60
4 weeks
40
2 weeks
30
2 weeks
25
2 weeks
20
2 weeks
15
1 week
10
1 week
5
1 week
Determine ALT and FVIII activity level weekly or twice weekly (as per study protocol).
For 
will
or
will
ab
F
ab
non-commercial
BAX 
ial 
BAX 
orticost
ercia
orticost
with th
me
with th
e obser
omm
e obser
unsche
-co
unsche
nd for c
non
nd for c
ll be
n
ll be
use 
oid tre
use
oid tre
8
u
8
only.
a redu
ly.
a redu

Takeda
CONFIDENTIAL
Page 38
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
In geographies where prednisolone cannot be sourced at the strengths required for the specified 
dosing regimen (eg, USA), prednisone will be provided. Prednisone is converted to the active 
metabolite prednisolone and is recommended by the AASLD and the EASL for the treatment of 
autoimmune hepatitis.
The purpose of the prophylactic treatment with the tapering course of prednisolone is to prevent 
clinical or subclinical hepatic inflammation and to support the potential for sustained transgenic 
factor VIII expression. 
Assessment of possible reactions to corticosteroids will be performed by the Investigator and
modification of treatment instituted as necessary after consultation with the Sponsor’s Medical 
Monitor. In such instances, consideration should be given to combination therapy with 
azathioprine/corticosteroid per AASLD guidelines or other drug as per standard of practice, in 
consultation with a hepatologist, so that the care can be individualized to the subject’s needs.
Recurrent elevations in transaminases after Year 1 should be evaluated and treated at the 
discretion of the investigator.
Full details on the procedures to be performed at each study visit, including screening, can be 
found in Section 19.1 (Study Flow Chart and Dose Escalation), Section 19.2 (Schedule of Study 
Procedures and Assessments), and Section 19.3 (Clinical Laboratory Assessments).
The following sections summarize the procedures and assessments to be performed at each visit.
7.2.1 Screen 1
Prior to Screen 1 visit, all subjects will undergo a minimum wash-out period of 5 days following 
their last FVIII therapy (on-demand or prophylaxis), after which blood samples will be collected 
to determine eligibility at Screen 1 visit. Baseline FVIII activity levels will be based on the 
central laboratory one-stage clotting assay and determined at the Screen 1 visit.
The following procedures and assessments will be performed:

Signed informed consent for Screen 1 visit.

Eligibility criteria checked.

Medical history including hemophilia history (confirmation of diagnosis and severity;
presence of any target joints; historical annualized bleed rate (ABR) based on documented 
data within the last 12 months), and documentation of all FVIII replacement therapies and 
other medications used within the last 12 months. Medical history to also include any 
surgeries, hospitalizations within the last 12 months, exposure to mutagenic agents, recent 
malignancy(ies), recent incidence or exacerbation of a pre-existing neurologic disorder, 
recent incidence or exacerbation of a prior rheumatologic or other autoimmune disorder, 
recent incidence of hematologic disorder. Full medical history could be collected 
throughout the screening period and finalized at the Screen 2 visit.
or 
man
r
man
F
reen 1
For
reen 1
F
non-commercial 
Escal
al
Escal
Clinica
rcia
Clinica
edures 
mme
edures 
will un
on
will un
nd or
no
nd or
use
udy
use
udy vi
se 
vi
y
se
y
lati
u
lati
only.
luate
y.
luate

Takeda
CONFIDENTIAL
Page 39
BAX 888
201501 Protocol Amendment 9
10 Nov 2021

Physical exam (examination of general appearance, head and neck, eyes and ears, nose and 
throat, chest, lungs, heart, abdomen, extremities and joints, lymph nodes, skin, and 
neurological), including height and weight.

Blood and urine collected for laboratory assessments:
Hematology, coagulation and clinical chemistry panels, hepatitis B surface antigen, hepatitis C 
antibody, hepatitis C virus (HCV) ribonucleic acid (RNA), markers of autoimmune-mediated 
hepatitis, fibrinogen activity, D-dimer, FVIII genotyping, FVIII activity level (central and local 
laboratories), FVIII antigen, FVIII inhibitor, antibody to FVIII and FVIII transgene product, 
neutralizing and binding antibodies to AAV8 and AAV2, cell-mediated immune (CMI) response 
to AAV8 and FVIII transgene products, and FibroSURETM, and urine protein.
If the Screen 1 visit occurs >180 days (±7 days) prior to the Screen 2 visit due to the 
implementation of Protocol Amendment 7, then study assessments may need to be repeated at 
the discretion of the Investigator and Sponsor. The study assessments to be repeated will be 
determined on a case-by-case basis. Sponsor approval should be received before moving forward 
with Screen 2 visit. Additionally, Screen 1 visit assessments that need to be repeated for subjects 
screened >180 days (±7 days) can be performed in a combined Screen 1 and Screen 2 visit.
7.2.2 Screen 2
The following procedures and assessments will be performed:

Signed informed consent for visits encompassing Screen 2 and all subsequent Study Visits.

Eligibility criteria checked.

Medical history (any additional information that was not captured at Screen 1 or occurred 
between Screen 1 and Screen 2)

Targeted physical exam (includes weight and examination of the liver, skin, and other 
organ systems as driven by signs, symptoms, and complaints).

Vital signs.

12-lead electrocardiogram (ECG).
Blood collected for laboratory assessments:
Hematology, coagulation, and clinical chemistry panels, FVIII inhibitor, neutralizing and 
binding antibodies to AAV8 and AAV2, Von Willebrand Factor (vWF) antigen, human 
leucocyte antigen (HLA) (MHC haplotype), HIV serology, and polymerase chain 
reaction (PCR) of vector genomes. Local laboratory LFTs including ALT, AST, and 
gamma-glutamyl transpeptidase (GGT). Whole genome sequencing if subject provides 
consent,
Blood collected for backup. 

Saliva, urine, stool, and semen collected for PCR of vector genomes.
For 
dition
or
dition
Scree
Fo
Scree
non-commercial 
co
l
co
will be
mm
will be
ts enco
com
ts enco
na
n
na
use
nts th
se 
nts th
mbin
us
mbin
only.
ments 
ly.
ments
d be rec
only
be rec
at
o
t

Takeda
CONFIDENTIAL
Page 40
BAX 888
201501 Protocol Amendment 9
10 Nov 2021

Bleeding episodes.

Concomitant medications (including FVIII usage).

Distribute electronic subject diaries (e-diary).

AEs.

Patient-reported outcomes (PROs).

Abdominal ultrasound to assess liver health (should be performed locally; may be 
scheduled on different day, as close to Screen 2 visit as possible)
If the Screen 2 visit occurs >70 days prior to the Day 0 visit due to the implementation of 
Protocol Amendment 7, then study assessments may need to be repeated at the discretion of the 
Investigator and Sponsor. The study assessments to be repeated will be determined on a 
case-by-case basis. Sponsor approval should be received before moving forward with Day 0 
visit.
7.2.3 Day 0
The following procedures and assessments will be performed:

Signed informed consent (if the infusion center is not the subject’s Hemophilia Treatment 
Center/local investigator’s institution).

Medical history (any additional relevant information that was not captured during 
screening visits or occurred between Screen 2 and Day 0)

Targeted physical exam (includes weight and examination of the liver and skin, and 
otherwise driven by signs, symptoms, and complaints).

Vital signs (up to 3 hours pre-infusion and at 5, 15, and 30 mins and 1, 2, 3, 4, 6, and 
8 hours post-infusion).

12-lead ECGs (up to 3 hours pre-infusion and at 1 hour and 6 hours post-infusion).

BAX 888 administration.

Blood collected for laboratory assessments:

Hematology, coagulation and clinical chemistry panels, serum cytokines 
(interleukin-6 and tumor necrosis factor-α).

FVIII activity level (central and local laboratories) and FVIII antigen (pre-infusion 
[up to 3 hours prior to infusion]).

Neutralizing antibody to AAV8 and AAV2 (up to 3 hours pre-infusion).

Collection of whole blood for transcriptome (up to 3 hours pre-infusion and 8 hours 
post-infusion) and plasma / serum for metabolomics if left over backup sample is 
available.

Blood collected for backup (8 hours post-infusion).
For
urs pre
For 
urs pre
non-commercial
nter is n
cial 
nter is n
ant info
mme
ant info
en Scre
om
en Scre
udes we
on-c
udes we
sy
n
ympto
non
mpto
ym
y
n
ym
y
use 
rmed:
use
rmed:
only.

Takeda
CONFIDENTIAL
Page 41
BAX 888
201501 Protocol Amendment 9
10 Nov 2021

Review e-diaries.

Concomitant medications (including FVIII usage).

Bleeding episodes.

AEs.

Recent physical activity.

Hemophilia Joint Health Score.
7.2.4 Day 1
The following procedures and assessments will be performed:

Targeted physical exam (examination of the liver and skin, and otherwise driven by signs, 
symptoms, and complaints).

Vital signs.

Blood collected for laboratory assessments:

Hematology, coagulation and clinical chemistry panels, serum cytokines, fibrinogen 
activity, D-dimer, FVIII activity level (central and local laboratories), and PCR of 
vector genomes.

Collection of whole blood for transcriptome and plasma / serum for metabolomics 
analysis 

Blood collected for backup.

Saliva, urine, stool, and semen collected for PCR of vector genomes.

Review e-diaries.

Concomitant medications (including FVIII usage).

Bleeding episodes.

AEs.

Recent physical activity.
7.2.5 Weeks 1-2
The following procedures and assessments will be performed weekly:

Medical history.

Targeted physical exam (examination of the liver and skin, and otherwise driven by signs, 
symptoms, and complaints).

Vital signs.
For 
ons 
Fo
ons (in
or
(in
non-commercial 
riptom
erci
riptom
n collec
n-c
n collec
use
y
se
y pa
se 
pa
y
se
y
al and
use
al and
only.
anel
o
anel

Takeda
CONFIDENTIAL
Page 42
BAX 888
201501 Protocol Amendment 9
10 Nov 2021

Blood collected for laboratory assessments:

Hematology, coagulation and clinical chemistry panels, HCV RNA (Week 1 only), 
fibrinogen activity, D-dimer, FVIII activity level (central and local laboratories), 
FVIII antigen, FVIII inhibitor, neutralizing antibody to AAV8 and AAV2 (Week 2 
only), CMI response to AAV8 and FVIII transgene products, and PCR of vector 
genomes (until results are negative for 2 consecutive time points).

Collection of whole blood for transcriptome and plasma / serum for metabolomics 
analysis.

Blood collected for backup.

Saliva, urine, stool, and semen collected for PCR of vector genomes (until results are 
negative for 2 consecutive time points).

Review e-diaries.

Concomitant medications (including FVIII usage).

Bleeding episodes.

AEs.

Recent physical activity.
7.2.6 Weeks 3-14
The procedures and assessments listed below will be performed at the first visit of the week 
(Clinic Visit). The Laboratory Visits are to include the local laboratory Liver Function Test, 
FVIII activity level assessment, and backup sample collection ONLY.

Medical history.

Targeted physical exam (examination of the liver and skin, and otherwise driven by signs, 
symptoms, and complaints).

Vital signs.

Blood collected for laboratory assessments:

Hematology, coagulation and clinical chemistry panels (Weeks 3, 5, 7, 9, 11, & 13), 
Liver Function Tests (central [Weeks 4, 6, 8, 10, 12, & 14], and local [Weeks 3-14]), 
HCV RNA (Week 6), fibrinogen activity, D-dimer, vWF antigen (Week 6), FVIII 
activity level (central and local laboratories), FVIII antigen, FVIII inhibitor, antibody
to FVIII and FVIII transgene product (Weeks 6 and 8 only), neutralizing antibody to 
AAV8 and AAV2 (Weeks 4, 8, and 12 only), CMI response to AAV8 and FVIII 
transgene products, and PCR of vector genomes (until results are negative for 
2 consecutive time points).

Collection of whole blood for transcriptome and plasma / serum for metabolomics 
analysis.
For 
(
F
(
non-commercial 
low wi
omm
low wi
are to in
co
are to in
d back
on
d back
use only.

Takeda
CONFIDENTIAL
Page 43
BAX 888
201501 Protocol Amendment 9
10 Nov 2021

Saliva, urine, stool, and semen collected for PCR of vector genomes (until results are 
negative for 2 consecutive time points).

Review e-diaries.

Concomitant medications (including FVIII usage).

Bleeding episodes.

AEs.

Recent physical activity.
The following laboratory assessments will be performed:

Liver function tests to include ALT, AST and GGT.

Central Laboratory LFTs @ Clinic Visits during Weeks 4, 6, 8, 10, 12, and 14

Local Laboratory LFTs @ every Clinic and Laboratory Visit during Weeks 3-14.

FVIII activity level.

Central Laboratory (one-stage and chromogenic assays) @ every Clinic and 
Laboratory Visit between Weeks 3-14.

Local Laboratory (one-stage or chromogenic assay) @ every Clinic and Laboratory
Visit between Weeks 3-14.

Blood collected for backup at every Laboratory Visit between Weeks 3-14.
7.2.7 Week 15-18
The following procedures and assessments will be performed weekly (Clinic Visit) except for the 
central laboratory LFTs:

Medical history.

Targeted physical exam (examination of the liver and skin, and otherwise driven by signs, 
symptoms, and complaints).

Vital signs.

Blood collected for laboratory assessments:

Hematology and clinical chemistry panels (Weeks 15 and 17 only), LFTs (central 
[Weeks 16 & 18], and local [Weeks 15 to 18]), coagulation panel, FVIII activity level 
(central and local laboratories), FVIII antigen, FVIII inhibitor, CMI response to 
AAV8 and FVIII transgene products, PCR of vector genomes (until results are 
negative for 2 consecutive time points).

Blood collected for backup.

Saliva, urine, stool, and semen collected for PCR of vector genomes (until results are 
negative for 2 consecutive time points).
For 
n-commercial
ogenic
cial 
ogenic
ab
mm
ab
no
orat
mme
orat
essmen
non
essmen
use
c as
se 
c as
only.
y
ssay
o
ssay

Takeda
CONFIDENTIAL
Page 44
BAX 888
201501 Protocol Amendment 9
10 Nov 2021

Review diaries.

Concomitant medications (including FVIII usage).

Bleeding episodes.

AEs.

Recent physical activity.
7.2.8 Months 5, 6, 9, 12
The following procedures and assessments will be performed:

Medical history (including hospitalizations, new malignancy[ies], new incidence or 
exacerbation of a pre-existing neurologic disorder, new incidence or exacerbation of a prior 
rheumatologic or other autoimmune disorder, new incidence of hematologic disorder, or 
any other new chronic medical conditions).

Targeted physical exam (examination of the liver and skin, and otherwise driven by signs, 
symptoms, and complaints), includes weight at Month 12 only.

Vital signs.

Blood collected for laboratory assessments:

Hematology, coagulation and clinical chemistry panels, fibrinogen activity, D-dimer, 
vWF antigen (Month 6), FVIII activity level (central and local laboratories), FVIII 
antigen, FVIII inhibitor, antibody to FVIII and FVIII transgene product (Months 6, 9 
and 12 only), neutralizing and binding antibodies to AAV8 and AAV2, CMI response 
to AAV8 and FVIII transgene products (Months 5, 6, and 12 only), and PCR of 
vector genomes (until results are negative for 2 consecutive time points). 

FibroSURE (Month 12 only).

Collection of whole blood for transcriptome and plasma / serum for metabolomics 
analysis.

Alpha fetoprotein (optional assessment at local laboratory at Month 12 only)

Blood collected for backup.

Saliva, urine, stool, and semen collected for PCR of vector genomes (until results are 
negative for 2 consecutive time points). 

Review e-diaries.

Concomitant medications (including FVIII usage).

Bleeding episodes.

AEs.

Recent physical activity.

Hemophilia Joint Health Score (at Month 12 only).
For
h 12 
or 
h 12 
ole b
Fo
ole b
mmercial 
chemi
rcia
chemi
ivity
mer
ivity le
erc
le
dy
m
dy to F
mm
to F
y
m
y
V
e
V
non-co
d bindi
com
d bindi
gene pr
n-co
gene pr
results a
on
results a
on
n
on
use only.
, and 
ly.
, and 
12 only
only
12 only

Takeda
CONFIDENTIAL
Page 45
BAX 888
201501 Protocol Amendment 9
10 Nov 2021

PROs (at Months 6 and 12 only for HRQoL).

Abdominal ultrasound to assess liver health (at Month 12 only; should be performed 
locally; may be scheduled on different day, but as close to Month 12 visit as possible)
Unscheduled visits will be performed if a >50% decrease in FVIII activity level from that of the 
last visit is observed at any time after Week 18. FVIII activity levels and liver enzyme levels will 
be assessed at these visits. Patients receiving corticosteroids may require additional visits to 
evaluate potential side effects of corticosteroid therapy and for dose adjustments, FVIII activity 
and liver enzyme levels will be measured at these visits.
7.2.9 Years 2-5 (Months 16, 20, 24, 28, 32, 36, 48, 60)
The following procedures and assessments will be performed:

Medical history (including hospitalizations, new malignancy[ies], new incidence or 
exacerbation of a pre-existing neurologic disorder, new incidence or exacerbation of a prior 
rheumatologic or other autoimmune disorder, new incidence of hematologic disorder, or 
any other new chronic medical conditions).

Physical exam (Months 24, 36, 48, and 60 only).

Weight (Months 24, 36, 48, and 60 only).

Vital signs.

Blood collected for laboratory assessments:

Hematology, coagulation and clinical chemistry panels, fibrinogen activity, D-dimer, 
FVIII activity level (central and local laboratories), FVIII antigen, FVIII inhibitor, 
antibody to FVIII and FVIII transgene product, and neutralizing and binding 
antibodies to AAV8 and AAV2. 
Alpha fetoprotein (optional assessment at local laboratory at Months 24, 36, 48, and 
60 only)

Blood collected for backup.

Saliva, urine, stool, and semen collected for PCR of vector genomes (until results are 
negative for 2 consecutive time points).

Review and collect (at Month 60) e-diary.

Concomitant medications (including FVIII usage).

Bleeding episodes.

AEs.

Recent physical activity.

Hemophilia Joint Health Score (Months 24, 36, 48, and 60 only).

