Clinical trial NCT03261167
Conditions: Spasticity, Post-Stroke
Keywords: Botulinum toxin A Safety post-stroke upper limb spasticity Efficacy GSK1358820 double blind
Sponsor: GlaxoSmithKline
Start date: 2017-08-02; Completion date: 2019-01-10
Enrollment: 124 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Botulinum toxin A (GSK1358820) is a sterile, purified type A botulinum neurotoxin complex. In Japan, 240 units of botulinum toxin A are approved as a maximum dose per administration for upper limb spasticity. This study is planned to evaluate the effectiveness and safety of 400 units of botulinum toxin A which can help to increase the maximum dose per administration to 400 units from 240 units as the treatment with 240 units is considered insufficient in subjects with post-stroke upper limb spasticity. Approximately 120 subjects will be randomized to receive either 400 or 240 units of botulinum toxin A in double blind phase followed by open-label phase in which 400 units of the study treatment will be injected in both the groups. The study period will be up to 52 weeks, consisting of a screening phase up to 4 weeks, minimum 12-week double blind phase (Part 1), maximum 36- week open-label phase (12 weeks per cycle with 3 treatment phases: Part 2, Part 3 and Part 4).

Detailed description:

Arms: arm 1: Subjects will receive a total dose of 400 units of botulinum toxin A of which 240 units will be injected into the muscles that act on finger (including thumb flexors) and wrist flexors, and a total of 160 units will be injected into the muscles that act on the elbow flexors. arm 2: Subjects will receive 240 units of botulinum toxin A injected into the muscles that act on the finger (including thumb flexors) and wrist flexors. Placebo will be injected into the muscles that act on the elbow flexors. arm 3: Subjects will receive botulinum toxin A with a dose of 400 units injected in a divided doses.
Interventions: intervention 1: Botulinum toxin A (GSK1358820) intervention 2: Placebo
Intervention descriptions: intervention 1: GSK1358820 is sterile, purified type A botulinum neurotoxin complex. GSK1358820 injection will contain botulinum toxin A (100 units), sodium chloride (0.9 milligrams \[mg\]), and human serum albumin (0.5 mg). It will be available with doses of 400 units and 240 units. intervention 2: Placebo injection will contain sodium chloride (0.9 mg).

Protocol documents:
Prot_000.pdf: 
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TITLE PAGE
Protocol Title: A phase III study (a placebo controlled, randomized, double-blind comparative study 
and an open-label, uncontrolled study) to evaluate the efficacy and safety of GSK1358820 in patients 
with post-stroke upper limb spasticity 
Protocol Number: 207660
Short Title: A phase III study to evaluate the efficacy and safety of GSK1358820 in patients with 
post-stroke upper limb spasticity
Compound Number:
GSK1358820
Sponsor 
GlaxoSmithKline K.K. (GSK)
6-15, Sendagaya 4-chome, Shibuya-ku, Tokyo 151-8566 Japan 
The person responsible for operation of the study:
Director of Development of 
Drugs for Neurological Diseases, Department of Development, Clinical Research Department
Medical Monitor Name and Contact Information are shown on SRM.
Regulatory Agency Identifying Number(s):NA
Approval Date: 04-APR-2017
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  Unauthorised 
copying or use of this information is prohibited.
PPD


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Signature of the Sponsor:
Director of Development of Drugs For Neurological Diseases, 
Department of Development, Clinical Research Department
GlaxoSmithKline K.K. (GSK) 
Date
The IMMS document approved is as follows:
  Unique ID :
  System Version:
  Effective Date:
PPD


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TABLE OF CONTENTS
PAGE
1.
SYNOPSIS .......................................................................................................................7
2.
SCHEDULE OF ACTIVITIES (SoA) ..............................................................................12
3.
INTRODUCTION............................................................................................................17
3.1.
Study Rationale....................................................................................................17
3.2.
Background..........................................................................................................17
3.3.
Benefit/Risk Assessment....................................................................................18
3.3.1.
Risk Assessment ........................................................................................19
3.3.2.
Benefit Assessment....................................................................................21
3.3.3.
Overall Benefit:Risk Conclusion...............................................................21
4.
OBJECTIVES AND ENDPOINTS..................................................................................22
5.
STUDY DESIGN.............................................................................................................23
5.1.
Overall Design......................................................................................................23
5.1.1.
Screening Phase (up to 4 weeks)..............................................................23
5.1.2.
Blind Period (minimum 12 Weeks): Placebo Controlled, 
Randomized, Double Blind Design ...........................................................24
5.1.3.
Open-Label Phase (maximum 36 weeks): Uncontrolled, Open-
Label Design................................................................................................24
5.1.3.1.
Eligibility Criteria for Injection in and after Part 2 ..........................24
5.2.
Number of Participants .......................................................................................25
5.3.
Participant and Study Completion.....................................................................25
5.4.
Scientific Rationale for Study.............................................................................25
5.5.
Dose Justification................................................................................................26
6.
STUDY POPULATION...................................................................................................26
6.1.
Inclusion Criteria..................................................................................................26
6.1.1.
Screening Phase (Day -28 to Day -1) ........................................................26
6.1.2.
Day 1 (prior to injection).............................................................................28
6.2.
Exclusion Criteria ................................................................................................28
6.2.1.
Screening Phase (Day -28 to Day -1) ........................................................28
6.2.2.
Day 1 (Prior to injection).............................................................................30
6.3.
Lifestyle Restrictions ..........................................................................................31
6.4.
Screen Failures ....................................................................................................31
7.
TREATMENTS...............................................................................................................32
7.1.
Treatments Administered ...................................................................................32
7.2.
Dose Modification................................................................................................34
7.3.
Method of Treatment Assignment .....................................................................34


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7.4.
Blinding.................................................................................................................34
7.5.
Preparation/Handling/Storage/Control..............................................................35
7.6.
Treatment Compliance........................................................................................35
7.7.
Concomitant Therapies.......................................................................................35
7.7.1.
Permitted Concomitant Drugs/Therapies.................................................36
7.7.2.
Contraindicated Medications/Therapies...................................................36
7.8.
Treatments after Completion of the Study........................................................37
8.
DISCONTINUATION CRITERIA....................................................................................37
8.1.
Discontinuation of Study Treatment..................................................................37
8.2.
Withdrawal from the Study .................................................................................37
8.2.1.
Liver Chemistry Stopping Criteria.............................................................37
8.2.2.
QTc Stopping Criteria.................................................................................40
8.2.3.
Treatment discontinuation due to treatment-related SAE......................40
8.2.4.
Treatment discontinuation due to pregnancy .........................................40
8.2.5.
Withdrawal 
of 
subjects 
who 
start 
receiving 
prohibited 
medications or therapies ...........................................................................40
8.2.6.
Prohibition of treatment resumption ........................................................41
8.3.
Lost to follow up ..................................................................................................41
9.
STUDY ASSESSMENTS AND PROCEDURES ...........................................................41
9.1.
Efficacy assessments .........................................................................................42
9.1.1.
Evaluation methods....................................................................................42
9.1.1.1.
Modified Ashworth Scale (MAS) .......................................................42
9.1.1.2.
Numeric Rating Scale (NRS) .............................................................43
9.1.1.3.
Disability Assessment Scale (DAS)..................................................44
9.1.1.4.
Clinical Global Impression of Change (CGI) assessed by a 
investigator .........................................................................................45
9.1.1.5.
Clinical Global Impression of Change (CGI) assessed by a 
patient..................................................................................................45
9.1.1.6.
Time to patient-reported onset of spasticity symptom relief 
(Visit 2):................................................................................................45
9.1.1.1.
Patient-reported benefit of injection (Visits 3, 4, and 5).................45
9.2.
Adverse events ....................................................................................................45
9.2.1.
Period subject to collection of data related to adverse events 
and SAEs, and the frequency of such data collection............................46
9.2.2.
Method used to detect adverse events and SAEs...................................46
9.2.3.
Follow up on adverse events and SAEs...................................................46
9.2.4.
Regulatory requirements of SAE reporting..............................................46


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9.2.5.
Cardiovascular events and death .............................................................47
9.2.6.
Pregnancy....................................................................................................47
9.3.
Management of overdosage...............................................................................47
9.4.
Safety assessments ............................................................................................48
9.4.1.
Physical examination..................................................................................48
9.4.2.
Vital signs ....................................................................................................48
9.4.3.
Height and weight .......................................................................................48
9.4.4.
ECG...............................................................................................................48
9.4.5.
Neutralizing antibody test..........................................................................49
9.4.6.
Clinical Safety Laboratory Assessments .................................................49
9.5.
Pharmacokinetics................................................................................................50
9.6.
Pharmacodynamics.............................................................................................50
9.7.
Genetics/Pharmacogenetics ..............................................................................50
9.8.
Biomarkers ...........................................................................................................50
9.9.
Pharmacoeconomics...........................................................................................50
10. STATISTICAL CONSIDERATIONS ..............................................................................51
10.1.
Sample Size Determination.................................................................................51
10.2.
Populations for Analyses....................................................................................51
10.3.
Statistical Analyses.............................................................................................51
10.3.1.
Efficacy Analyses........................................................................................51
10.3.2.
Safety Analysis............................................................................................52
10.3.3.
Other analyses.............................................................................................53
10.3.4.
Interim analyses..........................................................................................53
11. Reference ......................................................................................................................53
12. Appendices ...................................................................................................................55
12.1.
Appendix 1: Abbreviations and trademarks.....................................................55
12.2.
Appendix 2: Clinical Laboratory Tests..............................................................55
12.3.
APPENDIX 3: Study Governance Considerations............................................57
12.4.
APPENDIX 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting...........................................61
12.5.
APPENDIX 5: Contraceptive Guidance and Collection of Pregnancy 
Information ...........................................................................................................66
12.6.
APPENDIX 6: Liver Safety Required Actions and Follow up 
Assessments........................................................................................................70
12.7.
APPENDIX 7: COUNTRY SPECIFIC DESCRIPTIONS .......................................73
12.7.1.
Regulatory and Ethical Considerations....................................................73
12.7.2.
Obtaining of Informed Consent.................................................................73


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12.7.3.
Study Implementation Period ....................................................................73
12.7.4.
Study Conduct Structure ...........................................................................73


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1.
SYNOPSIS
Protocol Title: A phase III study (a placebo controlled, randomized, double-blind comparative study 
and an open-label, uncontrolled study) to evaluate the efficacy and safety of GSK1358820 in patients 
with post-stroke upper limb spasticity
Short Title: A phase III study to evaluate the efficacy and safety of GSK1358820 in patients with 
post-stroke upper limb spasticity
Rationale:
GSK1358820, botulinum toxin type A (hereafter referred as the product), is sterile, purified type A 
botulinum neurotoxin complex. Intramuscularly injected botulinum neurotoxin shows muscle relaxant 
effects by blocking the neuromuscular junction and inhibiting release of acetylcholine, a 
neurotransmitter. Since the approval of the product for strabismus and blepharospasm in US in 1989, 
the product is licensed for the treatment of various diseases, which respond to the muscle relaxant 
effects in more than 90 countries (as of Apr 2017).
In Japan, the product is licensed with 8 indications as an ethical drug so far: blepharospasm as a 
first indication in Oct 1996, followed by “hemifacial spasm” in Jan 2000, “spasmodic torticollis” in 
Jun 2001, “talipes equinus associated with lower limb spasticity in pediatric patients two years of age 
and older with cerebral palsy” in Feb 2009, “upper limb spasticity” and “lower limb spasticity” in Oct 
2010, “severe primary maschalephidrosis” in Nov 2012, and “strabismus” in Jun 2015. For “upper 
limb spasticity,” 240 units of the product is approved as a maximum dose per administration. In US, 
as a maximum dose per administration, 400 units of injection of the product have been approved for 
the treatment of upper limb spasticity in adult patients in 2015; therefore, the authorized dose of the 
product between US and Japan is different.
This study is a multicenter, double blind, placebo controlled phase III domestic study and aims to 
evaluate the efficacy and safety of 400 units of the product in patents with post-stroke upper limb 
spasticity. The study was planned to increase the maximum dose per administration in Japan to 400 
units from 240 because the treatment with 240 units of the product, a maximum dose per 
administration, is considered to be insufficient in some patients with post-stroke upper limb spasticity. 


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Objectives and Endpoints:
Objectives
Endpoint(s) 
Primary 
To evaluate the efficacy of the injections of 400 
units of the product at Week 6 (finger/ wrist 
flexors: 240 units, elbow flexors: 160 units), 
comparing to that of 240 units (finger/ wrist 
flexors: 240 units, elbow flexors: placebo).
The responder rate : The rate of the subjects that 
Modified Ashworth Scale (MAS) score was 
reduced at least 1 from baseline in the elbow 
flexors. 
Secondary
To evaluate the efficacy of 400 units of the 
product, comparing to 240 units of the product

The responder rate of MAS score from 
baseline in the finger, thumb and wrist 
flexors 

Changes in MAS score from baseline in 
the finger, thumb, wrist and elbow 
flexors 

Changes in Disability Assessment Scale 
(DAS) from baseline
To evaluate the safety and tolerability of the 
product of 400 units, comparing to 240 units of the 
product/ To evaluate the safety and tolerability of 
400 units of the product

Adverse events

Physical examinations

Clinical laboratory tests (haematology, 
blood biochemistry, urinalysis)

Vital signs (heart rate, blood pressure, 
body temperature)
Exploratory
To evaluate the efficacy of 400 units of the 
product 

Changes in MAS score from baseline in 
finger, thumb, wrist, elbow, pronation of 
the forearm and shoulder flexors
To evaluate the other efficacy of the product of 
400 units, comparing to 240 units of the product/ 
To evaluate the other efficacy of 400 units of the 
product

Changes in Numeric Rating Scale 
(NRS) for pain from baseline

Changes in other items of DAS from 
baseline 

Clinical Global Impression of Change 
(CGI) of functional disability by a 
investigator

CGI of functional disability by a patient

Time to patient-reported onset of 
spasticity symptom relief

Patient-reported benefit of injection

Time to qualification for retreatment
To evaluate neutralizing antibody production

Testing for neutralizing antibody 


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Overall Design:
This study is a 48-week multicenter, phase III study (a placebo controlled, randomized, double-
blind comparative study and an open-label, uncontrolled study) to evaluate the efficacy and safety of 
the product in patients with post-stroke upper limb spasticity. The study period is up to 52 weeks, 
consisting of a screening phase up to 4 weeks, minimum 12-week blind phase (Part 1), maximum 36-
week open-label phase (12 weeks per cycle with maximum 3 treatment phases: Part 2, Part 3 and Part 
4). 
BOTOX 400 U
BOTOX 240 U
+
Placebo
BOTOX 400 U
BOTOX 400 U
Screening
BOTOX 400 U
Double-blind treatment
(12 weeks)
Open-label treatment 
(36 weeks)
Part 3
Part 4
Part 1
Part 2
dose 
dose 
dose 
dose 
dose 
Number of Participants:
Approximately 120 subjects (approximately 60 in each group) will be randomized to obtain an 
evaluable subject sample of approximately 100 at Week 48 as subjects with completion of the study。
Treatment Groups and Duration:
Screening Phase (Day -28～Day -1)
Evaluation and screening tests will be performed 28 to 7 days (±3days) before initial injection 
(Day 1) as a starting point. The investigator will decide which arm to be injected during screening 
phase.
Blind Phase (minimum 12 Weeks): Placebo Controlled, Randomized, Double Blind 
Design
Subjects wkho meet the inclusion criteria will be randomly assigned 1:1 to either the 400 or the 240 
units group. 

In the 400 units group, a total of 240 units of the product will be injected into the muscles 
that act on the finger (including thumb flexors) and wrist flexors, and a total of 160 units 
into the muscles that act on the elbow flexors; a total of 400 units of the product will be 
injected.

In the 240 units group, a total of 240 units of the product will be injected into the muscles 
that act on the finger (including thumb flexors) and wrist flexors. Placebo will be injected 
into the muscles that act on the elbow flexors. A total of 240 units of the product will be 
injected. 


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If the total dose for the muscles that act on the finger and writs flexors is ensured by 240 units, and 
160 units for the muscles that act on the elbow flexors, the dose can be adjusted at a investigator’s 
discretion based on the subject’s symptoms.
Open-Label Phase (maximum 36 Weeks): Uncontrolled, Open-Label Design
The product of 400 units will be injected in both groups. The product can be injected up to 3 times 
after completion of Part 1 in the blind phase. In the open-label phase, subjects whom the investigator
considers eligible for the injections will be treated. The next injections cannot be performed until the 
eligibility of the subject has been confirmed by the investigator. 
In the open-label phase, the muscle to be injected and the dose will be decided by the investigator 
based on the patient’s symptoms, and a total dose of 400 units of the product will be injected in a 
divided dose. For the muscles that the investigator considers unnecessary to be treated, an injection 
may be skipped. The involving muscle and the dose do not have to be same each time always.
Injection Criteria in and after Part 2 in the Open-Label Phase
In the open-label phase (Part 2, Part 3, and Part 4), only the subjects whom the investigator 
considers eligible for the study will be injected. The eligibility is evaluated at a study visit after Week 
12 (V5. If a subject does not meet the criteria at V5, the eligibility is evaluated at QRV (Qualification 
for Retreatment Visit). Subjects are considered to be eligible if following criteria are all satisfied: 


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1)
At least 12 weeks (84 days) have passed since the preceding dose
2)
Among the finger, wrist or elbow flexors, 2 flexors have at least 2 on the MAS (except only the 
finger and wrist flexors of 2 on the MAS)
3)
Subject who request the injections
4)
Subjects whom a investigator considers an injection of 400 units of the product is appropriate
5)
Subjects who are considered to remain freedom from unacceptable safety concerns (including 
potential for serious adverse events, laboratory data, electrocardiogram or pulmonary function 
test value) due to the injections of 400 units of the product
6)
Subjects who have not experienced serious adverse events (SAE) associated with the injections 
of the product
If a subject meets above criteria at V5 or QRV, the following items are confirmed before V1 
injection: 

Body weight ≥ 40 kg 

Women of childbearing potential who have negative pregnancy test results in urine 


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2.
SCHEDULE OF ACTIVITIES (SoA)
Compliance with the protocol (including the list of the study conduct schedule) is important and 
required to conduct the study. Therefore, exemption or discharge cannot be allowed, except but 
emergency safety concerns arise. 
The study operation schedule is shown on Table 1. Examples of injections in the open-label phase 
based on evaluation of eligibility for injection are shown on Figure 1, Figure 2, Figure 3, and Figure 4. 


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13
Table 1 SCHEDULE OF ACTIVITIES (SoA)
Screening a
Blind phase
If a subject meets the eligibility at V5/ QRV, the subject will 
move forward to the open-label phase
Open-label phase
If a subject meets the eligibility at V5/QRV, the subject will move 
forward to the next treatment phase
Completion 
visit
Part 1
Eligibility 
evaluation b
Part 2/Part 3/ Part 4
Eligibility 
evaluation b
Visit
SV
V1
(Day 1)
V2
V3
V4
V5 c
(Eligibility 
evaluation)
QRV
V1
V2
V3
V4
V5 d
(Eligibility 
evaluation)
QRV
Final
Visit
Time from initial injection 
(Day 1) (Weeks)
―
0
2
4
6
12 
Allowable Week 16 to 
36e
―
―
―
―
―
Allowable Week 24 to 
36 e
48/
Withdrawal
Time from injection day in each 
treatment phase (Weeks)
―
0
2
4
6
12
16/ 20/ 24/ 28/ 32/ 
36
0
2
4
6
12
16/ 20/ 24
-
Acceptable visit windows (days) 
―
4
4
4
+4 f
14 g
+4
4
4
4
+4 f
14 g
4
Written informed consent
X h
Randomization
X i
Injections
X
X
Evaluation of eligibility
X
X
X
X
Inclusion/exclusion criteria j
X
X i
Subject demography
X
MAS k
X
X i
X
X
X
X
X
X i,t
X
X
X
X
X
X
NRS l
X i
X
X
X
X
X i,t
X
X
X
X
(X) r
DAS 
X i
X
X
X
X
X i,t
X
X
X
X
(X) r
CGI by a investigator
X
X
X
X
X
X
X
X
(X) r
CGI by a patient
X
X
X
X
X
X
X
X
(X) r
Time to patient-reported onset of 
spasticity symptom relief
X
X
Patient-reported benefit of 
injection
X
X
X
X
X
X
(X) r
Physical examination (complete 
version)
X
Physical examination (simplified 
version)
X i
X
X i,t
X
X
Medical history
X
X i
Vital signs m
X
X i
X
X i,t
X
X
Height
X
Body weight
X
X i
Electrocardiogram
X
X i
Pregnancy test n
X
X i
X i
(X)s
X
Laboratory test o
X
X
X
X
Adverse events p
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medications/therapies
X
X i
X
X
X
X
X
X i,t
X
X
X
X
X
X
Testing for neutralising 
antibodies q
X
X
X


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14
a.
Test items for screening must be performed 1 weeks before Day 1 visit (±3 days).
b.
Eligibility evaluation (Qualification for Retreatment Visit: QRV) will be performed at V5 as a starting point if a subject does not meet the criteria only. The evaluation is performed at a 4-week interval, 
V5 as a starting point, The QRV when a subject meets the criteria will be a same day as the injection in the next treatment period (refer to Figure 1, Figure 2, Figure 3, Figure 4). 
c.
If a subject is evaluated to meet the eligibility for the injection in the blind phase at V5, the subject will move forward to Part 2 in the open-label phase (Namely, V5 in Part 1 and V1 in Part 2 is a same 
day). If the subject does not meet the eligibility, QRV will be performed 4 weeks later, at V5 as s starting point. 
d.
If a subject is evaluated to meet the eligibility at V5 in the open-label phase, the subject will move forward to the next treatment phase (V5 and V1 in the next treatment phase is a same day). If the 
subject does not meet the eligibility, QRV is performed 4 weeks later, V5 as a starting point. If V5 in Part 4 is at Week 48 after initial injection, V5 will be considered to be completion visit (FV).
However, for the testing items, pre-scheduled tests at V5 and neutralizing antibody tests will be performed. If V5 in Parts 2 and 3 is performed at Week 36 or later, after completion of V5, completion 
visit will be performed at Week 48.
e.
QRV is allowable to perform from initial injection to Week 36. Eligibility evaluation (QRV) will not be performed after Week 36.  
f.
V5 must be performed at least 84 days after V1. 
g.
The acceptable visit windows will be -14 to +4 days if QRV is performed at Week 36.
h.
Must be performed earlier than any other procedures
i.
Must be performed before injection of the product
j.
For inclusion/exclusion criteria, the items to be observed are different between screening phase and Day 1. For details, refer to 6.1. and 6.2.
k.
For MAS evaluation, the items to be evaluated differ depending on the treatment phase. For details, refer to 9.1.1.1.
l.
MAS evaluation will be followed by NRS evaluation. For NRS evaluation, items to be evaluated differ. For details, refer to 9.1.1.2.
m.
Body temperature, heart rate, and blood pressure will be measured as vital signs. 
n.
Women of childbearing potential will be only performed. Serum hCG pregnancy test must be performed at screening, and urine hCG pregnancy test after randomization. The tests can be performed 
beyond the protocol specifications if a investigator considers to be necessary.  
o.
For laboratory test items, refer to 12.2. Attachment 2. Fasting is not required for blood collection. 
p.
Adverse events and serious adverse events collection period will be from the initial injection day (Day 1) to completion visit (FV).
q.
Neutralizing antibody testing is performed 3 times in each subject. The first test will be performed in screening phase, the second is at QRV in the blind phase, and the third is at completion visit.
r.
A subject who withdraws the study before 12 weeks after last injection will be performed. 
s.
Perform if V5 in Part 4 is at Week 48 after initial injection
t.
Not necessary to perform doubly as V1 assessment if the same assessment is performed at V5


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15
GSK1358820 
240 U
GSK1358820 
400 U
GSK1358820 
400 U
0
V1
2
V2
4
V3
6
V4
8
10
12
14
V2
16
V3
18
V4
20
22
24
GSK1358820 
400 U
GSK1358820 
400 U
Week
Intial treatment
3rd treatment
2nd Treatment
4th treatment
Part 1
Part 2
Part 3
Part 4
26
V2
28
30
32
34
36
38
40
42
44
46
48
FInal
Visit
：Visit week
Ex.1）If a subject is eligible for the injections at V5 in all the treatment phases
V3
V4
V2
V3
V4
V5/FV
Day1
V5/V1
V5/V1
V5/V1
Double-blind
Figure 1    Eligibility Evaluation in the Open-Label Phase (Example 1) 
If a subject is eligible for the injections at V5 in all the treatment phases, 4 injections will be performed 
throughout the study. Week 48 visit is performed also as a completion visit. 
GSK1358820
240 U
GSK1358820 
400 U
GSK1358820 
400 U
0
2
4
6
8
10
12
14
16
18
20
22
24
GSK1358820 
400 U
Week
Initial treatment
Part 1
Part 2
Part 3
26
28
30
32
34
36
38
40
42
44
46
48
Final
Visit
Evaluation will not be performed
：Visit week
Ex. 2）If a subject does not meet the eligibility at V5 in blind phase (Part 1), 
QRV will be performed at Week 16
V1       V2      V3     V4                           V5          QRV/V1   V2      V3     V4                       V5/V1    V2
V3      V4                           V5                                      FV
Day1
Not qualified
for retreatment
2nd treatment
3rd treatment
Double-blind
Figure 2   Eligibility Evaluation in the Open-Label Phase (Example 2) 
If a subject does not meet the eligibility at V5 in blind phase (Part 1), QRV will be performed at Week 16. V5 in Part 
3 is at Week 40, therefore, eligibility evaluation will not be performed. After V5 at Week 40, FV will be performed at 
Week 48. 


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GSK1358820 
240 U
GSK1358820 
400 U
GSK1358820
400 U
0
2
4
6
8
10
12
14
16
18
20
22
24
GSK1358820
400 U
week
Initial treatment
2ndtreatment
Part 1
Part 2
Part 3
26
28
30
32
34
36
38
40
42
44
46
48
Final
Visit
Not qualified 
For retreatment
3rd treatment
：Visit week
Ex. 3）If a subject does not meet the eligibility at V5, and evaluated to be eligible at 
QRV3 Week 24
V1       V2      V3     V4                           V5              QRV1
QRV2  
QRV3/V1  V2     V3     V4  
V5/V1    V2      V3     V4
V5/FV
Day1                                                                                                                
Not qualified 
For retreatment
Double-blind
Figure 3    Eligibility Evaluation in the Open-Label Phase (Example 3) 
If a subject does not meet the eligibility at V5 in the blind phase (Part 1), QRV will be performed until the eligibility 
have confirmed at 4 weeks intervals, at V5 as a starting point. If a subject is evaluated to be eligible at QRV3 Week 24, 
the injections in Part 2 will be performed on the same day as QRV3. V5 in Part 3 is in Week 48, therefore, at V5, 
completion visit (FV) will be also performed. 
GSK1358820 
240 U
GSK1358820 
400 U
GSK1358820 
400 U
0
2
4
6
8
10
12
14
16
18
20
22
24
week
Initial treatment
2ndtreatment
Part 1
Part 2
26
28
30
32
34
36
38
40
42
44
46
48
Final
visit
Not qualified
for retreatment
：Visit week
*if  not qualified at week 36,
Eligibility assessment will not be performed.
V1       V2      V3     V4                           V5   
QRV1
QRV2
QRV3/V1  V2     V3     V4 
V5                                     
FV
Day1
Ex. 4）If a subject does not meet the eligibility at Week 36
Not qualified
for retreatment
Not qualified
for retreatment
Double-blind
Figure 4    Eligibility Evaluation in the Open-Label Phase (Example 4)
QRV in Part 2 is Week 36, and if a subject does not meet the criteria, subsequent injections will not be performed, 
and Week 48 completion visit will be performed. 


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3.
INTRODUCTION 
3.1.
Study Rationale
GSK1358820, botulinum toxin type A (hereafter referred to as the product) is sterile, purified type 
A botulinum neurotoxin complex. Intramuscularly injected botulinum neurotoxin shows muscle 
relaxant effects by blocking the neuromuscular junction and inhibiting the release of acetylcholine, a 
neurotransmitter. Since the approval of the product for strabismus and blepharospasm in US in 1989, 
the product is licensed for the treatment of various diseases, which respond to the muscle relaxant 
effects in more than 90 countries (as of Apr 2017). 
In Japan, the product is licensed with 8 indications as an ethical drug so far: blepharospasm as first 
indication in Oct 1996, followed by “hemifacial spasm” in Jan 2000, “spasmodic torticollis” in Jun 
2001, “talipes equinus associated with lower limb spasticity in paediatric patients two years of age and 
older with cerebral palsy” in Feb 2009, “upper limb spasticity” and “lower limb spasticity” in Oct 
2010, “severe primary maschalephidrosis” in Nov 2012, and “strabismus” in Jun 2015. For “upper 
limb spasticity,” 240 units of the product is approved as a maximum dose per administration. 
This study is a multicenter, double blind, placebo controlled phase III domestic study in patients 
with upper limb spasticity and aims to confirm the efficacy and safety of 240 units of the product for 
post-stroke upper limb spasticity. The information of 400 units of the product in the study is expected 
to provide beneficial information because the treatment with 240 units of the product with a maximum 
dose per administration is considered to be insufficient in some patients with post-stroke upper limb 
spasticity.
3.2.
Background
Spasticity is a movement disorder that is characterized by increased myotatic reflex and is regarded 
as one of positive signs of the upper motor neuron signs (Kagamihara, 2012; Lance, 1980). Spasticity 
is caused by central nerve system injuries such as stroke, traumatic brain injury, or spinal cord injury 
and chronic neuropathies such as cerebral palsy or multiple sclerosis, etc. Abnormal postures of the 
upper limbs due to spasticity include thumb refraction, a clenched fist deformity, flexion of the wrist 
flexors, pronation of the forearms, flexion of the elbow flexors, and adduction/inner rotation of the 
shoulder flexors (Gracies, 2003; Kinoshita, 2015). 
Spasticity hampers rehabilitation therapy. In addition, limitation of flexors range of motion and 
persistent pain hinder from caregiving and decrease activity in daily life (Grazko, 1995); therefore, 
many of patients with stroke require treatments to ameliorate their dysfunction.
For the treatments of spasticity, rehabilitation therapy, oral medications, phenol blocks, and 
baclofen injections were used until botulinum therapy has been approved as a national health 
insurance coverage. These treatments were commonly challenging because of lack of effects, difficult 
procedures, or invasive interventions. Subsequently, in Oct 2010, the product was approved as a 
botulinum treatment for upper and lower limb spasticity in Japan. Since then, botulinum toxin has 
been used for the treatment of spasticity (Ohsawa, 2013). According to the “Japanese Guidelines for 
the Management of Stroke” (initial version in 2009, revised in 2015) (Ogawa, 2015; Shinohara, 2009), 
which was issued by the Japan Stroke Society, botulinum therapy is recommended for the treatment of 
spasticity as Grade A, and is considered to be effective for relief of upper limb spasticity, increase of 
range of motions in flexors, and reduction of the amount of assistance on daily life.


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In Japan, upper limb spasticity, a domestic phase II study involving the finger, wrist, and elbow 
flexors was performed from Dec 2001 through Mar 2003, and a domestic phase III study involving the 
finger and wrist flexors from May 2007 through Dec 2008. Consequently, the product was approved 
for the treatment of upper limb spasticity with a maximum dose of 240 units per administration in Oct 
2010. 
However, subsequently, the injections of the product at 240 units were found to be insufficient for 
the involving muscles because patients with extensive upper limb spasticity require dose adequate to 
inject into many of the involving muscles. Therefore, many medical institutions requested us to 
increase the maximum dose per administration of the product. Moreover, the specified drug-use 
survey from Jun 2011 through Apr 2014 identified that approximately 39% of the patients who use the 
product for upper limb spasticity were injected more than 240 units, a maximum dose per 
administration. The results suggest high patient needs for an increase of the maximum dose per 
administration of the product. 
In US, as a maximum dose per administration, 400 units of injections of the product have been 
approved for the treatment of upper limb spasticity in adult patients in 2015; therefore, the authorized 
dose between US and Japan is different. 
Based on these background, the study was planned to evaluate the efficacy and safety of 400 units 
of the product for upper limb spasticity in order to increase the maximum dose per administration to 
400 units. 
The study was planned based on the regulatory advice by the Pharmaceuticals and Medical Devices 
Agency (PMDA). 
3.3.
Benefit/Risk Assessment
For details of the known and anticipated benefit/risk and rationally expected adverse events are 
shown on the Investigator's Brochure (IB) and package insert. 


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3.3.1.
Risk Assessment
Important identified risks
Reports suggesting risks/ Outlines of rationale
Measures for risk minimization
Investigational product :GSK1358820
Hypersensitivity
Serious and/or immediate hypersensitivity reactions
(anaphylaxis, serum sickness, urticarial, soft tissue 
edema, or dyspnea, etc.) have been rarely reported. 
Patients who previously experienced allergic reactions 
due to botulinum toxin type A, an additive agent of 
sodium chloride, or human serum albumin are 
excluded from enrolment. Upon written informed 
consent process, subjects will be explained that any 
urticarial, swelling face, throat swelling, wheezing, 
dizziness, or dyspnoea should contact their 
investigator. 
Pre-existing neuromuscular disorder
Patients with neuromuscular junction diseases 
(myasthenia gravis, Lambert-Eaton myasthenic 
syndrome etc.) may increase the sensitivity to the 
product, resulting in excessive muscular weakness. 
For patients with myasthenia gravis, Eaton-Lambert 
syndrome (ELS), amyotrophic lateral sclerosis, or a 
serious disease and who use a concomitant drug (s) 
which may inhibit neuromuscular function, exclusion 
criteria will be set, and those patients will be excluded 
from enrolment in the study (refer to 6.2.1). 
distant spread of toxin
Adverse drug reactions in the remote muscles, except 
but the injected site, have been rarely reported. The 
adverse drug reactions include muscular weakness, 
constipation, dysuria, swallowing difficult, and non-
accidental entering of food or fluid in the lungs not via 
the stomach, but the trachea (pneumonia may occur). 
The patients who received the product at a higher dose 
are considered likely to have increased risks for these 
adverse drug reactions. 
In this study, a high dose of 400 units of the product 
will be injected. Therefore, the subjects will be 
followed up after 2, 4, 6, and 12 weeks of injection. 
The safety of the subjects will be observed carefully.
Use of at least one of the following guide tools 
(electromyogram, electrical stimulator, or 
ultrasonography) will be essential in the blind phase to 
ensure identification of the exact site of injection.


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Important identified risks
Reports suggesting risks/ Outlines of rationale
Measures for risk minimization
Immunogenicity, drug resistance, antibody production The important cause of neutralizing antibody 
production has not been fully clarified. A few studies 
suggested that the injection of the product at short 
intervals or at a high dose may lead to increased rate 
of antibody production[Jankovic, 2006; Klein, 2002]. 
Neutralizing antibody production against botulinum 
toxin type A may lead to inactivation of the biological 
activity of the product, resulting in decreased 
therapeutic effects of the product.
In this study, patients who were considered likely to 
have neutralizing antibody production based on the 
previous treatment experience of botulinum toxin type 
A will be excluded from enrolment in the study 
(Exclusion Criteria 6.2.1).
In addition, treatment schedule in the study was set to 
ensure at least a 12-week dosing interval. 
Other (If applicable)
Medication error (preparation with lidocaine)
One fatal case due to anaphylaxis has been reported. 
In this case, the patient died after 100 units of an 
injection of the product that prepared inappropriately 
with 5 mL of 1% lidocaine. The causal relationship of 
death to the product and lidocaine, or both has been 
unknown. 
In this study, the product will be prepared
appropriately with 0.9% normal saline. The 
preparation method will be described on the study 
reference manual (SRM).


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3.3.2.
Benefit Assessment
In patients with post-stroke upper limb spasticity, currently, the product is approved to inject up to 
240 units per administration in Japan. However, in patients with extensive upper limb spasticity, the 
treatment effects of the product is presumed to lack because of the dose limitation.
In US, the efficacy and safety of the product up to 400 units per dose for patients with upper limb 
spasticity is confirmed, and the clinical use of the product has been approved. The injections of 400 
units of the product in this study are expected to increase injectable sites and enhance the treatment 
effects in Japanese patients with upper limb spasticity, who did not have great benefits from 240 units 
of the product.
If a subject is assigned to the 240 units group in Part 1 and meets the eligibility criteria for injection in 
the open-label phase, 400 units of the product will be injected in and after Part 2. Therefore, all the 
subjects who participate in this study are given the opportunity to receive 400 units of the product 
(Refer to “5. STUDY DESIGN”). 
3.3.3.
Overall Benefit:Risk Conclusion
The known potential risks in the product is justified by the benefits which would provide for the 
patients with post-stroke upper limb spasticity, given the safety measures to minimize risks in subjects 
who enrol in the study. 


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4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoint(s)
Primary
To evaluate the efficacy of injection of 400 units 
of the product at Week 6 (finger/ wrist flexors: 
240 units, elbow flexors: 160 units), comparing to 
that of 240 units (finger/ wrist flexors: 240 units, 
elbow flexors: placebo).
The rate of the subjects that Modified Ashworth 
Scale (MAS) score was reduced at least 1 from 
baseline in the elbow flexors (the responder rate). 
Secondary
To evaluate the efficacy of 400 units of the 
product, comparing to 240 units of the product.

The responder rate of MAS score from 
baseline in finger, thumb and wrist 
flexors

Changes in MAS score from baseline in 
finger, thumb, wrist, elbow, pronation of 
forearms and shoulder flexors

Changes in Disability Assessment Scale 
(DAS) from baseline
To evaluate the safety and tolerability of the 
product of 400 units, comparing to 240 units of the 
product/ To evaluate the safety and tolerability of 
400 units of the product.

Adverse events

Physical examinations

Clinical laboratory tests (haematology, 
blood biochemistry, urinalysis)

Vital signs (heart rate, blood pressure, 
body temperature)
Exploratory
To evaluate the efficacy of 400 units of the 
product 

Changes in MAS score from baseline in 
finger, thumb, wrist, elbow, pronation of 
the forearm and shoulder flexors
To evaluate the other efficacy of the product of 
400 units, comparing to 240 units of the product/ 
To evaluate the other efficacy of 400 units of the 
product

Changes in Numeric Rating Scale 
(NRS) for pain from baseline

Changes in other items of DAS from 
baseline 

Clinical Global Impression of Change 
(CGI) of functional disability by a 
investigator

CGI of functional disability by a patient

Time to patient-reported onset of 
spasticity symptom relief

Patient-reported benefit of injection

Time to qualification for retreatment
To evaluate neutralizing antibody production

Testing for neutralizing antibody 


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5.
STUDY DESIGN
5.1.
Overall Design
This study is a 48-week multicenter, phase III study (a placebo controlled, randomized, double-blind 
comparative study and an open-label, uncontrolled study) to evaluate the efficacy and safety of the 
product in patients with post-stroke upper limb spasticity. The study period is up to 52 weeks, 
consisting of a screening phase up to 4 weeks, minimum 12-week blind phase (Part 1), maximum 36-
week open-label phase (12 weeks per cycle with maximum 3 treatment periods, Part 2, Part 3 and Part 
4). (Figure 5).
BOTOX 400 U
BOTOX 240 U
+
Placebo
BOTOX 400 U
BOTOX 400 U
Screening
BOTOX 400 U
Double-blind treatment
(12 weeks)
Open-label treatment 
(36 weeks)
Part 3
Part 4
Part 1
Part 2
dose 
dose 
dose 
dose 
dose 
Figure 5   Study Design
In this study, the efficacy of 400 units of the product at Week 6 is evaluated, comparing to that of 
240 units, and improvement tendencies are also evaluated in patients with post-stroke upper limb 
spasticity. The improvement will be defined as at least 1 reduction on the MAS score from baseline (a 
measurement value before injection of Day 1). The responder rate (the rate of the subjects that MAS 
score is reduced at least 1 from baseline) in the elbow flexors at Week 6 is set as an endpoint. As a 
point estimate, if the responder rate in the 400 units group outweighs that in the 240 units group, 
improvements tendencies will be considered to be positive. 
For injection, use of the following any one of the tools: EMG, electrical stimulator, or 
ultrasonography, is recommended to ensure identification of the exact injection site. In the blind phase, 
use of at least one of the following tools: EMG, electrical stimulator, or ultrasonography, will be 
essential to ensure identification of the muscle to be injected correctly. 
5.1.1.
Screening Phase (up to 4 weeks) 
Evaluation and screening tests will be performed 28 days to 7 days (+3 days) before initial injection 
(Day 1) as a starting point. The investigator will decide which arm to be injected during screening 
phase. Throughout the study period, the arm, which is decided to be injected at screening phase will 
be involved during the injections and evaluations, unless clearly specified otherwise by the sponsor. 


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5.1.2.
Blind Period (minimum 12 Weeks): Placebo Controlled, Randomized, Double 
Blind Design
Subjects who meet the inclusion criteria will be randomized 1:1 to either the 400 units or the 240 
units group. 

In the 400 units group, a total of 240 units of the product will be injected into the muscles 
that act on the finger (including thumb flexors) and wrist flexors, and a total of 160 units 
into the muscles that act on the elbow flexors; a total of 400 units of the product will be 
injected.

In the 240 units group, a total of 240 units of the product will be injected into the muscles 
that act on the finger (including thumb flexors) and wrist flexors. Placebo will be injected 
into the muscles that act on the elbow flexors. A total of 240 units of the product will be 
injected.
If the total dose for the muscles that act on the finger and writs flexors is ensured by 240 units, and 
160 units for the muscles that act on the elbow flexors, the dose can be adjusted at a investigator’s 
discretion based on the subject’s symptoms. (Refer to “7.1. Treatments Administered” Table 2).
5.1.3.
Open-Label Phase (maximum 36 weeks): Uncontrolled, Open-Label Design
The product of 400 units will be injected in both groups. The product can be injected up to 3 times 
after completion of Part 1 in the blind phase. In the open-label phase, subjects whom the investigator 
considers eligible for the injection will be treated (Refer to 5.1.3.1. Eligibility Criteria for Injection in 
and after Part 2). The next injection cannot be performed until the eligibility of the subject has been 
confirmed by the investigator (Refer to 5.1.3.1. Eligibility Criteria for Injection in and after Part 2).
In the open-label phase, the muscle to be injected and the dose will be decided by the investigator
based on the patient’s symptoms, and a total dose of 400 units of the product will be injected in a 
divided dose (Refer to "7.1. Treatments Administered” on Table 3). For the muscles that the 
investigator considers unnecessary to be treated, an injection may be skipped. The involving muscle 
and the dose do not have to be same each time always.
5.1.3.1.
Eligibility Criteria for Injection in and after Part 2
In the open-label phase (Part 2, Part 3, and Part 4), the subjects whom the investigator considers
eligible for the injections in the open-label phase only will be treated. The eligibility is evaluated at a 
study visit after Week 12 (V5, if a subject does not meet the eligibility criteria, the evaluation will be 
performed at QRV (Qualification for Retreatment Visit). A subject will be considered as eligible when 
he or she meets all the criteria. The eligibility evaluation will be performed after completion of Part 1 
in the blind phase, between Week 12 to Week 36. If a subject does not meet the eligibility at Week 36, 
subsequent evaluation will not be performed, and the product cannot be given (refer to Figure 1, 
Figure 2, Figure 3, and Figure 4).


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
At least 12 weeks (84 days) have passed since the preceding dose

Among the finger, wrist or elbow flexors, 2 flexors have at least 2 on the MAS (except only the 
finger and wrist flexors of 2 on the MAS)

Subject who request the injection

Subjects whom a investigator considers an injection of 400 units of the product is appropriate

Subjects who were considered to remain freedom from unacceptable safety concerns (including 
potential for serious adverse events, laboratory data, electrocardiogram or pulmonary function 
test value) due to the injection of 400 units of the product 

Subjects who have not experienced serious adverse events (SAE) associated with the injection 
of the product
If a subject meets the criteria above at V5 or QRV, before injection of V1, the following items will 
be confirmed: 

Subjects with ≥ 40 kg in body weight 

Women of childbearing potential who have negative pregnancy test results in urine 
5.2.
Number of Participants
Approximately 120 subjects (approximately 60 in each group) will be randomized to obtain an 
evaluable subject sample of approximately 100 at Week 48 as subjects who complete the study
5.3.
Participant and Study Completion
Subjects who completed all the study procedures, including a completion visit will be regarded as 
study completion. The completion date in this study will be defined as the last day performing the 
study procedure of last subject. 
5.4.
Scientific Rationale for Study
The study design was set to evaluate the efficacy and safety of 400 units of the product in patients 
with post-stroke upper limb spasticity. The primary endpoints employed the responder rate of the 
MAS score in the elbow flexors. The reasons for employing MAS score as an indicator include that 
MAS is highly reliable for evaluation of upper limb spasticity (Bohannon, 1987; Mutlu, 2008); 
especially, for evaluation of spasticity in the elbow flexors in the upper limbs (Gregson, 2000; Sloan, 
1992). 
Screening Phase
The screening phase up to 28 days before initial injection was set in order to confirm subjects meet 
the inclusion criteria and none of the exclusion criteria, and assess the condition of subjects at baseline. 
However, measurements of laboratory parameters at screening phase should be completed by 4 days 
before Day 1 (Day -28 to -4). 


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Treatment Phase 
In Part 1, a double blind comparative study was set to compare the efficacy of the product of 400 
units to 240 units, the currently approved dose for upper limb spasticity. In the blind phase, 240 units 
of the product will be injected into the muscles that act on the finger (including the thumb)/wrist 
flexors, and 160 units (the 400 units group) or placebo (the 240 units group) for the muscles that act 
on the elbow flexors. The improvement tendencies in the efficacy between the 240 units group, the 
total dose, and the 400 units groups will be compared by evaluating the responder rate tendencies on 
the MAS score in the elbow flexors in a blinded manner. In the previous confirmatory study (108509 
study) for approval of the product for upper limb spasticity, the elbow flexors were not involved. 
Therefore, in this study, the responder rate on the MAS score in the elbow flexors was decided to 
compare as the placebo group. 
Actually, in medical institutions, the product is injected into the whole upper limb, including the 
shoulder flexors. In addition, the dose for each muscle is decided at a investigator’s discretion. 
Previous studies reported that botulinum injections into the pectoralis major and teres major muscle 
relieved pain in patients with hemiplegia (Marciniak, 2012) and injections into the sub-scapula 
improved passive range of motion (Yelnik, 2007). Therefore, in and after Part 2 in the open-label 
phase, the product will be allowed to be injected not only into the muscles that acts to the finger 
(including the thumb), wrist, and elbow flexors, but also the muscles that act on the shoulder flexors, 
where applicable, enabling a investigator to decide the dose for each muscle. In addition, the study 
design included safety evaluation of the product at Week 48 after initial injection in all subjects as far 
as possible for safety evaluation purposes of 400 units. 
5.5.
Dose Justification
The product of 400 units is a maximum dose for upper limb spasticity, which was approved by the 
U.S. Food and Drug Administration (FDA), and this suggests that the efficacy and safety profiles are 
favourable. Evaluation of the efficacy and safety of 400 units of the product provides beneficial 
information in Japanese patients with severe post-stroke upper limb spasticity, who are considered 
injections of 400 units of the product are necessary. 
The dose of 240 units of the product, the controlled group, in the blind phase (Part 1) is the current 
authorized dose (a maximum dose per administration) for upper limb spasticity in Japan. In this study, 
the 240 units group was set as the control group in order to evaluate improvement tendencies, 
comparing the efficacy of 240 units of the product, the current approved dose, to that of 400 units of 
the product.  
6.
STUDY POPULATION
Inclusion of subjects despite expectation of deviation from the protocol, namely, exemption or 
discharge from the protocol, cannot be allowed.
6.1.
Inclusion Criteria
6.1.1.
Screening Phase (Day -28 to Day -1)
In the screening phase, subjects eligible for enrolment in the study must meet all of the following 
criteria. Laboratory parameters should be measured by 7 days (± 3 days) before initial injection
(Day 1). 


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Age
1. Between 20 and 80 years of age at the time of informed consent (ICF). 
Subjects and Characteristics of the Disease
2. Patients with at least a 3-month history of upper limb spasticity after the most recent stroke 
3. Patients who have spastic symptoms in the finger (including the thumb), wrist, and elbow flexors
whom the investigator considers the injections of 400 units of the product is necessary for the upper 
limb based on the muscle spasms and the symptoms of the patient
4. Patients who have a previous treatment history of 240 units of the product for the upper limb at 
least 16 weeks before screening (refer toTable 3 for muscles in the upper limbs) 
5. Patients who meet following criteria on MAS at screening (Test position : sitting)

At least 3 in for the elbow flexors
And

At least 2 in the finger or wrist flexors
6. Patients who have severe upper limb spasticity, which deserves to be treated with 400 units of the 
product in the divided dose and was previously injected 240 units of the product
7. Patients whom the investigator considers that enrolment in the study poses no problems based on 
the laboratory data results at screening
8. Patients who are free from a history of acute decreased lung function (hospitalization with 
aggravated asthma/COPD, pneumonia, or signs of pneumonia, or abnormal reactive airway diseases 
suggested on X-rays) within the last 3 months at screening and have stable pulmonary function 
Body Weight
9. Body weight ≥ 40 kg at screening
Sex
10. Male or female
a.
Male Subjects
Male subjects must content to use highly effective contraceptive methods, which are shown on 
attachment 5 of the protocol in detail during the study period, and sperm donation must be 
avoided. 
b.
Female Subjects
Female subjects who are not pregnant or lactating are considered eligible (refer to attachment 5) 
if at least one of the following criteria is met:
i)
Non-childbearing potential based on the definition on attachment 5
ii)
Women of childbearing potential who content to follow the guidance about contraception on 
attachment 5 during the study period and at least for 3 months after the last dose of the 
product.
iii)
No plan of pregnancy during the study period
Informed Consent
11. Patients who have ability to sign their name on the ICF, following the description on attachment 3, 
adhering to the requirements and limitations described on the ICF and the protocol. 


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6.1.2.
Day 1 (prior to injection)
Subjects eligible for enrolment in the study must meet all of the following criteria on Day 1 (prior 
to injection): 
Subjects and Characteristics of the Disease
31. Patients who meet the following criteria on MAS score: (Test position : sitting)

At least 3 in the elbow flexors
And

At least 2 in the finger or wrist flexors
Preceding Treatments and Concomitant Medications/Therapies
32. If centrally acting muscle relaxants, tetracycline antibiotics, anticholinergics, benzodiazepines, or 
benzamides are given, the dose and regimen must be stable at least for the last 2 months before 
Day 1; Patients who can maintain the same dosage and regimens at least in the blind phase after 
initial injection (dose reductions and discontinuation of the drugs are acceptable in the open-label 
phase. However, second dose increase, resumption, and or new treatment will not be performed). 
33. If intrathecal baclofen is given, the dose and regimen must be stable at least for the last 1 month 
before Day 1; Patients who can maintain the same dosage and regimens at least in the blind phase
after initial injection (intravenous bolus is not acceptable, dose reductions and discontinuation of 
the drugs are acceptable. However, second dose increase, resumption, and or new treatment will 
not be performed).
34. If antiepileptic agents are given, the dose and regimen must be stable at least for the 1 month 
before Day 1; Patients who can maintain the same dose and regimens at least in the blind phase 
after initial injection (dose reductions and discontinuation of the drugs are acceptable in the open-
label phase. However, second dose increase, resumption, and new treatment will not be 
performed).
35. If a physical therapy, occupational therapy, or a static splint on the study involvement upper 
limbs is given, the frequency and treatment regimen must be stable at least for the last 3 weeks 
before Day 1; Patients who can maintain the same dose and regimens at least in blind phase (In 
the open-label phase, the frequency and treatment regimen can be changed depending on the 
condition of spasticity).
6.2.
Exclusion Criteria
6.2.1.
Screening Phase (Day -28 to Day -1)
A subject will be excluded from enrolment in this study if any of the following criteria apply in the 
screening phase. Measurements of laboratory parameters at screening must be completed 7 days (±3 
days) before initial injection (Day 1).
Medical Condition
1.
Patients present with spasticity requiring treatment in the non-paralytic side of the upper limb
2. Patients who have fixed contracture* in the finger (upper limb), wrist, elbow or shoulder muscle,     
which will be involved in the study


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(*Positive effects were not confirmed in the previous treatment with GSK1358820, and 
contracture is considered to be the main cause of limited range of motion in the joint.)
3. Patients who have medically significant capsulitis or subluxation in any one of the fingers (upper 
limb), wrist, elbow and shoulder, which will be involved in the study, or whom a investigator
considers the complicated local signs of pain may affect the efficacy evaluation
4. Patient’s upper limb spasticity is attributed to other than stroke (traumatic brain injury, spinal cord 
injury, multiple sclerosis, or cerebral palsy)
5. Patients who have a 2-fold higher alanine aminotransferase (ALT) level than the upper limit of 
normal (ULN)
6. Patients who have a 1.5-fold higher bilirubin than the ULN (If a bilirubin fractionation shows direct 
bilirubin < 35%, a 1.5-fold higher free bilirubin than the ULN is acceptable).
7. Patients whom the investigator considers presence of a current medical history of unstable liver 
diseases or biliary tract diseases (the condition will be defined by development of ascites, 
encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice 
or hepatic cirrhosis)
Note:

If a patient with stable chronic liver diseases (Gilbert's syndrome, silent gallstone, and stable 
chronic hepatitis B or hepatitis C [Namely, hepatitis B surface antigen: HBsAg or hepatitis 
C virus: HCV antibody shows positive at screening or within 3 months before initiation of 
the study treatment] are included) meets other inclusion criteria, the patient can be enrolled 
in the study. 
8. Patients with QTc > 450 msec or QTc > 480 msec in patients with bundle branch block
Note:

QT intervals corrected by the Bazett method (QTcB); QT intervals corrected by the 
Fridericia method (QTcF) and/or QT intervals corrected by other methods; interpretation by 
a machine or manual re-interpretation will be used.

Prior to study initiation, the correction formula which is used for the subject’s 
inclusion/exclusion/discontinuation criteria will be determined. Namely, several different 
correction formula cannot be used for calculation of QTc in each subject. In addition, the 
lowest QTc level cannot be used for enrolment or discontinuation of subjects of the study. 
Preceding Treatments and Concomitant Medications/Therapies
9. Patients who use peripherally acting muscle relaxants (dantrolene sodium, suxamethonium chloride, 
pancuronium bromide, vecuronium bromide, rocuronium bromide, etc.) within 1 week of screening.
10. Patients who use antibiotic agents with neuromuscular junction inhibitory effects: Aminoglycoside 
antibiotic agents (streptomycin sulfate, kanamycin sulfate, gentamicin sulfate, neomycin sulfate, 
spectinomycin hydrochloride, etc.), polypeptides (polymyxin B sulfate), lincomycins (lincomycin 
hydrochloride, clindamycin), and enviomycin sulfate within 1 week of screening.
11. Patients who was diagnosed as having a malignant tumor, or have a history of a malignant tumor 
within the last 5 years (except completely resected basal cell carcinoma or planocellular carcinoma 
at least 12 weeks before screening)


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Previous Experience of Participation in a Clinical Studies/Current Participation in 
another Ongoing Study 
12. Patients who have participated in another study of an investigational product or other medical 
research (a clinical study of pharmacotherapy, non-pharmacotherapy, or interventional device) 
within 30 days before screening, or are currently participating in a study
Evaluation by Diagnosis
13. Patients who are concerned likely to have an increased risk for an underlying medical 
condition/neurological disease due to exposure of the product; patients who have myasthenia gravis, 
Eaton-Lambert syndrome, amyotrophic lateral sclerosis, or a serious disease and use of a 
concomitant drug which may inhibit neuromuscular function 
14. Patients with antihuman immunodeficiency virus (HIV) antibody positive
15. Patients who previously experienced allergic reactions or hypersensitivity due to botulinum toxin 
type A, an additive agent of sodium chloride, or human serum albumin
16. Patients who were previously suspected to have neutralizing antibody production by a investigator
during an injection of botulinum toxin type A  
17. Patients who have a skin disease such as infection at the site to be injected  
18. Patients who suffer from serious and unstable disease, which could pose problems for the safety of 
subjects and study procedure compliance
6.2.2.
Day 1 (Prior to injection)
A subject will be excluded from enrolment in this study if any of the following criteria apply on 
Day 1 (prior to injection): 
Medical condition
31. Patients who placed a surgical cast or a dynamic splint within 3 months before Day 1 study visit, 
and/or these interventions are planned to be placed on the upper limb to be involved in the study
Preceding Treatments and Concomitant Medications/Therapies
32. Patients who were treated with botulinum toxin for spasticity of upprt limb less than 16 weeks
before Day 1 visit
33. Patients who underwent surgical interventions, phenol block, ethanol block or Muscle Afferent 
Block (MAB) within 12 months before Day 1 visit, or these interventions are planned during the 
study period in any one of the finger (upper limb), wrist, elbow or shoulder muscles, which will 
be involved in the study
34. Patients who have aspiration pneumonia, relapse of lower respiratory tract infection, 
uncontrollable asthma, uncontrollable COPD, and/or underlying or a history of serious 
respiratory dysfunction, which were clinically considered to be respiratory function impairment 
by a investigator within 12 months before Day 1 visit
35. Patients who have a history of aspiration, or an underlying and/or a history of the symptoms that 
suggests high risks for aspiration by a investigator within 12 months before Day 1 (serious 
salivation requiring changing in a type of diet, chronic dysphagia that is difficult to swallow)


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36. Patients who were injected corticosteroid or an anesthetic agent into the finger (upper limb), 
wrist, or shoulder flexors, which will be involved in the study within 3 months before Day 1 visit, 
or these injections are planned during the study
37. Patients who received CIMT (constraint-induced movement therapy) within 3 months before Day 
1 visit or CIMT is planned during the study
38. Patients who underwent ultrasound therapy, TENS (transcutaneous electrical nerve stimulation ), 
electrical stimulation therapy, or acupuncture therapy in the upper arm, which will be involved in 
the study within 1 month before Day 1 visit, or these therapies are planned during the study
6.3.
Lifestyle Restrictions
No limitations are required. 
6.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are not 
subsequently [randomized/entered in the study]. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries from 
regulatory authorities. Minimal information includes demography, screen failure details, eligibility 
criteria, and any serious adverse events (SAEs).
Rescreening
If a patient does not meet the participation criteria in the study (dropout during screening), the 
patient may undergo second screening only 1 time. If a patient does not meet following items, contact 
the medical monitor of the sponsor and gain his/her consent because validity of rescreening in subjects 
who dropped out needs to be judged carefully in the light of medical aspects.

Subjects who did not meet the inclusion criteria for MAS (Inclusion criteria 5 at screening) 
and dropped out (However, the dropout period will be for within only 1 month from the 
dropout). 

For some reasons, a subject cannot make a study visit or undergo examination 

Sample collection or examination cannot be performed because of procedural or technical 
problems
The investigator must carefully consider the ethical aspects of subjects, and if other treatments are 
considered to give more treatment benefits for a subject, rescreening must not be conducted. 
The rescreened subjects will be allocated a different subject identification number as upon initial 
screening.


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7.
TREATMENTS
Study treatment product is defined as as any investigational treatment(s), and placebo to administer to 
a study participant according to the protocol. 
7.1.
Treatments Administered
Study Treatment 
Name: 
GSK1358820
(Nonproprietary name: 
Botulinum toxin type A)
Placebo
Dosage formulation: 
Injection
Injection
Ingredient and quantity 
(Per vial) 
Botulinum toxin A 100 units
Sodium chloride 0.9 mg
Human serum albumin 0.5 mg
Sodium chloride 0.9 mg
Packaging and 
Labeling 
It will be listed on the labelling in 
accordance with the regulatory 
requirements in Japan.
It will be listed on the labelling in 
accordance with the regulatory 
requirements in Japan.
Manufacturer
Allergan (Ireland) 
Allergan (Ireland)
Dose
400 units
240 units
Dose
Dosing instructions
Part 1: 240 or 400 units of the product will be injected into the muscles that act on the 
finger (including thumb flexors), wrist and elbow flexors, in accordance with Table 2.
In and after Part 2: 400 units of the product will be injected into the muscles that 
act on the finger (including thumb flexors), wrist, elbow and shoulder flexors in 
accordance with Table 3. For the muscles that the investigator considers 
unnecessary to be treated, an injection may be skipped. Dose intervals should be at 
least 12 weeks.
For adjustment of the product, the product will be dissolved with 2 ml of normal 
saline per 1 vial (100 units). The details will be described on Table.4. 
In the blind phase

A total of 240 units of product will be injected into the muscles that act on finger (including 
thumb flexors) and wrist flexors, and a total of 160 units of the product or placebo for the 
muscles that act on the elbow flexors in divided doses in accordance with Table 2.

The muscles which are not listed on Table2 must not be used.

All of the muscles descried on Table 2 must be used. If the subject with no symptoms with 
thumb, the investigator does not have to inject to thumb. 

If the total dose for the muscles that act on the finger and writs flexors is ensured by 240 
units, and 160 units for the muscles that act on the elbow flexors, the dose can be adjusted at 
a investigator’s discretion based on the symptoms of a subject.
In the open-label phase

The investigator will decide the dose and the muscle to be injected based on the symptoms 
of patients, and a total of 400 units will be injected in divided doses. For the muscles that 
the investigator considers unnecessary to be treated, an injection may be skipped.

The muscles to be injected must be chosen from Table 3, and the muscles which are not 
listed on Table 3 must not be used. For dose and number of injection site (sites/muscles), 
refer to Table 3 and will be decided by investigator. 


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Table 2    Muscle Involvement and Dose in the Blind Phase
Number
Muscles
The 400 units 
group
Dose (units)
The 240 units 
group
Dose (units)
Number of 
injection site (site 
and muscles)3
Joint
A1
Biceps brachii 
701
Placebo
2
A.Elbow 
A2
Brachialis
451
1
A3
Brachioradialis
451
1
B1
Flexor carpi radialis 
502
502
1
B.Wrist  
B2
Flexor carpi ulnaris 
502
502
1
C1
Flexor digitorum profundus 
502
502
1
C.Finger 
C2
Flexor digitorum superficialis
502
502
1
D1
Flexor pollicis longus 
202
202
1
D.Thumb
D2
Adductor pollicis 
202
202
1
Total
4002
2402
1
-
1: Within the limits of the total of 160 units (the elbow flexors), the dose will be decided by a investigator depending on the patient’s 
symptoms.
2: Within the limits of the total of 240 units (the finger and wrist flexors), the dose will be decided by a investigator depending on the 
patient’s symptoms.
3: When the dose exceeds 50 U per muscle, take into account the divided-injection.
Table 3    Muscle Involvement and Reference Dose in the Open-Label Phase
(Modified partially of “Dosing, Administration, and a Treatment Algorithm for Use of 
Botulinum Toxin A for Adult-Onset Spasticity.[Brin, 1997]”)
Number
Muscles1
Dose (units)2
Number of 
injection site
(Sites/muscles) 2
Joint
A1
Biceps brachii 
50-200
4
A.Elbow
A2
Brachialis
25-75
2
A3
Brachioradialis
25-75
2
B1
Flexor carpi radialis
25-100
2
B.Wrist
B2
Flexor carpi ulnaris
10-50
2
C1
Flexor digitorum profundus
25-100
2
C.Finger
C2
Flexor digitorum superficialis
25-75
4
C3
Lumbricales interossei
10-50/hand
3
D1
Flexor pollicis longus
5-25
1
D.Thumb
D2
Adductor pollicis
5-25
1
D3
Opponens
5-25
1
E1
Pronator teres
25-75
1
E.Forearms
E2
Pronator quadratus
10-50
1
F1
Teres major 
25-75
1
F.Shoulder
F2
Latissimus dorsi
50-150
4
F3
Pectoralis major 
75-150
4
F4
Subscapularis
25-75
1
(Brin MF and the Spasticity Study Group, 1997)
1: The muscles which are not listed on Table 3 must not be used
2: For dose and number of injection site (sites/muscles), refer to Table 3 and will be decided by investigator.


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Table 4    Muscle Involvement and Reference Dose in the Open-Label Phase
Dose (units)
Injection Volume (ml)
100
2.0 
95
1.9 
90
1.8 
85
1.7 
80
1.6 
75
1.5 
70
1.4 
65
1.3 
60
1.2 
55
1.1 
50
1.0 
45
0.9 
40
0.8 
35
0.7 
30
0.6 
25
0.5 
20
0.4 
15
0.3 
10
0.2 
5
0.1 
7.2.
Dose Modification
Not applicable
7.3.
Method of Treatment Assignment
After completion of all evaluations at screening phase/initiation of the blind phase, the subjects who 
met the inclusion criteria and none of the exclusion criteria will be given their randomization number
at a case registry center and randomized to either the 240 or 400 units group. The assigned 
randomization number cannot be re-used. The table of the allocation will be prepared via a computer 
in GSK, using the RandAll systems. 
Based on the MAS score (3 or 4) in the elbow flexors, subjects will be stratified at the time of 
randomization. 
The subjects who meet the eligibility for the injections in the open-label phase can move forward to 
the open-label phase and be injected (Refer to section 5.1.3). In the open-label phase, 400 units of the 
product will be given to all subjects. Other detailed information will be described on SRM.
7.4.
Blinding
This study consists of the blind phase (Part 1), followed by the open-label phase (Part 2 and 
subsequent Parts), and in the blind phase, following processes are applied. 
A Role of the Person Responsible for Investigational Product Assignment  
The person who is responsible for investigational product assignment will prepare an operating 
procedure for the assignment. The operation will be conducted in accordance with the operating 
procedure. The person who is responsible for the investigational product assignment will display the 
drug number on a container of the investigational product (investigational product and control drug) 


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after checking of the investigational product (investigational product and control drug) and the 
indistinguishability of packaging appearance. The confirmation of the investigational product 
(investigational product and control drug) and the indistinguishability of packaging appearance will be 
also performed after completion of the study. In addition, an operating procedure for occasion where 
the emergency treatment disclosure is required will be prepared. In response to the request of 
disclosure, unblinding procedures are performed for the requested drug only.
The unblinded subjects by the investigator will discontinue participation in the study. In addition, 
the major reasons for discontinuation (the event(s) or condition led to unblinding) will be described on 
case report form (CRF). 
The Global Clinical Safety and Pharmacovigilance (GCSP) of the sponsor may disclose the 
assigned treatment in the subject, who experienced serious adverse events. For serious adverse events 
requiring emergency report to the regulatory authority, a copy of an emergency report on the assigned 
treatment of the subject may be sent to the study involving investigator in accordance with the 
regulations, policy of the sponsor, or both.  
7.5.
Preparation/Handling/Storage/Control
1.
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported and 
resolved before use of the study treatment. 
2.
Only participants enrolled in the study may receive study treatment and only authorized site staff 
may supply or administer study treatment. All study treatments must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the investigator and authorized site staff. 
3.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
4.
Further guidance and information for the final disposition of unused study treatment are provided in the 
Study Reference Manual
.
7.6.
Treatment Compliance
Subjects will be intramuscularly injected the product at a medical institution. The injection will be 
recorded in the source documents, and described in the case report form. 
7.7.
Concomitant Therapies
The medications that are used by subjects at the time of enrolment in the study or all medications 
and vaccines to be used during the study (over the counter drugs or prescribed drugs, vitamins, and/or 
herbal supplements) must be recoded with the following items: 

Reasons for use

Initial date of administration and administration dates, including completion day

Regarding the dose, including dosage and number of administration


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Contact the medical monitor if there are any questions about concomitant therapies or preceding 
drugs.
7.7.1.
Permitted Concomitant Drugs/Therapies
Following drugs and therapies are permissible only if a subject is already using them before 
initiation of the study. However, the dosage and administration will not be changed from the screening 
through completion of the blind phase. In and after open-label phase, dose reduction and 
discontinuation of the drugs will be allowed. However, once dose is decreased, re-increase will not be 
performed. If the drug(s) is/are discontinued, the drugs cannot be resumed. No new treatment will not 
be started after screening phase. 
Rehabilitation therapies such as physical therapy, occupational therapy, and static splint are 
permissible. However, in the blind phase, the frequency and regimens (description of the therapy and 
intensiveness) for the upper limb, which involves in the study will not be changed. In addition, in the 
open-label phase, changing rehabilitation therapy to another one that seems to be the most appropriate 
for a subject is permissible based on the degree of improvements in spasticity. In such cases, the 
information will be described on CRF. Rehabilitation therapy will not be given on the day of 
investigational product injection. 

Central muscle relaxants
(baclofen, tizanidine hydrochloride, tolperisone hydrochloride, eperisone hydrochloride, 
chlorphenesin carbamate, afloqualone, etc.)

Tetracycline antibiotics
(tetracycline hydrochloride, doxycycline hydrochloride, minocycline hydrochloride, etc.)

Anticholinergics
(butylscopolammonium bromide, trihexyphenidyl hydrochloride, etc.)

Benzodiazepines
(diazepam, etizolam, etc.)

Benzamides
(tiapride hydrochloride, sulpiride, etc.)

Antiepileptic drugs
(phenytoin, etc.)

Intrathecal baclofen therapy
7.7.2.
Contraindicated Medications/Therapies 
Following drugs and therapies will be prohibited to use from screening phase through completion of 
the study:

Botulinum toxin preparations

Peripherally acting muscle relaxants

(dantrolene sodium, suxamethonium chloride, pancuronium bromide, vecuronium bromide, 
rocuronium bromide) 

Antibiotic agents with neuromuscular junction blocking effects

Aminoglycosides
(streptomycin sulfate, kanamycin sulfate, gentamicin sulfate, neomycin sulfate, 
spectinomycin hydrochloride, etc.)


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
Polypeptides
(polymyxin B sulfate)

Lincomycins 
(lincomycin hydrochloride, clindamycin)

Enviomycin sulfate

Nerve blocks such as phenol block, ethanol block and MAB for the upper limb

Surgical cast or a dynamic splint

A surgery for the upper limb (s)
Following drugs and therapies will be prohibited to use from screening phase through completion of 
the blinded-phase:

CIMT (constraint-induced movement therapy)
7.8.
Treatments after Completion of the Study
The investigator will take responsibility for subject’s medical care after completion of the study, 
whether the sponsor provides a certain treatment or not.
8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
The efficacy of the investigational product used in this study sustains for about 3 to 4 months 
following a single dose, and thus daily dosage is not required; accordingly, treatment discontinuation 
shall not be defined in this study, and will be considered to be identical to subject withdrawal from 
this study.
8.2.
Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, compliance 
or administrative reasons. 

If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 

If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must document this in the site study records. 

A subject discontinuing this study must visit the study site for study termination assessment 
promptly upon decision to discontinue the study.

Refer to the schedule of assessment (SoA), completion visit (FV), for the details of data to 
be collected at the study discontinuation, and additional assessment that must be completed.
8.2.1.
Liver Chemistry Stopping Criteria
A set of criteria for study discontinuation and follow-up investigation based on hepatic function 
test (in reference to FDA premarketing clinical liver safety guidance) is specified herein to ensure the 
safety of subjects and to evaluate the causes of hepatic events. The guidelines related to this protocol 


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are based on the FDA premarketing clinical liver safety guidance: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM1
74090.pdf.
The investigator should consider discontinuing the study treatment upon discovery of liver function 
test abnormal, and if the subject is applicable to any of the symptoms presented in the algorithm, or 
such discontinuation is determined to be the best choice for the subject as judged by the investigator.
Algorithm A: Phase III-IV Liver Chemistry Stopping and Increased Monitoring Algorithm
Liver Safety Required Actions and Follow up Assessments Section can be found in Appendix 6.


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Algorithm B: Phase III-IV Liver Chemistry Increased Monitoring Algorithm with Continued 
Therapy for ALT ≥3xULN but <8xULN
Liver Safety Required Actions and Follow up Assessments Section can be found in Appendix 6.


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8.2.2.
QTc Stopping Criteria

For a decision on a subject's eligibility or study discontinuation, the same method for 
correction of QT interval must be used in the subject throughout the study, and must not be 
changed once the subject is enrolled. 

For instance, if a subject is enrolled based on QTcB, decisions on the subject's 
withdrawal must be made based on QTcB. 

The method used for correction of QT interval pertinent to the enrollment of a subject 
must be used for all QTc data to be collected throughout the study for the data analysis 
on the subject; provided that such rule is not applicable to ECG intended to ensure 
safety and also ECG not defined in the protocol. 

QTc should be determined based on a single measurement of ECG or the mean of ECG 
measured at 3 timepoints in a short period of time (e.g., 5 to 10 minutes). If abnormality is 
detected in a single measurement, ECG should be measured again, this time, at 3 timepoints. 

The lowest value of QTc cannot be used for a decision to withdraw a subject. 
Refer to the schedule of assessment (SoA), completion visit (FV), for the details of data to be 
collected at the discontinuation of study treatment. Discontinue this study if the mean ECG is 
applicable to any of the following conditions:

QTc >500 msec or uncorrected QT >600 msec

Change in QTc from baseline >60 msec
The following withdrawal criteria should be applied for subjects with bundle branch block: 
Baseline for subjects with bundle branch block
Withdrawal criteria for subjects with bundle 
branch block
<450 msec
>500 msec
450 to 480msec
IJYO530 msec
8.2.3.
Treatment discontinuation due to treatment-related SAE
A subject should be withdrawn from this study if treatment-related serious adverse event has 
occurred.
8.2.4.
Treatment discontinuation due to pregnancy
A female subject who become pregnant during this study must be withdrawn from the study.
8.2.5.
Withdrawal of subjects who start receiving prohibited medications or 
therapies
If a prohibited medication or therapy (See section 7.7.2.) needs to be started during the study, the 
subject must be withdrawn from this study; in which case, the subject must make the study completion 
visit (FV) before starting the prohibited medication or therapy.


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8.2.6.
Prohibition of treatment resumption
Study treatment must not be resumed in subjects who are once withdrawn from this study for a 
reason associated with hepatic function test, QTc, treatment-related serious adverse event, pregnancy, 
or commencement of a prohibited medication or therapy.
8.3.
Lost to follow up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 

The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in the 
study.

Before a participant is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
9.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA. 

Protocol waivers or exemptions are not allowed. 

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue study 
treatment. 

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 

Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and was performed 
within the time frame defined in the SoA. 


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9.1.
Efficacy assessments
9.1.1.
Evaluation methods
9.1.1.1.
Modified Ashworth Scale (MAS)
According to "2. SCHEDULE OF ACTIVITIES (SoA)" the investigator will use MAS (Table 5) to 
evaluate the level of spasticity. MAS should be measured and evaluated by the investigator, 
physiotherapist, or occupational therapist who has been given the training as an assessor. 
The test should be performed on sitting position throughout the study. The affected parts should be 
extended as fast as possible to grade the flexor muscle tones. The final assessment will be made by the 
investigator in consideration of the information from physiotherapist or occupational therapist. The 
assessor should in principle remain unchanged throughout the study period.
Table 5    Modified Ashworth Scale (MAS)
0
No increase in muscle tone
1
Slight increase in muscle tone, manifested by a catch and release or by minimal resistance at 
the end of the range of motion when the affected part(s) is moved in flexion or extension
1+
Slight increase in muscle tone, manifested by a catch, followed by minimal resistance 
throughout the reminder (less than half) of the ROM (range of movement)
2
More marked increase in muscle tone through most of the ROM, but affected part(s) easily 
moved
3
Considerable increase in muscle tone passive, movement difficult
4
Affected part(s) rigid in flexion or extension

MAS measurement as inclusion criteria (Screening and Day 1)
The subject's wrist or fingers and elbow should all be evaluated as inclusion criteria. Subjects 
meeting the eligibility and randomized should be evaluated for MAS at Visit 1 of Treatment Period 1
on the same day; provided that measurement may be performed only once if the affected part to be 
evaluated is the same. The detail of inclusion criteria are shown in 6.1.

MAS measurement during the blinded period
The subject's wrist, fingers and thumb should all be evaluated during the blinded period. Likewise, 
the subject's wrist, fingers and thumb should all be evaluated for MAS at Visit 5 and QRV of the 
blinded period. Subjects meeting the eligibility and transferred to the open-label period should be 
evaluated for MAS at Visit 1 of Treatment Period 2 on the same day; provided that measurement may 
be performed only once if the affected part to be evaluated is the same. Meanwhile, MAS needs to be 
evaluated again if the affected part to be evaluated is not the same. 