PROs (Months 24, 36, 48, and 60 only for HRQoL).
For
d 
r
V8 an
For
V8 and
r 
d
(o
F
(o
non-commercial 
sments
mm
sments
and clin
-co
and clin
ntral an
on-
ntral an
FVII
no
FVII
use only.
ciden
y.
ciden
ence of 
nly
ence of 

Takeda
CONFIDENTIAL
Page 46
BAX 888
201501 Protocol Amendment 9
10 Nov 2021

Abdominal ultrasound to assess liver health (at Month 24, 36, 48, and 60 only; should be 
performed locally; may be scheduled on different day, but as close to annual visit as 
possible)
Unscheduled visits will be performed if a >50% decrease in FVIII activity level from that of the 
last visit is observed at any time after Week 18. FVIII activity levels and liver enzyme levels will 
be assessed at these visits by Central Lab.
7.2.10 Early Termination Visit
The following procedures and assessments will be performed:

Medical history (including hospitalizations, new malignancy[ies], new incidence or 
exacerbation of a pre-existing neurologic disorder, new incidence or exacerbation of a prior 
rheumatologic or other autoimmune disorder, new incidence of hematologic disorder, or 
any other new chronic medical conditions).

Physical exam.

Weight.

Vital signs.

Blood collected for laboratory assessments:

Hematology, coagulation and clinical chemistry panels, HCV RNA, fibrinogen 
activity, D-dimer, FVIII activity level (central and local laboratories), FVIII antigen, 
FVIII inhibitor, antibody to FVIII and FVIII transgene product, neutralizing antibody
to AAV8 and AAV2, and CMI response to AAV8 and FVIII transgene products.

Collection of whole blood for transcriptome and plasma / serum for metabolomics 
analysis.

Blood collected for backup.

Collect and review e-diary.

Concomitant medications (including FVIII usage).

Bleeding episodes.

AEs.

Recent physical activity.

Hemophilia Joint Health Score.

PROs.
For 
for ba
Fo
for ba
non-commercial 
cal che
merc
cal che
y
m
y level
mme
level
e
FVIII an
om
FVIII an
CMI
n-co
CMI re
co
re
ood fo
non
ood fo
use only.

Takeda
CONFIDENTIAL
Page 47
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
7.2.11 Further Management of Presumptive Vector-Related Hepatitis
Any subject who develops an ALT or AST level >3 × upper limit of normal (ULN) during the 
study will continue to be treated with prednisoloneix as outlined in the Prednisolone Tapering 
Regimen tables above in the Immunosuppression Section (Section 7.2). Additionally, the subject 
must have the test repeated and confirmed within 72 hours.
In addition, if an increase in transaminase ALT or AST of 3 × ULN is observed, the additional 
clinical and laboratory monitoring should be initiated by the investigator. To ensure subject 
safety and comply with regulatory guidance, the investigator is to consult with the Sponsor 
Medical Monitor regarding collection of specific recommended clinical information and 
follow-up laboratory tests. If the level remains >3 × ULN, a diagnostic workup of potential 
infectious and toxic/metabolic causes of hepatitis will be pursued, including consultation with a 
hepatologist. This workup of potential etiologies for hepatitis (that may be unrelated to the 
Investigational product) will include careful history to assess potential liver diseases resulting 
from toxic exposures including alcoholic liver disease and laboratory evaluation by Central lab 
for potential viral co-infection with HBV, HCV, hepatitis E virus, hepatitis A virus as well as for 
non-infectious etiologies for hepatitis including hemochromatosis, autoimmune hepatitis, 
Wilson’s disease, and alpha-1 antitrypsin deficiency.
The laboratory workup to be obtained includes the following studies, which may be 
supplemented by additional studies as determined to be appropriate for the individual case by the 
consulting hepatologist:
Potential viral co-infection: anti-HCV antibody, HCV RNA PCR, Hepatitis B surface antigen 
(HBsAg), anti-Hepatitis B core (HBc) immunoglobulin M (IgM) Ab, anti-Hepatitis A virus 
(HAV) IgM, anti-Hepatitis E virus (HEV) IgM.

Hemochromatosis: serum ferritin (elevated iron stores), transferrin saturation.

Autoimmune hepatitis: total serum immunoglobulin G (IgG), antinuclear antibody (ANA), 
SMA (smooth muscle antibody), anti- liver/kidney microsomes type 1 (LKM1) antibodies, 
anti- liver cytosol type 1 (LC 1 ), AMA (anti-mitochondrial antibody).

Alpha1-antitrypsin deficiency: serum alpha antitrypsin.

Wilson’s disease: serum and urine copper, serum ceruloplasmin.
                                                
ix
In geographies where prednisolone cannot be sourced at the strengths required for the specified dosing regimen 
(eg, USA), prednisone will be provided. Prednisone is converted to the active metabolite prednisolone, and is 
recommended by the AASLD and the EASL for the treatment of autoimmune hepatitis.
For
H
r
ore
Fo
ore (
For
(HB
or 
HB
vir
F
vir
mmercial 
c
y.
ci
y.
es the f
mer
es the f
m
non-com
termine
omm
termine
HCV 
no
HCV 
use
E vi
se 
E vi
hroma
use
hroma
only.
tentia
y.
tentia
boratory
only
boratory
irus,
o
irus

Takeda
CONFIDENTIAL
Page 48
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
Severe autoimmune hepatitis is defined by the American Association for the Study of Liver 
Diseases (AASLD) as an ALT or AST of ≥10 × ULN OR ALT or AST ≥5 × ULN with serum 
total IgG ≥2 × ULN or bridging necrosis on biopsy. Severe disease requires urgent treatment 
with corticosteroids. The AASLD evidence-based guidelines state that autoimmune hepatitis 
patients who have no, or only mild symptoms or laboratory abnormalities have very good 
immediate survival without corticosteroid therapy.
Management of presumptive vector-related hepatitis will be in accordance with a modified (more 
conservative) version of the most recent published guidelines by the AASLD: “Diagnosis and 
Management of Autoimmune Hepatitis” and the EASL for the treatment of autoimmune 
hepatitisx, (European Association for the Study of the Liver, 2015).
If no other cause of the elevated ALT is identified, consideration should be given to combination 
therapy with azathioprine/corticosteroid per AASLD guidelines or other drug regimens as per 
standard of practice, in consultation with a hepatologist. 
7.3 Duration of Study Period(s) and Subject Participation
The overall duration of the study is 8 years from study initiation (ie, first subject enrolled) to 
study completion (ie, last subject last visit). The recruitment period is expected to be about 
40 months.
The subject participation period is approximately 5.5 years including the screening period and 
the 5-year post gene transfer follow-up.
7.4 Outcome Measures
7.4.1 Primary Outcome Measure
The primary outcome measure is the incidence of BAX 888-related AEs (serious or non-serious) 
including development of FVIII inhibitory antibodies, clinically significant changes in standard 
laboratory parameters, physical exam, and vital signs that are reported as AEs.
7.4.2 Secondary Outcome Measures
7.4.2.1 Efficacy
1.
Circulating plasma FVIII activity and antigen levels.
2.
ABR in comparison to before gene transfer.
3.
Consumption of exogenous FVIII in comparison to before gene transfer.
                                                
x
https://www/aasld.org/sites/default/files/guideline_documents/autoimmunehepatitis2010.pdf:  date last 
accessioned: 14/Dec/2015.
For non-commercial
udy
ial
udy in
al 
in
y
al
y
recruit
ercia
recruit
roxima
com
roxima
-up.
on
-up.
use 
tion
se
tion
it
u
it
only.
r o

Takeda
CONFIDENTIAL
Page 49
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
7.4.2.2 Safety
1.
Development of inhibitory and total binding antibodies to FVIII.
2.
Humoral and cell-mediated immune response to AAV8 and FVIII proteins.
3.
Surveillance of AAV8 genome shedding in blood, saliva, semen, urine and stool.
7.4.3 Tertiary Outcome Measures
1.
Hemophilia Joint Health Score at screening and Months 12, 24, 36, 48, and 60 post-gene 
transfer.
2.
Changes in the following assessments:

HRQoL (post-gene transfer vs. baseline) measured by:

Generic: 36-item Short Form survey (SF-36v2), EuroQol-5D (EQ-5D).

Disease-specific: Hemophilia-Specific Quality of Life Index (Haemo-QoL-A).
3.
Patient Experience (baseline):

Adherence: Validated Hemophilia Regimen Treatment Adherence 
Scale-Prophylaxis (VERITAS-Pro).

Disease-specific patient experience: Patients' preference for hemophilia treatment 
questionnaire (HaemoPREF).
7.5 Randomization and Blinding
This is a non-randomized, open-label, active treatment, dose escalation clinical study.
7.6 Study Stopping Rules
Each subject will receive only one dose of BAX 888 during the course of the study; hence 
stopping rules apply only during the screening. Subjects who have been dosed with BAX 888 
will be followed to the end of the study as per protocol.
If any one of the following criteria are met, BAX 888 dosing will be paused and further 
enrollment will be halted until an independent DMC evaluates all available study data and makes 
a recommendation:

More than 3 × ULN increase in ALT, AST, or both in any subject after BAX 888 
administration that is not manageable by steroid rescue treatment implemented according 
to AASLD guidelines.

A serious adverse event (SAE) that may or may not be potentially related to BAX 888 and 
which poses either an immediate risk to subject’s health or is likely to adversely affect the 
subject’s health long term. This includes events classified as AEs qualifying for special 
notification (Brussels, 03/12/2009, ENTR/F/2/SF/dn D(2009) 35810; 
EMEA/CHMP/GTWP/60436/2007) if these are judged as potentially related to the IP.
For 
ly one
For
ly one
non-commercial 
Patie
al
Patie
active t
com
active t
use 
ents
u
ents
only.
reatme
on
reatme

Takeda
CONFIDENTIAL
Page 50
BAX 888
201501 Protocol Amendment 9
10 Nov 2021

The development, after having received BAX 888, of an inhibitor towards FVIII in any 
subject will lead to pausing of dosing and further investigations of the characteristics and 
potential contributing factors and causal relationships of the observed FVIII inhibitor.

Death of a subject, after having received BAX 888, that is judged as definitely, probably, 
or possibly attributed to BAX 888. The study will be temporarily stopped in order to 
undergo review by the Investigational Review Board (IRB), DMC and the FDA.

The occurrence of a malignancy at any point after gene transfer that is judged as probably 
or possibly related to BAX 888.
The study may be terminated, if one or more of the following criteria are met:
1.
The sponsor decides to stop enrollment into the study based upon its assessment of safety.
2.
The sponsor decides to stop enrollment into the study for administrative reasons.
7.7 Investigational Product(s)
7.7.1 Packaging, Labeling, and Storage
Product Name: BAX 888
Vector Name (Biologic Substance) 
Serotype: AAV8
Gene Insert: F8 Transgene
BAX 888 contains an AAV genome consisting of a modified (truncated) 320 bp transthyretin 
(pre-albumin, TTR) promoter/enhancer, followed by a 77 bp intron fragment from minute virus 
of mice-MVM, driving expression of a codon-optimized BDD F8 cDNA. The codon 
optimization algorithm results in conservation of the wild type FVIII amino acid sequence 
without any mutation introduced. The B domain of the FVIII is deleted with the SQ linker at the 
site of the deletion; this SQ linker is the same sequence that is used in the commercially available 
recombinant FVIII proteins Refacto® and Xyntha®. The gene insert has a synthetic short 
polyadenylation sequence (polyA). The insert is bounded by the 145 bp AAV2 inverted terminal 
repeats (ITR).
Both terminal repeats have the wild type 145 nucleotide sequence, so as to direct replication and 
packaging of conventional single strand AAV DNA sequences. The biological function of the 
gene expression cassette has been tested by transfection, viral vector packaging, and in vivo
intravenous injection into hemophilia A mice.
For
r/enha
For 
r/enha
essio
F
essio
non-commercial 
me co
no
me co
use only.

Takeda
CONFIDENTIAL
Page 51
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
The AAV is a physically stable capsid of approximately 25 nm. The virus structural proteins are 
VP1, VP2, and VP3, and occur in a reproducible ratio of 1:1:10, respectively; these proteins are 
routinely assayed by SDS-PAGE with silver staining. Figure 1 shows the vector DNA structure.
Figure 1. Vector DNA Structure
BAX 888 is provided as a clear and sterile aqueous solution in sterilized, pyrogen-free and 
low-virus-binding SiO2-coated glass vials as described on the label. The final product 
formulation consists of a solution of BAX 888 in 100 mM NaCl and 5% Trehalose. The product 
is filled at a target concentration of about 1 x 1013 cp/mL as described on the vial label; however, 
during the course of the study, a product with a higher concentration may become available. The 
information will be provided to the site to calculate the subject’s dose as described in the 
Pharmacy Manual.
BAX 888 will be manufactured and packaged under current Good Manufacturing Practice 
conditions.
BAX 888 will be stored at -60°C or below, in a secured location.
Handling and disposal of BAX 888 will comply with standards for Biosafety Level 1 vectors and 
universal precautions.
For additional information please refer to the BAX 888 IB and/or other specific instructions 
provided by the Sponsor.
7.7.2 Administration
BAX 888 is to be administered as a single peripheral IV infusion. All ancillary supplies will be 
provided to the infusion sites for use in preparation and infusion of the BAX 888 product.
The BAX 888 Study Pharmacy Manual provides detailed step-by-step guidance on handling and 
administration of the study drug.
Briefly, a qualified pharmacist and/or designee will thaw BAX 888 and pool the calculated 
amount into appropriate syringes and dispense the IP to the investigator. The individual infusion 
volume will be based on the subject’s assigned dose and body weight collected at the Screen 2 
Visit. 
For 
ommercial 
nder cu
erci
nder cu
non-c
elow, in
com
elow, in
88 wil
no
8 wil
use
bject
se 
bject
only.
cribed
ly.
cribed
ntration
only
ntration
t’s
o
t’s

Takeda
CONFIDENTIAL
Page 52
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
Initially, approximately 10% of the BAX 888 infusion volume will be administered by manual 
push followed by an observation period of 30 minutes to monitor for infusion reactions. The 
remaining 90% of the BAX 888 product will then be administered as specified in the Pharmacy
Manual.
7.7.2.1 Monitoring and Treatment of Allergic Reaction to BAX 888
All subjects will be monitored for allergic reactions following the initial infusion and the 
completion of the infusion of BAX 888.
Subjects who exhibit the following signs and symptoms will be treated accordingly (grading will 
be made in accordance with the Common Terminology Criteria for Adverse Events [CTCAE], 
Version 4.0, as described below) (Cancer Therapy Evaluation Program, 2009).
Grade 1 or 2 signs or symptoms consistent with allergic reaction: 
Subjects should be reassessed at 5-minute intervals. Symptomatic treatment (antihistamine, 
nonsteroidal anti-inflammatory drug, acetaminophen and corticosteroid) is permitted by oral or 
parenteral route, but the symptoms must resolve within 30 minutes to be considered Grade 1 or 
2. If the symptoms resolve within 30 minutes, an additional approximate 10% of the total dose of 
BAX 888 may be administered and an identical assessment performed over the subsequent 
30 minutes. If there is no recurrence of symptoms, the remainder of the dose may be 
administered as specified in the BAX 888 Pharmacy Manual. If symptoms do not resolve within 
30 minutes, the event will be considered Grade 3, and BAX 888 will be permanently
discontinued. If there is a recurrence of symptoms, the infusion will be permanently
discontinued. In all cases, the AE should be recorded and reported as per Section 11.1.
Grade 3 or higher signs or symptoms consistent with allergic reaction or anaphylaxis:
The infusion of BAX 888 must be permanently discontinued. The AE will be 
recorded and reported as per Section 11.1, and immediately reported to the Medical 
Monitor and DMC.
Additional assessment and treatment of the event should be at the investigator’s discretion.
7.7.3 Description of the Investigational Product
See Section 7.7.1.
7.7.4 Investigational Product Accountability
The investigator or his/her designee/pharmacist will ensure that the IP(s) is stored as specified in 
the protocol and that the storage area is secured, with access limited to authorized study
personnel. 
For 
AE s
or
AE s
ym
F
ym
commercial
ddition
ial 
ddition
assessm
ercia
assessm
ptoms, t
me
ptoms, t
8 Pharm
omm
8 Pharm
non-c
red Gra
-co
red Gra
ce of s
on
ce of s
sho
n
sho
use 
orti
e
orti
30 mi
use
30 mi
u
only.
matic trea
only
matic trea
ticost
on
ticost

Takeda
CONFIDENTIAL
Page 53
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
The investigator or his/her designee/pharmacist will maintain records that the IP(s) was received, 
including the date received, drug identity code, date of manufacture or expiration date, amount 
received, and disposition. IP(s) must be dispensed only at the infusion center. Records will be 
maintained that includes the subject identification code (SIC), dispensation date, and amount 
dispensed. All remaining partially used and/or unused IP(s) will be returned to the sponsor or 
sponsor’s representative after study completion/termination or destroyed with the permission of 
the sponsor in accordance with applicable state and federal laws, ICH-GCP guidelines, and study 
site procedures. If IP(s) is to be destroyed, the investigator or his/her designee/pharmacist will 
provide documentation in accordance with sponsor’s specifications.
7.8 Source Data
Per ICH GCP, source data are defined as all information in original records and certified copies 
of original records of clinical findings, observations, or other activities in a clinical trial that are 
necessary for the reconstruction and evaluation of the trial. Source data are contained in source 
documents (original records or certified copies), which may be in paper and/or electronic format. 
Source data for this study comprise the following: hospital records, medical records, clinical and 
office charts, laboratory notes, memoranda, subjects' diaries or evaluation checklists, outcomes 
reported by subjects, pharmacy dispensing records, recorded data from automated instruments, 
copies or transcriptions certified after verification as being accurate copies, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at 
the pharmacy, at the laboratories and at medico-technical departments involved in the clinical 
study.
No data will be entered directly onto the case report form (CRF).
For additional information on study documentation and eCRFs, see Section 16.2. The use of 
subject e-diaries is described in Section 9.5.
For
ly
Fo
ly ont
For 
ont
y
Fo
y
non-commercial 
dia
al
dia
ds, reco
cia
ds, reco
tion as 
merc
tion as 
netic m
mm
netic m
medic
com
medic
t
n
t
use
al rec
se 
al rec
aries
us
aries
only.
rce dat
ly.
rce da
be in pa
on y
be in pa