MAS measurement during the open-label period
During the open-label period, MAS should be evaluated for the flexors at which the muscle given 
the study treatment functions (fingers, thumb, wrist, elbow, fore-arm) (Table 6). If the subject is 
determined to be eligible, the V5/QRV and V1 would be on the same day, and therefore, the MAS 
measured at V5/QRV of the previous treatment period should not be measured again on V1; the 
measurement on V5/QRV should be used for the assessment (Figure 6). MAS on flexors to be newly 


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assessed on V1 should be evaluated before dose on V1. The MAS on the shoulder should be evaluated 
comprehensively for the adductor and invertor. 
Table 6    Regions to be evaluated for MAS during the open-label period
Number
Muscles to be injected
Regions to be evaluated 
for MAS 
A1
Biceps brachii
Elbow flexors (flexion)
A2
Brachialis
A3
Brachioradialis
B1
Flexor carpi radialis
Wrist flexors (flexion)
B2
Flexor carpi ulnaris
C1
Flexor digitorum profundus
Fingers (flexion)
C2
Flexor digitorum superficialis
C3
Lumbricales interossei
D1
Flexor pollicis longus
Thumb (flexion, 
adduction and opposition)
D2
Adductor pollicis
D3
Opponens pollicis
E1
Pronator teres
Forearm (pronate)
E2
Pronator quadratus
F1
Teres major
Shoulder (adduction and 
internal rotation)
F2
Latissimus dorsi
F3
Pectoralis major
F4
Subscapularis
Visit
SV V1 V2 V3 V4 V 5 V1 V2 V3 V4 V5 V1 V2 V3 V4 V 5 V1 V2 V3 V4 V5
A.Elbow
●
●
●
●
●
●
(○) ●
●
●
●
(○) ●
●
●
●
(○) ●
●
●
●
B.Wrist
●
●
●
●
●
●
●
●
●
●
●
(○) ●
●
●
●
C .Finger
●
●
●
●
●
●
(○) ●
●
●
●
(○) ●
●
●
●
(○) ●
●
●
●
D .Thum b
●
●
●
●
●
E.Forearm
●
●
●
●
●
(○) ●
●
●
●
(○) ●
●
●
●
F.Shoulder
●
●
●
●
●
●
●
●
●
●
Part 1
Part 2
Part 3
Part 4
●: MAS measurement (before treatment)
（○）: Use V5 or QRV MAS measurement
Figure 6    Subjects to be evaluated for MAS
9.1.1.2.
Numeric Rating Scale (NRS) 
According to "2. SCHEDULE OF ACTIVITIES (SoA)" the investigator (or subinvestigator) will 
use NRS (Figure 7) to evaluate the severity of flexors pain.
The investigator will perform the interview on NRS following the assessment of MAS. Each subject 
will be interviewed on the severity of pain on the treated part when extended based on a scale with 0 
being "no pain" and 10 being "the worst imaginable pain"; 1 response on the scale should be selected 
by the subject.


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0
1
2
3
4
5
6
7
8
9
10
No pain
Pain as 
bad as 
you can 
imagine
Figure 7    Numeric Rating Scale (NRS) for pain

NRS measurement during the blinded period
During the blinded period, the severity of pain in the elbow flexors will be evaluated. 

NRS measurement during the open-label period
During the open-label period, a major part with pain [specify 1 part from among fingers, thumb, 
wrist, elbow, fore-arm (pronate), and shoulder] will be evaluated for the severity of pain on Visit 1. 
The part to be evaluated does not have to be the same within each treatment period, but should be the 
same part as that evaluated for MAS. 
9.1.1.3.
Disability Assessment Scale (DAS)
According to "2. SCHEDULE OF ACTIVITIES (SoA)" the investigator (or subinvestigator) will 
use the 4 disability assessment parameters presented in Table 7 and evaluate all of them based on the 
scale presented in Table 8. Before starting the study treatment, the investigator shall discuss with the 
subject, and select and evaluate 1 parameter agreed with the subject as the "main assessment 
parameter." The assessor should in principle remain unchanged throughout the study period. The main 
assessment parameter should also remain unchanged throughout the study period.
Table 7    Disability assessment parameters
Content of assessment
Hygiene
The extent of maceration/ulceration and/or palmar infection, palm/hand 
cleanliness, ease of cleanliness, ease of nail trimming, and interference with 
hygiene-related disability in the subject's daily life
Pain
The intensity of pain/discomfort, and the interference that upper-limb pain-
related disability has in the patient’s daily life.
Dressing
The difficulty or ease for the subject in putting on the relevant clothing (e.g., 
shirts, jackets, gloves, etc.) and the interference that upper-limb dressing-related 
disability has in the patient's daily life.
Limb posture
The psychological and/or social interference that the disfigured upper limb has 
in the patient's daily life.
Table 8    Disability Assessment Scale
Description
0: No functional disability
No functional disability
1: Mild disability
Noticeable but does not interfere significantly with normal activities
2: Moderate disability
Normal activities require increased effort and/or assistance.
3: Severe disability
Normal activities limited.


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9.1.1.4.
Clinical Global Impression of Change (CGI) assessed by a investigator
The investigator (or subinvestigator) will evaluate CGI according to "2. SCHEDULE OF 
ACTIVITIES (SoA)”; Changes in spasticity (Clinical Global Impression) from baseline (before dose 
on Day 1) will be evaluated by 9 grades as shown in Table 9.
The investigator shall also consider the subject's clinical symptoms and adverse events pertinent to 
the assessment of CGI. Also, the therapeutic effect of the product injected in the subject's fingers, 
wrist, and elbow should be taken into an account. The assessor should in principle remain unchanged 
throughout the study period.
Table 9    Clinical Global Impression of Change (CGI)
-4
Very much worsened
-3
Much worsened
-2
Moderately worsened
-1
Slightly worsened
0
Unchanged
+1
Slightly improved
+2
Moderately improved
+3
Much improved
+4
Very much improved
9.1.1.5.
Clinical Global Impression of Change (CGI) assessed by a patient
According to "2. SCHEDULE OF ACTIVITIES (SoA))" the investigator (or subinvestigator) will 
use Table 9 to record subject-reported CGI. The investigator shall interview each subject on changes 
in spasticity from predose, and the subject will evaluate it using Table 9.
9.1.1.6.
Time to patient-reported onset of spasticity symptom relief (Visit 2):
According to "2. SCHEDULE OF ACTIVITIES (SoA)" the investigator (or subinvestigator) will 
record the time to alleviation of spasticity reported by subjects. The investigator shall ask the subject 
whether the product was effective on the spasticity, and if the subject's response to the question is 
positive, ask him/her "how many days did it take for the therapeutic effect to appear after the current 
dose?" and record the number of days.
9.1.1.1.
Patient-reported benefit of injection (Visits 3, 4, and 5)
According to "2. SCHEDULE OF ACTIVITIES (SoA)" the investigator (or subinvestigator) will 
record the efficacy of treatment reported by subjects. The investigator shall ask, "Was the product
effective?" and the subject shall respond either by "Yes" or "No."
9.2.
Adverse events
Definitions of adverse events and serious adverse events (SAE) are as specified in Appendix 4.
The investigator or a person assigned by the investigator is responsible for detecting, recording, and 
reporting events that match the definitions of adverse events and SAEs, and also, responsible for 
follow-up investigations on SAEs, as well as events related to the study drug or this study, and events 
that resulted in treatment discontinuation or subject withdrawal (See section 8). 


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9.2.1.
Period subject to collection of data related to adverse events and SAEs, and 
the frequency of such data collection

All SAEs will be collected from the start of treatment until Final Visit at the time points 
specified in the SoA (Section 2 ). 

All AEs will be collected from the start of treatment until Final Visit at the time points 
specified in the SoA (Section 2 ). 

Medical occurrences that begin before the start of study treatment but after obtaining 
informed consent will be recorded on the Medical History/Current Medical Conditions 
section of the case report form (CRF) not the AE section. 

All SAEs will be recorded and reported to the sponsor or designee within 24 hours, as 
indicated in Appendix 4 . The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available. 

Investigators are not obligated to actively seek AEs or SAEs in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a 
participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study treatment or study participation, the investigator must 
promptly notify the sponsor. 

The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 4 . 
9.2.2.
Method used to detect adverse events and SAEs
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and non-leading 
verbal questioning of the participant is the preferred method to inquire about AE occurrence.
9.2.3.
Follow up on adverse events and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each participant at 
subsequent visits/contacts. All SAEs will be followed until the event is resolved, stabilized, otherwise 
explained, or the participant is lost to follow-up (as defined in Section 8.3). Further information on 
follow-up procedures is given in Appendix 4.
9.2.4.
Regulatory requirements of SAE reporting

Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study treatment under clinical investigation are met. 

The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, Institutional Review Boards (IRB)/Independent Ethics 
Committees (IEC), and investigators. 

Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary. 


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
An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAE) from the sponsor will review 
and then file it along with the Investigator’s Brochure and will notify the IRB/IEC, if 
appropriate according to local requirements. 
9.2.5.
Cardiovascular events and death
For any cardiovascular events detailed in Appendix 4 and all deaths, whether or not they are 
considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF will be required to be 
completed. These sections include questions regarding cardiovascular (including sudden cardiac 
death) and non-cardiovascular death. 
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA terms. The 
CV information should be recorded in the specific cardiovascular section of the CRF within one week 
of receipt of a CV Event data query prompting its completion. 
The Death CRF is provided immediately after the occurrence or outcome of death is reported. Initial 
and follow-up reports regarding death must be completed within one week of when the death is 
reported.
9.2.6.
Pregnancy

Details of all pregnancies in female partners of male participants will be collected after the 
start of study treatment and until Final Visit. 

If a pregnancy is reported, the investigator should inform GSK within 24 hours of learning 
of the pregnancy and should follow the procedures outlined in Appendix [X]. 

Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAE. 
9.3.
Management of overdosage
A dosage of the product exceeding 400 units within 24 hours shall be considered as overdosage in 
this study. Overdosage may cause excessive pharmacodynamic responses such as hyposthenia, 
muscular paralysis, and other localized adverse reactions. Symptoms and signs may not immediately 
appear following dose. Moreover, blepharoptosis, dysarthria, dysphagia, dyspnea, myasthenia, and 
other events suspected to be an effect on other muscles distal to the treated muscle have been reported 
overseas. If such a symptom appears, the subject should be carefully monitored, and given appropriate 
interventions, if necessary with hospitalization. Also, supportive therapies such as artificial breathing 
should be considered for respiratory symptoms.
Upon confirmation of overdosage, the investigator should;
1.
Contact the Medical Monitor immediately.
Carefully monitor the adverse event/SAE, and laboratory abnormalities in the subject for at least 4 
weeks; and 
Document the quantity of the excess dose as well as the duration of the overdosing in the CRF.. 


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The investigator shall discuss with the sponsor's medical monitor on the clinical assessment of the 
subject, and upon which, decide whether or not to discontinue the study treatment.
9.4.
Safety assessments
Assessment timepoints for all safety parameters are as shown in SoA.
9.4.1.
Physical examination
Physical examination (complete version): Only during screening

The head and neck, skin, lungs, cardiovascular system, abdominal region (liver and spleen), 
gastrointestinal system, lymph node, and nervous system should be examined, and the 
results thereof should be recorded; these organs should be examined for the 
presence/absence of pre-existing conditions and abnormal findings, and if there is any 
suspected abnormality, detailed examinations should be performed. 

The pulmonary function test should be conducted in details if any sign of pulmonary 
impairment is found. For the pulmonary function test, spirometry by pulmonologists is 
recommended. 
Physical examination (simplified version): To be conducted only if an eligibility criterion is not met 
during the open-label period. 

At least, the lungs, cardiovascular system, and abdominal region (liver and spleen) should 
be examined, and the results thereof should be recorded. 

The investigator should pay attention to clinical signs and symptoms related to a history of 
serious disease. 
The physical examinations should be performed by doctors in accordance with the standard clinical 
guidelines of each study site.
9.4.2.
Vital signs

For the vital signs, body temperatures (oral, intra-aural, or axillary fossa), systolic/diastolic 
blood pressures, and pulse rates should be measured in a semi-recumbent position after a 5-
minute rest. 

If a temperature is to be measured orally, the subject must refrain from eating food or 
drinking beverage within 5 minutes before the measurement. The method for the 
measurement of body temperature must remain the same throughout the study. 

The blood pressures and pulse rates should be measured with an automated device. A 
manual method may be used only if there is no automated device available for use. 
9.4.3.
Height and weight
The standard clinical guidelines of each study site should be followed.
9.4.4.
ECG

QTc should be determined based on a single measurement of ECG or the mean of ECG 
measured at 3 timepoints in a short period of time (e.g., 5 to 10 minutes). 


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
An automated measurement in accordance with SoA should be used to collect data on the 
heart rates, PR, QRS, QT, and QTc interval. Refer to section 8.2.2. for QTc-related 
treatment discontinuation standard, and additional QTc to be measured as required. 

Each interval between timepoints for the measurement of ECG should be minimized as 
much possible (within 2 minutes). The measurement of ECG should be performed 3 times 
consecutively and completed within 5 to 10 minutes. 
9.4.5.
Neutralizing antibody test
The investigator shall draw blood for neutralizing antibody samples in accordance with the study 
schedule. The neutralizing antibody will be measured collectively by a central laboratories designated 
by GSK (Intertek Pharmaceutical Services Co. and Pacific BioLabs Co.). The screening samples will 
be retained temporarily by the central laboratories, and then, upon retrieval of samples from all 
subjects, will be collected and tested by Intertek for screening. Samples tested positive at Intertek will 
be separately sent to Pacific BioLabs for retest to finalize the results of neutralizing antibody test. The 
above procedures shall also be taken for samples collected for Week 12 visit during the blinded period, 
and upon completion of study treatment in all subjects.
9.4.6.
Clinical Safety Laboratory Assessments

Refer to Appendix 2 for the list of clinical laboratory parameters that should be tested, and 
to SoA for the timepoints and frequency of testing. 

The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal during 
participation in the study should be repeated until the values return to normal or baseline or 
are no longer considered significantly

If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified.

All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted 
in accordance with the laboratory manual and the SoA.

If a result of clinical laboratory test not scheduled in the protocol is obtained by a study site, 
which requires a change in the patient management, or is determined to be clinically 
important by the investigator, that is SAE, adverse event, an event requiring dose 
modification, or any other relevant event, the record thereof must be documented in the 
CRF. 

Follow-up investigation may be performed at any time during the study as determined to be 
necessary by the investigator, or required by the Japanese regulation. 


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9.5.
Pharmacokinetics
PK parameters are not evaluated in this study.
9.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
9.7.
Genetics/Pharmacogenetics
Genetics and pharmacogenetics are not evaluated in this study.
9.8.
Biomarkers
Biomarkers are not evaluated in this study.
9.9.
Pharmacoeconomics
Pharmacoeconomic parameters are not evaluated in this study.


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10. STATISTICAL CONSIDERATIONS
10.1.
Sample Size Determination
This study is not intended to verify a statistical hypothesis, but is rather intended to verify that the 
responder rate in the 400 units group exceeds that in the 240 units group, and for which, about 120 
subjects (60 in each treatment group) are to be enrolled.
During Treatment Period 1 of this study, 160 units of the product will be administered in the muscle 
which affects the elbow; thus, the sample size was determined in reference to an overseas phase III 
study (Study 127) in which a similar dosage as this study (150 units) was administered in the muscle 
which affects the elbow. The responder rate in the elbow at Week 6 of the initial dose in Study 127 
was 72.2% and 47.1% in the product 300 units group (150 units in the muscle which affects the elbow 
flexors) and placebo group, respectively. The number of subjects in the intention-to-treat (ITT) 
population was small in both the product 300 units group and placebo group of Study 127, which was 
18 subjects each; thus, considering the uncertainty of the results of Study 127, the responder rates in 
the product 400 units and 240 units groups in this study were conservatively assumed to be 70.0% and 
50.0%, respectively. Assuming that the sample size is 60 subjects in each group, the power of test to 
detect an intergroup difference in the responder rates would be about 62% with a two- sided
significance level of 5% while the probability of the responder rate in the product 400 units group to 
exceed that in the product 240 units group as a point-estimate would be 98%.
With about 120 subjects enrolled, 100 subjects are expected to complete Week 48 of the initial dose.
10.2.
Populations for Analyses
Populations for statistical analyses  in this study are defined as follows.
Population
Description
ITT
All subjects randomized in the study andhad at least 1 post-baseline 
efficacy assessment: ITT is the primary efficacy analysis population, and 
the subjects will be analyzed in line with the randomized treatment group. 
Safety 
All subjects randomized in the study and received study treatment at least 
once: The subjects will be analyzed based on the treatment actually given. 
10.3.
Statistical Analyses
10.3.1.
Efficacy Analyses
This study is not intended to verify a statistical hypothesis; thus, there will be no statistical test.
All of the efficacy analyses will be performed on the ITT population separately for the blinded 
period and the open-label period.


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Endpoints
Statistical Analysis Methods
Primary
The primary endpoint is the proportion of subjects whose MAS score on the elbow at 
Week 6 of the initial dose decreased by at least 1 level from the baseline (responder rate). 
The primary endpoint will be calculated as the proportion of subjects whose MAS score 
decreased by at least 1 level from the baseline in the ITT population. Also, a 95% 
confidence interval of the intergroup difference in the responder rate will be computed. 
Subjects with no MAS score available at Week 6 will not be counted as subjects whose 
MAS score decreased by at least 1 level from the baseline (that is, counted in as non-
responder). 
The MAS scores, 0, 1, 1+, 2, 3, and 4 will be encoded to 0, 1, 2, 3, 4, and 5, respectively, 
for the analysis purpose. 
Secondary
Unless specified otherwise, the data up to Week 12 of treatment will be summarized for 
each repeated dose during the open-label period. 
During the blinded period, a mixed model for repeated measurement (MMRM) will be 
used for the analysis on the endpoints specified below, and the least-square mean and 95% 
confidence interval will be calculated. The details of the model will be described in the 
statistical analysis plan. For the open-label period, only a summary statistics will be 
performed for each treatment group. Missing values will not be imputed. 
Change in MAS score in the fingers, thumb, wrist, and elbow from the baseline
Change in Disability Assessment Scale (primary endpoint) from the baseline 
The proportion of subjects in whom MAS score in the fingers, thumb, wrist, and elbow 
decreased by at least 1 level from the baseline (responder rate) during the blinded period 
will be analyzed with the same method as that for the primary endpoint. For the open-
label period, the denominator to be used for the calculation of responder rate shall be the 
number of subjects in each subgroup stratified by the number of injections given, not the 
ITT population. Also, a 95% confidence interval of the intergroup difference in the 
responder rate will not be calculated. 
Exploratory
Time to patient-reported onset of spasticity symptom relief will be evaluated for subjects 
who reported alleviation of spasticity at in 2 weeks postdose. The number of days from 
dose to the alleviation of spasticity will be summarized for each treatment group. 
Clinical Global Impression of Change (CGI) assessed by a investigator, CGI assessed by a 
patient, and Patient-reported benefit of injection will be summarized for each treatment 
group. Missing values will not be complemented. 
Other details will be specified in the statistical analysis plan. 
10.3.2.
Safety Analysis
Safety analyses will all be performed on the safety population separately for the blinded and open-
label periods.


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Endpoints
Statistical Analysis Method
Primary
Not applicable
Secondary
Adverse events that occurred in the overall study period, blinded period, and open-label 
period will be summarized for each treatment group. For the blinded period, 2 patterns of 
analyses on adverse events will be performed; one is on adverse events that occurred 
between the initial dose and the first dose in the open-label period (or at the completion 
of study if no dose is given in the open-label period or at the study withdrawal), and 
another one is on adverse events that occurred within 84 days from the initial dose. 
Adverse events will be summarized separately for SOC (system organ class) and PT 
(preferred term). Also, adverse events related to study treatment, adverse events that 
resulted indiscontinuation, adverse events by subgroups stratified by severity, and 
serious adverse events will be summarized. 
Laboratory findings and vital signs at each visit and their changes from baseline will be 
summarized for each treatment group. 
Exploratory
Will be specified in the statistical analysis plan. 
10.3.3.
Other analyses
Other analyses will be specified in the statistical analysis plan.
10.3.4.
Interim analyses
The details of the interim analysis plan will be specified in the statistical analysis plan.
When all subjects  (except for early termination) complete the visit at Week 24 of the initial dose, 
the data on all of the subjects until Week 24 of the initial dose may be locked, unblinded, and analyzed 
for reporting to authorities.
11. Reference
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Nemto A. Therapeutic method for treatment of spasticity, and conditions indicated for treatment. 
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Ogawa, Idee, Katayama. Treatment Guideline for Cerebral Stroke 2015. 2015. 
Ohsawa, Mezaki, Miyagi. Standard Neurotherapy: Botulinum treatment. Neurotherapy. 2013; 
30(4):473-94.
Shinohara, Ogawa, Suzuki et al. Treatment Guideline for Cerebral Stroke 2009. 2009. 
Sloan RL, Sinclair E, Thompson J, Taylor S, et al. Inter-rater reliability of the modified Ashworth 
Scale for spasticity in hemiplegic patients. Int J Rehabil Res. 1992;15:158-61.
Yelnik AP, Colle FM, Bonan IV, et al. Treatment of shoulder pain in spastic hemiplegia by reducing 
spasticity of the subscapular muscle:a randomised, double blind, placebo controlled study of 
botulinum toxin A. The Journal of Neurology, Neurosurgery, and Psychiatry. 2007;78:845-8.


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12. Appendices
12.1.
Appendix 1: Abbreviations and trademarks
Trademark
Trademark of Glaxo Smithcline Group
Trademarks that do not belong to Glaxo 
Smithcline Group
Botox
―
12.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 10 will be performed by central laboratory. 

A test needs to be performed by study sites only if the result cannot be obtained from the 
central laboratory in time for study treatment and/or assessment. Even if measurement is 
performed at a study site, another sample at the same assessment timepoint is separately 
required for measurement at central laboratory. If a result of measurement at the study site 
is to be used for a decision of study treatment and/or assessment, the result should be 
recorded in the CRF. 

Protocol-specific inclusion/exclusion criteria are as specified in section 6 of the protocol. 

Protocol-specific inclusion/exclusion criteria are as specified in section 6 of the protocol. 


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Table 10    Protocol-Required Safety Laboratory Assessments
Clinical 
laboratory
Parameters
Hematological 
tests
Platelet count
Erythrocyte indices: 
Mean corpuscular volume 
(MCV)
Mean corpuscular 
hemoglobin (MCH)
Reticulocyte count (%)
Percentage of white blood 
cell:
Neutrophil
Lymphocyte
Monocyte
Eosinophil
Basophil
RBC
Hemoglobin
Hematocrit
White blood cell count
Chemistry1
Urea 
nitrogen 
(BUN)
Potassium
Aspartate aminotransferase (AST) /
Serum glutamic oxaloacetic 
transaminase (SGOT) 1
Total bilirubin and 
direct bilirubin
Creatinine
Sodium
Alanine aminotransferase (ALT) / 
Serum glutamic pyruvic 
transaminase (SGPT) 1
Total protein
Calcium
Alkaline 
phosphatase
Urinalysis
Specific gravity
PH with test paper, glucose, protein, occult blood, ketone, bilirubin, urobilinogen, 
nitrite, and white blood cell esterase
Microscopy (if occult blood or protein is deviated)
Other tests

Pregnancy test (if necessary in a woman of child-bearing potential): 
Serum or urine human chorionic gonadotropin (hCG) 2
The following parameters should be tested during the screening period. 

Serological verification: HIV antibody

The following parameters should be tested only for subjects with chronic 
hepatitis B or C that is stabilized at screening, and subjects currently 
receiving or expected to receive immunosuppressant. 

Serological verification: Hepatitis B virus surface antigen (HBsAg), 
and hepatitis C virus antibody

The following parameter should be tested for women of no child-bearing 
potential. 

Follicle stimulating hormone and estradiol
Caution: 
1. Details of the discontinuation criteria based on hepatic function test, and the interventions and follow up 
necessary after the occurrence of hepatic events are specified in section 8.1 and Appendix 6. SAEs must 
be reported for all events with ALT IJYO3 times the upper limit of normal range (ULN), and at the same 
time, bilirubin IJYO2 times the ULN (direct bilirubin >35%), or ALT IJYO3 times the ULN, and at the 
same time, the international normalized ratio (INR) >1.5 if measured [which suggests a possibility of 
severe liver injury (applicable to Hy's Law)]. 
2. Pregnancy tests should be performed with serum samples at screening, and with urine samples for 
routine tests after randomization. 


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12.3.
APPENDIX 3: Study Governance Considerations
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.

Any amendments to the protocol will require IEC/IRB approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as required by IRB/IEC 
procedures

Providing oversight of the conduct of the study at the site and adherence to requirements of 
21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial certification 
or disclosure statements to the appropriate regulatory authorities. Investigators are responsible for 
providing information on financial interests during the course of the study and for 1 year after 
completion of the study.
Process of obtaining consent

The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding 
the study.

Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed consent 
that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health 
Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, and 
the IRB/IEC or study center.


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
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.
Data protection

Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant names 
or any information which would make the participant identifiable will not be transferred.

The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.

The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
Composition of committee
No committee will be established.
Publication Policy

The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor before 
submission. This allows the sponsor to protect proprietary information and to provide 
comments.

The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating investigator will be designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.
Dissemination of Clinical Study Data

Disclosure of a Clinical Study Report (CSR) after the evaluation by the regulatory 
authority(ies).

GSK may post the study information and tabulated-form study results on the website 
(www.ClinTrials.gov) of the U.S. National Institution of Health (NIH) or other websites 
open to the public 

GSK may post the study results to scientific journals that conduct peer review in order to 
report the study results.


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Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the sponsor or designee electronically (eg, laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.

The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.

The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.

The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.

Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study 
isbeing conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.

Records and documents, including signed ICF, pertaining to the conduct of this study must 
be retained by the investigator for 25 years from the issue of the final Clinical Study Report 
(CSR)/ equivalent summary unless local regulations or institutional policies require a longer 
retention period. No records may be destroyed during the retention period without the 
written approval of the sponsor. No records may be transferred to another location or party 
without written notification to the sponsor.
Source documents

Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available.

Definition of what constitutes source data can be found in the corresponding list of source 
documents.
Study and Site Closure
GSK or its designee reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of GSK. Study sites will be closed upon study completion. A study site is 
considered closed when all required documents and study supplies have been collected and a study-
site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are not 
limited to:


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
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study treatment development


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12.4.
APPENDIX 4: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study treatment, whether or not considered related to the study 
treatment.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other
safety assessments (eg, ECG, radiological scans, vital signs measurements), including those 
that worsen from baseline, considered clinically significant in the medical and scientific 
judgment of the investigator (ie, not related to progression of underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even though it may 
have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study treatment or 
a concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is an 
intentional overdose taken with possible suicidal/self-harming intent. Such overdoses should 
be reported regardless of sequelae.

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be reported 
as an AE or SAE. Such instances will be captured in the efficacy assessments. However, the 
signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be reported as 
AE or SAE if they fulfill the definition of an AE or SAE.

The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be reported 
as AE or SAE if they fulfill the definition of an AE or SAE. Also, "lack of efficacy" or 
"failure of expected pharmacological action" constitutes an AE or SAE.


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Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
Definition of an SAE
If an event does not correspond any of the above definitions of an AE, even if it is a serious condition, 
it will not be regarded as an SAE (e.g.; hospitalization due to the signs/symptoms of the disease being 
studied, death caused by exacerbation of the disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
results in death
b.
is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the subject was at 
risk of death at the time of the event. It does not refer to an event, which hypothetically might have 
caused death, if it were more severe.
c.
requires hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the subject has been detained (usually involving at least an 
overnight stay) at the hospital or emergency ward for observation and/or treatment that would not 
have been appropriate in the investigator’s office or out-patient setting. Complications that occur 
during hospitalization are AEs. If a complication prolongs hospitalization or fulfils any other serious 
criteria, the event is serious. When in doubt as to whether “hospitalization” occurred or was necessary, 
the AE should be considered serious. Hospitalization for elective treatment of a pre-existing condition 
that did not worsen from baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday life 
functions but do not constitute a substantial disruption.
e.
is congenital anomaly/birth defect


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f.
other important medical situations:

Medical or scientific judgement should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require medical or surgical intervention to prevent one of the other outcomes 
listed in the above definition. These should also be considered serious.
Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that 
do not result in hospitalization, or development of drug dependency or drug abuse.
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the following AEs 
and SAEs:

Myocardial infarction/angina unstable

Cardiac failure congestive

Arrhythmia

Valvular disease

Pulmonary hypertension

Cerebrovascular event/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep vein thrombosis/pulmonary embolism

Revascularisation
Recording of AEs and SAEs
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to GSK in lieu of completion of the GSK /AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are requested by 
GSK. In this case, all participant identifiers, with the exception of the participant number, 
will be redacted on the copies of the medical records before submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE.


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Assessment of intensity
The investigator will make an assessment of intensity for each AE and SAE reported during the study 
and classify it to one of the following categories:

Mild: An event that is easily tolerated by the subject, causing minimal discomfort and not 
interfering with everyday activities.

Moderate: An event that is sufficiently discomforting to interfere with normal everyday 
activities.

Severe: An event that prevents normal everyday activities - An AE that is assessed as severe 
will not be confused with an SAE. Severity is a category utilized for rating the intensity of 
an event; and both AEs and SAEs can be assessed as severe.
An event is defined as “serious”, not when it is assessed as severe but when it meets at least one of the 
pre-defined outcomes as described in the definition of an SAE.
Assessment of causality

The investigatoris obligated to assess the relationship between investigational product and 
the occurrence of each AE/SAE.

A “reasonable possibility” is meant to convey that there are facts/evidence or arguments to 
suggest a causal relationship, rather than a relationship cannot be ruled out.

The investigator will use clinical judgement to determine the relationship.

Alternative causes, such as natural history of the underlying diseases, concomitant therapy, 
other risk factors, and the temporal relationship of the event to the investigational product 
will be considered and investigated.

The investigator will also consult the IB, for marketed products, in the determination of 
his/her assessment.

The investigator  must record that he or she reviewed AEs and SAEs and assessed the 
causality in the medical record.

There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK. However, it is very important that the 
investigator always make an assessment of causality for every event prior to the initial 
transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up information, 
prepare and send the follow-up report of SAE by amending the assessment result of the 
causality accordingly.

The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.


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Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.

If a subject dies during participation in the study, the investigator will provide GSK with a 
copy of any post-mortem findings, including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit all updated SAE data to GSK within 24 hours after obtaining 
the information.
Reporting of SAEs to GSK
SAE Reporting to GSK via Electronic Data Collection Tool

The primary mechanism for reporting SAE to GSK will be the electronic data collection 
tool.

If the electronic system is unavailable for more than 24 hours, then the site will use the 
paper SAE data collection tool (see next section).

The site will enter the SAE data into the electronic system as soon as it becomes available.

The investigator or medically-qualified sub-investigator must show evidence within the 
eCRF (e.g., check review box, signature, etc.) of review and verification of the relationship 
of each SAE to IP/study participation (causality) within 72 hours of SAE entry into the 
eCRF.

After the study is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated data on 
a previously reported SAE after the electronic data collection tool has been taken off-line, 
then the site can report this information on a paper SAE form (see next section) or to the 
SAE coordinator by telephone.

Contacts for SAE reporting can be found in ATTACHMENT.
SAE Reporting to GSK via Paper CRF

Facsimile transmission of the SAE page of the CRF is the preferred method to transmit the 
information on SAEs to GSK. 

In rare circumstances and in the absence of facsimile equipment, initial notification by 
telephone is acceptable followed by a copy of the SAE page of the CRF sent by overnight 
mail or by courier. 

Initial notification via the telephone does not replace the need for the investigator (or 
subinvestigator) to complete and sign the SAE page of the CRF within the designated 
reporting time frames.

The ATTACHMENT 1 shows a contact information to which the SAEs should be reported.


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12.5.
APPENDIX 5: Contraceptive Guidance and Collection of Pregnancy 
Information
Definition
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below)
Women in the following categories are not considered WOCBP
1.
Premenarchal
Premenopausal female with ONE of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s: review of participant’s medical records, 
medical examination, or medical history interview.
Postmenopausal women

A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 12 
months of amenorrhea, a single FSH measurement is insufficient.

Females on HRT and whose menopausal status is in doubt will be required to use one of the 
non-hormonal highly effective contraception methods if they wish to continue their HRT 
during the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrollment.
Contraception Guidance
Male study subject

A male study subject who has a female partner of childbearing potential can participate in 
this study if he agrees to any of the following conditions: 

He must agree not to have a sex (sexual intercourse) with a person of the opposite sex as a 
normal favourable lifestyle (continuously having no sex for a long period of time) and also 
agree to keep that condition. 

If he has a sex with a woman of childbearing potential, he must agree to use a male condom
and use at least one of the contraception methods with an annual failure rate below 1% 
which are shown in Table 11.

A male study subject who has a pregnant or breastfeeding female partner must agree not to 
have a sex from the time during the study or use a male condom when having a sex. 

A male study subject must agree not to provide his sperm during the study. 


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Female study subject
A female study subject of childbearing potential can participate in this study if she agrees to use any 
of the extremely effective methods of contraception shown in Table 11 continuously and accurately. 
Among the methods of contraception shown in Table 11, those deleted with strikethrough lines have 
neither been approved nor been accepted in Japan.
Table 11    Extremely effective methods of contraception
User-dependent extremely effective methods of contraception a
Their annual failure rates are below 1% if they are used continuously and accurately.
Contraception by mixed (estrogen and progestogen-containing) hormone preparation (inhibit 
ovulation)b

Oral

Intravaginal

Transdermal
Contraception by only progestogen-containing hormone preparation (inhibit ovulation)b

Injection
User-independent extremely effective methods of contraception

Contraception by only progestogen-containing implantable hormone preparation (inhibit 
ovulation)b

Intrauterine device (IUD)

Intrauterine system (IUS)

Bilateral tubal occlusion
Male partner’s vasectomy
(If her male partner has been vasectomised, it is an extremely effective method of contraception for a 
woman of childbearing potential if that partner is the only man with whom she has a sex and it has 
been confirmed that he is sterile. Otherwise, he/she must use other additional extremely effective 
method(s) of contraception.)
Having no sexual relations
(If the subjects decides to refrain himself or herself from having a sex of the opposite sex for the entire 
period when there is a risk of the investigational product, abstinence is deemed to be an extremely 
effective method of contraception. However, the credibility of abstinence needs to be evaluated during 
the study period and from the perspectives of the subject’s normal favourable lifestyle.)
Notes:
a.
The usual failure rate is different from the rate when contraception is used continuously and 
accurately. The subjects should use the methods of contraception that match with regulations 
concerning the methods of contraception for study subjects in each country.
b.
The efficacy of contraception by hormone preparations may decrease as a result of the interaction 
with the investigational product. In that case, the subject should use two extremely effective 
methods of contraception during the treatment period and at least for 3 months after the last dose 
of the investigational product.


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Pregnancy test

A woman of childbearing potential can be enrolled to this study only if it is confirmed that 
she is negative in a highly sensitive serum pregnancy test along with her menstrual period. 

Pregnancy test should be performed if no menstruation occurred or she is suspected to be 
pregnant.

Analysis should be performed according to the package insert using a testing kit provided 
by GSK.
Collection of pregnancy information
If a male study subject’s partner becomes pregnant

Investigator will attempt to collect pregnancy information on any male participant’s female 
partner of a male study participant who becomes pregnant while participating in this study. 
This applies only to participants who receive study treatment.

After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the investigator will record pregnancy information on the appropriate form and 
submit it to GSK within 2 weeks of learning of the partner’s pregnancy.

Partner will also be followed to determine the outcome of the pregnancy. Information on the 
status of the mother and child will be forwarded to GSK

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery 
date. Any termination of the pregnancy will be reported regardless of fetal status (presence 
or absence of anomalies) or indication for procedure.
Female Participants who become pregnant

Investigator will collect pregnancy information on any female participant, who becomes 
pregnant while participating in this study. 

Information will be recorded on the appropriate form and submitted to GSK within 24 hours 
of learning of a participant's pregnancy. 

Participant will be followed to determine the outcome of the pregnancy. The investigator 
will collect follow up information on participant and neonate, which will be forwarded to 
GSK Generally, follow-up will not be required for longer than 6 to 8 weeks beyond the 
estimated delivery date.

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
or elective termination of a pregnancy will be reported as an AE or SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as such.

Any SAE occurring as a result of a post-study pregnancy which is considered reasonably 
related to the study treatment by the investigator, will be reported to GSK as described in 
Appendix 4. While the investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous reporting.


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For a female study subject who discovers her pregnancy while participating in this study, 

The administration of the investigational product will be discontinued. 


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12.6.
APPENDIX 6: Liver Safety Required Actions and Follow up Assessments
In order to secure the subject’s safety and evaluate the causes of liver event, the criteria for 
discontinuation and follow-up based on the liver function test values in the phase III-IV studies
will be stipulated.
Criteria for discontinuation based on the liver function test values in the phase III-IV studies 
and necessary follow-up
Criteria for discontinuation based on the liver function test values
ALT
ALT ≥ 8xULN
ALT increase ALT ≥ 5xULN but <8xULN persists for ≥2 weeks
ALT ≥ 3xULN but <5xULN persists for ≥4 weeks
Bilirubin1, 2
ALT ≥ 3xULN and bilirubin ≥ 2xULN (>35% direct bilirubin)
INR2
ALT ≥ 3xULN and INR>1.5, if INR measured
Cannot 
Monitor
ALT ≥ 5xULN but <8xULN and cannot be monitored weekly for ≥2 weeks
ALT ≥ 3xULN but <5xULN and cannot be monitored weekly for ≥4 weeks
Symptom 3
ALT ≥ 3xULN associated with symptoms (new or worsening) believed to be related 
to liver injury or hypersensitivity
Necessary measures and assessment items for liver event
Actions 
Follow Up Assessments 

Immediately discontinue the 
administration of the investigational 
product.

Report it to GSK within 24 hours.

Complete the liver event CRF and 
complete an SAE data collection tool if 
the event also meets the criteria for an 
SAE 2.

Perform liver event follow up 
assessments

Monitor the participant until liver 
chemistries resolve, stabilize, or return 
to within baseline (see MONITORING
below)

Do not restart/rechallenge participant 
with study treatment unless allowed per 
protocol and GSK Medical Governance 
approval is granted

If the resumption/re-administration of 
the investigational product is not 
stipulated in the protocol or approved
by GSK’s Medical Governance, the 
administration of the investigational 
product will be discontinued 

Viral hepatitis serology4

Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend

Only in those with underlying chronic 
Hepatitis B at study entry (identified by 
positive Hepatitis B surface antigen) 
quantitative Hepatitis B DNA and 
Hepatitis delta antibody5

Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin≥2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications 
on the concomitant medications report 
formincluding acetaminophen, herbal 
remedies, other over the counter 
medications.


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permanently and the follow-up 
prescribed in the protocol 8.1. will be 
conducted.
MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT,
AST, alkaline phosphatase, bilirubin) 
and perform liver event follow up 
assessments within 24 hrs

Monitor participants twice weekly until 
liver chemistries resolve, stabilize or 
return to within baseline

A specialist or hepatology consultation 
is recommended
For other criteria:

Repeat liver chemistries (include ALT, 
AST, alkaline phosphatase, bilirubin) 
and perform liver event follow up 
assessments within 24-72 hrs

Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

Record alcohol use on the liver event 
alcohol intake case report form (CRF) 
page
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG) or gamma globulins.

Liver imaging (ultrasound, magnetic 
resonance, or computerised 
tomography) and /or liver biopsy to
evaluate liver disease; complete Liver 
Imaging and/or Liver Biopsy CRF 
forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin 
fractionation is not immediately available, discontinue study treatment for that participant if ALT 
≥ 3xULN and bilirubin ≥ 2xULN. Additionally, if serum bilirubin fractionation testing is 
unavailable, record presence of detectable urinary bilirubin on dipstick, indicating direct bilirubin 
elevations and suggesting liver injury.
All events of ALT ≥ 3xULN and bilirubin ≥ 2xULN (>35% direct bilirubin) or ALT ≥ 3xULN and 
INR>1.5, if INR measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be 
reported as an SAE (excluding studies of hepatic impairment or cirrhosis); INR measurement is not 
required and the threshold value stated will not apply to participants receiving anticoagulants
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such 
as fever, rash or eosinophilia)
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen (HbsAg) and Hepatitis B Core 
Antibody (IgM); Hepatitis C RNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen 
IgM antibody (or if unavailable, obtain heterophile antibody or monospot testing); Hepatitis E IgM 
antibody
Criteria for follow-up with continued treatment based on the liver function test values in the 
phase III-IV studies


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Criteria for follow-up based on liver test function values – Liver events to be followed
Criteria
Actions
ALT ≥5xULN and <8xULN and bilirubin 
<2xULN without symptoms believed to be related 
to liver injury or hypersensitivity, and who can be 
monitored weekly for 2 weeks.
OR
ALT ≥3xULN and <5xULN and bilirubin 
<2xULN without symptoms believed to be related 
to liver injury or hypersensitivity, and who can be 
monitored weekly for 4 weeks. 

Notify the GSK medical monitor within 
24 hours of learning of the abnormality 
to discuss participant safety.

Participant can continue study treatment

Participant must return weekly for 
repeat liver chemistries (ALT, AST, 
alkaline phosphatase, bilirubin) until 
they resolve, stabilise or return to within 
baseline

If at any time participant meets the liver 
chemistry stopping criteria, proceed as 
described above

If ALT decreases from ALT ≥5xULN 
and <8xULN to ≥3xULN but <5xULN, 
continue to monitor liver chemistries 
weekly.

If, after 4 weeks of monitoring, ALT 
<3xULN and bilirubin <2xULN, 
monitor participants twice monthly until 
liver chemistries normalize or return to 
within baseline.


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12.7.
APPENDIX 7: COUNTRY SPECIFIC DESCRIPTIONS
12.7.1.
Regulatory and Ethical Considerations
This study will be conducted in compliance with the “Good Clinical Practice (GCP)” (MHW 
Ordinance No. 28, March 27, 1997) and the “Act on Securing Quality, Efficacy and Safety of 
Pharmaceuticals, Medical Devices, etc. (PMD Act)”. 
GSK will submit the CTN to the regulatory authorities in accordance with the PMD Act before 
concluding the study agreement with the medical institution
12.7.2.
Obtaining of Informed Consent
Prior to participation in the study, the investigator should fully inform the potential subject and/or 
his or her legally acceptable representative of the study using the information document. In doing so, 
the investigator should provide the subject sufficient time and opportunity to inquire about details of 
the study and obtain the subject and/or his or her legally acceptable representative’s signature or 
printed name and seal and date of consent on the consent form. The subject may take the informed 
consent form home to review it. The person who provided the explanation and the clinical research 
coordinator who provided the supplementary explanation should also sign or affix his or her printed 
name and seal on the consent form and enter the date of signature. If an impartial witness is needed, he 
or she should also sign or affix his or her printed name and seal on the consent form and enter the date 
of witness. The investigator should attach the original of the above signed or affixed with printed 
name/seal and dated consent form (and information document) to the original medical record such as 
medical chart (in accordance with the rules for records retention, if any, at each medical institution), 
retain it, and give a copy to the subject and/or his or her legally acceptable representative. 
12.7.3.
Study Implementation Period
July 2017 – February 2019
12.7.4.
Study Conduct Structure
The Attachment 1 shows the sponsor’s information. Also, the Attachment 2 shows a list of medical 
institutions and investigators. 


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TITLE PAGE
Protocol Title: A phase III study (a placebo controlled, randomized, double-blind comparative study 
and an open-label, uncontrolled study) to evaluate the efficacy and safety of GSK1358820 in patients 
with post-stroke upper limb spasticity 
Protocol Number: 01
Short Title: A phase III study to evaluate the efficacy and safety of GSK1358820 in patients with 
post-stroke upper limb spasticity
Compound Number:
GSK1358820
Sponsor 
GlaxoSmithKline K.K. (GSK)
6-15, Sendagaya 4-chome, Shibuya-ku, Tokyo 151-8566 Japan 
The person responsible for operation of the study:
Director of Development of 
Drugs for Neurological Diseases, Department of Development, Clinical Research Department
Medical Monitor Name and Contact Information are shown on SRM.
Regulatory Agency Identifying Number(s):NA
Approval Date: 24-MAY-2017
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  Unauthorised 
copying or use of this information is prohibited.
PPD


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Signature of the Sponsor:
Director of Development of Drugs For Neurological Diseases, 
Department of Development, Clinical Research Department
GlaxoSmithKline K.K. (GSK) 
Date
The IMMS document approved is as follows:
  Unique ID :
  System Version:
  Effective Date:
PPD


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY 
Document 
Date 
Amendment 1
24-MAY-2017
Original protocol
4-APR-2017
Amendment 1 : 24-MAY-2017
Overall Rationale for the Amendment:01
The protocol was changed based on the regulatory inquires by the Pharmaceuticals and Medical 
Devices Agency (PMDA).
Overall Rationale for the Amendment:01
Section # and Name 
Description of Change 
Brief Rationale 
1. SYNOPSIS
Add pulmonary test and 
description adjustment
Requested by PMDA
2. SCHEDULE OF 
ACTIVITIES (SoA)
Add pulmonary test and 
description adjustment
Requested by PMDA
5.1.3.1. Eligibility 
Criteria for Injection in 
and after Part 2
Add pulmonary test 
Requested by PMDA
6.1.1. Screening Phase 
(Day -28 to Day -1)
Add pulmonary test 
Requested by PMDA
6.2.2. Day 1 (Prior to 
injection)
Description adjustment
Establish consistency with section 7.7.2
6.4. Screen Failures
Description adjustment
Not shown due to minor changes
7.7.2. Contraindicated 
Medications/Therapies
Description adjustment
Establish consistency with section 6.2.2
9.1.1.4. Clinical Global 
Impression of Change 
(CGI) assessed by a 
investigator
Error correction
Not shown due to minor changes
9.4.4. Pulmonary test
Add pulmonary test
Requested by PMDA
9.4.5.ECG
Description adjustment
Add manual re-interpretation


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TABLE OF CONTENTS
Page
1.
SYNOPSIS .......................................................................................................................8
2.
SCHEDULE OF ACTIVITIES (SoA) ..............................................................................13
3.
INTRODUCTION............................................................................................................18
3.1.
Study Rationale....................................................................................................18
3.2.
Background..........................................................................................................18
3.3.
Benefit/Risk Assessment....................................................................................19
3.3.1.
Risk Assessment ........................................................................................20
3.3.2.
Benefit Assessment....................................................................................22
3.3.3.
Overall Benefit:Risk Conclusion...............................................................22
4.
OBJECTIVES AND ENDPOINTS..................................................................................23
5.
STUDY DESIGN.............................................................................................................24
5.1.
Overall Design......................................................................................................24
5.1.1.
Screening Phase (up to 4 weeks)..............................................................24
5.1.2.
Blind Period (minimum 12 Weeks): Placebo Controlled, 
Randomized, Double Blind Design ...........................................................25
5.1.3.
Open-Label Phase (maximum 36 weeks): Uncontrolled, Open-
Label Design................................................................................................25
5.1.3.1.
Eligibility Criteria for Injection in and after Part 2 ..........................25
5.2.
Number of Participants .......................................................................................26
5.3.
Participant and Study Completion.....................................................................26
5.4.
Scientific Rationale for Study.............................................................................26
5.5.
Dose Justification................................................................................................27
6.
STUDY POPULATION...................................................................................................27
6.1.
Inclusion Criteria..................................................................................................27
6.1.1.
Screening Phase (Day -28 to Day -1) ........................................................27
6.1.2.
Day 1 (prior to injection).............................................................................29
6.2.
Exclusion Criteria ................................................................................................29
6.2.1.
Screening Phase (Day -28 to Day -1) ........................................................29
6.2.2.
Day 1 (Prior to injection).............................................................................31
6.3.
Lifestyle Restrictions ..........................................................................................32
6.4.
Screen Failures ....................................................................................................32
7.
TREATMENTS...............................................................................................................33
7.1.
Treatments Administered ...................................................................................33
7.2.
Dose Modification................................................................................................35
7.3.
Method of Treatment Assignment .....................................................................35


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7.4.
Blinding.................................................................................................................35
7.5.
Preparation/Handling/Storage/Control..............................................................36
7.6.
Treatment Compliance........................................................................................36
7.7.
Concomitant Therapies.......................................................................................36
7.7.1.
Permitted Concomitant Drugs/Therapies.................................................37
7.7.2.
Contraindicated Medications/Therapies...................................................37
7.8.
Treatments after Completion of the Study........................................................38
8.
DISCONTINUATION CRITERIA....................................................................................38
8.1.
Discontinuation of Study Treatment..................................................................38
8.2.
Withdrawal from the Study .................................................................................38
8.2.1.
Liver Chemistry Stopping Criteria.............................................................39
8.2.2.
QTc Stopping Criteria.................................................................................41
8.2.3.
Treatment discontinuation due to treatment-related SAE......................41
8.2.4.
Treatment discontinuation due to pregnancy .........................................41
8.2.5.
Withdrawal 
of 
subjects
who 
start 
receiving 
prohibited 
medications or therapies ...........................................................................41
8.2.6.
Prohibition of treatment resumption ........................................................42
8.3.
Lost to follow up ..................................................................................................42
9.
STUDY ASSESSMENTS AND PROCEDURES ...........................................................42
9.1.
Efficacy assessments .........................................................................................43
9.1.1.
Evaluation methods....................................................................................43
9.1.1.1.
Modified Ashworth Scale (MAS) .......................................................43
9.1.1.2.
Numeric Rating Scale (NRS) .............................................................44
9.1.1.3.
Disability Assessment Scale (DAS)..................................................45
9.1.1.4.
Clinical Global Impression of Change (CGI) assessed by a 
investigator .........................................................................................46
9.1.1.5.
Clinical Global Impression of Change (CGI) assessed by a 
patient..................................................................................................46
9.1.1.6.
Time to patient-reported onset of spasticity symptom relief 
(Visit 2):................................................................................................46
9.1.1.1.
Patient-reported benefit of injection (Visits 3, 4, and 5).................46
9.2.
Adverse events ....................................................................................................46
9.2.1.
Period subject to collection of data related to adverse events 
and SAEs, and the frequency of such data collection............................47
9.2.2.
Method used to detect adverse events and SAEs...................................47
9.2.3.
Follow up on adverse events and SAEs...................................................47
9.2.4.
Regulatory requirements of SAE reporting..............................................47


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9.2.5.
Cardiovascular events and death .............................................................48
9.2.6.
Pregnancy....................................................................................................48
9.3.
Management of overdosage...............................................................................48
9.4.
Safety assessments ............................................................................................49
9.4.1.
Physical examination..................................................................................49
9.4.2.
Vital signs ....................................................................................................49
9.4.3.
Height and weight .......................................................................................49
9.4.4.
Pulmonary test ............................................................................................49
9.4.5.
ECG...............................................................................................................50
9.4.6.
Neutralizing antibody test..........................................................................50
9.4.7.
Clinical Safety Laboratory Assessments .................................................50
9.5.
Pharmacokinetics................................................................................................52
9.6.
Pharmacodynamics.............................................................................................52
9.7.
Genetics/Pharmacogenetics ..............................................................................52
9.8.
Biomarkers ...........................................................................................................52
9.9.
Pharmacoeconomics...........................................................................................52
10. STATISTICAL CONSIDERATIONS ..............................................................................53
10.1.
Sample Size Determination.................................................................................53
10.2.
Populations for Analyses....................................................................................53
10.3.
Statistical Analyses.............................................................................................53
10.3.1.
Efficacy Analyses........................................................................................53
10.3.2.
Safety Analysis............................................................................................54
10.3.3.
Other analyses.............................................................................................55
10.3.4.
Interim analyses..........................................................................................55
11. Reference ......................................................................................................................55
12. Appendices ...................................................................................................................57
12.1.
Appendix 1: Abbreviations and trademarks.....................................................57
12.2.
Appendix 2: Clinical Laboratory Tests..............................................................57
12.3.
APPENDIX 3: Study Governance Considerations............................................59
12.4.
APPENDIX 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting...........................................63
12.5.
APPENDIX 5: Contraceptive Guidance and Collection of Pregnancy 
Information ...........................................................................................................68
12.6.
APPENDIX 6: Liver Safety Required Actions and Follow
up 
Assessments........................................................................................................72
12.7.
APPENDIX 7: COUNTRY SPECIFIC DESCRIPTIONS .......................................75
12.7.1.
Regulatory and Ethical Considerations....................................................75


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12.7.2.
Obtaining of Informed Consent.................................................................75
12.7.3.
Study Implementation Period ....................................................................75
12.7.4.
Study Conduct Structure ...........................................................................75


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1.
SYNOPSIS
Protocol Title: A phase III study (a placebo controlled, randomized, double-blind comparative study 
and an open-label, uncontrolled study) to evaluate the efficacy and safety of GSK1358820 in patients 
with post-stroke upper limb spasticity
Short Title: A phase III study to evaluate the efficacy and safety of GSK1358820 in patients with 
post-stroke upper limb spasticity
Rationale:
GSK1358820, botulinum toxin type A (hereafter referred as the product), is sterile, purified type A 
botulinum neurotoxin complex. Intramuscularly injected botulinum neurotoxin shows muscle relaxant 
effects by blocking the neuromuscular junction and inhibiting release of acetylcholine, a 
neurotransmitter. Since the approval of the product for strabismus and blepharospasm in US in 1989, 
the product is licensed for the treatment of various diseases, which respond to the muscle relaxant 
effects in more than 90 countries (as of Apr 2017).
In Japan, the product is licensed with 8 indications as an ethical drug so far: blepharospasm as a 
first indication in Oct 1996, followed by “hemifacial spasm” in Jan 2000, “spasmodic torticollis” in 
Jun 2001, “talipes equinus associated with lower limb spasticity in pediatric patients two years of age 
and older with cerebral palsy” in Feb 2009, “upper limb spasticity” and “lower limb spasticity” in Oct 
2010, “severe primary maschalephidrosis” in Nov 2012, and “strabismus” in Jun 2015. For “upper 
limb spasticity,” 240 units of the product is approved as a maximum dose per administration. In US, 
as a maximum dose per administration, 400 units of injection of the product have been approved for 
the treatment of upper limb spasticity in adult patients in 2015; therefore, the authorized dose of the 
product between US and Japan is different.
This study is a multicenter, double blind, placebo controlled phase III domestic study and aims to 
evaluate the efficacy and safety of 400 units of the product in patents with post-stroke upper limb 
spasticity. The study was planned to increase the maximum dose per administration in Japan to 400 
units from 240 because the treatment with 240 units of the product, a maximum dose per 
administration, is considered to be insufficient in some patients with post-stroke upper limb spasticity. 


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Objectives and Endpoints:
Objectives
Endpoint(s) 
Primary 
To evaluate the efficacy of the injections of 400 
units of the product at Week 6 (finger/ wrist 
flexors: 240 units, elbow flexors: 160 units), 
comparing to that of 240 units (finger/ wrist 
flexors: 240 units, elbow flexors: placebo).
The responder rate : The rate of the subjects that 
Modified Ashworth Scale (MAS) score was 
reduced at least 1 from baseline in the elbow 
flexors. 
Secondary
To evaluate the efficacy of 400 units of the 
product, comparing to 240 units of the product

The responder rate of MAS score from 
baseline in the finger, thumb and wrist 
flexors 

Changes in MAS score from baseline in 
the finger, thumb, wrist and elbow 
flexors 

Changes in Disability Assessment Scale 
(DAS) from baseline
To evaluate the safety and tolerability of the 
product of 400 units, comparing to 240 units of the 
product/ To evaluate the safety and tolerability of 
400 units of the product

Adverse events

Physical examinations

Clinical laboratory tests (haematology, 
blood biochemistry, urinalysis)

Vital signs (heart rate, blood pressure, 
body temperature)
Exploratory
To evaluate the efficacy of 400 units of the 
product 

Changes in MAS score from baseline in 
finger, thumb, wrist, elbow, pronation of 
the forearm and shoulder flexors
To evaluate the other efficacy of the product of 
400 units, comparing to 240 units of the product/ 
To evaluate the other efficacy of 400 units of the 
product

Changes in Numeric Rating Scale 
(NRS) for pain from baseline

Changes in other items of DAS from 
baseline 

Clinical Global Impression of Change 
(CGI) of functional disability by a 
investigator

CGI of functional disability by a patient

Time to patient-reported onset of 
spasticity symptom relief

Patient-reported benefit of injection

Time to qualification for retreatment
To evaluate neutralizing antibody production

Testing for neutralizing antibody 


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Overall Design:
This study is a 48-week multicenter, phase III study (a placebo controlled, randomized, double-
blind comparative study and an open-label, uncontrolled study) to evaluate the efficacy and safety of 
the product in patients with post-stroke upper limb spasticity. The study period is up to 52 weeks, 
consisting of a screening phase up to 4 weeks, minimum 12-week blind phase (Part 1), maximum 36-
week open-label phase (12 weeks per cycle with maximum 3 treatment phases: Part 2, Part 3 and Part 
4). 
BOTOX 400 U
BOTOX 240 U
+
Placebo
BOTOX 400 U
BOTOX 400 U
Screening
BOTOX 400 U
Double-blind treatment
(12 weeks)
Open-label treatment 
(36 weeks)
Part 3
Part 4
Part 1
Part 2
dose 
dose 
dose 
dose 
dose 
Number of Participants:
Approximately 120 subjects (approximately 60 in each group) will be randomized to obtain an 
evaluable subject sample of approximately 100 at Week 48 as subjects with completion of the study。
Treatment Groups and Duration:
Screening Phase (Day -28～Day -1)
Evaluation and screening tests will be performed 28 to 7 days (±3days) before initial injection 
(Day 1) as a starting point. The investigator will decide which arm to be injected during screening 
phase.
Blind Phase (minimum 12 Weeks): Placebo Controlled, Randomized, Double Blind 
Design
Subjects wkho meet the inclusion criteria will be randomly assigned 1:1 to either the 400 or the 240 
units group. 

In the 400 units group, a total of 240 units of the product will be injected into the muscles 
that act on the finger (including thumb flexors) and wrist flexors, and a total of 160 units 
into the muscles that act on the elbow flexors; a total of 400 units of the product will be 
injected.

In the 240 units group, a total of 240 units of the product will be injected into the muscles 
that act on the finger (including thumb flexors) and wrist flexors. Placebo will be injected 
into the muscles that act on the elbow flexors. A total of 240 units of the product will be 
injected. 


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If the total dose for the muscles that act on the finger and writs flexors is ensured by 240 units, and 
160 units for the muscles that act on the elbow flexors, the dose can be adjusted at a investigator’s 
discretion based on the subject’s symptoms.
Open-Label Phase (maximum 36 Weeks): Uncontrolled, Open-Label Design
The product of 400 units will be injected in both groups. The product can be injected up to 3 times 
after completion of Part 1 in the blind phase. In the open-label phase, subjects whom the investigator
considers eligible for the injections will be treated. The next injections cannot be performed until the 
eligibility of the subject has been confirmed by the investigator. 
In the open-label phase, the muscle to be injected and the dose will be decided by the investigator 
based on the patient’s symptoms, and a total dose of 400 units of the product will be injected in a 
divided dose. For the muscles that the investigator considers unnecessary to be treated, an injection 
may be skipped. The involving muscle and the dose do not have to be same each time always.
Eligibility Criteria for Injection in and after Part 2
In the open-label phase (Part 2, Part 3, and Part 4), only the subjects whom the investigator 
considers eligible for the study will be injected. The eligibility is evaluated at a study visit after Week 
12 (V5. If a subject does not meet the criteria at V5, the eligibility is evaluated at QRV (Qualification 
for Retreatment Visit). Subjects are considered to be eligible if following criteria are all satisfied: 


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1)
At least 12 weeks (84 days) have passed since the preceding dose
2)
Among the finger, wrist or elbow flexors, 2 flexors have at least 2 on the MAS (except only the 
finger and wrist flexors of 2 on the MAS)
3)
Subject who request the injections
4)
Subjects whom a investigator considers an injection of 400 units of the product is appropriate
5)
Subjects who have not experienced serious adverse events (SAE) associated with the injections 
of the product
If subjects meet the criteria of the above 1) to 5) at V5 or QRV, body weight measurement, ECG, 
pulmonary function test, and pregnancy test will be performed to evaluate the following items. If 
subjects meet the following 6) to 8), the subjects will move forward to V1.
6)
Body weight ≥40 kg
7)
Subjects who the investigator considers there are no unacceptable safety concerns [potential 
for serious adverse events, laboratory data (V5), electrocardiogram (ECG) or pulmonary 
function value] due to 400 U of BOTOX
8)
Woman of childbearing potential who have negative pregnancy test result in urine
Pulmonary function test must be performed at V5 even if subjects do not meet the above 1) to 5) in 
accordance with the study operation schedule (SoA).


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2.
SCHEDULE OF ACTIVITIES (SoA)
Compliance with the protocol (including the list of the study conduct schedule) is important and 
required to conduct the study. Therefore, exemption or discharge cannot be allowed, except but 
emergency safety concerns arise. 
The study operation schedule is shown on Table 1. Examples of injections in the open-label phase 
based on evaluation of eligibility for injection are shown on Figure 1, Figure 2, Figure 3, and Figure 4. 


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Table 1 SCHEDULE OF ACTIVITIES (SoA)
Screening a
Blind phase
If a subject meets the eligibility at V5/ QRV, the subject will 
move forward to the open-label phase
Open-label phase
If a subject meets the eligibility at V5/QRV, the subject will move 
forward to the next treatment phase
Completion 
visit
Part 1
Eligibility 
evaluation b
Part 2/Part 3/ Part 4
Eligibility 
evaluation b
Visit
SV
V1
(Day 1)
V2
V3
V4
V5 c
(Eligibility 
evaluation)
QRV
V1
V2
V3
V4
V5 d
(Eligibility 
evaluation)
QRV
Final
Visit
Time from initial injection 
(Day 1) (Weeks)
―
0
2
4
6
12 
Allowable Week 16 to 
36e
―
―
―
―
―
Allowable Week 24 to 
36 e
48/
Withdrawal
Time from injection day in each 
treatment phase (Weeks)
―
0
2
4
6
12
16/ 20/ 24/ 28/ 32/ 
36
0
2
4
6
12
16/ 20/ 24
-
Acceptable visit windows (days) 
―
4
4
4
+4 f
14 g
+4
4
4
4
+4 f
14 g
4
Written informed consent
X h
Randomization
X i
Injections
X
X
Evaluation of eligibility
X
X
X
X
Inclusion/exclusion criteria j
X
X i
Subject demography
X
MAS k
X
X i
X
X
X
X
X
X i,t
X
X
X
X
X
X
NRS l
X i
X
X
X
X
X i,t
X
X
X
X
(X) r
DAS 
X i
X
X
X
X
X i,t
X
X
X
X
(X) r
CGI by a investigator
X
X
X
X
X
X
X
X
(X) r
CGI by a patient
X
X
X
X
X
X
X
X
(X) r
Time to patient-reported onset of 
spasticity symptom relief
X
X
Patient-reported benefit of 
injection
X
X
X
X
X
X
(X) r
Physical examination (complete 
version)
X
Physical examination (simplified 
version)
X i
X
X i,t
X
X
Medical history
X
X i
Vital signs m
X
X i
X
X i,t
X
X
Height
X
Body weight
X
X u
X u
X u
X u
Pulmonary function test
X
X
X
X u
X
X u
X
Electrocardiogram
X
X u
X u
X u
X u
Pregnancy test n
X
X i
X u
X u
Xs, u
X u
X
Laboratory test o
X
X
X
X
Adverse events p
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medications/therapies
X
X i
X
X
X
X
X
X
X
X
X
X
X
X


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a.
Test items for screening must be performed from 4 weeks to 1 weeks before Day 1 visit (±3 days).
b.
Eligibility evaluation (Qualification for Retreatment Visit: QRV) will be performed at V5 as a starting point if a subject does not meet the criteria only. The evaluation is performed at a 4-week interval, 
V5 as a starting point, The QRV when a subject meets the criteria will be a same day as the injection in the next treatment period (refer to Figure 1, Figure 2, Figure 3, Figure 4). 
c.
If a subject is evaluated to meet the eligibility for the injection in the blind phase at V5, the subject will move forward to Part 2 in the open-label phase (Namely, V5 in Part 1 and V1 in Part 2 is a same 
day). If the subject does not meet the eligibility, QRV will be performed 4 weeks later, at V5 as s starting point. 
d.
If a subject is evaluated to meet the eligibility at V5 in the open-label phase, the subject will move forward to the next treatment phase (V5 and V1 in the next treatment phase is a same day). If the 
subject does not meet the eligibility, QRV is performed 4 weeks later, V5 as a starting point. If V5 in each treatment phase is at Week 48 after initial injection, V5 will be considered to be completion
visit (FV). However, for the testing items, pre-scheduled tests at V5 and neutralizing antibody tests will be performed. If V5 in Parts 2 and 3 is performed at Week 36 or later, after completion of V5, 
completion visit will be performed at Week 48.
e.
QRV is allowable to perform from initial injection to Week 36. Eligibility evaluation (QRV) will not be performed after Week 36.  
f.
V5 must be performed at least 84 days after V1. 
g.
The acceptable visit windows will be -14 to +4 days if QRV is performed at Week 36.
h.
Must be performed earlier than any other procedures
i.
Must be performed before injection of the product
j.
For inclusion/exclusion criteria, the items to be observed are different between screening phase and Day 1. For details, refer to 6.1. and 6.2.
k.
For MAS evaluation, the items to be evaluated differ depending on the treatment phase. For details, refer to 9.1.1.1.
l.
MAS evaluation will be followed by NRS evaluation. For NRS evaluation, items to be evaluated differ. For details, refer to 9.1.1.2.
m.
Body temperature, heart rate, and blood pressure will be measured as vital signs. 
n.
Women of childbearing potential will be only performed. Serum hCG pregnancy test must be performed at screening, and urine hCG pregnancy test after randomization. The tests can be performed 
beyond the protocol specifications if a investigator considers to be necessary.  
o.
For laboratory test items, refer to 12.2. Attachment 2. Fasting is not required for blood collection. 
p.
Adverse events and serious adverse events collection period will be from the initial injection day (Day 1) to completion visit (FV).
q.
Neutralizing antibody testing is performed 3 times in each subject. The first test will be performed in screening phase, the second is at V5 in the blind phase, and the third is at completion visit.
r.
A subject who withdraws the study before 12 weeks after last injection will be performed. 
s.
Perform if V5 in each treatment phase is at Week 48 after initial injection
t.
Not necessary to perform doubly as V1 assessment if the same assessment is performed at V5 or QRV
u.
Evaluation of retreatment is performed only when the dosing conditions (1 to 5) of retreatment evaluation are met.
Testing for neutralising 
antibodies q
X
X
X


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GSK1358820 
240 U
GSK1358820 
400 U
GSK1358820 
400 U
0
V1
2
V2
4
V3
6
V4
8
10
12
14
V2
16
V3
18
V4
20
22
24
GSK1358820 
400 U
GSK1358820 
400 U
Week
Intial treatment
3rd treatment
2nd Treatment
4th treatment
Part 1
Part 2
Part 3
Part 4
26
V2
28
30
32
34
36
38
40
42
44
46
48
FInal
Visit
：Visit week
Ex.1）If a subject is eligible for the injections at V5 in all the treatment phases
V3
V4
V2
V3
V4
V5/FV
Day1
V5/V1
V5/V1
V5/V1
Double-blind
Figure 1    Eligibility Evaluation in the Open-Label Phase (Example 1) 
If a subject is eligible for the injections at V5 in all the treatment phases, 4 injections will be performed 
throughout the study. Week 48 visit is performed also as a completion visit. 
GSK1358820
240 U
GSK1358820 
400 U
GSK1358820 
400 U
0
2
4
6
8
10
12
14
16
18
20
22
24
GSK1358820 
400 U
Week
Initial treatment
Part 1
Part 2
Part 3
26
28
30
32
34
36
38
40
42
44
46
48
Final
Visit
Evaluation will not be performed
：Visit week
Ex. 2）If a subject does not meet the eligibility at V5 in blind phase (Part 1), 
QRV will be performed at Week 16
V1       V2      V3     V4                           V5          QRV/V1   V2      V3     V4                       V5/V1    V2
V3      V4                           V5                                      FV
Day1
Not qualified
for retreatment
2nd treatment
3rd treatment
Double-blind
Figure 2   Eligibility Evaluation in the Open-Label Phase (Example 2) 
If a subject does not meet the eligibility at V5 in blind phase (Part 1), QRV will be performed at Week 16. V5 in Part 
3 is at Week 40, therefore, eligibility evaluation will not be performed. After V5 at Week 40, FV will be performed at 
Week 48. 


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GSK1358820 
240 U
GSK1358820 
400 U
GSK1358820
400 U
0
2
4
6
8
10
12
14
16
18
20
22
24
GSK1358820
400 U
week
Initial treatment
2ndtreatment
Part 1
Part 2
Part 3
26
28
30
32
34
36
38
40
42
44
46
48
Final
Visit
Not qualified 
For retreatment
3rd treatment
：Visit week
Ex. 3）If a subject does not meet the eligibility at V5, and evaluated to be eligible at 
QRV3 Week 24
V1       V2      V3     V4                           V5              QRV1
QRV2  
QRV3/V1  V2     V3     V4  
V5/V1    V2      V3     V4
V5/FV
Day1                                                                                                                
Not qualified 
For retreatment
Double-blind
Figure 3    Eligibility Evaluation in the Open-Label Phase (Example 3) 
If a subject does not meet the eligibility at V5 in the blind phase (Part 1), QRV will be performed until the eligibility 
have confirmed at 4 weeks intervals, at V5 as a starting point. If a subject is evaluated to be eligible at QRV3 Week 24, 
the injections in Part 2 will be performed on the same day as QRV3. V5 in Part 3 is in Week 48, therefore, at V5, 
completion visit (FV) will be also performed. 
GSK1358820 
240 U
GSK1358820 
400 U
GSK1358820 
400 U
0
2
4
6
8
10
12
14
16
18
20
22
24
week
Initial treatment
2ndtreatment
Part 1
Part 2
26
28
30
32
34
36
38
40
42
44
46
48
Final
visit
Not qualified
for retreatment
：Visit week
*if  not qualified at week 36,
Eligibility assessment will not be performed.
V1       V2      V3     V4                           V5   
QRV1
QRV2
QRV3/V1  V2     V3     V4 
V5                                     
FV
Day1
Ex. 4）If a subject does not meet the eligibility at Week 36
Not qualified
for retreatment
Not qualified
for retreatment
Double-blind
Figure 4    Eligibility Evaluation in the Open-Label Phase (Example 4)
QRV in Part 2 is Week 36, and if a subject does not meet the criteria, subsequent injections will not be performed, 
and Week 48 completion visit will be performed. 


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3.
INTRODUCTION 
3.1.
Study Rationale
GSK1358820, botulinum toxin type A (hereafter referred to as the product) is sterile, purified type 
A botulinum neurotoxin complex. Intramuscularly injected botulinum neurotoxin shows muscle 
relaxant effects by blocking the neuromuscular junction and inhibiting the release of acetylcholine, a 
neurotransmitter. Since the approval of the product for strabismus and blepharospasm in US in 1989, 
the product is licensed for the treatment of various diseases, which respond to the muscle relaxant 
effects in more than 90 countries (as of Apr 2017). 
In Japan, the product is licensed with 8 indications as an ethical drug so far: blepharospasm as first 
indication in Oct 1996, followed by “hemifacial spasm” in Jan 2000, “spasmodic torticollis” in Jun 
2001, “talipes equinus associated with lower limb spasticity in paediatric patients two years of age and 
older with cerebral palsy” in Feb 2009, “upper limb spasticity” and “lower limb spasticity” in Oct 
2010, “severe primary maschalephidrosis” in Nov 2012, and “strabismus” in Jun 2015. For “upper 
limb spasticity,” 240 units of the product is approved as a maximum dose per administration. 
This study is a multicenter, double blind, placebo controlled phase III domestic study in patients 
with upper limb spasticity and aims to confirm the efficacy and safety of 240 units of the product for 
post-stroke upper limb spasticity. The information of 400 units of the product in the study is expected 
to provide beneficial information because the treatment with 240 units of the product with a maximum 
dose per administration is considered to be insufficient in some patients with post-stroke upper limb 
spasticity.
3.2.
Background
Spasticity is a movement disorder that is characterized by increased myotatic reflex and is regarded 
as one of positive signs of the upper motor neuron signs (Kagamihara, 2012; Lance, 1980). Spasticity 
is caused by central nerve system injuries such as stroke, traumatic brain injury, or spinal cord injury 
and chronic neuropathies such as cerebral palsy or multiple sclerosis, etc. Abnormal postures of the 
upper limbs due to spasticity include thumb refraction, a clenched fist deformity, flexion of the wrist 
flexors, pronation of the forearms, flexion of the elbow flexors, and adduction/inner rotation of the 
shoulder flexors (Gracies, 2003; Kinoshita, 2015). 
Spasticity hampers rehabilitation therapy. In addition, limitation of flexors range of motion and 
persistent pain hinder from caregiving and decrease activity in daily life (Grazko, 1995); therefore, 
many of patients with stroke require treatments to ameliorate their dysfunction.
For the treatments of spasticity, rehabilitation therapy, oral medications, phenol blocks, and 
baclofen injections were used until botulinum therapy has been approved as a national health 
insurance coverage. These treatments were commonly challenging because of lack of effects, difficult 
procedures, or invasive interventions. Subsequently, in Oct 2010, the product was approved as a 
botulinum treatment for upper and lower limb spasticity in Japan. Since then, botulinum toxin has 
been used for the treatment of spasticity (Ohsawa, 2013). According to the “Japanese Guidelines for 
the Management of Stroke” (initial version in 2009, revised in 2015) (Ogawa, 2015; Shinohara, 2009), 
which was issued by the Japan Stroke Society, botulinum therapy is recommended for the treatment of 
spasticity as Grade A, and is considered to be effective for relief of upper limb spasticity, increase of 
range of motions in flexors, and reduction of the amount of assistance on daily life.


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In Japan, upper limb spasticity, a domestic phase II study involving the finger, wrist, and elbow 
flexors was performed from Dec 2001 through Mar 2003, and a domestic phase III study involving the 
finger and wrist flexors from May 2007 through Dec 2008. Consequently, the product was approved 
for the treatment of upper limb spasticity with a maximum dose of 240 units per administration in Oct 
2010. 
However, subsequently, the injections of the product at 240 units were found to be insufficient for 
the involving muscles because patients with extensive upper limb spasticity require dose adequate to 
inject into many of the involving muscles. Therefore, many medical institutions requested us to 
increase the maximum dose per administration of the product. Moreover, the specified drug-use 
survey from Jun 2011 through Apr 2014 identified that approximately 39% of the patients who use the 
product for upper limb spasticity were injected more than 240 units, a maximum dose per 
administration. The results suggest high patient needs for an increase of the maximum dose per 
administration of the product. 
In US, as a maximum dose per administration, 400 units of injections of the product have been 
approved for the treatment of upper limb spasticity in adult patients in 2015; therefore, the authorized 
dose between US and Japan is different. 
Based on these background, the study was planned to evaluate the efficacy and safety of 400 units 
of the product for upper limb spasticity in order to increase the maximum dose per administration to 
400 units. 
The study was planned based on the regulatory advice by the Pharmaceuticals and Medical Devices 
Agency (PMDA). 
3.3.
Benefit/Risk Assessment
For details of the known and anticipated benefit/risk and rationally expected adverse events are 
shown on the Investigator's Brochure (IB) and package insert. 


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3.3.1.
Risk Assessment
Important identified risks
Reports suggesting risks/ Outlines of rationale
Measures for risk minimization
Investigational product :GSK1358820
Hypersensitivity
Serious and/or immediate hypersensitivity reactions
(anaphylaxis, serum sickness, urticarial, soft tissue 
edema, or dyspnea, etc.) have been rarely reported. 
Patients who previously experienced allergic reactions 
due to botulinum toxin type A, an additive agent of 
sodium chloride, or human serum albumin are 
excluded from enrolment. Upon written informed 
consent process, subjects will be explained that any 
urticarial, swelling face, throat swelling, wheezing, 
dizziness, or dyspnoea should contact their
investigator. 
Pre-existing neuromuscular disorder
Patients with neuromuscular junction diseases 
(myasthenia gravis, Lambert-Eaton myasthenic 
syndrome etc.) may increase the sensitivity to the 
product, resulting in excessive muscular weakness. 
For patients with myasthenia gravis, Eaton-Lambert 
syndrome (ELS), amyotrophic lateral sclerosis, or a 
serious disease and who use a concomitant drug (s) 
which may inhibit neuromuscular function, exclusion 
criteria will be set, and those patients will be excluded 
from enrolment in the study (refer to 6.2.1). 
distant spread of toxin
Adverse drug reactions in the remote muscles, except 
but the injected site, have been rarely reported. The 
adverse drug reactions include muscular weakness, 
constipation, dysuria, swallowing difficult, and non-
accidental entering of food or fluid in the lungs not via 
the stomach, but the trachea (pneumonia may occur). 
The patients who received the product at a higher dose 
are considered likely to have increased risks for these 
adverse drug reactions. 
In this study, a high dose of 400 units of the product 
will be injected. Therefore, the subjects will be 
followed up after 2, 4, 6, and 12 weeks of injection. 
The safety of the subjects will be observed carefully.
Use of at least one of the following guide tools 
(electromyogram, electrical stimulator, or 
ultrasonography) will be essential in the blind phase to 
ensure identification of the exact site of injection.