Takeda
CONFIDENTIAL
Page 54
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
8. SUBJECT SELECTION, WITHDRAWAL, AND DISCONTINUATION
8.1 Inclusion Criteria
Subjects who meet ALL of the following criteria are eligible for this study:
1.
Male, aged 18 to 75 years at the time of screening.
2.
Established severe hemophilia A (FVIII:C <1%, measured following ≥5 days without 
FVIII treatment), and/or documented intron 1 inversion or intron 22 inversion mutation in 
the F8 gene, consistent with severe hemophilia A, AND documented evidence of
≥3 hemorrhages over the previous 12 months requiring treatment with exogenous FVIII or
use of FVIII prophylaxis because of history of frequent bleeding episodes.
3.
History of >150 exposure days to exogenously administered FVIII concentrates or 
cryoprecipitate.
4.
Sexually active men must agree to use barrier contraception (combination of a condom and 
spermicide) or limit sexual intercourse to post-menopausal, surgically sterilized, or 
contraception-practicing partners for a minimum of 6 months after administration of 
BAX 888, or until BAX 888 genomes are no longer detected in the semen, whichever is 
sooner.
5.
Subject is willing and able to comply with the requirements of the protocol, including 
provision of semen samples, maintenance of a diary of bleeding episodes and FVIII protein 
use. 
6.
Signed informed consent.
8.2 Exclusion Criteria
Subjects who meet ANY of the following criteria are not eligible for this study:
1.
Bleeding disorder(s) other than hemophilia A.
2.
Personal laboratory evidence of having developed inhibitors to FVIII protein at any time 
(≥0.6 BU on any single test).
3.
Documented prior allergic reaction to any FVIII product.
4.
Anti-AAV8 neutralizing antibody titer ≥1:5. Subjects whose laboratory assessments are 
≤1:10 may be re-tested within the same Screening window and, if eligibility criterion is 
met on retest, may be enrolled after confirmation by the Sponsor Medical Monitor.
5.
Known hypersensitivity to prednisolone or prednisone, or to any of the excipients.
6.
Having a disease in which treatment with prednisolone or prednisone is not tolerated 
(including but not limited to osteoporosis with vertebral fractures, difficult to control 
hypertension, and difficult to control diabetes).
For
he foll
For 
he foll
non-commercial
he requ
cial 
he requ
e of a d
erc
e of a d
n
use
dete
se 
dete
only.
 (c(
al, surg
nly.
al, surg
months 
only
months 
cte
o
cte

Takeda
CONFIDENTIAL
Page 55
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
7.
Evidence of markers of potential underlying risk for autoimmune mediated hepatic disease:
a.
Anti-smooth muscle antibody assay results ≥40 (Inova QUANTA LiteTM Actin IgG 
enzyme-linked immunosorbent assay [ELISA]); values of 31 to 39 will be flagged as 
possibly abnormal and the Investigator and Medical Monitor will evaluate the subject 
for eligibility.
b.
Elevated anti- LKM1 titers.
c.
Total IgG >1.5 × ULN.
d.
Antinuclear antibody titer >1:320; OR ANA titer >1:80 if demonstrated concurrently 
with ALT that is >ULN.
8.
Active Hepatitis C: As indicated by detectable HCV RNA by PCR.
9.
Hepatitis B: If surface antigen is positive.
10. Seropositive for Human Immunodeficiency Virus (HIV).
11. Receiving systemic antiviral and/or interferon therapy within 4 weeks prior to enrollment.
12. Clinically significant infections (eg, systemic fungal infections) requiring systemic 
treatment.
13. Known immune disorder (including myeloma and lymphoma).
14. Concurrent chemotherapy or biological therapy for treatment of neoplastic disease or other 
disorders.
15. An absolute neutrophil count <1000 cells/mm3.
16. Markers of hepatic inflammation or cirrhosis as evidenced by 1 or more of the following:
a.
Platelet count of <150,000/µL.
b.
Serum albumin level is below the central laboratory’s lower limit of normal and 
FibroSURE is ≥0.48. (ie, Metavir staging of F2 or greater). Of note, in subjects with a 
known history of Gilbert’s syndrome, a Fibrotest cannot be used for fibrosis testing.
c.
Total bilirubin >1.5 × ULN and direct bilirubin ≥0.5 mg/dL.
d.
ALT or AST >1.0 × ULN.
e.
Alkaline phosphatase (AP) >2.0 × ULN.
f.
History of liver biopsy indicating moderate or severe fibrosis (Metavir staging of F2 or 
greater).
g.
History of ascites, varices, variceal hemorrhage, or hepatic encephalopathy.
h.
Any findings on screening ultrasound that would preclude the safe use of AAV gene 
therapy.
17. Prothrombin time (PT) international normalized ratio ≥1.4.
18. Serum creatinine >1.5 mg/dL.
19. Urine protein >30 mg/dL OR >0.5 g/day.
For
vel is b
For 
vel is b
48. (
Fo
48. (
non-commercial
and 
al 
and 
erapy
ercia
erapy f
cia
f
y
cia
y
0 cells/
omm
0 cells/
on or ci
n-co
on or ci
000/µL
non
000/µL
use 
e
ly
u
ly
u
only.
thin 4 w
ly.
thin 4 
fection
on
fection

Takeda
CONFIDENTIAL
Page 56
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
20. Body mass index >38.
21. Major surgery or an orthopedic surgical procedure planned within 6 months after 
enrollment.
22. Acute or chronic disease that, in the opinion of the investigator, would adversely affect 
subject safety or compliance or interpretation of study results.
23. Received an AAV vector previously or any other gene transfer agent in the previous 
12 months prior to Study Day 0.
24. Received an investigational intervention or participated in another clinical trial within 
4 weeks prior to enrollment or within 5 half-lives of the investigational drug 
administration, whichever is longer.
25. Significant cardiovascular disease (such as New York Heart Association Class III or IV 
cardiac disease, congestive heart failure, myocardial infarction within the previous 
6 months, unstable arrhythmias, or unstable angina) or significant pulmonary disease 
(including obstructive pulmonary disease).
26. Recent history of psychiatric illness or cognitive dysfunction (including drug or alcohol 
abuse) that in the opinion of the investigator, is likely to impair subject’s ability to comply 
with protocol mandated procedures.
27. Subject is a family member or employee of the investigator.
8.3 Withdrawal and Discontinuation
Any subject may voluntarily withdraw (ie, reduce the degree of participation in the study) 
consent for continued participation and data collection. The reason for withdrawal will be 
recorded on the End of Study eCRF. Assessments to be performed at the termination visit 
(including in cases of withdrawal or discontinuation) are described in Section 9.6 and 
Section 19.1.
Discontinuation (ie, complete withdrawal from study participation) may be due to dropout (ie, 
active discontinuation by subject) or loss to follow-up (ie, discontinuation by subject without 
notice or action). Additionally, the investigator and sponsor have the discretion to discontinue 
any subject from the study if, in their judgment, continued participation would pose an 
unacceptable risk for the subject.
Subjects also will be withdrawn during the screening period for the following reasons:

The subject develops a confirmed FVIII inhibitory antibody (≥0.6 BU by Nijmegen 
modification of the Bethesda assay).

The subject is non-compliant with study procedures, in the opinion of the investigator. 

The subject would require major emergency surgery within 6 months of dosing.
For
wal o
or 
wal o
non-commercial
he inv
ial 
he inv
e
o
e, redu
omm
, redu
nd data
n-co
nd data
RF. Ass
non
RF. Ass
or d
n
or d
use 
to
e
to
u
only.
nction (in
only
nction (in
o imp
on
o imp

Takeda
CONFIDENTIAL
Page 57
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
Subjects also may be discontinued from further study participation post-infusion for the 
following reason, although every effort to collect follow up safety data will be made:

The subject is non-compliant with study procedures, in the opinion of the investigator.
Subjects who received BAX 888 will not be replaced.
All withdrawn or discontinued subjects need to complete the final study assessments to be 
performed at the termination visit as described in Section 19.1.
For non-commercial use only.

Takeda
CONFIDENTIAL
Page 58
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
9. STUDY PROCEDURES
9.1 Informed Consent
Any subject who provides informed consent (ie, signs and dates the informed consent form [ICF] 
and assent form, if applicable) is considered a subject in the study.
9.2 Subject Identification Code
The following series of numbers will comprise the SIC: protocol identifier (eg, 201501) to be 
provided by the sponsor, 2- or 3-digit number study site number (eg, 02) to be provided by the 
sponsor, and 3- or 4-digit subject number (eg, 0003) reflecting the order of providing informed 
consent. For example, the third subject who signed an ICF at study site 02 will be identified as 
Subject 201501-020003. All study documents (eg, eCRFs, clinical documentation, sample 
containers, drug accountability logs, etc.) will be identified with the SIC. Additionally, a 
uniquely coded SIC(s) is permitted as long as it does not contain a combination of information 
that allows identification of a subject (eg, collection of a subject’s initials and birth date would 
not be permitted), in compliance with laws governing data privacy.
9.3 Screening and Study Visits
In general, subjects will undergo at least 2 screening visits (1 and 2) prior to dosing with 
BAX 888 (refer also to Section 7.2. Initially, subjects will provide consent for procedures and 
assessments to be performed at the first screening visit. The rationale for the Screen 1 visit is that 
it is expected that approximately 30 to 35% of the adult hemophilia population will have 
circulating antibodies that recognize and may neutralize AAV8. Treatment with BAX 888 is 
expected to be sub-therapeutic or non-therapeutic in the presence of such evidence of adaptive 
immunity. Therefore, subjects may elect to perform Screen 1 initially and to only complete the 
full Screen 2 if eligible based upon the results of Screen 1. Subjects who meet all inclusion and 
exclusion criteria will then advance to Screen 2, which will take place approximately 3 weeks 
but ≤70 days prior to dosing with BAX 888. Subjects will provide consent for all procedures and 
assessments to be performed at the Screen 2 and all following Study Visits. A targeted physical 
exam will be conducted at the Screen 2 visit. The rationale for the Screen 2 visit is to ensure that 
the subject does not have covert liver inflammation that has developed since the time of Screen 1 
and does not have unrecognized immune responses to AAV or FVIII that have developed since 
the time of Screen 1, because the new development of either of these findings might compromise 
the safety and efficacy of BAX 888 therapy. E-diaries to capture subject reported data including 
bleeding episodes and FVIII usage will also be distributed at the Screen 2 visit.
The study site is responsible for maintaining an enrollment/screening log that includes all 
subjects enrolled. The log also will serve to document the reason for screening failure. 
For 
gniz
or
gniz
F
tic or n
Fo
tic or n
n-commercial 
creening
me
creening
ally
om
ally, sub
omm
, sub
st scree
-co
st scree
no
0 to 35
on
0 to 35
ze a
no
ze a
use
ta priv
use 
ta priv
only.
in a com
nly.
in a co
ject’s in
on
ect’s in

Takeda
CONFIDENTIAL
Page 59
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
If a subject does not satisfy all screening criteria, the same subject may be re-screened at a later 
date. A complete or partial re-screen may also become necessary at the discretion of the 
investigator or sponsor. All screening data will be collected and reported in eCRFs, regardless of 
screening outcome. For the purpose of analysis, only the data from the most recent screening 
outcome will be used. If a subject is re-screened, the End of Study eCRF should be completed, 
and a new ICF, new SIC and new eCRF are required for that subject. Exemptions may be 
granted for administrative reasons (eg, delay in timely availability of laboratory results). 
9.4 Medications and Non-Drug Therapies 
The following medications and non-drug therapies are not permitted within 4 weeks prior to 
dosing and during the course of the study (unless stated otherwise):

Medications:

Systemic antiviral and/or interferon therapy (with the exception of antiretroviral 
therapy).

Concurrent chemotherapy or biological therapy for treatment of neoplastic disease or 
other disorders.

Received an AAV vector previously or any other gene transfer agent in the previous 
12 months prior to Study Day 0.

An investigational intervention within 4 weeks prior to dosing or within 5 half-lives of 
the investigational drug administration, whichever is longer.

Non-drug therapies:

Major surgery or an orthopedic surgical procedure planned within 6 months after 
dosing.
A subject who has taken any of these medications or anticipates receiving any of these non-drug 
therapies within the specified timeframe will be recorded as a protocol deviation.
The following medications and non-drug therapies are permitted within 4 weeks before study
entry and during the course of the study:

Medications:

Antiretroviral therapy.

Antihistamines, nonsteroidal anti-inflammatory drugs, acetaminophen, and 
corticosteroids by oral or parenteral route for the treatment of allergic reaction.

Hemostatic agents, such as tranexamic acid, are permitted, as indicated by the 
subject’s treating physician, to treat mucosal bleeding during the study.

FVIII products
For 
f
F
f
non-commercial
any
cia
any oth
al 
oth
within 4
mme
within 4
nistratio
omm
nistratio
thoped
no
hoped
use
for t
se 
for t
only.
excep
y.
excep
trea
o
trea

Takeda
CONFIDENTIAL
Page 60
BAX 888
201501 Protocol Amendment 9
10 Nov 2021

Any medications deemed necessary by the subject’s physician to treat or prevent any
medical condition (with the exception of any immunomodulating drug other than 
anti-retroviral chemotherapy, and any investigational drug or device).

Any over-the-counter medication used by the subject to treat symptoms or signs of any 
medical condition.

Supplemental vitamins, minerals.

Non-drug therapies:

Any non-drug therapy (eg, physiotherapy) deemed necessary by the subject’s 
physician to treat or prevent any medical condition.
9.4.1 Use of Exogenous FVIII Throughout the Study
Clinical bleeding episodes will be managed with infusion of exogenous FVIII. Usage of 
exogenous FVIII for the prevention (prophylactic treatment) or episodic management 
(on-demand FVIII treatment) of hemorrhages will be at the discretion of the investigator and/or 
local hemophilia physician, and in consultation with the study subject. However, in order to 
assess FVIII activity levels derived specifically from the BAX 888 transgene and not exogenous 
FVIII products, subjects will be asked to refrain from prophylactic FVIII usage between Weeks 3 
to 18 post-BAX 888 administration and during the 3 weeks prior to the Month 9 Visit. During 
these periods which are critical for the evaluation of sustained FVIII expression from the vector 
(as both an efficacy and safety evaluation), on-demand treatment that is required for clinical 
bleeding should, if possible, be performed using a standard half-life FVIII product (rather than an 
extended half-life FVIII concentrate). 
All use of exogenous FVIII will be recorded by the subject in the e-diary (source document) and 
transcribed by the site to the eCRF.
It is recognized and expected that suspected or evident bleeding episodes will be treated with 
infused FVIII protein as per the standard of care. If possible, study visits should be scheduled at 
least 3 to 5 days after a FVIII dose to minimize the chance that any FVIII activity level measured 
at the study visit results from exogenously administered FVIII. However, with the exception of 
Screen 1, study visits should not be postponed if the study subject has infused FVIII (eg, for the 
treatment of bleeding) within 4 days of the scheduled study visit. 
9.5 Subject Diary and Patient Reported Outcomes
9.5.1 Subject Diary
An e-diary will be provided to each subject at the Screen 2 visit to record the following 
information:
1.
Details of bleeding episodes.
For 
ll be
r
ll be
Fo
eCRF
For
eCRF
cial
p
3
ci
3 wee
cial 
wee
non-commer
on of su
erci
on of su
on
mm
on-dem
mme
-dem
ed usin
om
ed usin
. 
n
. 
e re
no
e re
use
AX
se 
AX
rophy
use
rophy
only.
retion
y.
retion
y
o
y subjec
only
subjec
y
o
y
X 88
o
X 88

Takeda
CONFIDENTIAL
Page 61
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
2.
Details of exogenous FVIII consumption.
3.
Concomitant medications and non-drug therapies.
4.
Untoward events.
5.
Patient reported outcomes (see Section 11.10).
For each bleeding episode, the following information will be recorded by the subject or by 
authorized, qualified personnel at the participating site:

Location of bleed, eg, joint, soft tissue, muscle, body cavity, intracranial, other.

Type of bleed, ie, spontaneous (definitely no injury/trauma), injury (definitely due to 
injury/trauma), or unknown.

Severity of bleed:

Minor: Early hemarthrosis, mild muscle bleeding (see Section 19.4.2), or mild oral 
bleeding, including epistaxis.

Moderate: Moderate bleeding into muscles, bleeding into the oral cavity, definite/more 
extensive hemarthroses, and known trauma.

Major, life-/limb-threatening: Significant gastrointestinal bleeding, intracranial, intra-
abdominal, or intrathoracic bleeding, central nervous system (CNS) bleeding, bleeding 
in the retropharyngeal or retroperitoneal spaces or iliopsoas sheath, fractures, head 
trauma.

Date and time of onset of bleed.