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Important identified risks
Reports suggesting risks/ Outlines of rationale
Measures for risk minimization
Immunogenicity, drug resistance, antibody production The important cause of neutralizing antibody 
production has not been fully clarified. A few studies 
suggested that the injection of the product at short 
intervals or at a high dose may lead to increased rate 
of antibody production[Jankovic, 2006; Klein, 2002]. 
Neutralizing antibody production against botulinum 
toxin type A may lead to inactivation of the biological 
activity of the product, resulting in decreased 
therapeutic effects of the product.
In this study, patients who were considered likely to 
have neutralizing antibody production based on the 
previous treatment experience of botulinum toxin type 
A will be excluded from enrolment in the study 
(Exclusion Criteria 6.2.1).
In addition, treatment schedule in the study was set to 
ensure at least a 12-week dosing interval. 
Other (If applicable)
Medication error (preparation with lidocaine)
One fatal case due to anaphylaxis has been reported. 
In this case, the patient died after 100 units of an 
injection of the product that prepared inappropriately 
with 5 mL of 1% lidocaine. The causal relationship of 
death to the product and lidocaine, or both has been 
unknown. 
In this study, the product will be prepared
appropriately with 0.9% normal saline. The 
preparation method will be described on the study 
reference manual (SRM).


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3.3.2.
Benefit Assessment
In patients with post-stroke upper limb spasticity, currently, the product is approved to inject up to 
240 units per administration in Japan. However, in patients with extensive upper limb spasticity, the 
treatment effects of the product is presumed to lack because of the dose limitation.
In US, the efficacy and safety of the product up to 400 units per dose for patients with upper limb 
spasticity is confirmed, and the clinical use of the product has been approved. The injections of 400 
units of the product in this study are expected to increase injectable sites and enhance the treatment 
effects in Japanese patients with upper limb spasticity, who did not have great benefits from 240 units 
of the product.
If a subject is assigned to the 240 units group in Part 1 and meets the eligibility criteria for injection in 
the open-label phase, 400 units of the product will be injected in and after Part 2. Therefore, all the 
subjects who participate in this study are given the opportunity to receive 400 units of the product 
(Refer to “5. STUDY DESIGN”). 
3.3.3.
Overall Benefit:Risk Conclusion
The known potential risks in the product is justified by the benefits which would provide for the 
patients with post-stroke upper limb spasticity, given the safety measures to minimize risks in subjects 
who enrol in the study. 


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4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoint(s)
Primary
To evaluate the efficacy of injection of 400 units 
of the product at Week 6 (finger/ wrist flexors: 
240 units, elbow flexors: 160 units), comparing to 
that of 240 units (finger/ wrist flexors: 240 units, 
elbow flexors: placebo).
The rate of the subjects that Modified Ashworth 
Scale (MAS) score was reduced at least 1 from 
baseline in the elbow flexors (the responder rate). 
Secondary
To evaluate the efficacy of 400 units of the 
product, comparing to 240 units of the product.

The responder rate of MAS score from 
baseline in finger, thumb and wrist 
flexors

Changes in MAS score from baseline in 
finger, thumb, wrist, elbow, pronation of 
forearms and shoulder flexors

Changes in Disability Assessment Scale 
(DAS) from baseline
To evaluate the safety and tolerability of the 
product of 400 units, comparing to 240 units of the 
product/ To evaluate the safety and tolerability of 
400 units of the product.

Adverse events

Physical examinations

Clinical laboratory tests (haematology, 
blood biochemistry, urinalysis)

Vital signs (heart rate, blood pressure, 
body temperature)
Exploratory
To evaluate the efficacy of 400 units of the 
product 

Changes in MAS score from baseline in 
finger, thumb, wrist, elbow, pronation of 
the forearm and shoulder flexors
To evaluate the other efficacy of the product of 
400 units, comparing to 240 units of the product/ 
To evaluate the other efficacy of 400 units of the 
product

Changes in Numeric Rating Scale 
(NRS) for pain from baseline

Changes in other items of DAS from 
baseline 

Clinical Global Impression of Change 
(CGI) of functional disability by a 
investigator

CGI of functional disability by a patient

Time to patient-reported onset of 
spasticity symptom relief

Patient-reported benefit of injection

Time to qualification for retreatment
To evaluate neutralizing antibody production

Testing for neutralizing antibody 


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5.
STUDY DESIGN
5.1.
Overall Design
This study is a 48-week multicenter, phase III study (a placebo controlled, randomized, double-blind 
comparative study and an open-label, uncontrolled study) to evaluate the efficacy and safety of the 
product in patients with post-stroke upper limb spasticity. The study period is up to 52 weeks, 
consisting of a screening phase up to 4 weeks, minimum 12-week blind phase (Part 1), maximum 36-
week open-label phase (12 weeks per cycle with maximum 3 treatment periods, Part 2, Part 3 and Part 
4). (Figure 5).
BOTOX 400 U
BOTOX 240 U
+
Placebo
BOTOX 400 U
BOTOX 400 U
Screening
BOTOX 400 U
Double-blind treatment
(12 weeks)
Open-label treatment 
(36 weeks)
Part 3
Part 4
Part 1
Part 2
dose 
dose 
dose 
dose 
dose 
Figure 5   Study Design
In this study, the efficacy of 400 units of the product at Week 6 is evaluated, comparing to that of 
240 units, and improvement tendencies are also evaluated in patients with post-stroke upper limb 
spasticity. The improvement will be defined as at least 1 reduction on the MAS score from baseline (a 
measurement value before injection of Day 1). The responder rate (the rate of the subjects that MAS 
score is reduced at least 1 from baseline) in the elbow flexors at Week 6 is set as an endpoint. As a 
point estimate, if the responder rate in the 400 units group outweighs that in the 240 units group, 
improvements tendencies will be considered to be positive. 
For injection, use of the following any one of the tools: EMG, electrical stimulator, or 
ultrasonography, is recommended to ensure identification of the exact injection site. In the blind phase, 
use of at least one of the following tools: EMG, electrical stimulator, or ultrasonography, will be 
essential to ensure identification of the muscle to be injected correctly. 
5.1.1.
Screening Phase (up to 4 weeks) 
Evaluation and screening tests will be performed 28 days to 7 days (+3 days) before initial injection 
(Day 1) as a starting point. The investigator will decide which arm to be injected during screening 
phase. Throughout the study period, the arm, which is decided to be injected at screening phase will 
be involved during the injections and evaluations, unless clearly specified otherwise by the sponsor. 


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5.1.2.
Blind Period (minimum 12 Weeks): Placebo Controlled, Randomized, Double 
Blind Design
Subjects who meet the inclusion criteria will be randomized 1:1 to either the 400 units or the 240 
units group. 

In the 400 units group, a total of 240 units of the product will be injected into the muscles 
that act on the finger (including thumb flexors) and wrist flexors, and a total of 160 units 
into the muscles that act on the elbow flexors; a total of 400 units of the product will be 
injected.

In the 240 units group, a total of 240 units of the product will be injected into the muscles 
that act on the finger (including thumb flexors) and wrist flexors. Placebo will be injected 
into the muscles that act on the elbow flexors. A total of 240 units of the product will be 
injected.
If the total dose for the muscles that act on the finger and writs flexors is ensured by 240 units, and 
160 units for the muscles that act on the elbow flexors, the dose can be adjusted at a investigator’s 
discretion based on the subject’s symptoms. (Refer to “7.1. Treatments Administered” Table 2).
5.1.3.
Open-Label Phase (maximum 36 weeks): Uncontrolled, Open-Label Design
The product of 400 units will be injected in both groups. The product can be injected up to 3 times 
after completion of Part 1 in the blind phase. In the open-label phase, subjects whom the investigator 
considers eligible for the injection will be treated (Refer to 5.1.3.1. Eligibility Criteria for Injection in 
and after Part 2). The next injection cannot be performed until the eligibility of the subject has been 
confirmed by the investigator (Refer to 5.1.3.1. Eligibility Criteria for Injection in and after Part 2).
In the open-label phase, the muscle to be injected and the dose will be decided by the investigator
based on the patient’s symptoms, and a total dose of 400 units of the product will be injected in a 
divided dose (Refer to "7.1. Treatments Administered” on Table 3). For the muscles that the
investigator considers unnecessary to be treated, an injection may be skipped. The involving muscle 
and the dose do not have to be same each time always.
5.1.3.1.
Eligibility Criteria for Injection in and after Part 2
In the open-label phase (Part 2, Part 3, and Part 4), the subjects whom the investigator considers
eligible for the injections in the open-label phase only will be treated. The eligibility is evaluated at a 
study visit after Week 12 (V5, if a subject does not meet the eligibility criteria, the evaluation will be 
performed at QRV (Qualification for Retreatment Visit). A subject will be considered as eligible when 
he or she meets all the criteria. The eligibility evaluation will be performed after completion of Part 1 
in the blind phase, between Week 12 to Week 36. If a subject does not meet the eligibility at Week 36, 
subsequent evaluation will not be performed, and the product cannot be given (refer to Figure 1, 
Figure 2, Figure 3, and Figure 4).
1)
At least 12 weeks (84 days) have passed since the preceding dose
2)
Among the finger, wrist or elbow flexors, 2 flexors have at least 2 on the MAS (except only the 
finger and wrist flexors of 2 on the MAS)
3)
Subject who request the injection


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4)
Subjects whom a investigator considers an injection of 400 units of the product is appropriate
5)
Subjects who have not experienced serious adverse events (SAE) associated with the injection 
of the product
If subjects meet the criteria of the above 1) to 5) at V5 or QRV, body weight measurement, ECG, 
pulmonary function test, and pregnancy test will be performed to evaluate the following items. If 
subjects meet the following 6) to 8), the subjects will move forward to V1.
Pulmonary function test must be performed at V5 even if subjects do not meet the above 1) to 5) in 
accordance with the study operation schedule (SoA).
1)
Body weight ≥40 kg
2)
Subjects who the investigator considers there are no unacceptable safety concerns [potential 
for serious adverse events, laboratory data (V5), electrocardiogram (ECG) or pulmonary 
function value] due to 400 U of BOTOX
3)
Woman of childbearing potential who have negative pregnancy test result in urine
5.2.
Number of Participants
Approximately 120 subjects (approximately 60 in each group) will be randomized to obtain an 
evaluable subject sample of approximately 100 at Week 48 as subjects who complete the study
5.3.
Participant and Study Completion
Subjects who completed all the study procedures, including a completion visit will be regarded as 
study completion. The completion date in this study will be defined as the last day performing the 
study procedure of last subject. 
5.4.
Scientific Rationale for Study
The study design was set to evaluate the efficacy and safety of 400 units of the product in patients 
with post-stroke upper limb spasticity. The primary endpoints employed the responder rate of the 
MAS score in the elbow flexors. The reasons for employing MAS score as an indicator include that 
MAS is highly reliable for evaluation of upper limb spasticity (Bohannon, 1987; Mutlu, 2008); 
especially, for evaluation of spasticity in the elbow flexors in the upper limbs (Gregson, 2000; Sloan, 
1992). 
Screening Phase
The screening phase up to 28 days before initial injection was set in order to confirm subjects meet 
the inclusion criteria and none of the exclusion criteria, and assess the condition of subjects at baseline. 
However, measurements of laboratory parameters at screening phase should be completed by 4 days 
before Day 1 (Day -28 to -4). 
Treatment Phase 
In Part 1, a double blind comparative study was set to compare the efficacy of the product of 400 
units to 240 units, the currently approved dose for upper limb spasticity. In the blind phase, 240 units 


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of the product will be injected into the muscles that act on the finger (including the thumb)/wrist 
flexors, and 160 units (the 400 units group) or placebo (the 240 units group) for the muscles that act 
on the elbow flexors. The improvement tendencies in the efficacy between the 240 units group, the 
total dose, and the 400 units groups will be compared by evaluating the responder rate tendencies on 
the MAS score in the elbow flexors in a blinded manner. In the previous confirmatory study (108509 
study) for approval of the product for upper limb spasticity, the elbow flexors were not involved. 
Therefore, in this study, the responder rate on the MAS score in the elbow flexors was decided to 
compare as the placebo group. 
Actually, in medical institutions, the product is injected into the whole upper limb, including the 
shoulder flexors. In addition, the dose for each muscle is decided at a investigator’s discretion. 
Previous studies reported that botulinum injections into the pectoralis major and teres major muscle 
relieved pain in patients with hemiplegia (Marciniak, 2012) and injections into the sub-scapula 
improved passive range of motion (Yelnik, 2007). Therefore, in and after Part 2 in the open-label 
phase, the product will be allowed to be injected not only into the muscles that acts to the finger 
(including the thumb), wrist, and elbow flexors, but also the muscles that act on the shoulder flexors, 
where applicable, enabling a investigator to decide the dose for each muscle. In addition, the study 
design included safety evaluation of the product at Week 48 after initial injection in all subjects as far 
as possible for safety evaluation purposes of 400 units. 
5.5.
Dose Justification
The product of 400 units is a maximum dose for upper limb spasticity, which was approved by the 
U.S. Food and Drug Administration (FDA), and this suggests that the efficacy and safety profiles are 
favourable. Evaluation of the efficacy and safety of 400 units of the product provides beneficial 
information in Japanese patients with severe post-stroke upper limb spasticity, who are considered 
injections of 400 units of the product are necessary. 
The dose of 240 units of the product, the controlled group, in the blind phase (Part 1) is the current 
authorized dose (a maximum dose per administration) for upper limb spasticity in Japan. In this study, 
the 240 units group was set as the control group in order to evaluate improvement tendencies, 
comparing the efficacy of 240 units of the product, the current approved dose, to that of 400 units of 
the product.  
6.
STUDY POPULATION
Inclusion of subjects despite expectation of deviation from the protocol, namely, exemption or 
discharge from the protocol, cannot be allowed.
6.1.
Inclusion Criteria
6.1.1.
Screening Phase (Day -28 to Day -1)
In the screening phase, subjects eligible for enrolment in the study must meet all of the following 
criteria. Laboratory parameters should be measured by 7 days (± 3 days) before initial injection 
(Day 1). 
Age
1. Between 20 and 80 years of age at the time of informed consent (ICF). 


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Subjects and Characteristics of the Disease
2. Patients with at least a 3-month history of upper limb spasticity after the most recent stroke 
3. Patients who have spastic symptoms in the finger (including the thumb), wrist, and elbow flexors
whom the investigator considers the injections of 400 units of the product is necessary for the upper 
limb based on the muscle spasms and the symptoms of the patient
4. Patients who have a previous treatment history of 240 units of the product for the upper limb at 
least 16 weeks before screening (refer toTable 3 for muscles in the upper limbs) 
5. Patients who meet following criteria on MAS at screening (Test position : sitting)

At least 3 in for the elbow flexors
And

At least 2 in the finger or wrist flexors
6. Patients who have severe upper limb spasticity, which deserves to be treated with 400 units of the 
product in the divided dose and was previously injected 240 units of the product
7. Patients whom the investigator considers that enrolment in the study poses no problems based on 
the laboratory data results at screening
8. Patients who are free from a history of acute decreased lung function (hospitalization with 
aggravated asthma/COPD, pneumonia, or signs of pneumonia, or abnormal reactive airway diseases 
suggested on X-rays) within the last 3 months at screening and have stable pulmonary function
(SpO2 [oxygen saturation] value is 95%)
Body Weight
9. Body weight ≥ 40 kg at screening
Sex
10. Male or female
a.
Male Subjects
Male subjects must content to use highly effective contraceptive methods, which are shown on 
attachment 5 of the protocol in detail during the study period, and sperm donation must be 
avoided. 
b.
Female Subjects
Female subjects who are not pregnant or lactating are considered eligible (refer to attachment 5) 
if at least one of the following criteria is met:
i)
Non-childbearing potential based on the definition on attachment 5
ii)
Women of childbearing potential who content to follow the guidance about contraception on 
attachment 5 during the study period and at least for 3 months after the last dose of the 
product.
iii)
No plan of pregnancy during the study period
Informed Consent
11. Patients who have ability to sign their name on the ICF, following the description on attachment 3, 
adhering to the requirements and limitations described on the ICF and the protocol. 


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6.1.2.
Day 1 (prior to injection)
Subjects eligible for enrolment in the study must meet all of the following criteria on Day 1 (prior 
to injection): 
Subjects and Characteristics of the Disease
31. Patients who meet the following criteria on MAS score: (Test position : sitting)

At least 3 in the elbow flexors
And

At least 2 in the finger or wrist flexors
Preceding Treatments and Concomitant Medications/Therapies
32. If centrally acting muscle relaxants, tetracycline antibiotics, anticholinergics, benzodiazepines, or 
benzamides are given, the dose and regimen must be stable at least for the last 2 months before 
Day 1; Patients who can maintain the same dosage and regimens at least in the blind phase after 
initial injection (dose reductions and discontinuation of the drugs are acceptable in the open-label 
phase. However, second dose increase, resumption, and or new treatment will not be performed). 
33. If intrathecal baclofen is given, the dose and regimen must be stable at least for the last 1 month 
before Day 1; Patients who can maintain the same dosage and regimens at least in the blind phase
after initial injection (intravenous bolus is not acceptable, dose reductions and discontinuation of 
the drugs are acceptable. However, second dose increase, resumption, and or new treatment will 
not be performed).
34. If antiepileptic agents are given, the dose and regimen must be stable at least for the 1 month 
before Day 1; Patients who can maintain the same dose and regimens at least in the blind phase 
after initial injection (dose reductions and discontinuation of the drugs are acceptable in the open-
label phase. However, second dose increase, resumption, and new treatment will not be 
performed).
35. If a physical therapy, occupational therapy, or a static splint on the study involvement upper 
limbs is given, the frequency and treatment regimen must be stable at least for the last 3 weeks 
before Day 1; Patients who can maintain the same dose and regimens at least in blind phase (In 
the open-label phase, the frequency and treatment regimen can be changed depending on the 
condition of spasticity).
6.2.
Exclusion Criteria
6.2.1.
Screening Phase (Day -28 to Day -1)
A subject will be excluded from enrolment in this study if any of the following criteria apply in the 
screening phase. Measurements of laboratory parameters at screening must be completed 7 days (±3 
days) before initial injection (Day 1).
Medical Condition
1.
Patients present with spasticity requiring treatment in the non-paralytic side of the upper limb
2. Patients who have fixed contracture* in the finger (upper limb), wrist, elbow or shoulder muscle,     
which will be involved in the study


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(*Positive effects were not confirmed in the previous treatment with GSK1358820, and 
contracture is considered to be the main cause of limited range of motion in the joint.)
3. Patients who have medically significant capsulitis or subluxation in any one of the fingers (upper 
limb), wrist, elbow and shoulder, which will be involved in the study, or whom a investigator
considers the complicated local signs of pain may affect the efficacy evaluation
4. Patient’s upper limb spasticity is attributed to other than stroke (traumatic brain injury, spinal cord 
injury, multiple sclerosis, or cerebral palsy)
5. Patients who have a 2-fold higher alanine aminotransferase (ALT) level than the upper limit of 
normal (ULN)
6. Patients who have a 1.5-fold higher bilirubin than the ULN (If a bilirubin fractionation shows direct 
bilirubin < 35%, a 1.5-fold higher free bilirubin than the ULN is acceptable).
7. Patients whom the investigator considers presence of a current medical history of unstable liver 
diseases or biliary tract diseases (the condition will be defined by development of ascites, 
encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice 
or hepatic cirrhosis)
Note:

If a patient with stable chronic liver diseases (Gilbert's syndrome, silent gallstone, and stable 
chronic hepatitis B or hepatitis C [Namely, hepatitis B surface antigen: HBsAg or hepatitis 
C virus: HCV antibody shows positive at screening or within 3 months before initiation of 
the study treatment] are included) meets other inclusion criteria, the patient can be enrolled 
in the study. 
8. Patients with QTc > 450 msec or QTc > 480 msec in patients with bundle branch block
Note:

QT intervals corrected by the Bazett method (QTcB); QT intervals corrected by the 
Fridericia method (QTcF) and/or QT intervals corrected by other methods; interpretation by 
a machine or manual re-interpretation will be used.

Prior to study initiation, the correction formula which is used for the subject’s 
inclusion/exclusion/discontinuation criteria will be determined. Namely, several different 
correction formula cannot be used for calculation of QTc in each subject. In addition, the 
lowest QTc level cannot be used for enrolment or discontinuation of subjects of the study. 
Preceding Treatments and Concomitant Medications/Therapies
9. Patients who use peripherally acting muscle relaxants (dantrolene sodium, suxamethonium chloride, 
pancuronium bromide, vecuronium bromide, rocuronium bromide, etc.) within 1 week of screening.
10. Patients who use antibiotic agents with neuromuscular junction inhibitory effects: Aminoglycoside 
antibiotic agents (streptomycin sulfate, kanamycin sulfate, gentamicin sulfate, neomycin sulfate, 
spectinomycin hydrochloride, etc.), polypeptides (polymyxin B sulfate), lincomycins (lincomycin 
hydrochloride, clindamycin), and enviomycin sulfate within 1 week of screening.
11. Patients who was diagnosed as having a malignant tumor, or have a history of a malignant tumor 
within the last 5 years (except completely resected basal cell carcinoma or planocellular carcinoma 
at least 12 weeks before screening)


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Previous Experience of Participation in a Clinical Studies/Current Participation in 
another Ongoing Study 
12. Patients who have participated in another study of an investigational product or other medical 
research (a clinical study of pharmacotherapy, non-pharmacotherapy, or interventional device) 
within 30 days before screening, or are currently participating in a study
Evaluation by Diagnosis
13. Patients who are concerned likely to have an increased risk for an underlying medical 
condition/neurological disease due to exposure of the product; patients who have myasthenia gravis, 
Eaton-Lambert syndrome, amyotrophic lateral sclerosis, or a serious disease and use of a 
concomitant drug which may inhibit neuromuscular function 
14. Patients with antihuman immunodeficiency virus (HIV) antibody positive
15. Patients who previously experienced allergic reactions or hypersensitivity due to botulinum toxin 
type A, an additive agent of sodium chloride, or human serum albumin
16. Patients who were previously suspected to have neutralizing antibody production by a investigator
during an injection of botulinum toxin type A  
17. Patients who have a skin disease such as infection at the site to be injected  
18. Patients who suffer from serious and unstable disease, which could pose problems for the safety of 
subjects and study procedure compliance
6.2.2.
Day 1 (Prior to injection)
A subject will be excluded from enrolment in this study if any of the following criteria apply on 
Day 1 (prior to injection): 
Medical condition
31. Patients who have aspiration pneumonia, relapse of lower respiratory tract infection, 
uncontrollable asthma, uncontrollable COPD, and/or underlying or a history of serious 
respiratory dysfunction, which were clinically considered to be respiratory function impairment 
by a investigator within 12 months before Day 1 visit
32. Patients who have a history of aspiration, or an underlying and/or a history of the symptoms that 
suggests high risks for aspiration by a investigator within 12 months before Day 1 (serious 
salivation requiring changing in a type of diet, chronic dysphagia that is difficult to swallow)
Preceding Treatments and Concomitant Medications/Therapies
33. Patients who were treated with botulinum toxin for spasticity of upprt limb less than 16 weeks
before Day 1 visit
34. Patients who underwent surgical interventions, phenol block, ethanol block or Muscle Afferent 
Block (MAB) within 12 months before Day 1 visit, or these interventions are planned during the 
study period in any one of the finger (upper limb), wrist, elbow or shoulder muscles, which will 
be involved in the study
35. Patients who placed a surgical cast or a dynamic splint within 3 months before Day 1 study visit, 
and/or these interventions are planned to be placed on the upper limb to be involved in the study


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36. Patients who were injected corticosteroid or an anesthetic agent into the finger (upper limb), 
wrist, or shoulder flexors, which will be involved in the study within 3 months before Day 1 visit, 
or these injections are planned during the study
37. Patients who received CIMT (constraint-induced movement therapy) within 3 months before Day 
1 visit or CIMT is planned during the blind phase
38. Patients who underwent ultrasound therapy, TENS (transcutaneous electrical nerve stimulation ), 
electrical stimulation therapy, or acupuncture therapy in the upper arm, which will be involved in 
the study within 1 month before Day 1 visit, or these therapies are planned during the study
6.3.
Lifestyle Restrictions
No limitations are required. 
6.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are not 
subsequently [randomized/entered in the study]. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries from 
regulatory authorities. Minimal information includes demography, screen failure details, and 
eligibility criteria.
Rescreening
If a patient does not meet the participation criteria in the study (dropout during screening), the 
patient may undergo second screening only 1 time. If a patient does not meet following items, contact 
the medical monitor of the sponsor and gain his/her consent because validity of rescreening in subjects 
who dropped out needs to be judged carefully in the light of medical aspects.

Subjects who did not meet the inclusion criteria for MAS (Inclusion criteria 5 at screening) 
and dropped out (However, the dropout period will be for within only 1 month from the 
dropout). 

For some reasons, a subject cannot make a study visit or undergo examination 

Sample collection or examination cannot be performed because of procedural or technical 
problems
The investigator must carefully consider the ethical aspects of subjects, and if other treatments are 
considered to give more treatment benefits for a subject, rescreening must not be conducted. 
The rescreened subjects will be allocated a different subject identification number as upon initial 
screening.


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7.
TREATMENTS
Study treatment product is defined as as any investigational treatment(s), and placebo to administer to 
a study participant according to the protocol. 
7.1.
Treatments Administered
Study Treatment 
Name: 
GSK1358820
(Nonproprietary name: 
Botulinum toxin type A)
Placebo
Dosage formulation: 
Injection
Injection
Ingredient and quantity 
(Per vial) 
Botulinum toxin A 100 units
Sodium chloride 0.9 mg
Human serum albumin 0.5 mg
Sodium chloride 0.9 mg
Packaging and 
Labeling 
It will be listed on the labelling in 
accordance with the regulatory 
requirements in Japan.
It will be listed on the labelling in 
accordance with the regulatory 
requirements in Japan.
Manufacturer
Allergan (Ireland) 
Allergan (Ireland)
Dose
400 units
240 units
Dose
Dosing instructions
Part 1: 240 or 400 units of the product will be injected into the muscles that act on the 
finger (including thumb flexors), wrist and elbow flexors, in accordance with Table 2.
In and after Part 2: 400 units of the product will be injected into the muscles that 
act on the finger (including thumb flexors), wrist, elbow and shoulder flexors in 
accordance with Table 3. For the muscles that the investigator considers 
unnecessary to be treated, an injection may be skipped. Dose intervals should be at 
least 12 weeks.
For adjustment of the product, the product will be dissolved with 2 ml of normal 
saline per 1 vial (100 units). The details will be described on Table.4. 
In the blind phase

A total of 240 units of product will be injected into the muscles that act on finger (including 
thumb flexors) and wrist flexors, and a total of 160 units of the product or placebo for the 
muscles that act on the elbow flexors in divided doses in accordance with Table 2.

The muscles which are not listed on Table2 must not be used.

All of the muscles descried on Table 2 must be used. If the subject with no symptoms with 
thumb, the investigator does not have to inject to thumb. 

If the total dose for the muscles that act on the finger and writs flexors is ensured by 240 
units, and 160 units for the muscles that act on the elbow flexors, the dose can be adjusted at 
a investigator’s discretion based on the symptoms of a subject.
In the open-label phase

The investigator will decide the dose and the muscle to be injected based on the symptoms 
of patients, and a total of 400 units will be injected in divided doses. For the muscles that 
the investigator considers unnecessary to be treated, an injection may be skipped.

The muscles to be injected must be chosen from Table 3, and the muscles which are not 
listed on Table 3 must not be used. For dose and number of injection site (sites/muscles), 
refer to Table 3 and will be decided by investigator. 


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Table 2    Muscle Involvement and Dose in the Blind Phase
Number
Muscles
The 400 units 
group
Dose (units)
The 240 units 
group
Dose (units)
Number of 
injection site (site 
and muscles)3
Joint
A1
Biceps brachii 
701
Placebo
2
A.Elbow 
A2
Brachialis
451
1
A3
Brachioradialis
451
1
B1
Flexor carpi radialis 
502
502
1
B.Wrist  
B2
Flexor carpi ulnaris 
502
502
1
C1
Flexor digitorum profundus 
502
502
1
C.Finger 
C2
Flexor digitorum superficialis
502
502
1
D1
Flexor pollicis longus 
202
202
1
D.Thumb
D2
Adductor pollicis 
202
202
1
Total
4002
2402
1
-
1: Within the limits of the total of 160 units (the elbow flexors), the dose will be decided by a investigator depending on the patient’s 
symptoms.
2: Within the limits of the total of 240 units (the finger and wrist flexors), the dose will be decided by a investigator depending on the 
patient’s symptoms.
3: When the dose exceeds 50 U per muscle, take into account the divided-injection.
Table 3    Muscle Involvement and Reference Dose in the Open-Label Phase
(Modified partially of “Dosing, Administration, and a Treatment Algorithm for Use of 
Botulinum Toxin A for Adult-Onset Spasticity.[Brin, 1997]”)
Number
Muscles1
Dose (units)2
Number of 
injection site
(Sites/muscles) 2
Joint
A1
Biceps brachii 
50-200
4
A.Elbow
A2
Brachialis
25-75
2
A3
Brachioradialis
25-75
2
B1
Flexor carpi radialis
25-100
2
B.Wrist
B2
Flexor carpi ulnaris
10-50
2
C1
Flexor digitorum profundus
25-100
2
C.Finger
C2
Flexor digitorum superficialis
25-75
4
C3
Lumbricales interossei
10-50/hand
3
D1
Flexor pollicis longus
5-25
1
D.Thumb
D2
Adductor pollicis
5-25
1
D3
Opponens
5-25
1
E1
Pronator teres
25-75
1
E.Forearms
E2
Pronator quadratus
10-50
1
F1
Teres major 
25-75
1
F.Shoulder
F2
Latissimus dorsi
50-150
4
F3
Pectoralis major 
75-150
4
F4
Subscapularis
25-75
1
(Brin MF and the Spasticity Study Group, 1997)
1: The muscles which are not listed on Table 3 must not be used
2: For dose and number of injection site (sites/muscles), refer to Table 3 and will be decided by investigator.


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Table 4    Muscle Involvement and Reference Dose in the Open-Label Phase
Dose (units)
Injection Volume (ml)
100
2.0 
95
1.9 
90
1.8 
85
1.7 
80
1.6 
75
1.5 
70
1.4 
65
1.3 
60
1.2 
55
1.1 
50
1.0 
45
0.9 
40
0.8 
35
0.7 
30
0.6 
25
0.5 
20
0.4 
15
0.3 
10
0.2 
5
0.1 
7.2.
Dose Modification
Not applicable
7.3.
Method of Treatment Assignment
After completion of all evaluations at screening phase/initiation of the blind phase, the subjects who 
met the inclusion criteria and none of the exclusion criteria will be given their randomization number
at a case registry center and randomized to either the 240 or 400 units group. The assigned 
randomization number cannot be re-used. The table of the allocation will be prepared via a computer 
in GSK, using the RandAll systems. 
Based on the MAS score (3 or 4) in the elbow flexors, subjects will be stratified at the time of 
randomization. 
The subjects who meet the eligibility for the injections in the open-label phase can move forward to 
the open-label phase and be injected (Refer to section 5.1.3). In the open-label phase, 400 units of the 
product will be given to all subjects. Other detailed information will be described on SRM.
7.4.
Blinding
This study consists of the blind phase (Part 1), followed by the open-label phase (Part 2 and 
subsequent Parts), and in the blind phase, following processes are applied. 
A Role of the Person Responsible for Investigational Product Assignment  
The person who is responsible for investigational product assignment will prepare an operating 
procedure for the assignment. The operation will be conducted in accordance with the operating 
procedure. The person who is responsible for the investigational product assignment will display the 
drug number on a container of the investigational product (investigational product and control drug) 


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after checking of the investigational product (investigational product and control drug) and the
indistinguishability of packaging appearance. The confirmation of the investigational product 
(investigational product and control drug) and the indistinguishability of packaging appearance will be 
also performed after completion of the study. In addition, an operating procedure for occasion where 
the emergency treatment disclosure is required will be prepared. In response to the request of 
disclosure, unblinding procedures are performed for the requested drug only.
The unblinded subjects by the investigator will discontinue participation in the study. In addition, 
the major reasons for discontinuation (the event(s) or condition led to unblinding) will be described on 
case report form (CRF). 
The Global Clinical Safety and Pharmacovigilance (GCSP) of the sponsor may disclose the 
assigned treatment in the subject, who experienced serious adverse events. For serious adverse events 
requiring emergency report to the regulatory authority, a copy of an emergency report on the assigned 
treatment of the subject may be sent to the study involving investigator in accordance with the 
regulations, policy of the sponsor, or both.  
7.5.
Preparation/Handling/Storage/Control
1.
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported and 
resolved before use of the study treatment. 
2.
Only participants enrolled in the study may receive study treatment and only authorized site staff 
may supply or administer study treatment. All study treatments must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the investigator and authorized site staff. 
3.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
4.
Further guidance and information for the final disposition of unused study treatment are provided in the 
Study Reference Manual
.
7.6.
Treatment Compliance
Subjects will be intramuscularly injected the product at a medical institution. The injection will be 
recorded in the source documents, and described in the case report form. 
7.7.
Concomitant Therapies
The medications that are used by subjects at the time of enrolment in the study or all medications 
and vaccines to be used during the study (over the counter drugs or prescribed drugs, vitamins, and/or 
herbal supplements) must be recoded with the following items: 

Reasons for use

Initial date of administration and administration dates, including completion day

Regarding the dose, including dosage and number of administration


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Contact the medical monitor if there are any questions about concomitant therapies or preceding 
drugs.
7.7.1.
Permitted Concomitant Drugs/Therapies
Following drugs and therapies are permissible only if a subject is already using them before 
initiation of the study. However, the dosage and administration will not be changed from the screening 
through completion of the blind phase. In and after open-label phase, dose reduction and 
discontinuation of the drugs will be allowed. However, once dose is decreased, re-increase will not be 
performed. If the drug(s) is/are discontinued, the drugs cannot be resumed. No new treatment will not 
be started after screening phase. 
Rehabilitation therapies such as physical therapy, occupational therapy, and static splint are 
permissible. However, in the blind phase, the frequency and regimens (description of the therapy and 
intensiveness) for the upper limb, which involves in the study will not be changed. In addition, in the 
open-label phase, changing rehabilitation therapy to another one that seems to be the most appropriate 
for a subject is permissible based on the degree of improvements in spasticity. In such cases, the 
information will be described on CRF. Rehabilitation therapy will not be given on the day of 
investigational product injection. 

Central muscle relaxants
(baclofen, tizanidine hydrochloride, tolperisone hydrochloride, eperisone hydrochloride, 
chlorphenesin carbamate, afloqualone, etc.)

Tetracycline antibiotics
(tetracycline hydrochloride, doxycycline hydrochloride, minocycline hydrochloride, etc.)

Anticholinergics
(butylscopolammonium bromide, trihexyphenidyl hydrochloride, etc.)

Benzodiazepines
(diazepam, etizolam, etc.)

Benzamides
(tiapride hydrochloride, sulpiride, etc.)

Antiepileptic drugs
(phenytoin, etc.)

Intrathecal baclofen therapy
7.7.2.
Contraindicated Medications/Therapies 
Following drugs and therapies will be prohibited to use from screening phase through completion of 
the study:

Botulinum toxin preparations

Peripherally acting muscle relaxants

(dantrolene sodium, suxamethonium chloride, pancuronium bromide, vecuronium bromide, 
rocuronium bromide) 

Antibiotic agents with neuromuscular junction blocking effects

Aminoglycosides
(streptomycin sulfate, kanamycin sulfate, gentamicin sulfate, neomycin sulfate, 
spectinomycin hydrochloride, etc.)


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
Polypeptides
(polymyxin B sulfate)

Lincomycins 
(lincomycin hydrochloride, clindamycin)

Enviomycin sulfate

Nerve blocks such as phenol block, ethanol block and MAB for the upper limb

Surgical cast or a dynamic splint

A surgery for the upper limb

A surgical cast or a dynamic splint for the upper limb

Corticosteroid injection or an anesthetic agent for the upper limb

Ultrasound therapy, TENS (transcutaneous electrical nerve stimulation ), electrical 
stimulation therapy, or acupuncture therapy for the upper limb
Following drugs and therapies will be prohibited to use from screening phase through completion of 
the blinded-phase:

CIMT (constraint-induced movement therapy)
7.8.
Treatments after Completion of the Study
The investigator will take responsibility for subject’s medical care after completion of the study, 
whether the sponsor provides a certain treatment or not.
8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
The efficacy of the investigational product used in this study sustains for about 3 to 4 months 
following a single dose, and thus daily dosage is not required; accordingly, treatment discontinuation 
shall not be defined in this study, and will be considered to be identical to subject withdrawal from 
this study.
8.2.
Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, compliance 
or administrative reasons. 

If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 

If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must document this in the site study records. 

A subject discontinuing this study must visit the study site for study termination assessment 
promptly upon decision to discontinue the study.

Refer to the schedule of assessment (SoA), completion visit (FV), for the details of data to 
be collected at the study discontinuation, and additional assessment that must be completed.


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8.2.1.
Liver Chemistry Stopping Criteria
A set of criteria for study discontinuation and follow-up investigation based on hepatic function 
test (in reference to FDA premarketing clinical liver safety guidance) is specified herein to ensure the 
safety of subjects and to evaluate the causes of hepatic events. The guidelines related to this protocol 
are based on the FDA premarketing clinical liver safety guidance: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM1
74090.pdf.
The investigator should consider discontinuing the study treatment upon discovery of liver function 
test abnormal, and if the subject is applicable to any of the symptoms presented in the algorithm, or 
such discontinuation is determined to be the best choice for the subject as judged by the investigator.
Algorithm A: Phase III-IV Liver Chemistry Stopping and Increased Monitoring Algorithm
Liver Safety Required Actions and Follow up Assessments Section can be found in Appendix 6.