Date and time of resolution of bleeding episode.
Subjects will be trained on use of the e-diary, which will be provided to the subject in electronic 
format at Screen 2 Visit and will remain with the subject for the duration of the study. The 
investigator will review the e-diary for completeness and request missing information 
periodically and in a timely manner. Untoward events recorded in the e-diary will be reported as 
AEs according to the investigator’s discretion and clinical judgment.
Subject entries in the e-diary will serve as source records. During study participation 
the investigator has access to the database holding the subject e-diary data.
After study closure, the investigator will receive the e-diary records for their subjects, including 
audit trail records, in PDF format. The data will be transmitted to the eCRF by a validated 
transfer.
9.5.2 Patient Reported Outcomes 
The PRO instruments to be measured in this study are described below. These measures will be 
administered in this study at the time points noted in Table 2.
For
e of th
For 
e of th
F
will
Fo
will
non-commercial
gastr
al 
gastr
entral n
rcia
entral n
neal sp
merc
neal sp
of bleed
on-
of bleed
h
n
h
use 
e
roi
u
roi
only.
e
ng
o
ng into
on
into

Takeda
CONFIDENTIAL
Page 62
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
1.
Short Form-36: The SF-36v2 is a self-administered, validated questionnaire designed to 
measure generic HRQoL. This 36-item questionnaire measures 8 domains, including: 
physical functioning, role-physical, bodily pain, general health, vitality, social functioning, 
role emotional, and mental health. Two summary scores can be calculated, the Physical 
Component Score and the Mental Component Score; additionally, scores can be calculated 
for each of the 8 domains. Higher scores indicate better health status.
2.
EuroQol-5D: The EQ-5D is a self-administered, standardized measure of health status that 
provides a generic measure of health for clinical and economic appraisal consisting of the 
following 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression each with 5 levels.
3.
Haemo-QoL-A: The Haemo-QoL-A is a validated hemophilia A–specific instrument 
covering 6 areas (physical functioning, role functioning, worry, consequences of bleeding, 
positive affect, and treatment concerns) (Rentz et al., 2008).
4.
VERITAS-Pro: VERITAS-Pro is a self/parent-reported questionnaire consisting of 
24 questions on 6 (4-item) subscales (Time, Dose, Plan, Remember, Skip, Communicate) 
to assess adherence to prophylactic treatment. Lower scores reflect higher adherence 
(Duncan et al., 2010).
5.
HaemoPREF: HaemoPREF is a 14-item questionnaire designed to measure ease of use 
and patients' preference for hemophilia treatment (Teal et al., 2014).
6.
Patient Activity Level: Subjects will be asked to estimate their activity levels. This will 
consist of a few questions asking subjects to rate their current level of activity.
After study closure, the investigator will receive the PRO records for their subjects, including 
audit trail records, in PDF format. The data will be transmitted to the eCRF by a validated 
transfer.
9.6 Subject Completion/Discontinuation
A subject is considered to have completed the study when he/she ceases active participation in 
the study because the subject has, or is presumed to have, completed all study procedures 
according with the protocol (with or without protocol deviations).
Reasons for completion/discontinuation will be reported on the Completion/Discontinuation 
eCRF, including: completed, screen failure, AE (eg, death), discontinuation by subject (eg, lost 
to follow-up [defined as 3 documented unsuccessful attempts to contact the subject], dropout), 
physician decision (eg, progressive disease, non-compliance with IP/protocol violation[s], 
recovery), study terminated by sponsor, or other (reason to be specified by the investigator, eg, 
technical problems). Regardless of the reason, all data available for the subject up to the time of 
completion/discontinuation should be recorded on the appropriate eCRF. 
For 
scont
Fo
scont
mmercial 
ent 
al
ent (
al
(
sked to
ercia
sked to
cts to ra
mer
cts to ra
non-co
l receiv
com
l receiv
he data
n-co
he data
use 
naire 
use
naire 
(
u
(Te
u
Te
only.
mem
y
mem
ores refl
nly.
ores ref

Takeda
CONFIDENTIAL
Page 63
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
Every effort will be made to have discontinued subjects complete the study 
completion/termination visit. If the completion/termination visit is done as an additional, 
unscheduled visit, the assessment results shall be recorded with the completion/termination visit. 
If a subject terminates participation in the study and does not return for the 
completion/termination visit, their last recorded assessments shall remain recorded with their last 
visit. The reason for discontinuation will be recorded, and the data collected up to the time of 
discontinuation will be used in the analysis and included in the clinical study report. If additional 
assessments are required, the assessments shall be recorded separately. Assessments to be 
performed at the termination visit (including in cases of withdraw or discontinuation) can be 
found in Table 2 and Table 3.
In the event of subject discontinuation due to an AE, clinical and/or laboratory investigations that 
are beyond the scope of the required study observations/assessments may be performed as part of 
the evaluation of the event. These investigations will take place under the direction of the 
investigator in consultation with the sponsor, and the details of the outcome may be reported to 
the appropriate regulatory authorities by the sponsor.
9.7 Procedures for Monitoring Subject Compliance
All study procedures are to be performed under the direct supervision of the investigator/a 
licensed healthcare professional at the study site, and thus, no separate procedures will be used to 
monitor subject compliance.
9.8 Communication with Sites 
Procedures will be in place to ensure information is communicated in a timely fashion to all 
Investigators across all participating sites. Decisions pertaining to dosing, DMC 
communications, and any relevant safety information will be communicated to the Investigators 
and the sites in the form of an email. An acknowledgement of receipt of the email from the 
Investigator or designee will be required. Failure to receive acknowledgment will result in 
redundant notification by overnight mail.
For
o ensu
For 
o ensu
ipa
F
ipa
non-commercial 
ce
al
ce
r the di
erc
r the di
y
m
y site, a
mme
site, a
y
m
y
use only.
unde
y
unde
of the ou
nly
of the ou

Takeda
CONFIDENTIAL
Page 64
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
10. ASSESSMENT OF EFFICACY
10.1 Circulating Plasma FVIII Activity and Antigen Levels 
The following assessments will be made at the time points presented in Table 3 as part of the 
analysis and interpretation of efficacy outcome measures:

FVIII genotyping.

FVIII activity level (Central Laboratory: one-stage clotting and chromogenic assays; Local 
Laboratory: one-stage clotting or chromogenic assay).

FVIII antigen.
10.2 Number of Bleeding Episodes Post-BAX 888 Infusion 
The primary measure of hemostatic efficacy is the number of bleeding episodes post-BAX 888 
administration. The number of bleeding episodes will be assessed based upon each individual 
bleeding episode, spontaneous or traumatic, recorded in the subject’s e-diary, and/or recorded in 
the physician/nurse/study site notes. Documented bleeding episodes in the 12 months prior to 
study enrollment will also be recorded in the eCRF.
A bleed is defined as subjective (eg, pain consistent with a joint bleed [see Section 19.4.1]) or 
objective evidence of bleeding which may or may not require treatment with FVIII. Bleeding 
episodes occurring at the same anatomical location (eg, right knee) with the same etiology
(eg, spontaneous vs. injury) within 72 hours of onset of the first episode will be considered a 
single bleeding episode. If a bleed occurs following resolution of the bleed, it will be considered 
to be a “new” bleed and recorded accordingly. Bleeding occurring at multiple locations related to 
the same injury (eg, knee and ankle bleeds following a fall) will be counted as a single bleeding 
episode.
Adverse events and the details of concomitant medication use coincident with the treatment of all 
acute bleeding episodes will be recorded. Note that bleeding episodes are not to be reported as 
AEs (Section 11.1).
Hemophilia-related events meeting the criteria for seriousness will be reported as SAEs and 
described on the SAER form.
10.3 Consumption of Exogenous FVIII Compared to before Gene Transfer
Data pertaining to the consumption of exogenous FVIII during the 12-month period prior to 
BAX 888 infusion will be collected and recorded as part of the medical history. Post-gene 
transfer consumption of exogenous FVIII will be measured at the time points in Table 2.
For 
ded a
or
ded a
F
d ankl
Fo
d ankl
mmercial 
tent wi
ercia
tent wi
r may
me
r may n
e
n
y
e
y
non-com
al locat
omm
al locat
 hours 
-co
 hours 
occurs
non
occurs
acco
no
acco
use
g epi
se 
g epi
only.
d bas
ly.
d bas
subject’s
only
ubject’s
isod
o
isod

Takeda
CONFIDENTIAL
Page 65
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
Weight-adjusted consumption of exogenous FVIII will be determined based upon the amount of 
exogenous FVIII infused, as recorded in the subject’s e-diary and the subject’s weight, as 
measured at the study site.
For non-commercial use only.

Takeda
CONFIDENTIAL
Page 66
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
11. ASSESSMENT OF SAFETY
11.1 Adverse Events
11.1.1 Definitions
An AE is defined as any untoward medical occurrence in a subject administered an IP that does 
not necessarily have a causal relationship with the treatment. An AE can therefore be any 
unfavorable and unintended sign (eg, an abnormal laboratory finding), symptom (eg, rash, pain, 
discomfort, fever, dizziness, etc.), disease (eg, peritonitis, bacteremia, etc.), or outcome of death 
temporally associated with the use of an IP, whether or not considered causally related to the IP.
11.1.1.1 Serious Adverse Event 
A serious adverse event is defined as an untoward medical occurrence that at any dose meets one 
or more of the following criteria:
1.
Outcome is fatal/results in death (including fetal death).
2.
Is life-threatening – defined as an event in which the subject was, in the judgment of the 
investigator, at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death had it been more severe.
3.
Requires inpatient hospitalization or results in prolongation of an existing 
hospitalization - inpatient hospitalization refers to any inpatient admission, regardless of 
length of stay.
4.
Results in persistent or significant disability/incapacity (ie, a substantial disruption of a 
person’s ability to conduct normal life functions).
5.
Is a congenital anomaly/birth defect.
6.
Is a medically important event – a medical event that may not be immediately
life-threatening or result in death or require hospitalization but may jeopardize the subject 
or may require medical or surgical intervention to prevent one of the other outcomes listed 
in the definitions above. Examples of such events are:

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 dependence or drug abuse.

Reviewed and confirmed seroconversion for, HAV, HBV, HCV, HEV, or parvovirus 
B19 (B19V).

Development of a confirmed inhibitor to FVIII with an inhibitor level ≥0.6 BU using 
the Nijmegen modification of the Bethesda assay.

Severe hypersensitivity/anaphylactic reactions to BAX 888.

Hospitalization for planned port placement or removal is not considered an SAE, 
however, any hospitalization required for an emergency port removal is considered an 
SAE. 
For 
birth
or
birth
nt ev
Fo
nt ev
non-commercial
t been
ial 
t been
lts in p
erc
lts in p
ion refe
mme
ion refe
ant disa
n-co
ant disa
normal 
non
normal 
h d
n
h d
use
e sub
se 
e sub
nt; it 
us
nt; it 
u
only.
.
o
.
jec
o
jec

Takeda
CONFIDENTIAL
Page 67
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
Uncomplicated pregnancies, following paternal exposure to IP are not considered an (S)AE; 
however, any pregnancy complication or pregnancy termination by therapeutic, elective, or 
spontaneous abortion shall be considered an SAE. 
Any pregnancy that occurs in the partner of the father after administration of IP but prior to 
clearance of BAX 888 genomes from the semen will be reported on a Pregnancy Report Form 
and followed-up at estimated date of delivery and 1 year post-delivery, if feasible.
11.1.1.2 Suspected Unexpected Serious Adverse Reaction (SUSAR)
Any suspected adverse reaction to study treatment (ie, including active comparators) that is both 
serious and unexpected. 
The event(s) must meet all of the following

Suspected adverse reaction

Serious

Unexpected

Assessed as related to study treatment
Once determined to meet the criteria for a SUSAR, a SAE should be submitted to regulatory
agencies expeditiously.
11.1.1.3 Non-Serious Adverse Event
A non-serious AE is an AE that does not meet the criteria of an SAE.
11.1.1.4 Unexpected Adverse Events
An unexpected adverse event is an AE whose nature, severity, specificity, or outcome is not 
consistent with the term, representation, or description used in the Reference Safety 
Information (RSI). “Unexpected” also refers to the AEs that are mentioned in the IB and/or 
prescribing information as occurring with a class of products or as anticipated from the 
pharmacological properties of the product, but are not specifically mentioned as occurring with 
the particular product under investigation. In addition, several human clinical trials using AAV2, 
AAV5 or AAV8 delivered via the systemic circulation have been associated with asymptomatic 
liver inflammation as evidenced by elevated liver transaminases (in particular, ALT elevations 
above the subject’s baseline) observed by laboratory evaluation. Liver enzyme elevation is a 
known complication for this drug class and is considered to be an expected complication of 
interest.
For 
rse Ev
Fo
rse Ev
non-commercial 
SAR, a 
erc
SAR, a 
t
does no
non
does no
use only.

Takeda
CONFIDENTIAL
Page 68
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
The expectedness of AEs will be determined by the sponsor using the IB and/or prescribing 
information as the RSI. This determination will include considerations such as the number of 
AEs previously observed, but not on the basis of what might be anticipated from the 
pharmacological properties of a product.
11.1.1.5 Preexisting Diseases
Preexisting diseases that are present before entry into the study are described in the medical 
history, and those that manifest with the same severity, frequency, or duration after IP exposure, 
will not be recorded as AEs. However, when there is an increase in the severity, duration, or 
frequency of a preexisting disease, the event must be described on the AE eCRF.
11.1.2 Assessment of Adverse Events
For the purposes of this study, the following non-serious events experienced after the first IP 
exposure are collected under other study endpoints and thus are not reportable on the AE eCRF, 
nor will they be included in the analysis of AEs:
1.
Hospital or study site visits for administration of FVIII.
2.
Hospitalization for routine bleeding episode management that could be managed in the 
clinic or home-setting but for which the subject was hospitalized.
3.
Hospitalizations for planned medical or surgical procedures, eg, placement of a central 
venous line (however, when there is an increase in the severity, duration, or frequency of a 
preexisting disease, the event must be described on the AE eCRF).
4.
Seroconversion after documented HAV/HBV vaccination prior to or during the study
period.
5.
Bleeding episodes/hemophilia-related events: Bleeding episodes are part of the underlying 
disease and therefore are not AEs. If a bleeding episode was caused by an injury (eg, a 
fall), the injury would not be reported as an AE, unless it resulted in a medical finding 
other than a bleeding episode (eg, abrasion of skin; fractured tibia). Therefore, any
hemophilia-related event (eg, hemarthrosis, bruising, hemorrhage) will not be reported as 
an AE, but these events will be recorded on the bleeding event eCRF. However, 
hemophilia-related events meeting the criteria for seriousness (eg, a gastrointestinal 
hemorrhage requiring hospitalization) will be reported as SAEs and described on the 
SAER form.
All other AEs from the first IP exposure until study completion/discontinuation will be described 
on the AE eCRF using the medical diagnosis (preferred), or, if no diagnosis could be established 
at the time of reporting the AE, a symptom or sign, in standard medical terminology in order to 
avoid the use of vague, ambiguous, or colloquial expressions (see definition in Section 11.1). 
Each AE will be evaluated by the investigator for:
1.
Seriousness as defined in Section 11.1.1.1.
For
mophili
For 
mophili
re n
Fo
re n
non-commercial 
anag
al
anag
ject wa
cial
ject wa
surgic
mer
surgic
an incr
mm
an incr
st be de
com
st be de
nted HA
on-c
nted HA
use 
III.
se
III.
gem
us
gem
only.
not r
y.
not r

Takeda
CONFIDENTIAL
Page 69
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
2.
Severity as defined in Section 11.1.2.1.
3.
Causal relationship to IP exposure or study procedure as defined in Section 11.1.2.2.
For each AE, the outcome (ie, recovering/resolving, recovered/resolved, recovered/resolved with 
sequelae, not recovered/not resolved, fatal, unknown) and if applicable action taken (ie, dose 
increased, dose not changed, dose reduced, drug interrupted, drug withdrawn, not applicable, or 
unknown) will also be recorded on the AE eCRF. Recovering/resolving AEs will be followed 
until resolution, medically stabilized, or 4 weeks after the study completion/termination visit, 
whichever comes first, and the follow-up information is to be documented in the eCRF. If the 
severity rating for an ongoing AE changes before the event resolves, the original AE report will 
be revised (ie, the event will not be reported as separate AE). During the course of any AE, the 
highest severity rating will be reported.
Deviations from the protocol-specified dosage (including overdosing, underdosing, abuse, and 
withdrawal), treatment errors (including incorrect route of administration, use of an incorrect 
product, and deviations from the protocol-defined dosing schedule), failures of expected 
pharmacological actions, and unexpected therapeutic or clinical benefits will be followed with 
regard to occurrence of AEs, lack of efficacy, and/or other observations because these events 
may be reportable to regulatory authorities.
If an investigator becomes aware of an SAE occurring in a subject after study completion, the 
SAE must be reported on the provided SAER form within 24 hours after awareness; no 
additional reporting on eCRFs is necessary.
11.1.2.1 Severity
The investigator will assess the severity of each AE using his/her clinical expertise and judgment 
based on the most appropriate description below:
1.
Mild

The AE is a transient discomfort and does not interfere in a significant manner with 
the subject’s normal functioning level.

The AE resolves spontaneously or may require minimal therapeutic intervention.
2.
Moderate

The AE produces limited impairment of function and may require therapeutic 
intervention.

The AE produces no sequela/sequelae.
3.
Severe

The AE results in a marked impairment of function and may lead to temporary
inability to resume usual life pattern.
For 
the s
Fo
the s
non-commercial 
r oth
al
r oth
E occur
mm
E occur
SAER 
com
SAER 
cessary
on-c
cessary
use
clinica
use 
clinica
her
u
her
only.
in
ministrat
nly.
ministra
hedule)
on
edule)

Takeda
CONFIDENTIAL
Page 70
BAX 888
201501 Protocol Amendment 9
10 Nov 2021

The AE produces sequela/sequelae, which require (prolonged) therapeutic 
intervention.
These severity definitions will also be used to assess the severity of an AE with a study-related 
procedure(s), if necessary.
11.1.2.2 Causality
Causality is a determination of whether there is a reasonable possibility that the IP is 
etiologically related to/associated with the AE. Causality assessment includes, eg, assessment of 
temporal relationships, dechallenge/rechallenge information, association (or lack of association) 
with underlying disease, presence (or absence) of a more likely cause, and physiological 
plausibility. For each AE, the investigator will assess the causal relationship between the IP and 
the AE using his/her clinical expertise and judgment according to the following most appropriate 
algorithm for the circumstances of the AE:
Related: The adverse event is clearly related to the investigational agent/procedure – ie, an event 
that follows a reasonable temporal sequence from administration of the study intervention, 
follows a known or expected response pattern to the suspected intervention, that is confirmed by
improvement on stopping and reappearance of the event on repeated exposure and that could not 
be reasonably explained by the known characteristics of the subject’s clinical state. 
Possibly Related: An adverse event that follows a reasonable temporal sequence from 
administration of the study intervention follows a known or expected response pattern to 
the suspected intervention, but that could readily have been produced by a number of other 
factors. 
Not Related: The adverse event is clearly not related to the investigational agent/procedure - ie, 
another cause of the event is most plausible; and/or a clinically plausible temporal sequence is 
inconsistent with the onset of the event and the study intervention and/or a causal relationship is 
considered biologically implausible.
For events assessed as not related or unlikely related and occurring within 14 weeks after the IP 
administration, the investigator shall provide the alternative etiology. These causality definitions 
will also be used to assess the relationship of an AE with a study-related procedure(s), if 
necessary.
11.2 Urgent Safety Measures
An urgent safety measure is an immediate action taken, which is not defined by the protocol, in 
order to protect subjects participating in a clinical trial from immediate harm. 
For 
vent
Fo
vent
non-commercial
event 
ial 
event 
ristics o
ercia
ristics o
follows
mm
follows
n follow
com
n follow
could 
on-c
could 
use 
rat
e
rat
pected
use
pected
u
only.
ional ag
nly
ional ag
tion o
on
tion o

Takeda
CONFIDENTIAL
Page 71
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
Urgent safety measures may be taken by the sponsor or clinical investigator, and may include 
any of the following: 
1.
Immediate change in study design or study procedures.
2.
Temporary or permanent halt of a given clinical trial or trials.
3.
Any other immediate action taken in order to protect clinical trial participants from 
immediate hazard to their health and safety.
The investigator may take appropriate urgent safety measures in order to protect subjects against 
any immediate hazard to their health or safety. The measures should be taken immediately and 
may be taken without prior authorization from the sponsor. In the event(s) of an apparent 
immediate hazard to the subject, the investigator will notify the sponsor immediately by phone 
and confirm notification to the sponsor in writing as soon as possible, but within 1 calendar day
after the change is implemented. The sponsor will also ensure the responsible EC and relevant 
competent authority(s) are notified of the urgent safety measures taken in such cases according to 
local regulations.
11.3 Untoward Medical Occurrences
Untoward medical occurrences occurring before the first exposure to IP are not considered AEs 
(according to the definition of AE, see Section 11.1). However, each serious untoward medical 
occurrence experienced before the first IP exposure (ie, from the time of signed informed 
consent up to but not including the first IP exposure) will be described on the AE eCRF and on 
the SAE Report Form. These events will not be considered as SAEs and will not be included in 
the analysis of SAEs.
For the purposes of this study, each non-serious untoward medical occurrence experienced by a 
subject undergoing study-related procedure(s) before the first IP exposure will be recorded on 
the AE eCRF; these events will not be considered as AEs and will not be included in the analysis 
of AEs.
For the purposes of this study, each of the following non-serious events experienced after the 
first IP exposure will not be considered an AE, and thus, not included in the analysis of AEs:

Hospital or study site visits for administration of BAX 888.

Hospitalization for routine bleeding episode management that could be managed in the 
study site or home-setting but for which the subject was hospitalized.

Hospitalizations for planned medical or surgical procedures, eg, placement of a central 
venous line.

Hospitalization or prolongation of hospitalization intended only for social reasons.
For 
y
F
y, ea
Fo
, ea
n-commercial 
the firs
rcia
the firs
n
m
n 11.1
mer
11.1)
r
)
exposu
mm
exposu
t IP exp
com
t IP exp
non
s will n
on-c
s will n
use only.
s take
ly.
s take

Takeda
CONFIDENTIAL
Page 72
BAX 888
201501 Protocol Amendment 9
10 Nov 2021

Hospital admittance without inpatient hospitalization or emergency room visit/admittance 
in itself (although the event triggering the visit may be an SAE).

Seroconversion after documented HBV vaccination prior to or during the study period.

Bleeding episodes/hemophilia-related events: 
Bleeding episodes are part of the underlying disease and therefore are not AEs. 
If a bleeding episode was caused by an injury (eg, a fall), the injury would not be reported 
as an AE, unless it resulted in a medical finding other than a bleeding episode (eg, abrasion 
of skin; fractured tibia). Therefore, any hemophilia-related event (eg, hemarthrosis, 
bruising, hemorrhage) will not be reported as an AE, but these events will be recorded 
on the bleeding episode eCRF. However, hemophilia-related events meeting the criteria 
for seriousness (eg, a gastrointestinal hemorrhage requiring hospitalization) will be 
reported as SAEs and described on the SAER form.
11.3.1 Pregnancies in Female Partners of Male Subjects
Male subjects will be instructed through the Informed Consent Form to immediately inform the 
investigator if their partner becomes pregnant during the study or within 6 months after infusion 
date. A Pregnancy Report eCRF should be completed by the investigator immediately (ie, no 
more than 24 hours after learning of the pregnancy) and submitted via the electronic data capture 
(EDC) system. Attempts should be made to collect and report details of the course and outcome 
of any pregnancy in the partner of a male subject exposed to BAX 888. The pregnant partner will 
need to sign an Authorization for Use and Disclosure of Pregnancy Health Information to allow 
for follow-up on her pregnancy. Once the authorization has been signed, the investigator will 
update the Pregnancy Report eCRF with additional information on the course and outcome of the 
pregnancy. An investigator who is contacted by the male subject or his pregnant partner may
provide information on the risks of the pregnancy and the possible effects on the fetus, 
to support an informed decision in cooperation with the treating physician and/or obstetrician. In 
the event that the EDC system is unavailable, follow reporting instructions provided for 
Congenital Anomalies/Birth Defects and Abortions. Any congenital anomaly/birth defect in a 
child born to a female partner of a male subject exposed to study drug should be classified as an 
SAE, recorded on the AE eCRF, and reported to the Sponsor immediately (ie, no more than 24 
hours after learning of the event). Any abortion performed in response to the identification of 
possible congenital anomaly/birth defect should be reported in the same fashion.
11.4 Non-Medical Complaints
A non-medical complaint (NMC) is any alleged product deficiency that relates to identity, 
quality, durability, reliability, safety and performance of the product but did not result in an 
AE. NMCs include but are not limited to the following:

A failure of a product to exhibit its expected pharmacological activity and/or design 
function, eg, reconstitution difficulty.
For
ks of
or 
ks of
F
sion in
Fo
sion in
mmercial
and r
ial 
and r
ct expo
erci
ct expo
isclosu
me
isclosu
non-com
e autho
omm
e autho
ith add
-co
ith add
s conta
non
s conta
f th
n
f th
use 
he in
e
he in
subm
use
subm
u
only.
orm
y
orm
y or with
only
y or with
inves
o
inves

Takeda
CONFIDENTIAL
Page 73
BAX 888
201501 Protocol Amendment 9
10 Nov 2021

Missing components.

Damage to the product or unit carton.

A mislabeled product (eg, potential counterfeiting/tampering).

A bacteriological, chemical, or physical change or deterioration of the product causing it to 
malfunction or to present a hazard or fail to meet label claims.
Any NMCs of the product will be documented on an NMC form and reported to the sponsor 
within 1 business day. If requested, defective product(s) will be returned to the sponsor for 
inspection and analysis according to procedures.
11.5 Medical, Medication, and Non-Drug Therapy History
At the Screen 1 visit, the subject’s medical history will be described for the following body
systems including severity (defined in Section 11.1.2.1) or surgery and start and end dates, if 
known: eyes, ears, nose, and throat; respiratory; cardiovascular; gastrointestinal; 
musculoskeletal; neurological; endocrine; hematopoietic/lymphatic; dermatological; and 
genitourinary. History will also include hemophilia history (confirmation of diagnosis and 
severity; presence of any target joints; historical ABR based on documented data within the 
previous 12 months) and documentation of all FVIII replacement therapies and other 
medications used within the last 12 months.
The historical ABR including treated and untreated bleeding episodes in the 12 months prior to 
study enrollment based on medical records should also be recorded in the eCRF.
Hospitalizations, exposure to mutagenic agents, recent malignancy(ies), recent incidence or 
exacerbation of a pre-existing neurologic disorder, recent incidence or exacerbation of a prior 
rheumatologic or other autoimmune disorder, and recent incidence of a hematologic disorder will 
be recorded from Month 5 up to study completion/discontinuation (see Table 2).
All medications taken and non-drug therapies received from 4 weeks before providing informed 
consent until completion/termination will be recorded on the concomitant medications and 
non-drug therapies eCRFs.
11.6 Physical Examinations
At the Screen 1 visit, a physical examination will be performed on all major organ systems (ie, 
general appearance, head and neck, eyes and ears, nose and throat, chest, lungs, heart, abdomen, 
extremities and joints, lymph nodes, skin, and neurological and others as indicated). At 
screening, if an abnormal condition is detected, the condition will be described on the medical 
history eCRF. 
For
mutag
or 
mutag
ng neu
Fo
ng neu
non-commercial 
R ba
al
R ba
VIII rep
rcia
VIII rep
nd untr
com
nd untr
ecords
n-c
ecords
ge
n
ge
use
ry
us
ry (co
se 
(co
y
us
y
ase
u
ase
only.
y a
y
r; gastro
nly.
r; gastr
mphatic
on
phatic

Takeda
CONFIDENTIAL
Page 74
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
At subsequent study visits (as described in Table 2), a targeted physical examination will be 
performed (ie, examination of the liver and skin, and otherwise driven by signs, symptoms, and 
complaints). At study visits, if a new abnormal or worsened abnormal pre-existing condition is 
detected, the condition will be described on the AE eCRF. If the abnormal value was not deemed 
an AE because it was due to an error, due to a preexisting disease (described in Section 11.1.1.5), 
not clinically significant, a symptom of a new/worsened condition already recorded as an AE, or 
due to another issue that will be specified, the investigator will record the justification on the 
source record.
Height (in or cm) and weight (lb. or kg) will be measured at the Screen 1 visit. Only weight (lb.
or kg) will be measured on Screen 2, Day 0, Month 12, Years 2 to 3 (Months 24, 36, 48, and 60), 
and at study completion/discontinuation.
11.7 Clinical Laboratory Parameters
Where applicable (see Section 14.7), assessments will be performed at a central laboratory, 
according to the laboratory manual. Blood samples that remain after study testing is done may be 
stored and used for additional testing. Samples will be destroyed after a maximum of 5 years 
from the time the final study report has been completed.
Details of blood sampling volumes are presented in the laboratory manual and master ICF.
The schedule for sample collection for laboratory analysis is described in Section 19.3.
11.7.1 Additional Sample Collection 
Backup samples taken and stored short-term may be used for example for re-testing, follow-up 
of an AE(s) or other test results, and/or assay development. After study testing is completed, the 
remaining samples may be stored in a coded form for no more than 5 years after the final study
report has been completed, and then the samples will be destroyed. 
If subjects provide consent, the samples may be made available for research or assay
development purposes, otherwise, samples will subsequently be destroyed.
11.7.2 Hematology, Coagulation, Clinical Chemistry, and Markers of Autoimmune 
Response
The hematology panel will consist of complete blood count (hemoglobin, hematocrit, 
erythrocytes [ie, red blood cell (RBC) count), and leukocytes [ie, white blood cell count]) with 
differential (ie, basophils, eosinophils, lymphocytes, monocytes, neutrophils), platelet counts, 
RBC distribution width, mean corpuscular volume, and mean corpuscular hemoglobin 
concentration. 
For
tored s
For 
tored s
lts
F
lts
non-commercial l
leted.
cial
leted.
nted in
me
nted in
labora
com
labora
ction
no
ction
use
main
se 
main
destro
us
destro
only.
formed 
only
formed 
n af
o
n af

Takeda
CONFIDENTIAL
Page 75
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
The coagulation studies will consist of PT, activated partial thromboplastin time, FVIII antigen, 
FVIII activity level (performed as one-stage assay and as chromogenic assay), FVIII Bethesda 
inhibitor, international normalized ratio, thrombin time, D-dimer, and fibrinogen activity.
The clinical chemistry panel will consist of sodium, potassium, chloride, carbon dioxide, blood 
urea nitrogen (BUN), creatinine, glucose, calcium, phosphate, magnesium, albumin, total 
protein, creatine kinase (CK), bilirubin (total & direct), ALT, AST, alkaline phosphatase, GGT, 
and lactate dehydrogenase (LDH).
The FibroSURE™ (Laboratory Corporation of America, Raritan, NJ, United States) will be 
measured at screening (Screen 1) and at Month 12.
Markers of autoimmune-mediated hepatitis will include ANA, total IgG, SMA, and anti-LKM1 
titers. Serum cytokines will also be measured.
Blood will be obtained for assessment of hematology and clinical chemistry parameters and 
markers of autoimmune response at the study visits presented in Table 3.
Hematology and clinical chemistry assessments will be performed on 
ethylenediamine-tetraacetic acid-anticoagulated whole blood and serum, respectively, at the 
central laboratory. The FVIII activity assay will be performed at both local and central 
laboratories. ALT (liver transaminases) will be performed at local laboratories at time points 
specified in Table 3 (ie, Weeks 3-18).
11.7.3 Viral Serology
Viral serology testing will include HIV-1 and HIV-2 antibody, Hepatitis B core antibody, 
HBsAg, HCV antibody and HCV RNA. The HCV titer will be confirmed by PCR for all subjects 
reported as HCV positive. All assessments will be performed at the Screen 1 visit, except HIV-1 
and HIV-2 antibody which will be performed at the Screen 2 visit. HCV RNA will also be 
performed at Weeks 1 and 6, and at the Early Study Termination Visit. Any positive test in 
HBsAg will be repeated using a new blood sample.
11.7.4 Gene Mutation and HLA
Assessment of F8 gene mutations (FVIII genotyping) and human leukocyte antigen (HLA) 
genotype (MHC haplotype) will be performed at screening (Screen 1 and Screen 2 visits 
respectively).
F8 gene mutation will be performed at the University of Bonn and HLA genotype testing will be 
performed at Central laboratory.
For 
nclude 
For
nclude 
C
F
C
non-commercial
l be p
ial 
l be p
whole 
rcia
whole 
will be p
mer
will be p
will be p
omm
will be p
use
ted 
e 
ted 
per
u
per
only.
nical che
only
nical che
in
o
in T

Takeda
CONFIDENTIAL
Page 76
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
The results will be provided to the sites. The investigator will be responsible for informing the 
subject of the test results. If results for FVIII gene mutation analysis and HLA genotyping are 
already available at the study site, this information will be recorded in the eCRF. Nevertheless, 
the analyses will be performed for the study at the central laboratory regardless. 
11.7.5 Immunogenicity
The presence of binding antibodies to FVIII (anti-FVIII antibodies) and binding antibodies to 
FVIII transgene product (BDD-FVIII), binding and neutralizing antibodies to AAV8 and AAV2, 
and CMI response to AAV8 and FVIII transgene products based on an ELISPOT assay will be 
determined at the time points presented in Table 3.
Immunogenicity assessments for the proposed study will include:

Neutralizing Antibodies to AAV8 and AAV2: Study subjects will be screened and 
monitored for the presence of AAV8 (vector used in this study) specific neutralizing 
antibodies at a central facility using validated protocol. Subjects will also be monitored for 
binding and neutralizing antibodies against AAV2 that infects humans with high 
prevalence.

Binding antibodies to AAV8 will be assessed using validated enzyme linked-
immunosorbent assays (ELISAs) at a qualified laboratory. Binding antibodies to AAV2 
will be monitored using a ELISA-based validated assay.

CMI Assessment: The AAV8 and FVIII specific cell mediated immunity will be assessed 
using validated interferon-γ (IFN-γ) ELISPOT assays at screening and throughout the 
study period.

Binding antibodies to FVIII and BDD-FVIII will be determined using validated 
FVIII-specific ELISA assays. The assays will be performed at a qualified laboratory.

FVIII Inhibitor: Development of antibodies that inhibit FVIII activity (FVIII Inhibitors) 
will be measured at a central laboratory using validated clot-based assays following 
the Nijmegen modification. 
Immunogenicity values are to be recorded on the eCRF. For each value, the investigator will 
determine whether the value is considered an AE (see definition in Section 11.1 and 
Section 11.1.1.1, and record the sign, symptom, or medical diagnosis on the AE eCRF).
Additional tests and other evaluations required to establish the significance or etiology of an 
abnormal result, or to monitor the course of an AE should be obtained when clinically indicated. 
Any abnormal value that persists should be followed at the discretion of the investigator.
11.7.6 Vector Genomes
Serum and bodily secretions will be obtained at the time points presented in Table 3 to assess 
BAX 888 genomes until 2 consecutive measurements are negative.
For
VII
r
VII
assay
For
assays
r 
s
F
non-commercial
d usin
ial 
d usin
fied lab
rcia
fied lab
validat
merc
validat
FVIII s
omm
FVIII s
-γ
c
-γ)
co
) EL
com
EL
II an
no
II an
use 
e
ng
u
ng
only.
tudy
y.
tudy)
y.
)
y.
)
Subjects
nly
Subjects
infect
on
infect

Takeda
CONFIDENTIAL
Page 77
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
Quantitative PCR will be used to detect BAX 888 vector genomes in blood, saliva, urine, stool, 
and semen.
An infectious center assay is used as a quality control and part of the characterization of the 
stocks of the investigational product. No viral growth-based assay is used in the evaluation of the 
body fluids of the treated subject.
11.7.7 Assessment of Laboratory Values
The investigator’s assessment of each laboratory value will be recorded on the eCRF. For each 
abnormal laboratory value, the investigator will determine whether the value is considered 
clinically significant or not. For clinically significant values, the investigator will indicate if the 
value constitutes an new AE (see definition in Section 11.1, and record the sign, symptom, or 
medical diagnosis on the AE eCRF), is a symptom or related to a previously recorded AE, is due 
to a pre-existing disease (described in Section 11.1.1.5), or is due to another issue that will be 
specified. If the abnormal value was not clinically significant, the investigator will indicate the 
reason, ie, because it is due to a preexisting disease, due to a laboratory error, or due to another 
issue that will be specified. Additional tests and other evaluations required to establish the 
significance or etiology of an abnormal value, or to monitor the course of an AE should be 
obtained when clinically indicated. Any abnormal value that persists should be followed at the 
discretion of the investigator. 
11.8 Vital Signs and 12-Lead Electrocardiogram
Vital signs will include body temperature (°C or °F), respiratory rate (breaths/min), pulse rate 
(beats/min), and systolic and diastolic blood pressure (mmHg).
Vital signs will be measured at Screen 2, on Day 0 up to 3 hours before administration of IP and 
5, 15, 30 minutes, 1, 2, 3, 4, 6, and 8 hours after administration of IP, at each subsequent study
visit, and at study completion/discontinuation. Blood pressure will be measured when subjects 
are in the supine position.
Vital sign and 12-lead ECG values are to be recorded on the eCRF. For each value, the 
investigator will determine whether the value is considered an AE (see definition in 
Section 11.1) and record the sign, symptom, or medical diagnosis on the AE eCRF. Additional 
tests and other evaluations required to establish the significance or etiology of an abnormal 
result, or to monitor the course of an AE should be obtained when clinically indicated. Any
abnormal value that persists should be followed at the discretion of the investigator.
For
diasto
or 
diasto
non-commercial
moni
ial 
moni
al valu
ercia
al valu
ocardio
com
ocardio
peratur
non
peratur
oli
n
oli
use 
a l
e
a l
valuati
use
valuati
ito
u
ito
only.
to 
the inve
nly
the inv
labora
on
labora

Takeda
CONFIDENTIAL
Page 78
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
11.9 Hemophilia Joint Health Score
The Hemophilia Joint Health Score (HJHS) measures the health of joints most 
commonly affected by bleeding in hemophilia (ie, the knees, ankles, and elbows) 
(Feldman et al., 2011). The HJHS will be measured on Day 0, Months 12, 24, 36, 48, and 
60 post-gene transfer, and at study termination/discontinuation visit.
11.10 Patient Reported Outcomes
Patient reported outcomes, based on relevant questionnaires, will be captured in electronic 
diaries (see Section 9.5) at the time points presented in Table 2.
The PRO instruments to be measured in this study are described below:
PRO
Assessment
Time of Measurement
HRQoL
Generic: SF-36v2, EQ-5D
Disease-specific: Haemo-QoL-A
Screen 2, Months 6, 12, 24, 36, 48, and 60
Patient Experience
Adherence: VERITAS-Pro
Disease-specific: HaemoPREF
Screen 2 
11.11 Evaluation of Liver Health
Abdominal ultrasound examination will be performed locally at the timepoints presented in 
Table 2 to assess liver health. In addition, and at the discretion of the Investigator serum alpha 
fetoprotein level, an exploratory biomarker for hepatocellular carcinoma, will be measured at 
local laboratories at the time points specified in Table 3.
11.12 Exploratory Assays
Exploratory evaluations of the AAV2 binding and neutralizing antibodies, transcriptome and 
metabolome as well as whole genome sequencing (if subjects provide additional consent) will be 
performed to explore the underlying immunologic and other patient-specific features that may
affect the transduction and gene delivery by the gene therapy vector (including polymorphisms 
in immune regulatory genes), the expression and circulation of FVIII, and the changes of the 
subject’s expression of immune-related and other genes before and after gene delivery
(T-lymphocyte profiling; transcriptome and genome analysis). These studies will seek to increase 
the understanding of the variability in gene expression that exists between individuals with 
hemophilia treated with gene therapy.
For 
oint
r
oint
n-commercial l
be perfo
omm
be perfo
ion,
c
ion,
no
an
co
an
iomark
on
iomark
ts sp
no
ts sp
use
Scr
se 
Scr
us
only.
een 2, M
ly.
een 2, M
ree
o
ree
o

Takeda
CONFIDENTIAL
Page 79
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
11.13 Assessment of Pharmacodynamics
The pharmacodynamic activity of BAX 888 will be evaluated using the following assessments:

FVIII activity level (central laboratory one-stage clotting assay) and FVIII antigen 
(protein) levels in plasma.