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Algorithm B: Phase III-IV Liver Chemistry Increased Monitoring Algorithm with Continued 
Therapy for ALT ≥3xULN but <8xULN
Liver Safety Required Actions and Follow up Assessments Section can be found in Appendix 6.


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8.2.2.
QTc Stopping Criteria

For a decision on a subject's eligibility or study discontinuation, the same method for 
correction of QT interval must be used in the subject throughout the study, and must not be 
changed once the subject is enrolled. 

For instance, if a subject is enrolled based on QTcB, decisions on the subject's 
withdrawal must be made based on QTcB. 

The method used for correction of QT interval pertinent to the enrollment of a subject 
must be used for all QTc data to be collected throughout the study for the data analysis 
on the subject; provided that such rule is not applicable to ECG intended to ensure 
safety and also ECG not defined in the protocol. 

QTc should be determined based on a single measurement of ECG or the mean of ECG 
measured at 3 timepoints in a short period of time (e.g., 5 to 10 minutes). If abnormality is 
detected in a single measurement, ECG should be measured again, this time, at 3 timepoints. 

The lowest value of QTc cannot be used for a decision to withdraw a subject. 
Refer to the schedule of assessment (SoA), completion visit (FV), for the details of data to be 
collected at the discontinuation of study treatment. Discontinue this study if the mean ECG is 
applicable to any of the following conditions:

QTc >500 msec or uncorrected QT >600 msec

Change in QTc from baseline >60 msec
The following withdrawal criteria should be applied for subjects with bundle branch block: 
Baseline for subjects with bundle branch block
Withdrawal criteria for subjects with bundle 
branch block
<450 msec
>500 msec
450 to 480msec
IJYO530 msec
8.2.3.
Treatment discontinuation due to treatment-related SAE
A subject should be withdrawn from this study if treatment-related serious adverse event has 
occurred.
8.2.4.
Treatment discontinuation due to pregnancy
A female subject who become pregnant during this study must be withdrawn from the study.
8.2.5.
Withdrawal of subjects who start receiving prohibited medications or 
therapies
If a prohibited medication or therapy (See section 7.7.2.) needs to be started during the study, the 
subject must be withdrawn from this study; in which case, the subject must make the study completion 
visit (FV) before starting the prohibited medication or therapy.


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8.2.6.
Prohibition of treatment resumption
Study treatment must not be resumed in subjects who are once withdrawn from this study for a 
reason associated with hepatic function test, QTc, treatment-related serious adverse event, pregnancy, 
or commencement of a prohibited medication or therapy.
8.3.
Lost to follow up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 

The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in the 
study.

Before a participant is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
9.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA. 

Protocol waivers or exemptions are not allowed. 

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue study 
treatment. 

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 

Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and was performed 
within the time frame defined in the SoA. 


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9.1.
Efficacy assessments
9.1.1.
Evaluation methods
9.1.1.1.
Modified Ashworth Scale (MAS)
According to "2. SCHEDULE OF ACTIVITIES (SoA)" the investigator will use MAS (Table 5) to 
evaluate the level of spasticity. MAS should be measured and evaluated by the investigator, 
physiotherapist, or occupational therapist who has been given the training as an assessor. 
The test should be performed on sitting position throughout the study. The affected parts should be 
extended as fast as possible to grade the flexor muscle tones. The final assessment will be made by the 
investigator in consideration of the information from physiotherapist or occupational therapist. The 
assessor should in principle remain unchanged throughout the study period.
Table 5    Modified Ashworth Scale (MAS)
0
No increase in muscle tone
1
Slight increase in muscle tone, manifested by a catch and release or by minimal resistance at 
the end of the range of motion when the affected part(s) is moved in flexion or extension
1+
Slight increase in muscle tone, manifested by a catch, followed by minimal resistance 
throughout the reminder (less than half) of the ROM (range of movement)
2
More marked increase in muscle tone through most of the ROM, but affected part(s) easily 
moved
3
Considerable increase in muscle tone passive, movement difficult
4
Affected part(s) rigid in flexion or extension

MAS measurement as inclusion criteria (Screening and Day 1)
The subject's wrist or fingers and elbow should all be evaluated as inclusion criteria. Subjects 
meeting the eligibility and randomized should be evaluated for MAS at Visit 1 of Treatment Period 1
on the same day; provided that measurement may be performed only once if the affected part to be 
evaluated is the same. The detail of inclusion criteria are shown in 6.1.

MAS measurement during the blinded period
The subject's wrist, fingers and thumb should all be evaluated during the blinded period. Likewise, 
the subject's wrist, fingers and thumb should all be evaluated for MAS at Visit 5 and QRV of the 
blinded period. Subjects meeting the eligibility and transferred to the open-label period should be 
evaluated for MAS at Visit 1 of Treatment Period 2 on the same day; provided that measurement may 
be performed only once if the affected part to be evaluated is the same. Meanwhile, MAS needs to be 
evaluated again if the affected part to be evaluated is not the same. 

MAS measurement during the open-label period
During the open-label period, MAS should be evaluated for the flexors at which the muscle given 
the study treatment functions (fingers, thumb, wrist, elbow, fore-arm) (Table 6). If the subject is 
determined to be eligible, the V5/QRV and V1 would be on the same day, and therefore, the MAS 
measured at V5/QRV of the previous treatment period should not be measured again on V1; the 
measurement on V5/QRV should be used for the assessment (Figure 6). MAS on flexors to be newly


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assessed on V1 should be evaluated before dose on V1. The MAS on the shoulder should be evaluated 
comprehensively for the adductor and invertor. 
Table 6    Regions to be evaluated for MAS during the open-label period
Number
Muscles to be injected
Regions to be evaluated 
for MAS 
A1
Biceps brachii
Elbow flexors (flexion)
A2
Brachialis
A3
Brachioradialis
B1
Flexor carpi radialis
Wrist flexors (flexion)
B2
Flexor carpi ulnaris
C1
Flexor digitorum profundus
Fingers (flexion)
C2
Flexor digitorum superficialis
C3
Lumbricales interossei
D1
Flexor pollicis longus
Thumb (flexion, 
adduction and opposition)
D2
Adductor pollicis
D3
Opponens pollicis
E1
Pronator teres
Forearm (pronate)
E2
Pronator quadratus
F1
Teres major
Shoulder (adduction and
internal rotation)
F2
Latissimus dorsi
F3
Pectoralis major
F4
Subscapularis
Visit
SV V1 V2 V3 V4 V 5 V1 V2 V3 V4 V5 V1 V2 V3 V4 V 5 V1 V2 V3 V4 V5
A.Elbow
●
●
●
●
●
●
(○) ●
●
●
●
(○) ●
●
●
●
(○) ●
●
●
●
B.Wrist
●
●
●
●
●
●
●
●
●
●
●
(○) ●
●
●
●
C .Finger
●
●
●
●
●
●
(○) ●
●
●
●
(○) ●
●
●
●
(○) ●
●
●
●
D .Thum b
●
●
●
●
●
E.Forearm
●
●
●
●
●
(○) ●
●
●
●
(○) ●
●
●
●
F.Shoulder
●
●
●
●
●
●
●
●
●
●
Part 1
Part 2
Part 3
Part 4
●: MAS measurement (before treatment)
（○）: Use V5 or QRV MAS measurement
Figure 6    Subjects to be evaluated for MAS
9.1.1.2.
Numeric Rating Scale (NRS) 
According to "2. SCHEDULE OF ACTIVITIES (SoA)" the investigator (or subinvestigator) will 
use NRS (Figure 7) to evaluate the severity of flexors pain.
The investigator will perform the interview on NRS following the assessment of MAS. Each subject 
will be interviewed on the severity of pain on the treated part when extended based on a scale with 0 
being "no pain" and 10 being "the worst imaginable pain"; 1 response on the scale should be selected 
by the subject.


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0
1
2
3
4
5
6
7
8
9
10
No pain
Pain as 
bad as 
you can 
imagine
Figure 7    Numeric Rating Scale (NRS) for pain

NRS measurement during the blinded period
During the blinded period, the severity of pain in the elbow flexors will be evaluated. 

NRS measurement during the open-label period
During the open-label period, a major part with pain [specify 1 part from among fingers, thumb, 
wrist, elbow, fore-arm (pronate), and shoulder] will be evaluated for the severity of pain on Visit 1. 
The part to be evaluated does not have to be the same within each treatment period, but should be the 
same part as that evaluated for MAS. 
9.1.1.3.
Disability Assessment Scale (DAS)
According to "2. SCHEDULE OF ACTIVITIES (SoA)" the investigator (or subinvestigator) will 
use the 4 disability assessment parameters presented in Table 7 and evaluate all of them based on the 
scale presented in Table 8. Before starting the study treatment, the investigator shall discuss with the 
subject, and select and evaluate 1 parameter agreed with the subject as the "main assessment 
parameter." The assessor should in principle remain unchanged throughout the study period. The main 
assessment parameter should also remain unchanged throughout the study period.
Table 7    Disability assessment parameters
Content of assessment
Hygiene
The extent of maceration/ulceration and/or palmar infection, palm/hand 
cleanliness, ease of cleanliness, ease of nail trimming, and interference with 
hygiene-related disability in the subject's daily life
Pain
The intensity of pain/discomfort, and the interference that upper-limb pain-
related disability has in the patient’s daily life.
Dressing
The difficulty or ease for the subject in putting on the relevant clothing (e.g., 
shirts, jackets, gloves, etc.) and the interference that upper-limb dressing-related 
disability has in the patient's daily life.
Limb posture
The psychological and/or social interference that the disfigured upper limb has 
in the patient's daily life.
Table 8    Disability Assessment Scale
Description
0: No functional disability
No functional disability
1: Mild disability
Noticeable but does not interfere significantly with normal activities
2: Moderate disability
Normal activities require increased effort and/or assistance.
3: Severe disability
Normal activities limited.


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9.1.1.4.
Clinical Global Impression of Change (CGI) assessed by a investigator
The investigator (or subinvestigator) will evaluate CGI according to "2. SCHEDULE OF 
ACTIVITIES (SoA)”; Changes in spasticity (Clinical Global Impression) from baseline (V1 in each 
treatment phase) will be evaluated by 9 grades as shown in Table 9.
The investigator shall also consider the subject's clinical symptoms and adverse events pertinent to 
the assessment of CGI. Also, the therapeutic effect of the product injected in the subject's fingers, 
wrist, and elbow should be taken into an account. The assessor should in principle remain unchanged 
throughout the study period.
Table 9    Clinical Global Impression of Change (CGI)
-4
Very much worsened
-3
Much worsened
-2
Moderately worsened
-1
Slightly worsened
0
Unchanged
+1
Slightly improved
+2
Moderately improved
+3
Much improved
+4
Very much improved
9.1.1.5.
Clinical Global Impression of Change (CGI) assessed by a patient
According to "2. SCHEDULE OF ACTIVITIES (SoA))" the investigator (or subinvestigator) will 
use Table 9 to record subject-reported CGI. The investigator shall interview each subject on changes 
in spasticity from predose, and the subject will evaluate it using Table 9.
9.1.1.6.
Time to patient-reported onset of spasticity symptom relief (Visit 2):
According to "2. SCHEDULE OF ACTIVITIES (SoA)" the investigator (or subinvestigator) will 
record the time to alleviation of spasticity reported by subjects. The investigator shall ask the subject 
whether the product was effective on the spasticity, and if the subject's response to the question is 
positive, ask him/her "how many days did it take for the therapeutic effect to appear after the current 
dose?" and record the number of days.
9.1.1.1.
Patient-reported benefit of injection (Visits 3, 4, and 5)
According to "2. SCHEDULE OF ACTIVITIES (SoA)" the investigator (or subinvestigator) will 
record the efficacy of treatment reported by subjects. The investigator shall ask, "Was the product
effective?" and the subject shall respond either by "Yes" or "No."
9.2.
Adverse events
Definitions of adverse events and serious adverse events (SAE) are as specified in Appendix 4.
The investigator or a person assigned by the investigator is responsible for detecting, recording, and 
reporting events that match the definitions of adverse events and SAEs, and also, responsible for 
follow-up investigations on SAEs, as well as events related to the study drug or this study, and events 
that resulted in treatment discontinuation or subject withdrawal (See section 8). 


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9.2.1.
Period subject to collection of data related to adverse events and SAEs, and 
the frequency of such data collection

All SAEs will be collected from the start of treatment until Final Visit at the time points 
specified in the SoA (Section 2 ). 

All AEs will be collected from the start of treatment until Final Visit at the time points 
specified in the SoA (Section 2 ). 

Medical occurrences that begin before the start of study treatment but after obtaining 
informed consent will be recorded on the Medical History/Current Medical Conditions 
section of the case report form (CRF) not the AE section. 

All SAEs will be recorded and reported to the sponsor or designee within 24 hours, as 
indicated in Appendix 4 . The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available. 

Investigators are not obligated to actively seek AEs or SAEs in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a 
participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study treatment or study participation, the investigator must 
promptly notify the sponsor. 

The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 4 . 
9.2.2.
Method used to detect adverse events and SAEs
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and non-leading 
verbal questioning of the participant is the preferred method to inquire about AE occurrence.
9.2.3.
Follow up on adverse events and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each participant at 
subsequent visits/contacts. All SAEs will be followed until the event is resolved, stabilized, otherwise 
explained, or the participant is lost to follow-up (as defined in Section 8.3). Further information on 
follow-up procedures is given in Appendix 4.
9.2.4.
Regulatory requirements of SAE reporting

Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study treatment under clinical investigation are met. 

The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, Institutional Review Boards (IRB)/Independent Ethics 
Committees (IEC), and investigators. 

Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary. 


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
An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAE) from the sponsor will review 
and then file it along with the Investigator’s Brochure and will notify the IRB/IEC, if 
appropriate according to local requirements. 
9.2.5.
Cardiovascular events and death
For any cardiovascular events detailed in Appendix 4 and all deaths, whether or not they are 
considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF will be required to be 
completed. These sections include questions regarding cardiovascular (including sudden cardiac 
death) and non-cardiovascular death. 
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA terms. The 
CV information should be recorded in the specific cardiovascular section of the CRF within one week 
of receipt of a CV Event data query prompting its completion. 
The Death CRF is provided immediately after the occurrence or outcome of death is reported. Initial 
and follow-up reports regarding death must be completed within one week of when the death is 
reported.
9.2.6.
Pregnancy

Details of all pregnancies in female partners of male participants will be collected after the 
start of study treatment and until Final Visit. 

If a pregnancy is reported, the investigator should inform GSK within 24 hours of learning 
of the pregnancy and should follow the procedures outlined in Appendix [X]. 

Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAE. 
9.3.
Management of overdosage
A dosage of the product exceeding 400 units within 24 hours shall be considered as overdosage in 
this study. Overdosage may cause excessive pharmacodynamic responses such as hyposthenia, 
muscular paralysis, and other localized adverse reactions. Symptoms and signs may not immediately 
appear following dose. Moreover, blepharoptosis, dysarthria, dysphagia, dyspnea, myasthenia, and 
other events suspected to be an effect on other muscles distal to the treated muscle have been reported 
overseas. If such a symptom appears, the subject should be carefully monitored, and given appropriate 
interventions, if necessary with hospitalization. Also, supportive therapies such as artificial breathing 
should be considered for respiratory symptoms.
Upon confirmation of overdosage, the investigator should;
1.
Contact the Medical Monitor immediately.
Carefully monitor the adverse event/SAE, and laboratory abnormalities in the subject for at least 4 
weeks; and 
Document the quantity of the excess dose as well as the duration of the overdosing in the CRF.. 


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The investigator shall discuss with the sponsor's medical monitor on the clinical assessment of the 
subject, and upon which, decide whether or not to discontinue the study treatment.
9.4.
Safety assessments
Assessment timepoints for all safety parameters are as shown in SoA.
9.4.1.
Physical examination
Physical examination (complete version): Only during screening

The head and neck, skin, lungs, cardiovascular system, abdominal region (liver and spleen), 
gastrointestinal system, lymph node, and nervous system should be examined, and the 
results thereof should be recorded; these organs should be examined for the 
presence/absence of pre-existing conditions and abnormal findings, and if there is any 
suspected abnormality, detailed examinations should be performed. 

The pulmonary function test should be conducted in details if any sign of pulmonary 
impairment is found. For the pulmonary function test, spirometry by pulmonologists is 
recommended. 
Physical examination (simplified version): To be conducted only if an eligibility criterion is not met 
during the open-label period. 

At least, the lungs, cardiovascular system, and abdominal region (liver and spleen) should 
be examined, and the results thereof should be recorded. 

The investigator should pay attention to clinical signs and symptoms related to a history of 
serious disease. 
The physical examinations should be performed by doctors in accordance with the standard clinical 
guidelines of each study site.
9.4.2.
Vital signs

For the vital signs, body temperatures (oral, intra-aural, or axillary fossa), systolic/diastolic 
blood pressures, and pulse rates should be measured in a semi-recumbent position after a 5-
minute rest. 

If a temperature is to be measured orally, the subject must refrain from eating food or 
drinking beverage within 5 minutes before the measurement. The method for the 
measurement of body temperature must remain the same throughout the study. 

The blood pressures and pulse rates should be measured with an automated device. A 
manual method may be used only if there is no automated device available for use. 
9.4.3.
Height and weight
The standard clinical guidelines of each study site should be followed.
9.4.4.
Pulmonary test

Refer to SoA for the timepoints and frequency of testing.


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
If post-injection SpO2 is decreased by 3% or more from the baseline, medical examination 
by pulmonologist is recommended.

If a medical institution has no pulmonologist, visit other hospitals for medical examination 
by specialists. For the pulmonary function test, spirometry by pulmonologists is 
recommended.
9.4.5.
ECG

QTc should be determined based on a single measurement of ECG or the mean of ECG 
measured at 3 timepoints in a short period of time (e.g., 5 to 10 minutes). 

An automated measurement and manual re-interpretation in accordance with SoA should be 
used to collect data on the heart rates, PR, QRS, QT, and QTc interval. Refer to section 
8.2.2. for QTc-related treatment discontinuation standard, and additional QTc to be 
measured as required. 

Each interval between timepoints for the measurement of ECG should be minimized as 
much possible (within 2 minutes). The measurement of ECG should be performed 3 times 
consecutively and completed within 5 to 10 minutes. 
9.4.6.
Neutralizing antibody test
The investigator shall draw blood for neutralizing antibody samples in accordance with the study 
schedule. The neutralizing antibody will be measured collectively by a central laboratories designated 
by GSK (Intertek Pharmaceutical Services Co. and Pacific BioLabs Co.). The screening samples will 
be retained temporarily by the central laboratories, and then, upon retrieval of samples from all 
subjects, will be collected and tested by Intertek for screening. Samples tested positive at Intertek will 
be separately sent to Pacific BioLabs for retest to finalize the results of neutralizing antibody test. The 
above procedures shall also be taken for samples collected for Week 12 visit during the blinded period, 
and upon completion of study treatment in all subjects.
9.4.7.
Clinical Safety Laboratory Assessments

Refer to Appendix 2 for the list of clinical laboratory parameters that should be tested, and 
to SoA for the timepoints and frequency of testing. 

The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal during 
participation in the study should be repeated until the values return to normal or baseline or 
are no longer considered significantly

If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified.

All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted 
in accordance with the laboratory manual and the SoA.


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
If a result of clinical laboratory test not scheduled in the protocol is obtained by a study site, 
which requires a change in the patient management, or is determined to be clinically 
important by the investigator, that is SAE, adverse event, an event requiring dose 
modification, or any other relevant event, the record thereof must be documented in the 
CRF. 

Follow-up investigation may be performed at any time during the study as determined to be 
necessary by the investigator, or required by the Japanese regulation. 


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9.5.
Pharmacokinetics
PK parameters are not evaluated in this study.
9.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
9.7.
Genetics/Pharmacogenetics
Genetics and pharmacogenetics are not evaluated in this study.
9.8.
Biomarkers
Biomarkers are not evaluated in this study.
9.9.
Pharmacoeconomics
Pharmacoeconomic parameters are not evaluated in this study.


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10. STATISTICAL CONSIDERATIONS
10.1.
Sample Size Determination
This study is not intended to verify a statistical hypothesis, but is rather intended to verify that the 
responder rate in the 400 units group exceeds that in the 240 units group, and for which, about 120 
subjects (60 in each treatment group) are to be enrolled.
During Treatment Period 1 of this study, 160 units of the product will be administered in the muscle 
which affects the elbow; thus, the sample size was determined in reference to an overseas phase III 
study (Study 127) in which a similar dosage as this study (150 units) was administered in the muscle 
which affects the elbow. The responder rate in the elbow at Week 6 of the initial dose in Study 127 
was 72.2% and 47.1% in the product 300 units group (150 units in the muscle which affects the elbow 
flexors) and placebo group, respectively. The number of subjects in the intention-to-treat (ITT) 
population was small in both the product 300 units group and placebo group of Study 127, which was 
18 subjects each; thus, considering the uncertainty of the results of Study 127, the responder rates in 
the product 400 units and 240 units groups in this study were conservatively assumed to be 70.0% and 
50.0%, respectively. Assuming that the sample size is 60 subjects in each group, the power of test to 
detect an intergroup difference in the responder rates would be about 62% with a two- sided
significance level of 5% while the probability of the responder rate in the product 400 units group to 
exceed that in the product 240 units group as a point-estimate would be 98%.
With about 120 subjects enrolled, 100 subjects are expected to complete Week 48 of the initial dose.
10.2.
Populations for Analyses
Populations for statistical analyses in this study are defined as follows.
Population
Description
ITT
All subjects randomized in the study andhad at least 1 post-baseline 
efficacy assessment: ITT is the primary efficacy analysis population, and 
the subjects will be analyzed in line with the randomized treatment group. 
Safety 
All subjects randomized in the study and received study treatment at least 
once: The subjects will be analyzed based on the treatment actually given. 
10.3.
Statistical Analyses
10.3.1.
Efficacy Analyses
This study is not intended to verify a statistical hypothesis; thus, there will be no statistical test.
All of the efficacy analyses will be performed on the ITT population separately for the blinded 
period and the open-label period.


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Endpoints
Statistical Analysis Methods
Primary
The primary endpoint is the proportion of subjects whose MAS score on the elbow at 
Week 6 of the initial dose decreased by at least 1 level from the baseline (responder rate). 
The primary endpoint will be calculated as the proportion of subjects whose MAS score 
decreased by at least 1 level from the baseline in the ITT population. Also, a 95% 
confidence interval of the intergroup difference in the responder rate will be computed. 
Subjects with no MAS score available at Week 6 will not be counted as subjects whose 
MAS score decreased by at least 1 level from the baseline (that is, counted in as non-
responder). 
The MAS scores, 0, 1, 1+, 2, 3, and 4 will be encoded to 0, 1, 2, 3, 4, and 5, respectively, 
for the analysis purpose. 
Secondary
Unless specified otherwise, the data up to Week 12 of treatment will be summarized for 
each repeated dose during the open-label period. 
During the blinded period, a mixed model for repeated measurement (MMRM) will be 
used for the analysis on the endpoints specified below, and the least-square mean and 95% 
confidence interval will be calculated. The details of the model will be described in the 
statistical analysis plan. For the open-label period, only a summary statistics will be 
performed for each treatment group. Missing values will not be imputed. 
Change in MAS score in the fingers, thumb, wrist, and elbow from the baseline
Change in Disability Assessment Scale (primary endpoint) from the baseline 
The proportion of subjects in whom MAS score in the fingers, thumb, wrist, and elbow 
decreased by at least 1 level from the baseline (responder rate) during the blinded period 
will be analyzed with the same method as that for the primary endpoint. For the open-
label period, the denominator to be used for the calculation of responder rate shall be the 
number of subjects in each subgroup stratified by the number of injections given, not the 
ITT population. Also, a 95% confidence interval of the intergroup difference in the 
responder rate will not be calculated. 
Exploratory
Time to patient-reported onset of spasticity symptom relief will be evaluated for subjects 
who reported alleviation of spasticity at in 2 weeks postdose. The number of days from 
dose to the alleviation of spasticity will be summarized for each treatment group. 
Clinical Global Impression of Change (CGI) assessed by a investigator, CGI assessed by a 
patient, and Patient-reported benefit of injection will be summarized for each treatment 
group. Missing values will not be complemented. 
Other details will be specified in the statistical analysis plan. 
10.3.2.
Safety Analysis
Safety analyses will all be performed on the safety population separately for the blinded and open-
label periods.


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Endpoints
Statistical Analysis Method
Primary
Not applicable
Secondary
Adverse events that occurred in the overall study period, blinded period, and open-label 
period will be summarized for each treatment group. For the blinded period, 2 patterns of 
analyses on adverse events will be performed; one is on adverse events that occurred 
between the initial dose and the first dose in the open-label period (or at the completion 
of study if no dose is given in the open-label period or at the study withdrawal), and 
another one is on adverse events that occurred within 84 days from the initial dose. 
Adverse events will be summarized separately for SOC (system organ class) and PT 
(preferred term). Also, adverse events related to study treatment, adverse events that 
resulted indiscontinuation, adverse events by subgroups stratified by severity, and 
serious adverse events will be summarized. 
Laboratory findings and vital signs at each visit and their changes from baseline will be 
summarized for each treatment group. 
Exploratory
Will be specified in the statistical analysis plan. 
10.3.3.
Other analyses
Other analyses will be specified in the statistical analysis plan.
10.3.4.
Interim analyses
The details of the interim analysis plan will be specified in the statistical analysis plan.
When all subjects  (except for early termination) complete the visit at Week 24 of the initial dose, 
the data on all of the subjects until Week 24 of the initial dose may be locked, unblinded, and analyzed 
for reporting to authorities.
11. Reference
Bohannon RW, Smith MB. Interrater reliability of a modified Ashworth scale of muscle spasticity. 
Phys Ther. 1987;67:206-7.
Brin MF, the Spasticity Study Group. Dosing, Administration, and a Treatment Algorithm for Use of 
Botulinum Toxin A for Adult-Onset Spasticity. Muscle & Nerve. 1997;20 (Supplement 6):S208-20.
Gracies JM, Hefter H, Simpson DM, et al. Handbook of Botulinum Toxin Treatment, 2nd ed. .Oxford, 
UK:Blackwell Science Ltd. 2003;219-71.
Grazko MA, Polo KB, Jabbari B. Botulinum toxin A for spasticity, muscle spasm, and rigidity. 
Neurology. 1995;45:712-7.
Gregson JM, Leathley MJ, Moore AP, , et al. Reliability of measurements of muscle tone and muscle 
power in stroke patients. Age and Ageing. 2000;29:223-8.
Jankovic J. Botulinum toxin therapy for cervical dystonia. Neurotox Res. 2006 Apr;9(2-3):145-8.
Kagamihara. Mechanism of spasticity, and method of its evaluation. JOURNAL OF CLINICAL 
REHABILITATION. 2012; 21(10):936-43.


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Kinoshita Y. Spasticity and botulinum therapy. BRAIN NURSING. 2015; 31(2):191-4.
Klein AW. Complications and adverse reactions with the use of botulinum toxin. Dis Mon. 2002 
May;48(5):336-56.
Lance JW. Symposium synopsis. Spasticity, disordered motor control . Year Book Medical Publishers, 
Chicago. 1980.
Marciniak CM, Harvey RL, Gagnon CM. Does botulinum toxin type A decrease pain and lessen 
disability in hemiplegic survivors of stroke with shoulder pain and spasticity?. Physical Medicine and 
Rehabilitation.2012;91:1007-19.
Mutlu A, Livanelioglu A, Gunel MK. Reliability of Ashworth and modified Ashworth scales in 
children with spastic cerebral palsy. BMC Musculoskeletal Disorders. 2008;9:44.
Nemto A. Therapeutic method for treatment of spasticity, and conditions indicated for treatment. 
JOURNAL OF CLINICAL REHABILITATION. 2012; 21(10):944-51.
Ogawa, Idee, Katayama. Treatment Guideline for Cerebral Stroke 2015. 2015. 
Ohsawa, Mezaki, Miyagi. Standard Neurotherapy: Botulinum treatment. Neurotherapy. 2013; 
30(4):473-94.
Shinohara, Ogawa, Suzuki et al. Treatment Guideline for Cerebral Stroke 2009. 2009. 
Sloan RL, Sinclair E, Thompson J, Taylor S, et al. Inter-rater reliability of the modified Ashworth 
Scale for spasticity in hemiplegic patients. Int J Rehabil Res. 1992;15:158-61.
Yelnik AP, Colle FM, Bonan IV, et al. Treatment of shoulder pain in spastic hemiplegia by reducing 
spasticity of the subscapular muscle:a randomised, double blind, placebo controlled study of 
botulinum toxin A. The Journal of Neurology, Neurosurgery, and Psychiatry. 2007;78:845-8.


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12. Appendices
12.1.
Appendix 1: Abbreviations and trademarks
Trademark
Trademark of Glaxo Smithcline Group
Trademarks that do not belong to Glaxo 
Smithcline Group
Botox
―
12.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 10 will be performed by central laboratory. 

A test needs to be performed by study sites only if the result cannot be obtained from the 
central laboratory in time for study treatment and/or assessment. Even if measurement is 
performed at a study site, another sample at the same assessment timepoint is separately 
required for measurement at central laboratory. If a result of measurement at the study site 
is to be used for a decision of study treatment and/or assessment, the result should be 
recorded in the CRF. 

Protocol-specific inclusion/exclusion criteria are as specified in section 6 of the protocol. 

Protocol-specific inclusion/exclusion criteria are as specified in section 6 of the protocol. 


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Table 10    Protocol-Required Safety Laboratory Assessments
Clinical 
laboratory
Parameters
Hematological 
tests
Platelet count
Erythrocyte indices: 
Mean corpuscular volume 
(MCV)
Mean corpuscular 
hemoglobin (MCH)
Reticulocyte count (%)
Percentage of white blood 
cell:
Neutrophil
Lymphocyte
Monocyte
Eosinophil
Basophil
RBC
Hemoglobin
Hematocrit
White blood cell count
Chemistry1
Urea 
nitrogen 
(BUN)
Potassium
Aspartate aminotransferase (AST) /
Serum glutamic oxaloacetic 
transaminase (SGOT) 1
Total bilirubin and 
direct bilirubin
Creatinine
Sodium
Alanine aminotransferase (ALT) / 
Serum glutamic pyruvic 
transaminase (SGPT) 1
Total protein
Calcium
Alkaline 
phosphatase
Urinalysis
Specific gravity
PH with test paper, glucose, protein, occult blood, ketone, bilirubin, urobilinogen, 
nitrite, and white blood cell esterase
Microscopy (if occult blood or protein is deviated)
Other tests

Pregnancy test (if necessary in a woman of child-bearing potential): 
Serum or urine human chorionic gonadotropin (hCG) 2
The following parameters should be tested during the screening period. 

Serological verification: HIV antibody

The following parameters should be tested only for subjects with chronic 
hepatitis B or C that is stabilized at screening, and subjects currently 
receiving or expected to receive immunosuppressant. 

Serological verification: Hepatitis B virus surface antigen (HBsAg), 
and hepatitis C virus antibody

The following parameter should be tested for women of no child-bearing 
potential. 

Follicle stimulating hormone and estradiol
Caution: 
1. Details of the discontinuation criteria based on hepatic function test, and the interventions and follow up 
necessary after the occurrence of hepatic events are specified in section 8.1 and Appendix 6. SAEs must 
be reported for all events with ALT IJYO3 times the upper limit of normal range (ULN), and at the same 
time, bilirubin IJYO2 times the ULN (direct bilirubin >35%), or ALT IJYO3 times the ULN, and at the 
same time, the international normalized ratio (INR) >1.5 if measured [which suggests a possibility of 
severe liver injury (applicable to Hy's Law)]. 
2. Pregnancy tests should be performed with serum samples at screening, and with urine samples for 
routine tests after randomization. 


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12.3.
APPENDIX 3: Study Governance Considerations
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.

Any amendments to the protocol will require IEC/IRB approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as required by IRB/IEC 
procedures

Providing oversight of the conduct of the study at the site and adherence to requirements of 
21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial certification 
or disclosure statements to the appropriate regulatory authorities. Investigators are responsible for 
providing information on financial interests during the course of the study and for 1 year after 
completion of the study.
Process of obtaining consent

The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding 
the study.

Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed consent 
that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health 
Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, and 
the IRB/IEC or study center.


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
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.
Data protection

Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant names 
or any information which would make the participant identifiable will not be transferred.

The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.

The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
Composition of committee
No committee will be established.
Publication Policy

The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor before 
submission. This allows the sponsor to protect proprietary information and to provide 
comments.

The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating investigator will be designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.
Dissemination of Clinical Study Data

Disclosure of a Clinical Study Report (CSR) after the evaluation by the regulatory 
authority(ies).

GSK may post the study information and tabulated-form study results on the website 
(www.ClinTrials.gov) of the U.S. National Institution of Health (NIH) or other websites 
open to the public 

GSK may post the study results to scientific journals that conduct peer review in order to 
report the study results.


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Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the sponsor or designee electronically (eg, laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.

The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.

The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.

The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.

Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study 
isbeing conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.

Records and documents, including signed ICF, pertaining to the conduct of this study must 
be retained by the investigator for 25 years from the issue of the final Clinical Study Report 
(CSR)/ equivalent summary unless local regulations or institutional policies require a longer 
retention period. No records may be destroyed during the retention period without the 
written approval of the sponsor. No records may be transferred to another location or party 
without written notification to the sponsor.
Source documents

Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available.

Definition of what constitutes source data can be found in the corresponding list of source 
documents.
Study and Site Closure
GSK or its designee reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of GSK. Study sites will be closed upon study completion. A study site is 
considered closed when all required documents and study supplies have been collected and a study-
site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are not 
limited to:


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
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study treatment development


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12.4.
APPENDIX 4: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study treatment, whether or not considered related to the study 
treatment.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other
safety assessments (eg, ECG, radiological scans, vital signs measurements), including those 
that worsen from baseline, considered clinically significant in the medical and scientific 
judgment of the investigator (ie, not related to progression of underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even though it may 
have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study treatment or 
a concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is an 
intentional overdose taken with possible suicidal/self-harming intent. Such overdoses should 
be reported regardless of sequelae.

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be reported 
as an AE or SAE. Such instances will be captured in the efficacy assessments. However, the 
signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be reported as 
AE or SAE if they fulfill the definition of an AE or SAE.

The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be reported 
as AE or SAE if they fulfill the definition of an AE or SAE. Also, "lack of efficacy" or 
"failure of expected pharmacological action" constitutes an AE or SAE.


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Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
Definition of an SAE
If an event does not correspond any of the above definitions of an AE, even if it is a serious condition, 
it will not be regarded as an SAE (e.g.; hospitalization due to the signs/symptoms of the disease being 
studied, death caused by exacerbation of the disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
results in death
b.
is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the subject was at 
risk of death at the time of the event. It does not refer to an event, which hypothetically might have 
caused death, if it were more severe.
c.
requires hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the subject has been detained (usually involving at least an 
overnight stay) at the hospital or emergency ward for observation and/or treatment that would not 
have been appropriate in the investigator’s office or out-patient setting. Complications that occur 
during hospitalization are AEs. If a complication prolongs hospitalization or fulfils any other serious 
criteria, the event is serious. When in doubt as to whether “hospitalization” occurred or was necessary, 
the AE should be considered serious. Hospitalization for elective treatment of a pre-existing condition 
that did not worsen from baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday life 
functions but do not constitute a substantial disruption.
e.
is congenital anomaly/birth defect


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f.
other important medical situations:

Medical or scientific judgement should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require medical or surgical intervention to prevent one of the other outcomes 
listed in the above definition. These should also be considered serious.
Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that 
do not result in hospitalization, or development of drug dependency or drug abuse.
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the following AEs 
and SAEs:

Myocardial infarction/angina unstable

Cardiac failure congestive

Arrhythmia

Valvular disease

Pulmonary hypertension

Cerebrovascular event/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep vein thrombosis/pulmonary embolism

Revascularisation
Recording of AEs and SAEs
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to GSK in lieu of completion of the GSK /AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are requested by 
GSK. In this case, all participant identifiers, with the exception of the participant number, 
will be redacted on the copies of the medical records before submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE.


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Assessment of intensity
The investigator will make an assessment of intensity for each AE and SAE reported during the study 
and classify it to one of the following categories:

Mild: An event that is easily tolerated by the subject, causing minimal discomfort and not 
interfering with everyday activities.

Moderate: An event that is sufficiently discomforting to interfere with normal everyday 
activities.

Severe: An event that prevents normal everyday activities - An AE that is assessed as severe 
will not be confused with an SAE. Severity is a category utilized for rating the intensity of 
an event; and both AEs and SAEs can be assessed as severe.
An event is defined as “serious”, not when it is assessed as severe but when it meets at least one of the 
pre-defined outcomes as described in the definition of an SAE.
Assessment of causality

The investigatoris obligated to assess the relationship between investigational product and 
the occurrence of each AE/SAE.

A “reasonable possibility” is meant to convey that there are facts/evidence or arguments to 
suggest a causal relationship, rather than a relationship cannot be ruled out.

The investigator will use clinical judgement to determine the relationship.

Alternative causes, such as natural history of the underlying diseases, concomitant therapy, 
other risk factors, and the temporal relationship of the event to the investigational product 
will be considered and investigated.

The investigator will also consult the IB, for marketed products, in the determination of 
his/her assessment.

The investigator  must record that he or she reviewed AEs and SAEs and assessed the 
causality in the medical record.

There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK. However, it is very important that the 
investigator always make an assessment of causality for every event prior to the initial 
transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up information, 
prepare and send the follow-up report of SAE by amending the assessment result of the 
causality accordingly.

The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.


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Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.

If a subject dies during participation in the study, the investigator will provide GSK with a 
copy of any post-mortem findings, including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit all updated SAE data to GSK within 24 hours after obtaining 
the information.
Reporting of SAEs to GSK
SAE Reporting to GSK via Electronic Data Collection Tool

The primary mechanism for reporting SAE to GSK will be the electronic data collection 
tool.

If the electronic system is unavailable for more than 24 hours, then the site will use the 
paper SAE data collection tool (see next section).

The site will enter the SAE data into the electronic system as soon as it becomes available.