Antibodies to FVIII and FVIII transgene product.

Neutralizing antibodies against AAV8 

CMI response to AAV8 and FVIII transgene product.
Graphical displays over time may be used. Pharmacokinetic and pharmacodynamic analyses and 
modeling may be conducted to assess the time course of FVIII and potential factors affecting the 
time course of FVIII. This optional work may be reported separately. Analyses and modeling 
may include, but are not limited to, FVIII activity, FVIII antigen concentration, clinical 
chemistry values, vector shedding values, subject demographics, antibody titers, concomitant 
drug use, clinical measures of effect, AEs etc. 
For non-commercial use only.
, antib
ly.
, antib

Takeda
CONFIDENTIAL
Page 80
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
12. STATISTICS
All details regarding the statistical analysis and the preparation of tables, listings, and figures will 
be described in the statistical analysis plan (SAP).
12.1 Sample Size and Power Calculations
The sample size is expected to range from 2 to 12 evaluable subjects depending on the actual 
number of cohorts and the actual number of subjects in each cohort. This sample size was chosen 
to provide sufficient evidence of safety and exploration of signs of efficacy for this indication 
and is not based on formal statistical considerations. The sample size and escalation plan are 
designed to minimize the risk to subjects of experiencing significant toxicity or receiving a 
sub-therapeutic dose. If a given dose shows lack of efficacy, enrollment will be limited to 
2 subjects in the cohort.
With the limited number of subjects per group, statistical analyses will be primarily conducted in 
a descriptive fashion. There are no inferential procedures planned.
12.2 Analysis Sets
Classification into the Safety Analysis Set will be conducted prior to database lock. The Safety
Analysis Set will consist of all subjects that have received 1 administration of the IP. All safety 
analyses (including the primary analysis) will be performed on the Safety Analysis Set.
12.3 Handling of Missing, Unused, and Spurious Data
Since the statistical analyses will be presented in descriptive summary tables and individual data 
listings, no action will be taken to handle missing data. All data will be evaluated as observed; no 
imputation method for missing values will be used. A subject who withdraws prior to the last 
planned observation in a trial period will be included in the analyses up to the time of 
withdrawal.
12.4 Methods of Analysis
In general, descriptive summaries will be presented for the primary, secondary, and tertiary
outcome measures. Continuous variables will be summarized using mean, standard deviation 
(SD), maximum, minimum, median, and other percentiles as appropriate. Categorical variables 
will be summarized using frequency counts and percentages. Analyses will be performed within 
each cohort separately and overall. The primary outcome of the incidence of BAX 888-related 
AEs will be analyzed as a categorical variable. More detailed information about summarization 
of data, graphical representations, and analysis conventions will be provided in the SAP.
For
will b
For 
will b
ken t
Fo
ken t
non-commercial 
be cond
erci
be cond
have re
mme
have re
) will b
om
) will b
d, and
on
d, and
n
use 
a
e
a
only.
yses wil
nly.
yses wi
nned.
on
nned.

Takeda
CONFIDENTIAL
Page 81
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
12.4.1 Primary Outcome Measure
The number and proportion of subjects experiencing product-related AEs (seriousness and as 
well as severity) occurring up to 5 years after the BAX 888 administration will be summarized 
by cohort and overall. 
In support of the primary outcome measure, a similar display will be presented by cohort and 
overall for all AEs (seriousness and severity) occurring up to 5 years after the BAX 888 
administration. 
An exploratory, descriptive analysis will also be performed for events categorized as 
development of inhibitory antibodies to FVIII and total binding antibodies to FVIII, severe 
allergic reactions, and thrombosis-associated events.
12.4.2 Secondary Outcome Measures
12.4.2.1 Efficacy
The secondary efficacy outcome measures (see Section 7.4.2.1) will be assessed using 
descriptive summaries appropriate for the measure (eg, number and percent for categorical 
measures and mean, SD, median, minimum, and maximum for continuous measures). For each 
measure, baseline is the last non-missing reported prior to the infusion of study product.
The change from baseline to each scheduled assessment for FVIII activity level (based on values 
obtained from the central laboratory one-stage clotting assay) and antigen levels will be 
summarized for each cohort. The historical ABR as well as the number of post-BAX 888 bleeds, 
12 months post-infusion, and 5 years post-infusion will be reported separately for each cohort. 
The proportion of subjects with a reduction in exogenous FVIII consumption 12 months 
post-infusion and 5 years post-infusion compared to the historical consumption will be tabulated 
by cohort.
12.4.2.2 Safety
The secondary safety outcome measures (see Section 7.4.2.2) will be assessed using descriptive 
summaries appropriate for the measure (eg, number and percent for categorical measures and 
mean, SD, median, minimum, and maximum for continuous measures).
The number and proportion of subjects will be summarized by cohort for developing the 
following occurrences at each scheduled assessment: inhibitory antibodies to FVIII (Nijmegen
assay) and total binding antibodies to FVIII (IgG and IgM).
or 
ye
r
ye
Fo
with a r
For
with a r
i
F
i
n-commercial
aximu
ial 
aximu
ed prio
ercia
ed prio
ed asse
mm
ed asse
non
ne-
c
ne-stag
com
stag
istorica
on-
istorica
n
ars p
no
ars p
use 
2.
e
2.
numb
use
numb
u
only.
1
o
1)
o
) w
o
w

Takeda
CONFIDENTIAL
Page 82
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
12.4.3 Tertiary Outcome Measures 
The tertiary efficacy outcome measures (see Section 7.4.3) will be assessed using descriptive 
summaries appropriate for the measure (eg, number and percent for categorical measures and 
mean, SD, median, minimum, and maximum for continuous measures).
The HRQoL assessments will be characterized descriptively by cohort for the lead-in period and 
at the scheduled post-transfusion assessment. 
12.5 Planned Interim Analysis of the Study
No formal interim analysis is planned. In addition to a safety data review by the DMC, additional 
analyses on efficacy and safety data may be performed by the Sponsor at study milestones (eg, 
when the initial two subjects in the first cohort finishes the Week 18 visit), or otherwise up to 
2 times every year for the duration of the study. Analyses due to different trigger points may be 
waived or combined for efficiency.
For non-commercial use only.

Takeda
CONFIDENTIAL
Page 83
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
13. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS
The investigator/study site will cooperate and provide direct access to study documents and data, 
including source documentation for monitoring by the study monitor, audits by the sponsor or 
sponsor’s representatives, review by the EC, and inspections by applicable regulatory authorities, 
as described in the Clinical Study Agreement. If contacted by an applicable regulatory authority, 
the investigator will notify the sponsor of contact, cooperate with the authority, provide the 
sponsor with copies of all documents received from the authority, and allow the sponsor to 
comment on any responses, as described in the Clinical Study Agreement.
For non-commercial use only.

Takeda
CONFIDENTIAL
Page 84
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
14. QUALITY CONTROL AND QUALITY ASSURANCE
14.1 Investigator’s Responsibility
The investigator will comply with the protocol (which has been approved/given favorable 
opinion by the EC), ICH GCP, and applicable regulatory requirements as described in the 
Clinical Study Agreement. The investigator is ultimately responsible for the conduct of all 
aspects of the study at the study site and verifies by signature the integrity of all data transmitted 
to the sponsor. The term “investigator” as used in this protocol as well as in other study
documents, refers to the investigator or authorized study personnel that the investigator has 
designated to perform certain duties. Sub-investigators or other authorized study personnel are 
eligible to sign for the investigator, except where the investigator’s signature is specifically
required.
14.1.1 Final Clinical Study Report 
All investigators, or the coordinating investigator for multicenter studies, will sign the clinical 
study report. The coordinating investigator will be selected before study start.
14.2 Training
The study monitor will ensure that the investigator and study site personnel understand all 
requirements of the protocol, the investigational status of the IP, and his/her regulatory
responsibilities as an investigator. Training may be provided at an investigator’s meeting, at the 
study site, and/or by instruction manuals. In addition, the study monitor will be available for 
consultation with the investigator and will serve as the liaison between the study site and the 
sponsor.
14.3 Monitoring
The study monitor is responsible for ensuring and verifying that each study site conducts the 
study according to the protocol, standard operating procedures, other written 
instructions/agreements, ICH GCP, and applicable regulatory guidelines/requirements. The 
investigator will permit the study monitor to visit the study site at appropriate intervals, as 
described in the Clinical Study Agreement. Monitoring processes specific to the study will be 
described in the clinical monitoring plan.
14.4 Auditing
The sponsor and/or sponsor’s representatives may conduct audits to evaluate study conduct and 
compliance with the protocol, standard operating procedures, other written 
instructions/agreements, ICH GCP, and applicable regulatory guidelines/requirements. 
For 
o
ommercial 
gator an
merc
gator an
tional s
mm
tional s
on-co
ning m
com
ning m
nuals. I
on-c
nuals. I
n
and w
no
and w
use
d bef
se 
d bef
only.
nter stu
only
nter stu
fore
o
fore

Takeda
CONFIDENTIAL
Page 85
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
The investigator will permit auditors to visit the study site, as described in the Clinical Study
Agreement. Auditing processes specific to the study will be described in the audit plan.
14.5 Safety Monitoring
This study will be monitored by a DMC. The DMC is a group of individuals with pertinent 
expertise that reviews on a regular basis accumulating data from an ongoing clinical study. For 
this study, the DMC will be composed of recognized experts in the field of hemophilia clinical 
care and research who are not actively recruiting subjects. The DMC can stop a trial if it finds 
toxicities or if treatment is proven to be not beneficial.
If any one of the following criteria (Cancer Therapy Evaluation Program 2009) is met, further 
enrollment will be halted until an independent DMC evaluates all available study data and makes 
a recommendation:
1.
Any severe or life threatening AE.
2.
Any moderate AE that does not resolve within 14 days.
3.
ALT or AST >3 × upper ULN, repeated and confirmed within 72 hours.
4.
Development of FVIII inhibitor.
14.6 Non-Compliance with the Protocol
The investigator may deviate from the protocol only to eliminate an apparent immediate hazard 
to the subject. In the event(s) of an apparent immediate hazard to the subject, the investigator 
will notify the sponsor immediately by phone and confirm notification to the sponsor in writing 
as soon as possible, but within 1 calendar day after the change is implemented. The sponsor 
(Takeda) will also ensure the responsible EC is notified of the urgent measures taken in such 
cases according to local regulations.
If monitoring and/or auditing identify serious and/or persistent non-compliance with the 
protocol, the sponsor may terminate the investigator’s participation. The sponsor will notify the 
EC and applicable regulatory authorities of any investigator termination.
14.7 Laboratory and Reader Standardization
Not applicable, a central laboratory will be used for all clinical laboratory assessments.
For
n 1 ca
For 
n 1 ca
e resp
Fo
e resp
non-commercial 
protoco
com
protoco
pparen
n-c
pparen
ely
n
ly by
non
 by
y
n
y y
p
n
p
y
n
y
l
n
l
use 
s
rmed 
use
rmed 
only.

Takeda
CONFIDENTIAL
Page 86
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
15. ETHICS
15.1 Subject Privacy
The investigator will comply with applicable subject privacy regulations/guidance as described 
in the Clinical Study Agreement.
15.2 Ethics Committee and Regulatory Authorities
Before subjects participate in this study, the protocol, ICF, any promotional 
material/advertisements, and any other written information provided will be reviewed and 
approved/given favorable opinion by the EC and applicable regulatory authorities. The IB will be 
provided for review. The EC’s composition or a statement that the EC’s composition meets 
applicable regulatory criteria will be documented. The study will commence only upon the 
sponsor’s receipt of approval/favorable opinion from the EC and, if required, upon the sponsor’s 
notification of applicable regulatory authority(s) approval, as described in the Clinical Study
Agreement. 
If the protocol or other information that is given to the subject is amended, the revised 
documents will be reviewed and approved/given favorable opinion by the EC and applicable 
regulatory authorities, where applicable. The protocol amendment will only be implemented 
upon the sponsor’s receipt of approval and, if required, upon the sponsor’s notification of 
applicable regulatory authority(s) approval.
15.3 Informed Consent
Investigators will choose subjects for participation considering the study eligibility criteria. The 
investigator will exercise no selectivity so that no bias is introduced from this source. 
All subjects must sign an ICF before entering into the study according to applicable regulatory
requirements and ICH GCP. Before use, the ICF will be reviewed by the sponsor and approved 
by the EC and regulatory authority(s), where applicable (see Section 15.2). The ICF will include 
a comprehensive explanation of the proposed treatment without any exculpatory statements, in 
accordance with the elements required by ICH GCP and applicable regulatory requirements. 
Subjects will be allowed sufficient time to consider participation in the study. By signing the 
ICF, subjects agree that they will complete all evaluations required by the study, unless they
withdraw voluntarily or are terminated from the study for any reason.
The sponsor will provide to the investigator in written form any new information that
significantly bears on the subjects’ risks associated with IP exposure. The informed consent will 
be updated, if necessary. 
For
bjects f
For 
bjects f
sel
F
sel
non-commercial
e s
l
e s
favorab
cial 
favorab
rotocol
merc
rotocol
 if requ
mme
 if requ
val.
com
val.
use 
ubje
us
ubje
only.
escribe
nly.
escribe

Takeda
CONFIDENTIAL
Page 87
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
This new information and/or revised ICF, which have been approved by the applicable EC and 
regulatory authorities, where applicable, will be provided by the investigator to the subjects who 
consented to participate in the study.
15.4 Data Monitoring Committee
An external DMC consisting of recognized medical experts in the fields of Hematology, 
Hepatology, Clinical Immunology, and Gene Therapy as well as one biostatistician will be 
utilized in this study. This group of individuals with pertinent expertise and who are not active 
investigators of the current study will review accumulating data on a regular basis. To ensure 
proper communication between the DMC, study team, ethics committees, and IRBs, procedures 
will be implemented to provide an exchange of information among the various parties who share 
responsibility for the successful conduct of the study. Following each DMC meeting, the DMC 
recommendations will be communicated to Investigators. Specifically, DMC recommendations 
regarding study continuation with or without modification, dose escalation, and any relevant 
summary safety information the DMC chair assess as appropriate to include to support the 
DMC’s recommendations will be communicated to Investigators. Questions from Investigators 
regarding DMC decisions and any responses from the Sponsor regarding DMC-related issues 
will be communicated to the DMC Chair to ensure that the intent of the DMC is correctly 
understood by all parties.
For 
ial 
e Sp
al
e Sp
non-commerci
e that t
cia
e that t
use
tigato
se 
tigato
pon
us
pon
only.
e escal
ly.
e escal
riate to
on y
riate to

Takeda
CONFIDENTIAL
Page 88
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
16. DATA HANDLING AND RECORD KEEPING
16.1 Confidentiality Policy
The investigator will comply with the confidentiality policy as described in the Clinical Study
Agreement. 
16.2 Study Documentation and Case Report Forms
The investigator will maintain complete and accurate paper format study documentation in a 
separate file. Study documentation may include information defined as “source data” (see 
Section 7.8), records detailing the progress of the study for each subject, signed ICFs, 
correspondence with the EC and the study monitor/sponsor, screening information, eCRFs, 
SAERs, laboratory reports (if applicable), and data clarifications requested by the sponsor. 
The investigator will comply with the procedures for data recording and reporting. Any 
corrections to paper study documentation must be performed as follows: 1) the first entry will be 
crossed out entirely, remaining legible; and 2) each correction must be dated and initialed by the 
person correcting the entry; the use of correction fluid and erasing are prohibited.
The investigator is responsible for the procurement of data and for the quality of data recorded 
on the eCRFs. Case report forms will be provided in electronic form. 
If eCRFs are provided by the sponsor, only authorized study site personnel will record or change 
data on the eCRFs. If data is not entered on the eCRFs during the study visit, the data will be 
recorded on paper, and this documentation will be considered source documentation. Changes to 
an eCRF will require documentation of the reason for each change. An identical 
(electronic/paper) version of the complete set of CRFs for each subject will remain in the 
investigator file at the study site in accordance with the data retention policy (see Section 16.3).
The handling of data by the sponsor, including data quality assurance, will comply with 
regulatory guidelines (eg, ICH GCP) and the standard operating procedures of the sponsor. Data 
management and control processes specific to the study will be described in the data 
management plan. 
16.3 Document and Data Retention 
The investigator will retain study documentation and data (paper and electronic forms) in 
accordance with applicable regulatory requirements and the document and data retention policy, 
as described in the Clinical Study Agreement.
For 
cum
r
cum
entatio
For
entatio
h
F
h
non-commercial 
d a
l
d a
ment of 
erci
ment of 
vided i
me
vided i
only a
co
only a
ntered o
on-
ntered o
menta
no
menta
use
tion 
se 
tion 
nd er
us
nd er
only.
ding a
ly.
ding a
as follo
only
as follo
mu
o
mu

Takeda
CONFIDENTIAL
Page 89
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
17. FINANCING AND INSURANCE
The investigator will comply with investigator financing, investigator/sponsor insurance, and 
subject compensation policies, if applicable, as described in the Clinical Study Agreement.
For non-commercial use only.

Takeda
CONFIDENTIAL
Page 90
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
18. PUBLICATION POLICY
The investigator will comply with the publication policy as described in the Clinical Study
Agreement.
For non-commercial use only.

For non-commercial use only.

For non-commercial use only.

Takeda
CONFIDENTIAL
Page 93
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
19.2 Schedule of Study Procedures and Assessments
Table 2. Schedule of Study Procedures and Assessments
Procedures/
Assessments
Screening Visits
Study Visits 
Screen 1
Screen 2
Day 0a
(BAX 
888 
Dose)
Day 1 Weeks 1-2
Once 
Weekly 
Visits
(Clinic 
Visits only)
Weeks 3-14
Twice Weekly 
Visits
(Clinic Visit 
and Laboratory 
Visit)s
Week 15-18
Once Weekly 
Visits
(Clinic Visits 
only)
Months 
5, 6, 9, 12
Years 2-3
(Months 
16, 20, 24, 
28, 32, 36)
Years 4-5
(Months 48 
and 60
Early Study 
Termination
Visitb
Window
Screen 1u to 
occur <180 
days 
(±7 days) 
prior to the 
Screen 2 Visit 
AND ≥5 days 
after last 
FVIII dose
Screen 2v,
to occur 
≤70 days 
of Day 0
N/A
N/A
±1 day
±1 day for 
Clinic Visit
Laboratory 
Visit to occur 
3-4 days after 
that week’s 
Clinic Visit
±1 day
±4 days
±7 days
±30 days
Visit Numbers
1
2
3
4
5 - 6
7 - 30
31 - 34
35 - 38
39 - 44
45-46
NA
Informed Consent
Xc, q
Xr
Xd
Eligibility Criteria
X
X
Medical Historye
X
X
X
X
X
X
X
X
X
X
Physical Exam
Xf
Months 24g
& 36g
X
Xg
Targeted Physical 
Examh
Xg
Xg
X
X
Xt
X
Xg
Vital Signs
X
Xi
X
X
Xt
X
X
X
X
X
12-lead ECG
X
Xj
Laboratory 
Assessmentsk
X
X
X
X
X
X
X
X
X
X
X
BAX 888 
Administration
Xl
Bleeding Episodes
X
X
X
X
Xt
X
X
X
X
X
For r
or non-commercial 
ek’s
al
ek’s
ic Visit
cia
ic Visit
m
om
om
om
om
om
c
X
o
X
on
n
use 
er 
u
er 
us
only.
day
ly
day

Takeda
CONFIDENTIAL
Page 94
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
Table 2. Schedule of Study Procedures and Assessments
Procedures/
Assessments
Screening Visits
Study Visits 
Screen 1
Screen 2
Day 0a
(BAX 
888 
Dose)
Day 1 Weeks 1-2
Once 
Weekly 
Visits
(Clinic 
Visits only)
Weeks 3-14
Twice Weekly 
Visits
(Clinic Visit 
and Laboratory 
Visit)s
Week 15-18
Once Weekly 
Visits
(Clinic Visits 
only)
Months 
5, 6, 9, 12
Years 2-3
(Months 
16, 20, 24, 
28, 32, 36)
Years 4-5
(Months 48 
and 60
Early Study 
Termination
Visitb
Window
Screen 1u to 
occur <180 
days 
(±7 days) 
prior to the 
Screen 2 Visit 
AND ≥5 days 
after last 
FVIII dose
Screen 2v,
to occur 
≤70 days 
of Day 0
N/A
N/A
±1 day
±1 day for 
Clinic Visit
Laboratory 
Visit to occur 
3-4 days after 
that week’s 
Clinic Visit
±1 day
±4 days
±7 days
±30 days
Visit Numbers
1
2
3
4
5 - 6
7 - 30
31 - 34
35 - 38
39 - 44
45-46
NA
Concomitant 
Medications 
(including FVIII)
X
X
X
X
Xt
X
X
X
X
X
Distribute /collect/ 
review diarym
X
X
X
X
Xt
X
X
X
X
X
AEs
X
X
X
X
Xt
X
X
X
X
X
Review Subject’s 
Recent Physical 
Activityn
X
X
X
Xt
X
X
X
X
X
Unscheduled Visito
X
X
X
Hemophilia Joint 
Health Score
X
Month 
12
Months 
24 & 36
X
X
PROs:p
HRQoL:
SF-36v2
EQ-5D
Haemo-QoL-A
X
Months 
6 & 12
(with 
exclusion 
of 
Months 
24 & 36
(with 
exclusion of 
VERITAS-
X
(with 
exclusion of 
VERITAS-
Pro and 
X
(with 
exclusion of 
VERITAS-Pro 
or
X
or
X
r r
For
or
X
Fo
X
For
or
or non-commercial 
7 
e
7 -
rc
- 30
rc
30
cia
X
e
X
e
om
X
n
X
co
no
no
use 
us
only.

Takeda
CONFIDENTIAL
Page 95
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
Table 2. Schedule of Study Procedures and Assessments
Procedures/
Assessments
Screening Visits
Study Visits 
Screen 1
Screen 2
Day 0a
(BAX 
888 
Dose)
Day 1 Weeks 1-2
Once 
Weekly 
Visits
(Clinic 
Visits only)
Weeks 3-14
Twice Weekly 
Visits
(Clinic Visit 
and Laboratory 
Visit)s
Week 15-18
Once Weekly 
Visits
(Clinic Visits 
only)
Months 
5, 6, 9, 12
Years 2-3
(Months 
16, 20, 24, 
28, 32, 36)
Years 4-5
(Months 48 
and 60
Early Study 
Termination
Visitb
Window
Screen 1u to 
occur <180 
days 
(±7 days) 
prior to the 
Screen 2 Visit 
AND ≥5 days 
after last 
FVIII dose
Screen 2v,
to occur 
≤70 days 
of Day 0
N/A
N/A
±1 day
±1 day for 
Clinic Visit
Laboratory 
Visit to occur 
3-4 days after 
that week’s 
Clinic Visit
±1 day
±4 days
±7 days
±30 days
Visit Numbers
1
2
3
4
5 - 6
7 - 30
31 - 34
35 - 38
39 - 44
45-46
NA
Patient 
Experience
Validated 
Hemophilia 
Regimen 
Treatment 
Adherence 
Scale –
Prophylaxis 
(VERITAS-
Pro)
Disease-
specific patient 
experience 
(HaemoPREF)
VERITAS-
Pro and 
HaemoPR
EF)
Pro and 
HaemoPREF)
HaemoPREF
)
and 
HaemoPREF)
Abdominal 
ultrasound to 
assess liver 
healthw
X
Month 12
Months 24 
and 36
X
For 
or non-commercial 
7 
e
7 -
rc
- 30
rc
30
cia
e
om
use 
us
only.

Takeda
CONFIDENTIAL
Page 96
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
Table 2. Schedule of Study Procedures and Assessments
Procedures/
Assessments
Screening Visits
Study Visits 
Screen 1
Screen 2
Day 0a
(BAX 
888 
Dose)
Day 1 Weeks 1-2
Once 
Weekly 
Visits
(Clinic 
Visits only)
Weeks 3-14
Twice Weekly 
Visits
(Clinic Visit 
and Laboratory 
Visit)s
Week 15-18
Once Weekly 
Visits
(Clinic Visits 
only)
Months 
5, 6, 9, 12
Years 2-3
(Months 
16, 20, 24, 
28, 32, 36)
Years 4-5
(Months 48 
and 60
Early Study 
Termination
Visitb
Window
Screen 1u to 
occur <180 
days 
(±7 days) 
prior to the 
Screen 2 Visit 
AND ≥5 days 
after last 
FVIII dose
Screen 2v,
to occur 
≤70 days 
of Day 0
N/A
N/A
±1 day
±1 day for 
Clinic Visit
Laboratory 
Visit to occur 
3-4 days after 
that week’s 
Clinic Visit
±1 day
±4 days
±7 days
±30 days
Visit Numbers
1
2
3
4
5 - 6
7 - 30
31 - 34
35 - 38
39 - 44
45-46
NA
a.
Subjects will be monitored for the first 8 hours. Following the 8-hour evaluation, at the discretion of the Investigator, the subject and may remain in the 
infusion center for 24 hours following BAX 888 infusion or return to the center for follow-up at 24 hours post-infusion (Day 1 Study Visit).
b.
Includes for cases of withdrawn or discontinuation.
c.
Occurs prior to any study-specific procedure.
d.
An additional separate consent to be obtained if the infusion center is not the subject’s Hemophilia Treatment Center/local investigator’s institution.
e.
Medical history to include hospitalizations, new malignancy(ies), new incidence or exacerbation of a pre-existing neurologic disorder, new incidence or 
exacerbation of a prior rheumatologic or other autoimmune disorder, new incidence of hematologic disorder, or any other new chronic medical conditions. 
Screen 1 Visit Medical history to also include hemophilia history (confirmation of diagnosis & severity; presence of any target joints; historical ABR 
based on documented data within the last 12 months), documentation of all FVIII replacement therapies used within the last 12 months and other 
medications, hospitalizations within the last 12 months, and surgeries over entire lifetime.
f.
Includes height and weight.
g.
Includes weight (Screen 2, Day 0, Months 12, 24, 36, 48, and 60).
h.
Targeted physical exam includes examination of the liver, skin, and other organ systems as driven by signs, symptoms, and complaints.
i.
Time points for Day 0 Vital Signs: (a) pre-infusion: up to 3 hours prior to BAX 888 infusion, and (b) post-infusion: 5 mins (±5 mins), 15 mins (±5 mins), 
30 mins (±5 mins), 1 hour (±10 mins), 2 hours (±10 mins), 3 hours (±10 mins), 4 hours (±10 mins), 6 hours (±15 mins), and 8 hours (±15 mins)
j.
Time points for Day 0 ECGs: (a) pre-infusion: up to 3 hours prior to BAX 888 infusion, and (b) post-infusion: 1 hour (±10 mins), 6 hours (±15 mins)
k.
For laboratory assessments, see Table 3.
l.
BAX 888 dose to be determined based on subject’s weight obtained at Screen 2 visit.
For
mmune
or 
mmune
ophilia
For
ophilia
s) d
F
s) d
ercial 
7 
e
7 -
rc
- 30
rc
30
cia
on-comme
evaluati
me
evaluati
to the ce
mm
to the ce
on cente
on
on cente
n
ncy(ies
no
ncy(ies
e d
n
e d
e
use 
us
only.

Takeda
CONFIDENTIAL
Page 97
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
Table 2. Schedule of Study Procedures and Assessments
Procedures/
Assessments
Screening Visits
Study Visits 
Screen 1
Screen 2
Day 0a
(BAX 
888 
Dose)
Day 1 Weeks 1-2
Once 
Weekly 
Visits
(Clinic 
Visits only)
Weeks 3-14
Twice Weekly 
Visits
(Clinic Visit 
and Laboratory 
Visit)s
Week 15-18
Once Weekly 
Visits
(Clinic Visits 
only)
Months 
5, 6, 9, 12
Years 2-3
(Months 
16, 20, 24, 
28, 32, 36)
Years 4-5
(Months 48 
and 60
Early Study 
Termination
Visitb
Window
Screen 1u to 
occur <180 
days 
(±7 days) 
prior to the 
Screen 2 Visit 
AND ≥5 days 
after last 
FVIII dose
Screen 2v,
to occur 
≤70 days 
of Day 0
N/A
N/A
±1 day
±1 day for 
Clinic Visit
Laboratory 
Visit to occur 
3-4 days after 
that week’s 
Clinic Visit
±1 day
±4 days
±7 days
±30 days
Visit Numbers
1
2
3
4
5 - 6
7 - 30
31 - 34
35 - 38
39 - 44
45-46
NA
m. Subject electronic diaries (e-diaries) to capture data including concomitant medications, FVIII consumption, bleeding episodes, untoward events, and 
physical activity related to a bleeding episode. To be reviewed by sites at each visit through Week 4 visit, every 2 weeks thereafter through Month 12 
visit, once every month during Years 2-3, and then once every year during Years 4-5.
n.
Capture the nature and duration of physical activity performed with 48 hours of study visit. 
o.
Unscheduled visit(s) encompassing FVIII laboratory assessments to be performed if after Week 18, a >50% decrease in FVIII activity level is observed 
from the previous visit. Weekly visits to continue until stabilization of FVIII activity levels over 3 weeks. 
p.
See Section 11.10.
q.
Screen 1 Visit ICF: Encompasses all procedures and assessments to be completed at Screen 1 Visit only.
r.
Screen 2 Visit ICF: Encompasses all procedures and assessments to be completed at Screen 2 and all subsequent Study Visits.
s.
Between Weeks 3-14, subjects will attend twice weekly study visits: (1) Weekly Clinic Visit for all specified procedures and complete assessments and
(2) Laboratory Visit for collection of laboratory samples only.
t.
To be performed only during the weekly Clinic Visits and not the Laboratory Visits.
u.
If the Screen 1 visit occurs >180 days (±7 days) prior to the Screen 2 visit, then the Screen 1 visit assessments may need to be repeated at the discretion of 
the Investigator and Sponsor.
v.
If the Screen 2 visit occurs >70 days of Day 0, then the Screen 2 visit assessments may need to be repeated at the discretion of the Investigator and 
Sponsor.
w. To be performed locally, may be scheduled on different day, but as close to actual visit as possible
For 
F
nd asses
For
nd asses
d as
F
d as
ercial 
7 
e
7 -
rc
- 30
rc
30
cia
n-comme
itant me
me
itant me
ites at e
mm
ites at e
ear duri
com
ear duri
non
d w
n-c
d with 4
n-co
ith 4
sments t
on
sments t
abiliza
no
abiliza
e
use 
us
only.

Takeda
CONFIDENTIAL
Page 98
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
19.3 Clinical Laboratory Assessments
Table 3. Clinical Laboratory Assessments
Laboratory 
Assessments 
Screening Visits
Study Visits
Screen 1
Screen 2
Day 0b
(BAX 
888 Dose)
Day 1
Week 1-2
Once 
Weekly 
Visits
(Clinic 
Visits only)
Weeks 3-14
Twice Weekly 
Visits
(Clinic Visit 
and Laboratory 
Visit)o
Week 15-18
Once 
Weekly 
Visits
(Clinic Visits
only)
Months
5, 6, 9, 
12
Years 2-3 
(Months 
16, 20, 24, 
28, 32, 
36)
Years 4-5
(Months 48, 
60)
Early Study 
Termination 
Visita
Window
Screen 1s to 
occur <180 days 
(±7 days) prior 
to the Screen 2 
Visit AND 
≥5 days after 
last FVIII dose
Screen 2t
to occur 
<70 days 
of Day 0
N/A
N/A
±1 day 
±1 day for 
Clinic Visit
Laboratory 
Visit to occur 
3-4 days after 
that week’s 
Clinic Visit
±1 day
±4 days
±7 days
±30 days
Visit Numbers
1
2
3
4
5 - 6
7 - 30
31 - 34
35 - 38
39 - 44
45-46
NA
Hematologyc
X
X
Xd
X
X
Weeksq 3, 5, 
7, 9, 11, & 
13
Weeks 15 
& 17
X
X
X
X
Coagulatione
X
X
Xd
X
X
Xq
X
X
X
X
X
Clinical chemistriesf
X
X
Xd
X
X
Weeksq 3, 5, 
7, 9, 11, & 
13
Weeks 15 
& 17
X
X
X
X
Liver Function Test
(Central and/or 
Local Laboratories)
Xp
Xp
X
HIV serology
X
MHC haplotypeg
X
Hepatitis B surface 
antigen
X
Hepatitis C antibody
X
HCV RNA
X
Week 1
Week 6q
X
vWF antigen 
X
Week 6q
Month 6
For 
or
F
non-commercial 
hat w
al
hat w
Clinic
cia
Clinic
ci
e
X
me
X
n-c
X
co
n
X
no
X
on
use 
ccur 
se
ccur 
ys afte
use
ys afte
eek
u
eek
only.
y
±1 d
ly.
±1 d
o

Takeda
CONFIDENTIAL
Page 99
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
Table 3. Clinical Laboratory Assessments
Laboratory 
Assessments 
Screening Visits
Study Visits
Screen 1
Screen 2
Day 0b
(BAX 
888 Dose)
Day 1
Week 1-2
Once 
Weekly 
Visits
(Clinic 
Visits only)
Weeks 3-14
Twice Weekly 
Visits
(Clinic Visit 
and Laboratory 
Visit)o
Week 15-18
Once 
Weekly 
Visits
(Clinic Visits
only)
Months
5, 6, 9, 
12
Years 2-3 
(Months 
16, 20, 24, 
28, 32, 
36)
Years 4-5
(Months 48, 
60)
Early Study 
Termination 
Visita
Window
Screen 1s to 
occur <180 days 
(±7 days) prior 
to the Screen 2 
Visit AND 
≥5 days after 
last FVIII dose
Screen 2t
to occur 
<70 days 
of Day 0
N/A
N/A
±1 day 
±1 day for 
Clinic Visit
Laboratory 
Visit to occur 
3-4 days after 
that week’s 
Clinic Visit
±1 day
±4 days
±7 days
±30 days
Visit Numbers
1
2
3
4
5 - 6
7 - 30
31 - 34
35 - 38
39 - 44
45-46
NA
FibroSUREh
X
Month 
12
Collection of whole 
blood for 
transcriptome and 
plasma/serum for 
metabolomics 
analysis 
Pre-
infusion 
and 8 h 
post-
infusionu
X
X
Xq
X
X
Markers of 
autoimmune-
mediated hepatitisi
X
Serum cytokinesj
Xd
X
FVIII genotyping
X
FVIII activity 
(One-stage and 
chromogenic assays; 
central and local 
laboratories)k
X
Pre-
infusion
X
X
Xm
X
X
X
X
X
FVIII antigen
X
Pre-
infusion
X
Xq
X
X
X
X
X
For
or r
or non-commercial 
7 
al
7 -
l
-
al
e
X
me
X
me
n
e
use 
k’s
e
k’s
Visit
use
Visit
30
u
30
us
only.
r 
o
r 
o