The investigator or medically-qualified sub-investigator must show evidence within the 
eCRF (e.g., check review box, signature, etc.) of review and verification of the relationship 
of each SAE to IP/study participation (causality) within 72 hours of SAE entry into the 
eCRF.

After the study is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated data on 
a previously reported SAE after the electronic data collection tool has been taken off-line, 
then the site can report this information on a paper SAE form (see next section) or to the 
SAE coordinator by telephone.

Contacts for SAE reporting can be found in ATTACHMENT.
SAE Reporting to GSK via Paper CRF

Facsimile transmission of the SAE page of the CRF is the preferred method to transmit the 
information on SAEs to GSK. 

In rare circumstances and in the absence of facsimile equipment, initial notification by 
telephone is acceptable followed by a copy of the SAE page of the CRF sent by overnight 
mail or by courier. 

Initial notification via the telephone does not replace the need for the investigator (or 
subinvestigator) to complete and sign the SAE page of the CRF within the designated 
reporting time frames.

The ATTACHMENT 1 shows a contact information to which the SAEs should be reported.


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12.5.
APPENDIX 5: Contraceptive Guidance and Collection of Pregnancy 
Information
Definition
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below)
Women in the following categories are not considered WOCBP
1.
Premenarchal
Premenopausal female with ONE of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s: review of participant’s medical records, 
medical examination, or medical history interview.
Postmenopausal women

A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 12 
months of amenorrhea, a single FSH measurement is insufficient.

Females on HRT and whose menopausal status is in doubt will be required to use one of the 
non-hormonal highly effective contraception methods if they wish to continue their HRT 
during the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrollment.
Contraception Guidance
Male study subject

A male study subject who has a female partner of childbearing potential can participate in 
this study if he agrees to any of the following conditions: 

He must agree not to have a sex (sexual intercourse) with a person of the opposite sex as a 
normal favourable lifestyle (continuously having no sex for a long period of time) and also 
agree to keep that condition. 

If he has a sex with a woman of childbearing potential, he must agree to use a male condom
and use at least one of the contraception methods with an annual failure rate below 1% 
which are shown in Table 11.

A male study subject who has a pregnant or breastfeeding female partner must agree not to 
have a sex from the time during the study or use a male condom when having a sex. 

A male study subject must agree not to provide his sperm during the study. 


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Female study subject
A female study subject of childbearing potential can participate in this study if she agrees to use any 
of the extremely effective methods of contraception shown in Table 11continuously and accurately. 
Among the methods of contraception shown in Table 11, those deleted with strikethrough lines have 
neither been approved nor been accepted in Japan.
Table 11    Extremely effective methods of contraception
User-dependent extremely effective methods of contraception a
Their annual failure rates are below 1% if they are used continuously and accurately.
Contraception by mixed (estrogen and progestogen-containing) hormone preparation (inhibit 
ovulation)b

Oral

Intravaginal

Transdermal
Contraception by only progestogen-containing hormone preparation (inhibit ovulation)b

Injection
User-independent extremely effective methods of contraception

Contraception by only progestogen-containing implantable hormone preparation (inhibit 
ovulation)b

Intrauterine device (IUD)

Intrauterine system (IUS)

Bilateral tubal occlusion
Male partner’s vasectomy
(If her male partner has been vasectomised, it is an extremely effective method of contraception for a 
woman of childbearing potential if that partner is the only man with whom she has a sex and it has 
been confirmed that he is sterile. Otherwise, he/she must use other additional extremely effective 
method(s) of contraception.)
Having no sexual relations
(If the subjects decides to refrain himself or herself from having a sex of the opposite sex for the entire 
period when there is a risk of the investigational product, abstinence is deemed to be an extremely 
effective method of contraception. However, the credibility of abstinence needs to be evaluated during 
the study period and from the perspectives of the subject’s normal favourable lifestyle.)
Notes:
a.
The usual failure rate is different from the rate when contraception is used continuously and 
accurately. The subjects should use the methods of contraception that match with regulations 
concerning the methods of contraception for study subjects in each country.
b.
The efficacy of contraception by hormone preparations may decrease as a result of the interaction 
with the investigational product. In that case, the subject should use two extremely effective 
methods of contraception during the treatment period and at least for 3 months after the last dose 
of the investigational product.


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Pregnancy test

A woman of childbearing potential can be enrolled to this study only if it is confirmed that 
she is negative in a highly sensitive serum pregnancy test along with her menstrual period. 

Pregnancy test should be performed if no menstruation occurred or she is suspected to be 
pregnant.

Analysis should be performed according to the package insert using a testing kit provided 
by GSK.
Collection of pregnancy information
If a male study subject’s partner becomes pregnant

Investigator will attempt to collect pregnancy information on any male participant’s female 
partner of a male study participant who becomes pregnant while participating in this study. 
This applies only to participants who receive study treatment.

After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the investigator will record pregnancy information on the appropriate form and 
submit it to GSK within 2 weeks of learning of the partner’s pregnancy.

Partner will also be followed to determine the outcome of the pregnancy. Information on the 
status of the mother and child will be forwarded to GSK

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery 
date. Any termination of the pregnancy will be reported regardless of fetal status (presence 
or absence of anomalies) or indication for procedure.
Female Participants who become pregnant

Investigator will collect pregnancy information on any female participant, who becomes 
pregnant while participating in this study. 

Information will be recorded on the appropriate form and submitted to GSK within 24 hours 
of learning of a participant's pregnancy. 

Participant will be followed to determine the outcome of the pregnancy. The investigator 
will collect follow up information on participant and neonate, which will be forwarded to 
GSK Generally, follow-up will not be required for longer than 6 to 8 weeks beyond the 
estimated delivery date.

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
or elective termination of a pregnancy will be reported as an AE or SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as such.

Any SAE occurring as a result of a post-study pregnancy which is considered reasonably 
related to the study treatment by the investigator, will be reported to GSK as described in 
Appendix 4. While the investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous reporting.


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For a female study subject who discovers her pregnancy while participating in this study, 

The administration of the investigational product will be discontinued. 


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12.6.
APPENDIX 6: Liver Safety Required Actions and Follow up Assessments
In order to secure the subject’s safety and evaluate the causes of liver event, the criteria for 
discontinuation and follow-up based on the liver function test values in the phase III-IV studies
will be stipulated.
Criteria for discontinuation based on the liver function test values in the phase III-IV studies
and necessary follow-up
Criteria for discontinuation based on the liver function test values
ALT
ALT ≥ 8xULN
ALT increase ALT ≥ 5xULN but <8xULN persists for ≥2 weeks
ALT ≥ 3xULN but <5xULN persists for ≥4 weeks
Bilirubin1, 2
ALT ≥ 3xULN and bilirubin ≥ 2xULN (>35% direct bilirubin)
INR2
ALT ≥ 3xULN and INR>1.5, if INR measured
Cannot 
Monitor
ALT ≥ 5xULN but <8xULN and cannot be monitored weekly for ≥2 weeks
ALT ≥ 3xULN but <5xULN and cannot be monitored weekly for ≥4 weeks
Symptom 3
ALT ≥ 3xULN associated with symptoms (new or worsening) believed to be related 
to liver injury or hypersensitivity
Necessary measures and assessment items for liver event
Actions 
Follow Up Assessments 

Immediately discontinue the 
administration of the investigational 
product.

Report it to GSK within 24 hours.

Complete the liver event CRF and 
complete an SAE data collection tool if 
the event also meets the criteria for an 
SAE 2.

Perform liver event follow up 
assessments

Monitor the participant until liver 
chemistries resolve, stabilize, or return 
to within baseline (see MONITORING
below)

Do not restart/rechallenge participant 
with study treatment unless allowed per 
protocol and GSK Medical Governance 
approval is granted

If the resumption/re-administration of 
the investigational product is not 
stipulated in the protocol or approved
by GSK’s Medical Governance, the 
administration of the investigational 
product will be discontinued 

Viral hepatitis serology4

Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend

Only in those with underlying chronic 
Hepatitis B at study entry (identified by 
positive Hepatitis B surface antigen) 
quantitative Hepatitis B DNA and 
Hepatitis delta antibody5

Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin≥2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications 
on the concomitant medications report 
formincluding acetaminophen, herbal 
remedies, other over the counter 
medications.


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permanently and the follow-up 
prescribed in the protocol 8.1. will be 
conducted.
MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, 
AST, alkaline phosphatase, bilirubin) 
and perform liver event follow up 
assessments within 24 hrs

Monitor participants twice weekly until 
liver chemistries resolve, stabilize or 
return to within baseline

A specialist or hepatology consultation 
is recommended
For other criteria:

Repeat liver chemistries (include ALT, 
AST, alkaline phosphatase, bilirubin) 
and perform liver event follow up 
assessments within 24-72 hrs

Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

Record alcohol use on the liver event 
alcohol intake case report form (CRF) 
page
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG) or gamma globulins.

Liver imaging (ultrasound, magnetic 
resonance, or computerised 
tomography) and /or liver biopsy to
evaluate liver disease; complete Liver 
Imaging and/or Liver Biopsy CRF 
forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin 
fractionation is not immediately available, discontinue study treatment for that participant if ALT 
≥ 3xULN and bilirubin ≥ 2xULN. Additionally, if serum bilirubin fractionation testing is 
unavailable, record presence of detectable urinary bilirubin on dipstick, indicating direct bilirubin 
elevations and suggesting liver injury.
All events of ALT ≥ 3xULN and bilirubin ≥ 2xULN (>35% direct bilirubin) or ALT ≥ 3xULN and 
INR>1.5, if INR measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be 
reported as an SAE (excluding studies of hepatic impairment or cirrhosis); INR measurement is not 
required and the threshold value stated will not apply to participants receiving anticoagulants
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such 
as fever, rash or eosinophilia)
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen (HbsAg) and Hepatitis B Core 
Antibody (IgM); Hepatitis C RNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen 
IgM antibody (or if unavailable, obtain heterophile antibody or monospot testing); Hepatitis E IgM 
antibody
Criteria for follow-up with continued treatment based on the liver function test values in the 
phase III-IV studies


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Criteria for follow-up based on liver test function values – Liver events to be followed
Criteria
Actions
ALT ≥5xULN and <8xULN and bilirubin 
<2xULN without symptoms believed to be related 
to liver injury or hypersensitivity, and who can be 
monitored weekly for 2 weeks.
OR
ALT ≥3xULN and <5xULN and bilirubin 
<2xULN without symptoms believed to be related 
to liver injury or hypersensitivity, and who can be 
monitored weekly for 4 weeks. 

Notify the GSK medical monitor within 
24 hours of learning of the abnormality 
to discuss participant safety.

Participant can continue study treatment

Participant must return weekly for 
repeat liver chemistries (ALT, AST, 
alkaline phosphatase, bilirubin) until 
they resolve, stabilise or return to within 
baseline

If at any time participant meets the liver 
chemistry stopping criteria, proceed as 
described above

If ALT decreases from ALT ≥5xULN 
and <8xULN to ≥3xULN but <5xULN, 
continue to monitor liver chemistries 
weekly.

If, after 4 weeks of monitoring, ALT 
<3xULN and bilirubin <2xULN, 
monitor participants twice monthly until 
liver chemistries normalize or return to 
within baseline.


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12.7.
APPENDIX 7: COUNTRY SPECIFIC DESCRIPTIONS
12.7.1.
Regulatory and Ethical Considerations
This study will be conducted in compliance with the “Good Clinical Practice (GCP)” (MHW 
Ordinance No. 28, March 27, 1997) and the “Act on Securing Quality, Efficacy and Safety of 
Pharmaceuticals, Medical Devices, etc. (PMD Act)”. 
GSK will submit the CTN to the regulatory authorities in accordance with the PMD Act before 
concluding the study agreement with the medical institution
12.7.2.
Obtaining of Informed Consent
Prior to participation in the study, the investigator should fully inform the potential subject and/or 
his or her legally acceptable representative of the study using the information document. In doing so, 
the investigator should provide the subject sufficient time and opportunity to inquire about details of 
the study and obtain the subject and/or his or her legally acceptable representative’s signature or 
printed name and seal and date of consent on the consent form. The subject may take the informed 
consent form home to review it. The person who provided the explanation and the clinical research 
coordinator who provided the supplementary explanation should also sign or affix his or her printed 
name and seal on the consent form and enter the date of signature. If an impartial witness is needed, he 
or she should also sign or affix his or her printed name and seal on the consent form and enter the date 
of witness. The investigator should attach the original of the above signed or affixed with printed 
name/seal and dated consent form (and information document) to the original medical record such as 
medical chart (in accordance with the rules for records retention, if any, at each medical institution), 
retain it, and give a copy to the subject and/or his or her legally acceptable representative. 
12.7.3.
Study Implementation Period
July 2017 – February 2019
12.7.4.
Study Conduct Structure
The Attachment 1 shows the sponsor’s information. Also, the Attachment 2 shows a list of medical 
institutions and investigators. 


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TITLE PAGE
Protocol Title: A phase III study (a placebo controlled, randomized, double-blind comparative study 
and an open-label, uncontrolled study) to evaluate the efficacy and safety of GSK1358820 in patients 
with post-stroke upper limb spasticity 
Protocol Number: 02
Short Title: A phase III study to evaluate the efficacy and safety of GSK1358820 in patients with 
post-stroke upper limb spasticity
Compound Number:
GSK1358820
Sponsor 
GlaxoSmithKline K.K. (GSK)
1-8-1 Akasaka, Minato-ku, Tokyo 107-0052 Japan 
The person responsible for operation of the study:
Director of Development of 
Drugs for Neurological Diseases, Department of Development, Clinical Research Department
Medical Monitor Name and Contact Information are shown on SRM.
Regulatory Agency Identifying Number(s):NA
Approval Date: 6-OCT -2017
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  Unauthorised 
copying or use of this information is prohibited.
PPD


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Signature of the Sponsor:
Director of Development of Drugs For Neurological Diseases, 
Department of Development, Clinical Research Department
GlaxoSmithKline K.K. (GSK) 
Date
The IMMS document approved is as follows:
  Unique ID :
  System Version:
  Effective Date:
PPD


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY 
Document 
Date 
Amendment 2
6-OCT-2017
Amendment 1
24-MAY-2017
Original protocol
4-APR-2017
Amendment 1 : 24-MAY-2017
Overall Rationale for the Amendment:01
The protocol was changed based on the regulatory inquires by the Pharmaceuticals and Medical 
Devices Agency (PMDA).
Overall Rationale for the Amendment:01
Section # and Name 
Description of Change 
Brief Rationale 
1. SYNOPSIS
Add pulmonary test and 
description adjustment
Requested by PMDA
2. SCHEDULE OF 
ACTIVITIES (SoA)
Add pulmonary test and 
description adjustment
Requested by PMDA
5.1.3.1. Eligibility 
Criteria for Injection in 
and after Part 2
Add pulmonary test 
Requested by PMDA
6.1.1. Screening Phase 
(Day -28 to Day -1)
Add pulmonary test 
Requested by PMDA
6.2.2. Day 1 (Prior to 
injection)
Description adjustment
Establish consistency with section 7.7.2
6.4. Screen Failures
Description adjustment
Not shown due to minor changes
7.7.2. Contraindicated 
Medications/Therapies
Description adjustment
Establish consistency with section 6.2.2
9.1.1.4. Clinical Global 
Impression of Change 
(CGI) assessed by a 
investigator
Error correction
Not shown due to minor changes
9.4.4. Pulmonary test
Add pulmonary test 
Requested by PMDA
9.4.5.ECG
Description adjustment
Add manual re-interpretation
Amendment 2 : 6-OCT-2017
Overall Rationale for the Amendment: 02
The protocol was changed on the basis of the regulatory inquires by the Pharmaceuticals and Medical 
Devices Agency (PMDA).


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Overall Rationale for the Amendment: 02
Section # and 
Name 
Description of Change 
Brief Rationale 
Cover
Change of address
Office relocation
1. SYNOPSIS, 
Delete laboratory data from the 
Eligibility Criteria for Injection in and 
after Part 2.
Add eligibility criteria regarding the 
pulmonary test.
GSK1358820 is unlikely to affect laboratory test 
data.
Specify the acceptable range of SpO2 values.
2. SCHEDULE 
OF ACTIVITIES 
(SoA)
Add a footnote.
Clarify the procedure for V1 assessment in and 
after Part 2.
5.1.3.1. Eligibility 
Criteria for 
Injection in and 
after Part 2
Delete laboratory data from the 
Eligibility Criteria for Injection in and 
after Part 2.
Add eligibility criteria regarding the 
pulmonary test.
GSK1358820 is unlikely to affect laboratory test
data.
Specify the acceptable range of SpO2 values.
6.2.2. Day 1 (Prior 
to injection)
Add eligibility criteria regarding the 
pulmonary test.
Specify the acceptable range of SpO2 values to 
ensure the safety.
7.1. Treatments 
Administered
Table 2. Muscle 
Involvement and 
Dose in the Blind 
Phase
Table 3. Muscle 
Involvement and 
Reference Dose in 
the Open-Label 
Phase
Description adjustment
Not shown due to minor changes.
7.7.1. Permitted 
Concomitant 
Drugs/Therapies
Description adjustment
Delete tolperisone hydrochloride, which has 
been withdrawn from the market.
7.7.1. Permitted 
Concomitant 
Drugs/Therapies
Add a description regarding 
rehabilitation therapies.
Specify acceptable rehabilitation therapies and 
the procedure for collecting rehabilitation 
therapy related information.
9.1.1.1. Modified 
Ashworth Scale 
(MAS)
Description adjustment
Add a description regarding MAS assessment on 
the thumb.
9.1.1.1. Modified 
Ashworth Scale 
(MAS)
Table 6. Regions 
to be evaluated for 
MAS during the 
open-label period
Description adjustment
Not shown due to minor changes
9.4.2. Vital signs
Add a description regarding 
measurement in a sitting position.
Add an instruction for vital sign measurement.
9.4.4. Pulmonary 
Add a description regarding the 
Specify the acceptable range of SpO2 values to 


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Section # and 
Name 
Description of Change 
Brief Rationale 
Test
pulmonary test.
ensure the safety.


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TABLE OF CONTENTS
Page
1.
SYNOPSIS .....................................................................................................................10
2.
SCHEDULE OF ACTIVITIES (SoA) ..............................................................................15
3.
INTRODUCTION............................................................................................................21
3.1.
Study Rationale....................................................................................................21
3.2.
Background..........................................................................................................21
3.3.
Benefit/Risk Assessment....................................................................................22
3.3.1.
Risk Assessment ........................................................................................23
3.3.2.
Benefit Assessment....................................................................................25
3.3.3.
Overall Benefit:Risk Conclusion...............................................................25
4.
OBJECTIVES AND ENDPOINTS..................................................................................26
5.
STUDY DESIGN.............................................................................................................27
5.1.
Overall Design......................................................................................................27
5.1.1.
Screening Phase (up to 4 weeks)..............................................................27
5.1.2.
Blind Period (minimum 12 Weeks): Placebo Controlled, 
Randomized, Double Blind Design ...........................................................28
5.1.3.
Open-Label Phase (maximum 36 weeks): Uncontrolled, Open-
Label Design................................................................................................28
5.1.3.1.
Eligibility Criteria for Injection in and after Part 2 ..........................28
5.2.
Number of Participants .......................................................................................29
5.3.
Participant and Study Completion.....................................................................29
5.4.
Scientific Rationale for Study.............................................................................29
5.5.
Dose Justification................................................................................................30
6.
STUDY POPULATION...................................................................................................30
6.1.
Inclusion Criteria..................................................................................................31
6.1.1.
Screening Phase (Day -28 to Day -1) ........................................................31
6.1.2.
Day 1 (prior to injection).............................................................................32
6.2.
Exclusion Criteria ................................................................................................33
6.2.1.
Screening Phase (Day -28 to Day -1) ........................................................33
6.2.2.
Day 1 (Prior to injection).............................................................................34
6.3.
Lifestyle Restrictions ..........................................................................................35
6.4.
Screen Failures ....................................................................................................35
7.
TREATMENTS...............................................................................................................37
7.1.
Treatments Administered ...................................................................................37
7.2.
Dose Modification................................................................................................39
7.3.
Method of Treatment Assignment .....................................................................39


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7.4.
Blinding.................................................................................................................39
7.5.
Preparation/Handling/Storage/Control..............................................................40
7.6.
Treatment Compliance........................................................................................40
7.7.
Concomitant Therapies.......................................................................................40
7.7.1.
Permitted Concomitant Drugs/Therapies.................................................41
7.7.2.
Contraindicated Medications/Therapies...................................................42
7.8.
Treatments after Completion of the Study........................................................42
8.
DISCONTINUATION CRITERIA....................................................................................42
8.1.
Discontinuation of Study Treatment..................................................................42
8.2.
Withdrawal from the Study .................................................................................42
8.2.1.
Liver Chemistry Stopping Criteria.............................................................43
8.2.2.
QTc Stopping Criteria.................................................................................45
8.2.3.
Treatment discontinuation due to treatment-related SAE......................45
8.2.4.
Treatment discontinuation due to pregnancy .........................................45
8.2.5.
Withdrawal 
of 
subjects 
who 
start 
receiving 
prohibited 
medications or therapies ...........................................................................45
8.2.6.
Prohibition of treatment resumption ........................................................46
8.3.
Lost to follow up ..................................................................................................46
9.
STUDY ASSESSMENTS AND PROCEDURES ...........................................................46
9.1.
Efficacy assessments .........................................................................................47
9.1.1.
Evaluation methods....................................................................................47
9.1.1.1.
Modified Ashworth Scale (MAS) .......................................................47
9.1.1.2.
Numeric Rating Scale (NRS) .............................................................48
9.1.1.3.
Disability Assessment Scale (DAS)..................................................49
9.1.1.4.
Clinical Global Impression of Change (CGI) assessed by 
an investigator....................................................................................50
9.1.1.5.
Clinical Global Impression of Change (CGI) assessed by a 
patient..................................................................................................50
9.1.1.6.
Time to patient-reported onset of spasticity symptom relief 
(Visit 2):................................................................................................50
9.1.1.7.
Patient-reported benefit of injection (Visits 3, 4, and 5).................50
9.2.
Adverse events ....................................................................................................51
9.2.1.
Period subject to collection of data related to adverse events 
and SAEs, and the frequency of such data collection............................51
9.2.2.
Method used to detect adverse events and SAEs...................................51
9.2.3.
Follow up on adverse events and SAEs...................................................51
9.2.4.
Regulatory requirements of SAE reporting..............................................51


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9.2.5.
Cardiovascular events and death .............................................................52
9.2.6.
Pregnancy....................................................................................................52
9.3.
Management of overdosage...............................................................................52
9.4.
Safety assessments ............................................................................................53
9.4.1.
Physical examination..................................................................................53
9.4.2.
Vital signs ....................................................................................................53
9.4.3.
Height and weight .......................................................................................54
9.4.4.
Pulmonary test ............................................................................................54
9.4.5.
ECG...............................................................................................................54
9.4.6.
Neutralizing antibody test..........................................................................54
9.4.7.
Clinical Safety Laboratory Assessments .................................................55
9.5.
Pharmacokinetics................................................................................................56
9.6.
Pharmacodynamics.............................................................................................56
9.7.
Genetics/Pharmacogenetics ..............................................................................56
9.8.
Biomarkers ...........................................................................................................56
9.9.
Pharmacoeconomics...........................................................................................56
10. STATISTICAL CONSIDERATIONS ..............................................................................57
10.1.
Sample Size Determination.................................................................................57
10.2.
Populations for Analyses....................................................................................57
10.3.
Statistical Analyses.............................................................................................57
10.3.1.
Efficacy Analyses........................................................................................57
10.3.2.
Safety Analysis............................................................................................58
10.3.3.
Other analyses.............................................................................................59
10.3.4.
Interim analyses..........................................................................................59
11. Reference ......................................................................................................................59
12. Appendices ...................................................................................................................61
12.1.
Appendix 1: Abbreviations and trademarks.....................................................61
12.2.
Appendix 2: Clinical Laboratory Tests..............................................................61
12.3.
APPENDIX 3: Study Governance Considerations............................................63
12.4.
APPENDIX 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting...........................................67
12.5.
APPENDIX 5: Contraceptive Guidance and Collection of Pregnancy 
Information ...........................................................................................................72
12.6.
APPENDIX 6: Liver Safety Required Actions and Follow up 
Assessments........................................................................................................76
12.7.
APPENDIX 7: COUNTRY SPECIFIC DESCRIPTIONS .......................................79
12.7.1.
Regulatory and Ethical Considerations....................................................79


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12.7.2.
Obtaining of Informed Consent.................................................................79
12.7.3.
Study Implementation Period ....................................................................79
12.7.4.
Study Conduct Structure ...........................................................................79
12.8.
APPENDIX 8: PROTOCOL AMENDMENT SUMMARY OF CHANGES 
TABLE ...................................................................................................................79


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1.
SYNOPSIS
Protocol Title: A phase III study (a placebo controlled, randomized, double-blind comparative study 
and an open-label, uncontrolled study) to evaluate the efficacy and safety of GSK1358820 in patients 
with post-stroke upper limb spasticity
Short Title: A phase III study to evaluate the efficacy and safety of GSK1358820 in patients with 
post-stroke upper limb spasticity
Rationale:
GSK1358820, botulinum toxin type A (hereafter referred as the product), is sterile, purified type A 
botulinum neurotoxin complex. Intramuscularly injected botulinum neurotoxin shows muscle relaxant 
effects by blocking the neuromuscular junction and inhibiting release of acetylcholine, a 
neurotransmitter. Since the approval of the product for strabismus and blepharospasm in US in 1989, 
the product is licensed for the treatment of various diseases, which respond to the muscle relaxant 
effects in more than 90 countries (as of Apr 2017).
In Japan, the product is licensed with 8 indications as an ethical drug so far: blepharospasm as a 
first indication in Oct 1996, followed by “hemifacial spasm” in Jan 2000, “spasmodic torticollis” in 
Jun 2001, “talipes equinus associated with lower limb spasticity in pediatric patients two years of age 
and older with cerebral palsy” in Feb 2009, “upper limb spasticity” and “lower limb spasticity” in Oct 
2010, “severe primary maschalephidrosis” in Nov 2012, and “strabismus” in Jun 2015. For “upper 
limb spasticity,” 240 units of the product is approved as a maximum dose per administration. In US, 
as a maximum dose per administration, 400 units of injection of the product have been approved for 
the treatment of upper limb spasticity in adult patients in 2015; therefore, the authorized dose of the 
product between US and Japan is different.
This study is a multicenter, double blind, placebo controlled phase III domestic study and aims to 
evaluate the efficacy and safety of 400 units of the product in patents with post-stroke upper limb 
spasticity. The study was planned to increase the maximum dose per administration in Japan to 400 
units from 240 because the treatment with 240 units of the product, a maximum dose per 
administration, is considered to be insufficient in some patients with post-stroke upper limb spasticity. 


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Objectives and Endpoints:
Objectives
Endpoint(s) 
Primary 
To evaluate the efficacy of the injections of 400 
units of the product at Week 6 (finger/ wrist 
flexors: 240 units, elbow flexors: 160 units), 
comparing to that of 240 units (finger/ wrist 
flexors: 240 units, elbow flexors: placebo).
The responder rate: The rate of the subjects that 
Modified Ashworth Scale (MAS) score was 
reduced at least 1 from baseline in the elbow 
flexors. 
Secondary
To evaluate the efficacy of 400 units of the 
product, comparing to 240 units of the product

The responder rate of MAS score from 
baseline in the finger, thumb and wrist 
flexors 

Changes in MAS score from baseline in 
the finger, thumb, wrist and elbow 
flexors 

Changes in Disability Assessment Scale 
(DAS) from baseline
To evaluate the safety and tolerability of the 
product of 400 units, comparing to 240 units of the
product/ To evaluate the safety and tolerability of 
400 units of the product

Adverse events

Physical examinations

Clinical laboratory tests (haematology, 
blood biochemistry, urinalysis)

Vital signs (heart rate, blood pressure, 
body temperature)
Exploratory
To evaluate the efficacy of 400 units of the 
product 

Changes in MAS score from baseline in 
finger, thumb, wrist, elbow, pronation of 
the forearm and shoulder flexors
To evaluate the other efficacy of the product of 
400 units, comparing to 240 units of the product/ 
To evaluate the other efficacy of 400 units of the 
product

Changes in Numeric Rating Scale 
(NRS) for pain from baseline

Changes in other items of DAS from 
baseline 

Clinical Global Impression of Change 
(CGI) of functional disability by an
investigator

CGI of functional disability by a patient

Time to patient-reported onset of 
spasticity symptom relief

Patient-reported benefit of injection

Time to qualification for retreatment
To evaluate neutralizing antibody production

Testing for neutralizing antibody 


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Overall Design:
This study is a 48-week multicenter, phase III study (a placebo controlled, randomized, double-
blind comparative study and an open-label, uncontrolled study) to evaluate the efficacy and safety of 
the product in patients with post-stroke upper limb spasticity. The study period is up to 52 weeks, 
consisting of a screening phase up to 4 weeks, minimum 12-week blind phase (Part 1), maximum 36-
week open-label phase (12 weeks per cycle with maximum 3 treatment phases: Part 2, Part 3 and Part 
4). 
BOTOX 400 U
BOTOX 240 U
+
Placebo
BOTOX 400 U
BOTOX 400 U
Screening
BOTOX 400 U
Double-blind treatment
(12 weeks)
Open-label treatment 
(36 weeks)
Part 3
Part 4
Part 1
Part 2
dose 
dose 
dose 
dose 
dose 
Number of Participants:
Approximately 120 subjects (approximately 60 in each group) will be randomized to obtain an 
evaluable subject sample of approximately 100 at Week 48 as subjects with completion of the study。
Treatment Groups and Duration:
Screening Phase (Day -28～Day -1)
Evaluation and screening tests will be performed 28 to 7 days (±3days) before initial injection 
(Day 1) as a starting point. The investigator will decide which arm to be injected during screening 
phase.
Blind Phase (minimum 12 Weeks): Placebo Controlled, Randomized, Double Blind 
Design
Subjects who meet the inclusion criteria will be randomly assigned 1:1 to either the 400 or the 240 
units group. 

In the 400 units group, a total of 240 units of the product will be injected into the muscles 
that act on the finger (including thumb flexors) and wrist flexors, and a total of 160 units 
into the muscles that act on the elbow flexors; a total of 400 units of the product will be 
injected.

In the 240 units group, a total of 240 units of the product will be injected into the muscles 
that act on the finger (including thumb flexors) and wrist flexors. Placebo will be injected 
into the muscles that act on the elbow flexors. A total of 240 units of the product will be 
injected. 


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If the total dose for the muscles that act on the finger and writs flexors is ensured by 240 units, and 
160 units for the muscles that act on the elbow flexors, the dose can be adjusted at an investigator’s 
discretion based on the subject’s symptoms.
Open-Label Phase (maximum 36 Weeks): Uncontrolled, Open-Label Design
The product of 400 units will be injected in both groups. The product can be injected up to 3 times 
after completion of Part 1 in the blind phase. In the open-label phase, subjects whom the investigator
considers eligible for the injections will be treated. The next injections cannot be performed until the 
eligibility of the subject has been confirmed by the investigator. 
In the open-label phase, the muscle to be injected and the dose will be decided by the investigator 
on the basis of the patient’s symptoms, and a total dose of 400 units of the product will be injected in a 
divided dose. For the muscles that the investigator considers unnecessary to be treated, an injection 
may be skipped. The involving muscle and the dose do not have to be same each time always.
Eligibility Criteria for Injection in and after Part 2
In the open-label phase (Part 2, Part 3, and Part 4), only the subjects whom the investigator 
considers eligible for the study will be injected. The eligibility is evaluated at a study visit after Week 
12 (V5. If a subject does not meet the criteria at V5, the eligibility is evaluated at QRV (Qualification 
for Retreatment Visit). Subjects are considered to be eligible if the following criteria are all satisfied: 


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1)
At least 12 weeks (84 days) have passed since the preceding dose
2)
Among the finger, wrist or elbow flexors, 2 flexors have at least 2 on the MAS (except only the 
finger and wrist flexors of 2 on the MAS)
3)
Subject who request the injections
4)
Subjects whom an investigator considers an injection of 400 units of the product is appropriate
5)
Subjects who have not experienced serious adverse events (SAE) associated with the injections 
of the product
If subjects meet the criteria of the above 1) to 5) at V5 or QRV, body weight measurement, ECG, 
pulmonary function test, and pregnancy test will be performed to evaluate the following items. If 
subjects meet the following 6) to 8), the subjects will move forward to V1.
6)
Body weight ≥40 kg
7)
Subjects who the investigator considers there are no unacceptable safety concerns [potential 
for serious adverse events, electrocardiogram (ECG) or abnormal pulmonary function
value*] due to 400 U of BOTOX
* This study will use SpO2 (oxygen saturation) as a parameter of pulmonary function. A subject 
who has a 3% reduction from the pre-injection SpO2 (Day 1) in post-injection SpO2 or whose 
SpO2 value is <95% should be referred to a pulmonologist. A subject with pulmonary 
dysfunction due to study treatment also should be referred to a pulmonologist. If the subject is 
considered by the pulmonologist to have no concerns about pulmonary function, the investigator 
should carefully consider whether to start the study treatment.
8)
Women of childbearing potential who have negative pregnancy test result in urine
A pulmonary function test must be performed at V5 even if subjects do not meet the above 1) to 5) in 
accordance with the study operation schedule (SoA).


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2.
SCHEDULE OF ACTIVITIES (SoA)
Compliance with the protocol (including the list of the study conduct schedule) is important and 
required to conduct the study. Therefore, exemption or discharge cannot be allowed, except but 
emergency safety concerns arise. 
The study operation schedule is shown on Table 1. Examples of injections in the open-label phase 
based on evaluation of eligibility for injection are shown on Figure 1, Figure 2, Figure 3, and Figure 4. 


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Table 1 SCHEDULE OF ACTIVITIES (SoA)
Screening a
Blind phase
If a subject meets the eligibility at V5/ QRV, the subject will 
move forward to the open-label phase
Open-label phase
If a subject meets the eligibility at V5/QRV, the subject will move 
forward to the next treatment phase
Completion 
visit
Part 1
Eligibility 
evaluation b
Part 2/Part 3/ Part 4
Eligibility 
evaluation b
Visit
SV
V1
(Day 1)
V2
V3
V4
V5 c
(Eligibility 
evaluation)
QRV
V1
V2
V3
V4
V5 d
(Eligibility 
evaluation)
QRV
Final
Visit
Time from initial injection 
(Day 1) (Weeks)
―
0
2
4
6
12 
Allowable Week 16 to 
36e
―
―
―
―
―
Allowable Week 24 to 
36 e
48/
Withdrawal
Time from injection day in each 
treatment phase (Weeks)
―
0
2
4
6
12
16/ 20/ 24/ 28/ 32/ 
36
0
2
4
6
12
16/ 20/ 24
-
Acceptable visit windows (days) 
―
4
4
4
+4 f
14 g
(+4)v
4
4
4
+4 f
14 g
4
Written informed consent
X h
Randomization
X i
Injections
X
X
Evaluation of eligibility
X
X
X
X
Inclusion/exclusion criteria j
X
X i
Subject demography
X
MAS k
X
X i
X
X
X
X
X
X i,t
X
X
X
X
X
X
NRS l
X i
X
X
X
X
X i,t
X
X
X
X
(X) r
DAS 
X i
X
X
X
X
X i,t
X
X
X
X
(X) r
CGI by a investigator
X
X
X
X
X
X
X
X
(X) r
CGI by a patient
X
X
X
X
X
X
X
X
(X) r
Time to patient-reported onset of 
spasticity symptom relief
X
X
Patient-reported benefit of 
injection
X
X
X
X
X
X
(X) r
Physical examination (complete 
version)
X
Physical examination (simplified 
version)
X i
X
X i,t
X
X
Medical history
X
X i
Vital signs m
X
X i
X
X i,t
X
X
Height
X
Body weight
X
X u
X u
X u
X u
Pulmonary function test
X
X
X
X u
X
X u
X
Electrocardiogram
X
X u
X u
X u
X u
Pregnancy test n
X
X i
X u
X u
Xs, u
X u
X
Laboratory test o
X
X
X
X
Adverse events p
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medications/therapies
X
X i
X
X
X
X
X
X
X
X
X
X
X
X


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a.
Test items for screening must be performed from 4 weeks to 1 weeks before Day 1 visit (±3 days).
b.
Eligibility evaluation (Qualification for Retreatment Visit: QRV) will be performed at V5 as a starting point if a subject does not meet the criteria only. The evaluation is performed at a 4-week interval, 
V5 as a starting point, The QRV when a subject meets the criteria will be a same day as the injection in the next treatment period (refer to Figure 1, Figure 2, Figure 3, Figure 4). 
c.
If a subject is evaluated to meet the eligibility for the injection in the blind phase at V5, the subject will move forward to Part 2 in the open-label phase (Namely, V5 in Part 1 and V1 in Part 2 is a same 
day). If the subject does not meet the eligibility, QRV will be performed 4 weeks later, at V5 as s starting point. 
d.
If a subject is evaluated to meet the eligibility at V5 in the open-label phase, the subject will move forward to the next treatment phase (V5 and V1 in the next treatment phase is a same day). If the 
subject does not meet the eligibility, QRV is performed 4 weeks later, V5 as a starting point. If V5 in each treatment phase is at Week 48 after initial injection, V5 will be considered to be completion
visit (FV). However, for the testing items, pre-scheduled tests at V5 and neutralizing antibody tests will be performed. If V5 in Parts 2 and 3 is performed at Week 36 or later, after completion of V5, 
completion visit will be performed at Week 48.
e.
QRV is allowable to perform from initial injection to Week 36. Eligibility evaluation (QRV) will not be performed after Week 36.  
f.
V5 must be performed at least 84 days after V1. 
g.
The acceptable visit windows will be -14 to +4 days if QRV is performed at Week 36.
h.
Must be performed earlier than any other procedures
i.
Must be performed before injection of the product
j.
For inclusion/exclusion criteria, the items to be observed are different between screening phase and Day 1. For details, refer to 6.1. and 6.2.
k.
For MAS evaluation, the items to be evaluated differ depending on the treatment phase. For details, refer to 9.1.1.1.
l.
MAS evaluation will be followed by NRS evaluation. For NRS evaluation, items to be evaluated differ. For details, refer to 9.1.1.2.
m.
Body temperature, heart rate, and blood pressure will be measured as vital signs. 
n.
Women of childbearing potential will be only performed. Serum hCG pregnancy test must be performed at screening, and urine hCG pregnancy test after randomization. The tests can be performed 
beyond the protocol specifications if an investigator considers to be necessary.  
o.
For laboratory test items, refer to 12.2. Attachment 2. Fasting is not required for blood collection. 
p.
Adverse events and serious adverse events collection period will be from the initial injection day (Day 1) to completion visit (FV).
q.
Neutralizing antibody testing is performed 3 times in each subject. The first test will be performed in screening phase, the second is at V5 in the blind phase, and the third is at completion visit.
r.
A subject who withdraws the study before 12 weeks after last injection will be performed. 
s.
Perform if V5 in each treatment phase is at Week 48 after initial injection
t.
Not necessary to perform doubly as V1 assessment if the same assessment is performed at V5 or QRV. If V1 assessment or retreatment cannot be performed on the same day as V5 or QRV, MAS
assessment should be performed again on the day of visit for the V1 assessment.
u.
Evaluation of retreatment is performed only when the dosing conditions (1 to 5) of retreatment evaluation are met. If V1 assessment or retreatment cannot be performed on the same day as V5 or QRV,
body weight, pulmonary function test, electrocardiogram, and pregnancy test should not be performed again on the day of visit for V1 assessment.
v.
V1 assessment in Part 2 or subsequent parts should be performed as a rule on the same day as V5 or QRS (when eligibility was confirmed) of the previous part. If this is not possible, the V1 assessment 
may be performed on another day but within the acceptable visit window. 
Testing for neutralising 
antibodies q
X
X
X


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GSK1358820 
240 U
GSK1358820 
400 U
GSK1358820 
400 U
0
V1
2
V2
4
V3
6
V4
8
10
12
14
V2
16
V3
18
V4
20
22
24
GSK1358820 
400 U
GSK1358820 
400 U
Week
Intial treatment
3rd treatment
2nd Treatment
4th treatment
Part 1
Part 2
Part 3
Part 4
26
V2
28
30
32
34
36
38
40
42
44
46
48
FInal
Visit
：Visit week
Ex.1）If a subject is eligible for the injections at V5 in all the treatment phases
V3
V4
V2
V3
V4
V5/FV
Day1
V5/V1
V5/V1
V5/V1
Double-blind
Figure 1    Eligibility Evaluation in the Open-Label Phase (Example 1) 
If a subject is eligible for the injections at V5 in all the treatment phases, 4 injections will be performed 
throughout the study. Week 48 visit is performed also as a completion visit. 
GSK1358820
240 U
GSK1358820 
400 U
GSK1358820 
400 U
0
2
4
6
8
10
12
14
16
18
20
22
24
GSK1358820 
400 U
Week
Initial treatment
Part 1
Part 2
Part 3
26
28
30
32
34
36
38
40
42
44
46
48
Final
Visit
Evaluation will not be performed
：Visit week
Ex. 2）If a subject does not meet the eligibility at V5 in blind phase (Part 1), 
QRV will be performed at Week 16
V1       V2      V3     V4                           V5          QRV/V1   V2      V3     V4                       V5/V1    V2
V3      V4                           V5                                      FV
Day1
Not qualified
for retreatment
2nd treatment
3rd treatment
Double-blind
Figure 2   Eligibility Evaluation in the Open-Label Phase (Example 2) 
If a subject does not meet the eligibility at V5 in blind phase (Part 1), QRV will be performed at Week 16. V5 in Part 
3 is at Week 40; therefore, eligibility evaluation will not be performed. After V5 at Week 40, FV will be performed at 
Week 48. 