Takeda
CONFIDENTIAL
Page 100
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
Table 3. Clinical Laboratory Assessments
Laboratory 
Assessments 
Screening Visits
Study Visits
Screen 1
Screen 2
Day 0b
(BAX 
888 Dose)
Day 1
Week 1-2
Once 
Weekly 
Visits
(Clinic 
Visits only)
Weeks 3-14
Twice Weekly 
Visits
(Clinic Visit 
and Laboratory 
Visit)o
Week 15-18
Once 
Weekly 
Visits
(Clinic Visits
only)
Months
5, 6, 9, 
12
Years 2-3 
(Months 
16, 20, 24, 
28, 32, 
36)
Years 4-5
(Months 48, 
60)
Early Study 
Termination 
Visita
Window
Screen 1s to 
occur <180 days 
(±7 days) prior 
to the Screen 2 
Visit AND 
≥5 days after 
last FVIII dose
Screen 2t
to occur 
<70 days 
of Day 0
N/A
N/A
±1 day 
±1 day for 
Clinic Visit
Laboratory 
Visit to occur 
3-4 days after 
that week’s 
Clinic Visit
±1 day
±4 days
±7 days
±30 days
Visit Numbers
1
2
3
4
5 - 6
7 - 30
31 - 34
35 - 38
39 - 44
45-46
NA
FVIII inhibitor 
(Bethesda assay; 
central laboratory)
X
X
X
Xq
X
X
X
X
Antibodies to FVIII 
and FVIII transgene 
productl
X
Weeksq 6 & 
8
Months 
6, 9 & 12
X
X
X
Neutralizing and 
binding antibodies to 
AAV8 and AAV2
X
X
Pre-
infusion
Week 2
Weeksq 4, 8, 
& 12
X
X
X
X
PBMCs for CMI 
response to AAV8 
and FVIII transgene 
products
X
X
Xq
X
Months
5, 6, & 
12
X
Vector genomes via 
PCR in blood, saliva,
urine, stool, and 
semen
Xr
X
Xn
Xn,q
Xn
Xn
Xn
Xn
Xn
Urine protein, total
X
Alpha fetoprotein 
(optional assessment 
at local laboratories)
Month 
12
Months 
24 and 
36
X
Backup samples
X
8h
X
X
Xo
X
X
X
X
X
For 
or
or
or
or
or
or non-commercial 
7 
al
7 -
l
-
X
cia
X
al
e
m
n-c
n
use 
k’s
e
k’s
Visit
use
Visit
30
u
30
us
only.
r 
o
r 
o

Takeda
CONFIDENTIAL
Page 101
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
Table 3. Clinical Laboratory Assessments
Laboratory 
Assessments 
Screening Visits
Study Visits
Screen 1
Screen 2
Day 0b
(BAX 
888 Dose)
Day 1
Week 1-2
Once 
Weekly 
Visits
(Clinic 
Visits only)
Weeks 3-14
Twice Weekly 
Visits
(Clinic Visit 
and Laboratory 
Visit)o
Week 15-18
Once 
Weekly 
Visits
(Clinic Visits
only)
Months
5, 6, 9, 
12
Years 2-3 
(Months 
16, 20, 24, 
28, 32, 
36)
Years 4-5
(Months 48, 
60)
Early Study 
Termination 
Visita
Window
Screen 1s to 
occur <180 days 
(±7 days) prior 
to the Screen 2 
Visit AND 
≥5 days after 
last FVIII dose
Screen 2t
to occur 
<70 days 
of Day 0
N/A
N/A
±1 day 
±1 day for 
Clinic Visit
Laboratory 
Visit to occur 
3-4 days after 
that week’s 
Clinic Visit
±1 day
±4 days
±7 days
±30 days
Visit Numbers
1
2
3
4
5 - 6
7 - 30
31 - 34
35 - 38
39 - 44
45-46
NA
a.
Includes for cases of withdrawn or discontinuation.
b. At the discretion of the investigator, subjects will be monitored for the first 8 hours and may remain in the infusion center for 24 hours following infusion 
or return to the center for follow-up at 24 hours post-infusion (Day 1 Visit).
c.
Hematology panel includes: complete blood count (hemoglobin, hematocrit, erythrocytes [i.e., RBC count], and leukocytes [ie, white blood cell count]) 
with differential (ie, basophils, eosinophils, lymphocytes, monocytes, neutrophils), platelet counts, RBC distribution width, mean corpuscular volume, and 
mean corpuscular hemoglobin concentration.
d.
Time points for Day 0 sample collection: (a) pre-infusion: up to 3 hours prior to BAX 888 infusion, and (b) post-infusion: 30 mins (±5 mins), 4 hours (±10 
mins), and 8 hours (±15 mins).
e.
Coagulation studies include: prothrombin time, activated partial thromboplastin time, international normalized ratio, thrombin time, D-dimer, 
fibrinogen activity. 
f.
Clinical chemistry panel includes: sodium, potassium, chloride, carbon dioxide, BUN, creatinine, glucose, calcium, phosphate, magnesium, albumin, total 
protein, CK, bilirubin (total & direct), ALT, AST, ALP, GGT, and LDH.
g.
4-digit analysis of the following loci: HLA-A, HLA-B, HLA-C, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1, HLA-DRB1, and 
HLA-DRB3/4/5
h.
FibroSURE Score provided based on an algorithm that includes following laboratory results: ALT, alpha-2-macroglobulin, apolipoprotein A1, total 
bilirubin, gamma glutamyl transferase
i.
ANA, Total IgG, anti-smooth muscle antibody, anti-LKM1 titers. To be assessed if no results within 6 months of screening are available.
j.
Serum cytokines including IL-6 and TNFα
k.
FVIII activity level assessment with one-stage assay will be utilized for all FVIII activity level assessments and will be performed at the central laboratory. 
Chromogenic assay will be assessed by the central laboratory in addition to the one-stage assay. FVIII activity levels will also be assessed by the local 
laboratory at all of the indicated time points and at the Clinic and Laboratory Visits (Weeks 3-14). The local laboratory may use either the one-stage FVIII 
For 
ted pa
or 
ted pa
m, c
F
m, c
non-commercial 
7 
al
7 -
l
-
t 8 hour
erc
t 8 hour
sit).
m
sit).
matocrit,
mm
matocrit,
ytes, neu
com
ytes, neu
p to 3 h
on-
p to 3 h
arti
n
arti
al use 
k’s
e
k’s
Visit
use
Visit
30
u
30
us
only.
r 
o
r 
o

Takeda
CONFIDENTIAL
Page 102
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
Table 3. Clinical Laboratory Assessments
Laboratory 
Assessments 
Screening Visits
Study Visits
Screen 1
Screen 2
Day 0b
(BAX 
888 Dose)
Day 1
Week 1-2
Once 
Weekly 
Visits
(Clinic 
Visits only)
Weeks 3-14
Twice Weekly 
Visits
(Clinic Visit 
and Laboratory 
Visit)o
Week 15-18
Once 
Weekly 
Visits
(Clinic Visits
only)
Months
5, 6, 9, 
12
Years 2-3 
(Months 
16, 20, 24, 
28, 32, 
36)
Years 4-5
(Months 48, 
60)
Early Study 
Termination 
Visita
Window
Screen 1s to 
occur <180 days 
(±7 days) prior 
to the Screen 2 
Visit AND 
≥5 days after 
last FVIII dose
Screen 2t
to occur 
<70 days 
of Day 0
N/A
N/A
±1 day 
±1 day for 
Clinic Visit
Laboratory 
Visit to occur 
3-4 days after 
that week’s 
Clinic Visit
±1 day
±4 days
±7 days
±30 days
Visit Numbers
1
2
3
4
5 - 6
7 - 30
31 - 34
35 - 38
39 - 44
45-46
NA
activity assay or the chromogenic FVIII activity assay, depending upon which assay is the standard in the individual local laboratory and provides the most 
rapid result; however, the same assay must be used consistently throughout the study.
l.
Neutralizing antibodies to full-length FVIII as well as total binding antibodies to full-length and transgene-derived FVIII will be assessed at each of the 
specified time points. Testing for neutralizing antibodies to the FVIII transgene product will be triggered only if binding antibodies to the transgene-
derived FVIII is observed
m. To be performed during the weekly Clinic Visit and the Laboratory Visit between Weeks 3-14 (see also footnote k).
n.
Vector shedding assessed at Screen 2, Day 1, weekly at Clinic Visits between Weeks 1-18, and at Months 5,6, 9, 12, 16, 20, 24, 28, 32, 36, 48, and 60, 
until two consecutive negative results are obtained in the sample.
o.
Clinic Visit to include all indicated laboratory assessments; Laboratory Visit to include the local laboratory Liver Function Test, FVIII activity level 
assessment, and backup sample collection ONLY. Backup sample collection to be performed once a week between Weeks 3-18 during the Laboratory 
Visit only.
p.
Liver Function Test to include: ALT, AST, and GGT; Local laboratory LFTs performed at Screen 2, then twice weekly at Clinic Visit and at the 
Laboratory Visit between Weeks 3-18. Central laboratory LFTs performed at Clinic Visits at Weeks 4, 6, 8, 10, 12, 14, 16, 18.
q.
To be performed during the Clinic Visit and not during the Laboratory Visit.
r.
Whole genome sequencing will be performed on a Screen 2 sample if subject provides consent.
s.
If the Screen 1 visit occurs >180 days (± 7 days) prior to the Screen 2 visit, then the Screen 1 visit assessments may need to be repeated at the discretion of 
the Investigator and Sponsor. Screen 1 visit assessments that need to be repeated for subjects screened >180 days (±7 days) can be performed in a 
combined Screen 1 and Screen 2 visit.
t.
If the Screen 2 visit occurs >70 days of Day 0, then the Screen 2 visit assessments may need to be repeated at the discretion of the Investigator and 
Sponsor. 
u.
The collection of whole blood for transcriptome analysis on Day 0 will occur at the pre-infusion and 8 hours post infusion time points and the 
plasma/serum sample for the metabolomics analysis will be obtained from the back-up sample.
For 
ments;
or 
ments;
Backup 
For
Backup 
al 
7 
al
7 -
l
-
non-commercial
h assay 
cia
h assay 
ut the stu
erc
ut the stu
bodies t
me
bodies t
I transg
mm
I transg
atory V
-co
atory V
nic Visit
on-
nic Visit
sample
no
ample
L
n
L
al use 
k’s
e
k’s
Visit
use
Visit
30
u
30
us
only.
r 
o
r 
o

Takeda
CONFIDENTIAL
Page 103
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
19.4 Definitions
19.4.1 Joint Bleeds
Features of an acute joint bleed include some or all of the following: ‘aura’, pain, swelling, 
warmth of the skin over the joint, decreased range of motion and difficulty in using the limb 
compared with baseline or loss of function.
The earliest clinical signs of a joint bleed are increased warmth over the area and discomfort with 
movement, particularly at the ends of range.
Later symptoms and signs include pain at rest, swelling, tenderness, and extreme loss of motion.
In patients with advanced arthropathy it may be difficult to distinguish pain-related arthritis from 
that associated with an acute bleed. Rapid resolution of pain following infusion of factor 
concentrates (typical of an acute hemarthrosis) or improvement of pain associated with activity
soon after a period of rest (typical of chronic arthritis) can help distinguish between the two.
In infants and young children, reluctance to use the limb alone may be indicative of a 
joint/muscle bleed.
19.4.2 Muscle Bleeds
Muscle bleeds can occur in any muscle of the body, usually from a direct blow or a sudden 
stretch. A muscle bleed is defined as an episode of bleeding into a muscle, determined clinically 
and/or by imaging studies, generally associated with pain and/or swelling and functional 
impairment over baseline.
For further definitions of CNS, gastrointestinal, and abdominal hemorrhages see the Guidelines 
for the Management of Hemophilia from the World Federation of Hemophilia 
(World Federation of Hemophilia Treatment Guidelines Working Group, 2012).
For 
S g
F
S g
non-commercial 
f the bo
omm
f the bo
an episo
co
an episo
y asso
on-
y asso
use 
b alone
use
b alone
only.
of p
y
of pa
y.
a
lp distin
only
lp distin

Takeda
CONFIDENTIAL
Page 104
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
20. REFERENCES
Ahmet, A., Kim, H. and Spier, S. 2011. Adrenal suppression: a practical guide to the screening 
and management of this under-recognized complication of inhaled corticosteroid therapy. 
Allergy, Asthma & Clinical Immunology, 7, 13.
Baldo, A., van den Akker, E., Bergmans, H. E., Lim, F. and Pauwels, K. 2013. General 
Considerations on the Biosafety of Virus-derived Vectors Used in Gene Therapy and 
Vaccination. Current Gene Therapy, 13, 385-394.
Cancer Therapy Evaluation Program 2009. Common terminology criteria for adverse events 
(CTCAE).
Committee for Medicinal Products for Human Use 2009. Guideline on the clinical investigation 
of recombinant and human plasma-derived factor VIII products. 
MEA/CHMP/BPWP/144533/2009., 19.
Crudele, J. M., Finn, J. D., Siner, J. I., Martin, N. B., Niemeyer, G. P., Zhou, S., et al. 2015. 
AAV liver expression of FIX-Padua prevents and eradicates FIX inhibitor without 
increasing thrombogenicity in hemophilia B dogs and mice. Blood, 125, 1553-1561.
Czaja, A. J. and Manns, M. P. 2010. Advances in the Diagnosis, Pathogenesis, and Management 
of Autoimmune Hepatitis. Gastroenterology, 139, 58-72.
Duncan, N., Kronenberger, W., Roberson, C. and Shapiro, A. 2010. VERITAS-Pro: a new 
measure of adherence to prophylactic regimens in haemophilia. Haemophilia, 16, 247-
255.
European Association for the Study of the Liver 2015. EASL Clinical Practice Guidelines: 
Autoimmune hepatitis. Journal of Hepatology, 63, 971-1004.
Fardet, L., Cabane, J., Lebbé, C., Morel, P. and Flahault, A. 2007. Incidence and risk factors for 
corticosteroid-induced lipodystrophy: a prospective study. Journal of the American 
Academy of Dermatology, 57, 604-609.
Feldman, B. M., Funk, S. M., Bergstrom, B. M., Zourikian, N., Hillard, P., van der Net, J., et al. 
2011. Validation of a new pediatric joint scoring system from the international 
hemophilia prophylaxis study group: Validity of the hemophilia joint health score 
(HJHS). Arthritis Care Res, 63, 223-230.
Kattenhorn, L. M., Tipper, C. H., Stoica, L., Geraghty, D. S., Wright, T. L., Clark, K. R., et al. 
2016. Adeno-Associated Virus Gene Therapy for Liver Disease. Human Gene Therapy,
27, 947-961.
Liu, D., Ahmet, A., Ward, L., Krishnamoorthy, P., Mandelcorn, E. D., Leigh, R., et al. 2013. A 
practical guide to the monitoring and management of the complications of systemic 
corticosteroid therapy. Allergy, Asthma & Clinical Immunology, 9, 30.
Manno, C. S., Arruda, V. R., Pierce, G. F., Glader, B., Ragni, M., Rasko, J., et al. 2006. 
Successful transduction of liver in hemophilia by AAV-Factor IX and limitations 
imposed by the host immune response. Nat Med, 12, 342-347.
Manns, M. P., Czaja, A. J., Gorham, J. D., Krawitt, E. L., Mieli-Vergani, G., Vergani, D., et al. 
2010. Diagnosis and management of autoimmune hepatitis. Hepatology, 51, 2193-2213.
For
y
, Berg
For 
, Berg
a new
Fo
a new
non-commercial
p
l
p
mens in
ial 
mens in
ver 20
me
ver 20
Hepato
mm
Hepato
el, P. an
com
el, P. an
dy
o
dystroph
on-c
stroph
57, 6
non
57, 6
use 
58
se
58-7
e
-7
ro, A
us
ro, A
u
only.
ice. 
ly
ice. B
y.
B
sis, Path
only
sis, Path
72.
o
72

Takeda
CONFIDENTIAL
Page 105
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
Mazepa, M. A., Monahan, P. E., Baker, J. R., Riske, B. K. and Soucie, J. M. 2016. Men with 
severe hemophilia in the United States: birth cohort analysis of a large national database. 
Blood, 127, 3073-3081.
Nathwani, A. C., Reiss, U. M., Tuddenham, E. G. D., Rosales, C., Chowdary, P., McIntosh, J., et 
al. 2014. Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N. 
Engl. J. Med, 371, 1994-2004.
Nienhuis, A. W., Nathwani, A. C. and Davidoff, A. M. 2016. Gene therapy for hemophilia. Hum 
Gene Ther, 27, 305-308.
Perrin, G. Q., Zolotukhin, I., Sherman, A., Biswas, M., De Jong, Y. P., Terhorst, C., et al. 2016. 
Dynamics of antigen presentation to transgene product-specific CD4+ T cells and of Treg 
induction upon hepatic AAV gene transfer. Molecular Therapy.Methods & Clinical 
Development, 3, 16083.
Rangarajan, S., Walsh, L., Lester, W., Perry, D., Madan, B., Laffan, M., et al. 2017. AAV5-
Factor VIII Gene Transfer in Severe Hemophilia A. N Engl J Med, 377, 2519-2530.
Rentz, A., Flood, E., Altisent, C., Bullinger, M., Klamroth, R., Garrido, R. P., et al. 2008. Cross-
cultural development and psychometric evaluation of a patient-reported health-related 
quality of life questionnaire for adults with haemophilia. Haemophilia, 14, 1023-1034.
Soloway, R. D., Summerskill, W. H., Baggenstoss, A. H., Geall, M. G., Gitnik, G. L., Elveback, 
I. R., et al. 1972. Clinical, biochemical, and histological remission of severe chronic 
active liver disease: a controlled study of treatments and early prognosis. 
Gastroenterology, 63, 820-833.
Teal, S., Brohan, E., Hettema, Y., Humphrey, L., Willgoss, T., Hudgens, S., et al. 2014. 
Development and psychometric evaluation of a novel tool for assessing patient 
perception and preference for haemophilia treatment (HaemoPREF). Haemophilia, 20, 
666-673.
van Staa, T. P., Leufkens, H. G. and Cooper, C. 2002. The epidemiology of corticosteroid-
induced osteoporosis: a meta-analysis. Osteoporos. Int, 13, 777-787.
World Federation of Hemophilia Treatment Guidelines Working Group 2012. Guidelines for the 
management of hemophilia 2nd Edition. 80.
Zolotukhin, I., Markusic, D. M., Palaschak, B., Hoffman, B. E., Srikanthan, M. A. and Herzog, 
R. W. 2016. Potential for cellular stress response to hepatic factor VIII expression from 
AAV vector. Mol Ther Methods Clin Dev, 3, 16063.
r
Fo
a met
For 
a met
hilia
Fo
hilia
ercial
st
l
st
eatmen
ial 
eatmen
mm
y
non-com
, L., W
me
, L., W
valuatio
omm
valuatio
haemop
com
haemop
nd Co
no
nd Co
n
use
 Gea
se 
 Gea
ologi
us
ologi
only.
arri
patient
nly.
patien
lia.
on
lia. Ha
nly
Ha
ll
o
ll

Takeda
CONFIDENTIAL
Page 106
BAX 888
201501 Protocol Amendment 9
10 Nov 2021
21. SUMMARY OF CHANGES
Protocol 201501: Amendment 9 2021 10 NOV
Replaces: Protocol 201501: Amendment 8, 2021 MAR 22
Summary of Changes
Updated Sponsor information and Protocol History
Title Page
Protocol Signature Page
Section 14.6
Figure 2
Figure 3
For non-commercial use only.