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GSK1358820 
240 U
GSK1358820 
400 U
GSK1358820
400 U
0
2
4
6
8
10
12
14
16
18
20
22
24
GSK1358820
400 U
week
Initial treatment
2ndtreatment
Part 1
Part 2
Part 3
26
28
30
32
34
36
38
40
42
44
46
48
Final
Visit
Not qualified 
For retreatment
3rd treatment
：Visit week
Ex. 3）If a subject does not meet the eligibility at V5, and evaluated to be eligible at 
QRV3 Week 24
V1       V2      V3     V4                           V5              QRV1
QRV2  
QRV3/V1  V2     V3     V4  
V5/V1    V2      V3     V4
V5/FV
Day1                                                                                                                
Not qualified 
For retreatment
Double-blind
Figure 3    Eligibility Evaluation in the Open-Label Phase (Example 3) 
If a subject does not meet the eligibility at V5 in the blind phase (Part 1), QRV will be performed until the eligibility 
have confirmed at 4 weeks intervals, at V5 as a starting point. If a subject is evaluated to be eligible at QRV3 Week 24, 
the injections in Part 2 will be performed on the same day as QRV3. V5 in Part 3 is in Week 48, therefore, at V5, 
completion visit (FV) will be also performed. 
GSK1358820 
240 U
GSK1358820 
400 U
GSK1358820 
400 U
0
2
4
6
8
10
12
14
16
18
20
22
24
week
Initial treatment
2ndtreatment
Part 1
Part 2
26
28
30
32
34
36
38
40
42
44
46
48
Final
visit
Not qualified
for retreatment
：Visit week
*if  not qualified at week 36,
Eligibility assessment will not be performed.
V1       V2      V3     V4                           V5   
QRV1
QRV2
QRV3/V1  V2     V3     V4 
V5                                     
FV
Day1
Ex. 4）If a subject does not meet the eligibility at Week 36
Not qualified
for retreatment
Not qualified
for retreatment
Double-blind
Figure 4    Eligibility Evaluation in the Open-Label Phase (Example 4)
QRV in Part 2 is Week 36, and if a subject does not meet the criteria, subsequent injections will not be performed, 
and Week 48 completion visit will be performed. 


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3.
INTRODUCTION 
3.1.
Study Rationale
GSK1358820, botulinum toxin type A (hereafter referred to as the product) is sterile, purified type 
A botulinum neurotoxin complex. Intramuscularly injected botulinum neurotoxin shows muscle 
relaxant effects by blocking the neuromuscular junction and inhibiting the release of acetylcholine, a 
neurotransmitter. Since the approval of the product for strabismus and blepharospasm in US in 1989, 
the product is licensed for the treatment of various diseases, which respond to the muscle relaxant 
effects in more than 90 countries (as of Apr 2017). 
In Japan, the product is licensed with 8 indications as an ethical drug so far: blepharospasm as first 
indication in Oct 1996, followed by “hemifacial spasm” in Jan 2000, “spasmodic torticollis” in Jun 
2001, “talipes equinus associated with lower limb spasticity in paediatric patients two years of age and 
older with cerebral palsy” in Feb 2009, “upper limb spasticity” and “lower limb spasticity” in Oct 
2010, “severe primary maschalephidrosis” in Nov 2012, and “strabismus” in Jun 2015. For “upper 
limb spasticity,” 240 units of the product is approved as a maximum dose per administration. 
This study is a multicenter, double blind, placebo controlled phase III domestic study in patients 
with upper limb spasticity and aims to confirm the efficacy and safety of 240 units of the product for 
post-stroke upper limb spasticity. The information of 400 units of the product in the study is expected 
to provide beneficial information because the treatment with 240 units of the product with a maximum 
dose per administration is considered to be insufficient in some patients with post-stroke upper limb 
spasticity.
3.2.
Background
Spasticity is a movement disorder that is characterized by increased myotatic reflex and is regarded 
as one of positive signs of the upper motor neuron signs (Kagamihara, 2012; Lance, 1980). Spasticity 
is caused by central nerve system injuries such as stroke, traumatic brain injury, or spinal cord injury 
and chronic neuropathies such as cerebral palsy or multiple sclerosis, etc. Abnormal postures of the 
upper limbs due to spasticity include thumb refraction, a clenched fist deformity, flexion of the wrist 
flexors, pronation of the forearms, flexion of the elbow flexors, and adduction/inner rotation of the 
shoulder flexors (Gracies, 2003; Kinoshita, 2015). 
Spasticity hampers rehabilitation therapy. In addition, limitation of flexors range of motion and 
persistent pain hinder from caregiving and decrease activity in daily life (Grazko, 1995); therefore, 
many of patients with stroke require treatments to ameliorate their dysfunction.
For the treatments of spasticity, rehabilitation therapy, oral medications, phenol blocks, and 
baclofen injections were used until botulinum therapy has been approved as a national health 
insurance coverage. These treatments were commonly challenging because of lack of effects, difficult 
procedures, or invasive interventions. Subsequently, in Oct 2010, the product was approved as a 
botulinum treatment for upper and lower limb spasticity in Japan. Since then, botulinum toxin has 
been used for the treatment of spasticity (Ohsawa, 2013). According to the “Japanese Guidelines for 
the Management of Stroke” (initial version in 2009, revised in 2015) (Ogawa, 2015; Shinohara, 2009), 
which was issued by the Japan Stroke Society, botulinum therapy is recommended for the treatment of 
spasticity as Grade A, and is considered to be effective for relief of upper limb spasticity, increase of 
range of motions in flexors, and reduction of the amount of assistance on daily life.


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In Japan, upper limb spasticity, a domestic phase II study involving the finger, wrist, and elbow 
flexors was performed from Dec 2001 through Mar 2003, and a domestic phase III study involving the 
finger and wrist flexors from May 2007 through Dec 2008. Consequently, the product was approved 
for the treatment of upper limb spasticity with a maximum dose of 240 units per administration in Oct 
2010. 
However, subsequently, the injections of the product at 240 units were found to be insufficient for 
the involving muscles because patients with extensive upper limb spasticity require dose adequate to 
inject into many of the involving muscles. Therefore, many medical institutions requested us to 
increase the maximum dose per administration of the product. Moreover, the specified drug-use 
survey from Jun 2011 through Apr 2014 identified that approximately 39% of the patients who use the 
product for upper limb spasticity were injected more than 240 units, a maximum dose per 
administration. The results suggest high patient needs for an increase of the maximum dose per 
administration of the product. 
In US, as a maximum dose per administration, 400 units of injections of the product have been 
approved for the treatment of upper limb spasticity in adult patients in 2015; therefore, the authorized 
dose between US and Japan is different. 
Based on these background, the study was planned to evaluate the efficacy and safety of 400 units 
of the product for upper limb spasticity in order to increase the maximum dose per administration to 
400 units. 
The study was planned based on the regulatory advice by the Pharmaceuticals and Medical Devices 
Agency (PMDA). 
3.3.
Benefit/Risk Assessment
For details of the known and anticipated benefit/risk and rationally expected adverse events are 
shown on the Investigator's Brochure (IB) and package insert. 


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3.3.1.
Risk Assessment
Important identified risks
Reports suggesting risks/ Outlines of rationale
Measures for risk minimization
Investigational product: GSK1358820
Hypersensitivity
Serious and/or immediate hypersensitivity reactions
(anaphylaxis, serum sickness, urticarial, soft tissue 
edema, or dyspnea, etc.) have been rarely reported. 
Patients who previously experienced allergic reactions 
due to botulinum toxin type A, an additive agent of 
sodium chloride, or human serum albumin are 
excluded from enrolment. Upon written informed 
consent process, subjects will be explained that any 
urticarial, swelling face, throat swelling, wheezing, 
dizziness, or dyspnoea should contact their
investigator. 
Pre-existing neuromuscular disorder
Patients with neuromuscular junction diseases 
(myasthenia gravis, Lambert-Eaton myasthenic 
syndrome etc.) may increase the sensitivity to the 
product, resulting in excessive muscular weakness. 
For patients with myasthenia gravis, Eaton-Lambert 
syndrome (ELS), amyotrophic lateral sclerosis, or a 
serious disease and who use a concomitant drug (s) 
which may inhibit neuromuscular function, exclusion 
criteria will be set, and those patients will be excluded 
from enrolment in the study (refer to 6.2.1). 
distant spread of toxin
Adverse drug reactions in the remote muscles, except 
but the injected site, have been rarely reported. The 
adverse drug reactions include muscular weakness, 
constipation, dysuria, swallowing difficult, and non-
accidental entering of food or fluid in the lungs not via 
the stomach, but the trachea (pneumonia may occur). 
The patients who received the product at a higher dose 
are considered likely to have increased risks for these 
adverse drug reactions. 
In this study, a high dose of 400 units of the product 
will be injected. Therefore, the subjects will be 
followed up after 2, 4, 6, and 12 weeks of injection. 
The safety of the subjects will be observed carefully.
Use of at least one of the following guide tools 
(electromyogram, electrical stimulator, or 
ultrasonography) will be essential in the blind phase to 
ensure identification of the exact site of injection.


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Important identified risks
Reports suggesting risks/ Outlines of rationale
Measures for risk minimization
Immunogenicity, drug resistance, antibody production The important cause of neutralizing antibody 
production has not been fully clarified. A few studies 
suggested that the injection of the product at short 
intervals or at a high dose may lead to increased rate 
of antibody production[Jankovic, 2006; Klein, 2002]. 
Neutralizing antibody production against botulinum 
toxin type A may lead to inactivation of the biological 
activity of the product, resulting in decreased 
therapeutic effects of the product.
In this study, patients who were considered likely to 
have neutralizing antibody production based on the 
previous treatment experience of botulinum toxin type 
A will be excluded from enrolment in the study 
(Exclusion Criteria 6.2.1).
In addition, treatment schedule in the study was set to 
ensure at least a 12-week dosing interval. 
Other (If applicable)
Medication error (preparation with lidocaine)
One fatal case due to anaphylaxis has been reported. 
In this case, the patient died after 100 units of an 
injection of the product that prepared inappropriately 
with 5 mL of 1% lidocaine. The causal relationship of 
death to the product and lidocaine, or both has been 
unknown. 
In this study, the product will be prepared
appropriately with 0.9% normal saline. The 
preparation method will be described on the study 
reference manual (SRM).


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3.3.2.
Benefit Assessment
In patients with post-stroke upper limb spasticity, currently, the product is approved to inject up to 
240 units per administration in Japan. However, in patients with extensive upper limb spasticity, the 
treatment effects of the product are presumed to lack because of the dose limitation.
In US, the efficacy and safety of the product up to 400 units per dose for patients with upper limb 
spasticity is confirmed, and the clinical use of the product has been approved. The injections of 400 
units of the product in this study are expected to increase injectable sites and enhance the treatment 
effects in Japanese patients with upper limb spasticity, who did not have great benefits from 240 units 
of the product.
If a subject is assigned to the 240 units group in Part 1 and meets the eligibility criteria for injection in 
the open-label phase, 400 units of the product will be injected in and after Part 2. Therefore, all the 
subjects who participate in this study are given the opportunity to receive 400 units of the product 
(Refer to “5. STUDY DESIGN”). 
3.3.3.
Overall Benefit:Risk Conclusion
The known potential risks in the product is justified by the benefits which would provide for the 
patients with post-stroke upper limb spasticity, given the safety measures to minimize risks in subjects 
who enrol in the study. 


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4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoint(s)
Primary
To evaluate the efficacy of injection of 400 units 
of the product at Week 6 (finger/ wrist flexors: 
240 units, elbow flexors: 160 units), comparing to 
that of 240 units (finger/ wrist flexors: 240 units, 
elbow flexors: placebo).
The rate of the subjects that Modified Ashworth 
Scale (MAS) score was reduced at least 1 from 
baseline in the elbow flexors (the responder rate). 
Secondary
To evaluate the efficacy of 400 units of the 
product, comparing to 240 units of the product.

The responder rate of MAS score from 
baseline in finger, thumb and wrist 
flexors

Changes in MAS score from baseline in 
finger, thumb, wrist, elbow, pronation of 
forearms and shoulder flexors

Changes in Disability Assessment Scale 
(DAS) from baseline
To evaluate the safety and tolerability of the 
product of 400 units, comparing to 240 units of the 
product/ To evaluate the safety and tolerability of 
400 units of the product.

Adverse events

Physical examinations

Clinical laboratory tests (haematology, 
blood biochemistry, urinalysis)

Vital signs (heart rate, blood pressure, 
body temperature)
Exploratory
To evaluate the efficacy of 400 units of the 
product 

Changes in MAS score from baseline in 
finger, thumb, wrist, elbow, pronation of 
the forearm and shoulder flexors
To evaluate the other efficacy of the product of 
400 units, comparing to 240 units of the product/ 
To evaluate the other efficacy of 400 units of the 
product

Changes in Numeric Rating Scale 
(NRS) for pain from baseline

Changes in other items of DAS from 
baseline 

Clinical Global Impression of Change 
(CGI) of functional disability by an
investigator

CGI of functional disability by a patient

Time to patient-reported onset of 
spasticity symptom relief

Patient-reported benefit of injection

Time to qualification for retreatment
To evaluate neutralizing antibody production

Testing for neutralizing antibody 


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5.
STUDY DESIGN
5.1.
Overall Design
This study is a 48-week multicenter, phase III study (a placebo controlled, randomized, double-blind 
comparative study and an open-label, uncontrolled study) to evaluate the efficacy and safety of the 
product in patients with post-stroke upper limb spasticity. The study period is up to 52 weeks, 
consisting of a screening phase up to 4 weeks, minimum 12-week blind phase (Part 1), maximum 36-
week open-label phase (12 weeks per cycle with maximum 3 treatment periods, Part 2, Part 3 and Part 
4). (Figure 5).
BOTOX 400 U
BOTOX 240 U
+
Placebo
BOTOX 400 U
BOTOX 400 U
Screening
BOTOX 400 U
Double-blind treatment
(12 weeks)
Open-label treatment 
(36 weeks)
Part 3
Part 4
Part 1
Part 2
dose 
dose 
dose 
dose 
dose 
Figure 5   Study Design
In this study, the efficacy of 400 units of the product at Week 6 is evaluated, comparing to that of 
240 units, and improvement tendencies are also evaluated in patients with post-stroke upper limb 
spasticity. The improvement will be defined as at least 1 reduction on the MAS score from baseline (a 
measurement value before injection of Day 1). The responder rate (the rate of the subjects that MAS 
score is reduced at least 1 from baseline) in the elbow flexors at Week 6 is set as an endpoint. As a 
point estimate, if the responder rate in the 400 units group outweighs that in the 240 units group, 
improvements tendencies will be considered to be positive. 
For injection, use of the following any one of the tools: EMG, electrical stimulator, or 
ultrasonography, is recommended to ensure identification of the exact injection site. In the blind phase, 
use of at least one of the following tools: EMG, electrical stimulator, or ultrasonography, will be 
essential to ensure identification of the muscle to be injected correctly. 
5.1.1.
Screening Phase (up to 4 weeks) 
Evaluation and screening tests will be performed 28 days to 7 days (+3 days) before initial injection 
(Day 1) as a starting point. The investigator will decide which arm to be injected during screening 
phase. Throughout the study period, the arm, which is decided to be injected at screening phase will 
be involved during the injections and evaluations, unless clearly specified otherwise by the sponsor. 


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5.1.2.
Blind Period (minimum 12 Weeks): Placebo Controlled, Randomized, Double 
Blind Design
Subjects who meet the inclusion criteria will be randomized 1:1 to either the 400 units or the 240 
units group. 

In the 400 units group, a total of 240 units of the product will be injected into the muscles 
that act on the finger (including thumb flexors) and wrist flexors, and a total of 160 units 
into the muscles that act on the elbow flexors; a total of 400 units of the product will be 
injected.

In the 240 units group, a total of 240 units of the product will be injected into the muscles 
that act on the finger (including thumb flexors) and wrist flexors. Placebo will be injected 
into the muscles that act on the elbow flexors. A total of 240 units of the product will be 
injected.
If the total dose for the muscles that act on the finger and writs flexors is ensured by 240 units, and 
160 units for the muscles that act on the elbow flexors, the dose can be adjusted at an investigator’s 
discretion based on the subject’s symptoms. (Refer to “7.1. Treatments Administered” Table 2).
5.1.3.
Open-Label Phase (maximum 36 weeks): Uncontrolled, Open-Label Design
The product of 400 units will be injected in both groups. The product can be injected up to 3 times 
after completion of Part 1 in the blind phase. In the open-label phase, subjects whom the investigator 
considers eligible for the injection will be treated (Refer to 5.1.3.1. Eligibility Criteria for Injection in 
and after Part 2). The next injection cannot be performed until the eligibility of the subject has been 
confirmed by the investigator (Refer to 5.1.3.1. Eligibility Criteria for Injection in and after Part 2).
In the open-label phase, the muscle to be injected and the dose will be decided by the investigator
based on the patient’s symptoms, and a total dose of 400 units of the product will be injected in a 
divided dose (Refer to "7.1. Treatments Administered” on Table 3). For the muscles that the 
investigator considers unnecessary to be treated, an injection may be skipped. The involving muscle 
and the dose do not have to be same each time always.
5.1.3.1.
Eligibility Criteria for Injection in and after Part 2
In the open-label phase (Part 2, Part 3, and Part 4), the subjects whom the investigator considers
eligible for the injections in the open-label phase only will be treated. The eligibility is evaluated at a 
study visit after Week 12 (V5, if a subject does not meet the eligibility criteria, the evaluation will be 
performed at QRV (Qualification for Retreatment Visit). A subject will be considered as eligible when 
he or she meets all the criteria. The eligibility evaluation will be performed after completion of Part 1 
in the blind phase, between Week 12 to Week 36. If a subject does not meet the eligibility at Week 36, 
subsequent evaluation will not be performed, and the product cannot be given (refer to Figure 1, 
Figure 2, Figure 3, and Figure 4).
1)
At least 12 weeks (84 days) have passed since the preceding dose
2)
Among the finger, wrist or elbow flexors, 2 flexors have at least 2 on the MAS (except only the 
finger and wrist flexors of 2 on the MAS)
3)
Subject who request the injection


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4)
Subjects whom an investigator considers an injection of 400 units of the product is appropriate
5)
Subjects who have not experienced serious adverse events (SAE) associated with the injection 
of the product
If subjects meet the criteria of the above 1) to 5) at V5 or QRV, body weight measurement, ECG, 
pulmonary function test, and pregnancy test will be performed to evaluate the following items. If 
subjects meet the following 6) to 8), the subjects will move forward to V1.
A pulmonary function test must be performed at V5 even if subjects do not meet the above 1) to 5) in 
accordance with the study operation schedule (SoA).
6)
Body weight ≥40 kg
7)
Subjects who the investigator considers there are no unacceptable safety concerns [potential 
for serious adverse events, electrocardiogram (ECG) or abnormal pulmonary function
value*] due to 400 U of BOTOX
* This study will use SpO2 (oxygen saturation) as a parameter of pulmonary function. A 
subject who has a 3% reduction from the pre-injection SpO2 (Day 1) in post-injection 
SpO2 or whose SpO2 value is <95% should be referred to a pulmonologist. A subject with 
pulmonary dysfunction due to study treatment also should be referred to a pulmonologist. If 
the subject is considered by the pulmonologist to have no concerns about pulmonary 
function, the investigator should carefully consider whether to start the study treatment.
8)
Women of childbearing potential who have negative pregnancy test result in urine
5.2.
Number of Participants
Approximately 120 subjects (approximately 60 in each group) will be randomized to obtain an 
evaluable subject sample of approximately 100 at Week 48 as subjects who complete the study
5.3.
Participant and Study Completion
Subjects who completed all the study procedures, including a completion visit will be regarded as 
study completion. The completion date in this study will be defined as the last day performing the 
study procedure of last subject. 
5.4.
Scientific Rationale for Study
The study design was set to evaluate the efficacy and safety of 400 units of the product in patients 
with post-stroke upper limb spasticity. The primary endpoints employed the responder rate of the 
MAS score in the elbow flexors. The reasons for employing MAS score as an indicator include that 
MAS is highly reliable for evaluation of upper limb spasticity (Bohannon, 1987; Mutlu, 2008); 
especially, for evaluation of spasticity in the elbow flexors in the upper limbs (Gregson, 2000; Sloan, 
1992). 
Screening Phase
The screening phase up to 28 days before initial injection was set in order to confirm subjects meet 
the inclusion criteria and none of the exclusion criteria, and assess the condition of subjects at baseline. 


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However, measurements of laboratory parameters at screening phase should be completed by 4 days 
before Day 1 (Day -28 to -4). 
Treatment Phase 
In Part 1, a double blind comparative study was set to compare the efficacy of the product of 400 
units to 240 units, the currently approved dose for upper limb spasticity. In the blind phase, 240 units 
of the product will be injected into the muscles that act on the finger (including the thumb)/wrist 
flexors, and 160 units (the 400 units group) or placebo (the 240 units group) for the muscles that act 
on the elbow flexors. The improvement tendencies in the efficacy between the 240 units group, the 
total dose, and the 400 units groups will be compared by evaluating the responder rate tendencies on 
the MAS score in the elbow flexors in a blinded manner. In the previous confirmatory study (108509 
study) for approval of the product for upper limb spasticity, the elbow flexors were not involved. 
Therefore, in this study, the responder rate on the MAS score in the elbow flexors was decided to 
compare as the placebo group. 
Actually, in medical institutions, the product is injected into the whole upper limb, including the 
shoulder flexors. In addition, the dose for each muscle is decided at an investigator’s discretion. 
Previous studies reported that botulinum injections into the pectoralis major and teres major muscle 
relieved pain in patients with hemiplegia (Marciniak, 2012) and injections into the sub-scapula 
improved passive range of motion (Yelnik, 2007). Therefore, in and after Part 2 in the open-label 
phase, the product will be allowed to be injected not only into the muscles that acts to the finger 
(including the thumb), wrist, and elbow flexors, but also the muscles that act on the shoulder flexors, 
where applicable, enabling an investigator to decide the dose for each muscle. In addition, the study 
design included safety evaluation of the product at Week 48 after initial injection in all subjects as far 
as possible for safety evaluation purposes of 400 units. 
5.5.
Dose Justification
The product of 400 units is a maximum dose for upper limb spasticity, which was approved by the 
U.S. Food and Drug Administration (FDA), and this suggests that the efficacy and safety profiles are 
favourable. Evaluation of the efficacy and safety of 400 units of the product provides beneficial 
information in Japanese patients with severe post-stroke upper limb spasticity, who are considered 
injections of 400 units of the product are necessary. 
The dose of 240 units of the product, the controlled group, in the blind phase (Part 1) is the current 
authorized dose (a maximum dose per administration) for upper limb spasticity in Japan. In this study, 
the 240 units group was set as the control group in order to evaluate improvement tendencies, 
comparing the efficacy of 240 units of the product, the current approved dose, to that of 400 units of 
the product.  
6.
STUDY POPULATION
Inclusion of subjects despite expectation of deviation from the protocol, namely, exemption or 
discharge from the protocol, cannot be allowed.


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6.1.
Inclusion Criteria
6.1.1.
Screening Phase (Day -28 to Day -1)
In the screening phase, subjects eligible for enrolment in the study must meet all of the following 
criteria. Laboratory parameters should be measured by 7 days (± 3 days) before initial injection 
(Day 1). 
Age
1. Between 20 and 80 years of age at the time of informed consent (ICF). 
Subjects and Characteristics of the Disease
2. Patients with at least a 3-month history of upper limb spasticity after the most recent stroke 
3. Patients who have spastic symptoms in the finger (including the thumb), wrist, and elbow flexors
whom the investigator considers the injections of 400 units of the product is necessary for the upper 
limb based on the muscle spasms and the symptoms of the patient
4. Patients who have a previous treatment history of 240 units of the product for the upper limb at 
least 16 weeks before screening (refer toTable 3 for muscles in the upper limbs) 
5. Patients who meet following criteria on MAS at screening (Test position: sitting)

At least 3 in for the elbow flexors
And

At least 2 in the finger or wrist flexors
6. Patients who have severe upper limb spasticity, which deserves to be treated with 400 units of the 
product in the divided dose and was previously injected 240 units of the product
7. Patients whom the investigator considers that enrolment in the study poses no problems based on 
the laboratory data results at screening
8. Patients who are free from a history of acute decreased lung function (hospitalization with 
aggravated asthma/COPD, pneumonia, or signs of pneumonia, or abnormal reactive airway diseases 
suggested on X-rays) within the last 3 months at screening and have stable pulmonary function
(SpO2 value is 95%)
Body Weight
9. Body weight ≥ 40 kg at screening
Sex
10. Male or female
a.
Male Subjects
Male subjects must content to use highly effective contraceptive methods, which are shown on 
attachment 5 of the protocol in detail during the study period, and sperm donation must be 
avoided. 
b.
Female Subjects
Female subjects who are not pregnant or lactating are considered eligible (refer to attachment 5) 
if at least one of the following criteria is met:
i)
Non-childbearing potential based on the definition on attachment 5


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ii)
Women of childbearing potential who content to follow the guidance about contraception on 
attachment 5 during the study period and at least for 3 months after the last dose of the 
product.
iii)
No plan of pregnancy during the study period
Informed Consent
11. Patients who have ability to sign their name on the ICF, following the description on attachment 3, 
adhering to the requirements and limitations described on the ICF and the protocol. 
6.1.2.
Day 1 (prior to injection)
Subjects eligible for enrolment in the study must meet all of the following criteria on Day 1 (prior 
to injection): 
Subjects and Characteristics of the Disease
31. Patients who meet the following criteria on MAS score: (Test position : sitting)

At least 3 in the elbow flexors
And

At least 2 in the finger or wrist flexors
Preceding Treatments and Concomitant Medications/Therapies
32. If centrally acting muscle relaxants, tetracycline antibiotics, anticholinergics, benzodiazepines, or 
benzamides are given, the dose and regimen must be stable at least for the last 2 months before 
Day 1; Patients who can maintain the same dosage and regimens at least in the blind phase after 
initial injection (dose reductions and discontinuation of the drugs are acceptable in the open-label 
phase. However, second dose increase, resumption, and or new treatment will not be performed). 
33. If intrathecal baclofen is given, the dose and regimen must be stable at least for the last 1 month 
before Day 1; Patients who can maintain the same dosage and regimens at least in the blind phase
after initial injection (intravenous bolus is not acceptable, dose reductions and discontinuation of 
the drugs are acceptable. However, second dose increase, resumption, and or new treatment will 
not be performed).
34. If antiepileptic agents are given, the dose and regimen must be stable at least for the 1 month 
before Day 1; Patients who can maintain the same dose and regimens at least in the blind phase 
after initial injection (dose reductions and discontinuation of the drugs are acceptable in the open-
label phase. However, second dose increase, resumption, and new treatment will not be 
performed).
35. If a physical therapy, occupational therapy, or a static splint on the study involvement upper 
limbs is given, the frequency and treatment regimen must be stable at least for the last 3 weeks 
before Day 1; Patients who can maintain the same dose and regimens at least in blind phase (In 
the open-label phase, the frequency and treatment regimen can be changed depending on the 
condition of spasticity).


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6.2.
Exclusion Criteria
6.2.1.
Screening Phase (Day -28 to Day -1)
A subject will be excluded from enrolment in this study if any of the following criteria apply in the 
screening phase. Measurements of laboratory parameters at screening must be completed 7 days (±3 
days) before initial injection (Day 1).
Medical Condition
1.
Patients present with spasticity requiring treatment in the non-paralytic side of the upper limb
2. Patients who have fixed contracture* in the finger (upper limb), wrist, elbow or shoulder muscle, 
which will be involved in the study
(*Positive effects were not confirmed in the previous treatment with GSK1358820, and 
contracture is considered to be the main cause of limited range of motion in the joint.)
3. Patients who have medically significant capsulitis or subluxation in any one of the fingers (upper 
limb), wrist, elbow and shoulder, which will be involved in the study, or whom an investigator
considers the complicated local signs of pain may affect the efficacy evaluation
4. Patient’s upper limb spasticity is attributed to other than stroke (traumatic brain injury, spinal cord 
injury, multiple sclerosis, or cerebral palsy)
5. Patients who have a 2-fold higher alanine aminotransferase (ALT) level than the upper limit of 
normal (ULN)
6. Patients who have a 1.5-fold higher bilirubin than the ULN (If a bilirubin fractionation shows direct 
bilirubin < 35%, a 1.5-fold higher free bilirubin than the ULN is acceptable).
7. Patients whom the investigator considers presence of a current medical history of unstable liver 
diseases or biliary tract diseases (the condition will be defined by development of ascites, 
encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice 
or hepatic cirrhosis)
Note:

If a patient with stable chronic liver diseases (Gilbert's syndrome, silent gallstone, and stable 
chronic hepatitis B or hepatitis C [Namely, hepatitis B surface antigen: HBsAg or hepatitis 
C virus: HCV antibody shows positive at screening or within 3 months before initiation of 
the study treatment] are included) meets other inclusion criteria, the patient can be enrolled 
in the study. 
8. Patients with QTc > 450 msec or QTc > 480 msec in patients with bundle branch block
Note:

QT intervals corrected by the Bazett method (QTcB); QT intervals corrected by the 
Fridericia method (QTcF) and/or QT intervals corrected by other methods; interpretation by 
a machine or manual re-interpretation will be used.

Prior to study initiation, the correction formula which is used for the subject’s 
inclusion/exclusion/discontinuation criteria will be determined. Namely, several different 
correction formulae cannot be used for calculation of QTc in each subject. In addition, the 
lowest QTc level cannot be used for enrolment or discontinuation of subjects of the study. 


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Preceding Treatments and Concomitant Medications/Therapies
9. Patients who use peripherally acting muscle relaxants (dantrolene sodium, suxamethonium chloride, 
pancuronium bromide, vecuronium bromide, rocuronium bromide, etc.) within 1 week of screening.
10. Patients who use antibiotic agents with neuromuscular junction inhibitory effects: Aminoglycoside 
antibiotic agents (streptomycin sulfate, kanamycin sulfate, gentamicin sulfate, neomycin sulfate, 
spectinomycin hydrochloride, etc.), polypeptides (polymyxin B sulfate), lincomycins (lincomycin 
hydrochloride, clindamycin), and enviomycin sulfate within 1 week of screening.
11. Patients who was diagnosed as having a malignant tumor, or have a history of a malignant tumor 
within the last 5 years (except completely resected basal cell carcinoma or planocellular carcinoma 
at least 12 weeks before screening)
Previous Experience of Participation in a Clinical Studies/Current Participation in 
another Ongoing Study 
12. Patients who have participated in another study of an investigational product or other medical 
research (a clinical study of pharmacotherapy, non-pharmacotherapy, or interventional device) 
within 30 days before screening, or are currently participating in a study
Evaluation by Diagnosis
13. Patients who are concerned likely to have an increased risk for an underlying medical 
condition/neurological disease due to exposure of the product; patients who have myasthenia gravis, 
Eaton-Lambert syndrome, amyotrophic lateral sclerosis, or a serious disease and use of a 
concomitant drug which may inhibit neuromuscular function 
14. Patients with antihuman immunodeficiency virus (HIV) antibody positive
15. Patients who previously experienced allergic reactions or hypersensitivity due to botulinum toxin 
type A, an additive agent of sodium chloride, or human serum albumin
16. Patients who were previously suspected to have neutralizing antibody production by an
investigator during an injection of botulinum toxin type A  
17. Patients who have a skin disease such as infection at the site to be injected  
18. Patients who suffer from serious and unstable disease, which could pose problems for the safety of 
subjects and study procedure compliance
6.2.2.
Day 1 (Prior to injection)
A subject will be excluded from enrolment in this study if any of the following criteria apply on 
Day 1 (prior to injection): 
Medical condition
31. Patients who have aspiration pneumonia, relapse of lower respiratory tract infection, 
uncontrollable asthma, uncontrollable COPD, and/or underlying or a history of serious 
respiratory dysfunction, which were clinically considered to be respiratory function impairment 
(e.g., SpO2 <95%) by an investigator within 12 months before Day 1 visit
32. Patients who have a history of aspiration, or an underlying and/or a history of the symptoms that 
suggests high risks for aspiration by an investigator within 12 months before Day 1 (serious 
salivation requiring changing in a type of diet, chronic dysphagia that is difficult to swallow)


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Preceding Treatments and Concomitant Medications/Therapies
33. Patients who were treated with botulinum toxin for spasticity of upper limb less than 16 weeks 
before Day 1 visit
34. Patients who underwent surgical interventions, phenol block, ethanol block or Muscle Afferent 
Block (MAB) within 12 months before Day 1 visit, or these interventions are planned during the 
study period in any one of the finger (upper limb), wrist, elbow or shoulder muscles, which will 
be involved in the study
35. Patients who placed a surgical cast or a dynamic splint within 3 months before Day 1 study visit, 
and/or these interventions are planned to be placed on the upper limb to be involved in the study
36. Patients who were injected corticosteroid or an anesthetic agent into the finger (upper limb), 
wrist, or shoulder flexors, which will be involved in the study within 3 months before Day 1 visit, 
or these injections are planned during the study
37. Patients who received CIMT (constraint-induced movement therapy) within 3 months before Day 
1 visit or CIMT is planned during the blind phase
38. Patients who underwent ultrasound therapy, TENS (transcutaneous electrical nerve stimulation), 
electrical stimulation therapy, or acupuncture therapy in the upper arm, which will be involved in 
the study within 1 month before Day 1 visit, or these therapies are planned during the study
6.3.
Lifestyle Restrictions
No limitations are required. 
6.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are not 
subsequently [randomized/entered in the study]. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries from 
regulatory authorities. Minimal information includes demography, screen failure details, and 
eligibility criteria.
Rescreening
If a patient does not meet the participation criteria in the study (dropout during screening), the 
patient may undergo second screening only 1 time. If a patient does not meet following items, contact 
the medical monitor of the sponsor and gain his/her consent because validity of rescreening in subjects 
who dropped out needs to be judged carefully in the light of medical aspects.

Subjects who did not meet the inclusion criteria for MAS (Inclusion criteria 5 at screening) 
and dropped out (However, the dropout period will be for within only 1 month from the 
dropout). 

For some reasons, a subject cannot make a study visit or undergo examination 

Sample collection or examination cannot be performed because of procedural or technical 
problems


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The investigator must carefully consider the ethical aspects of subjects, and if other treatments are 
considered to give more treatment benefits for a subject, rescreening must not be conducted. 
The rescreened subjects will be allocated a different subject identification number as upon initial 
screening.


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7.
TREATMENTS
Study treatment product is defined as any investigational treatment(s), and placebo to administer to a 
study participant according to the protocol. 
7.1.
Treatments Administered
Study Treatment 
Name: 
GSK1358820
(Nonproprietary name: 
Botulinum toxin type A)
Placebo
Dosage formulation: 
Injection
Injection
Ingredient and quantity 
(Per vial) 
Botulinum toxin A 100 units
Sodium chloride 0.9 mg
Human serum albumin 0.5 mg
Sodium chloride 0.9 mg
Packaging and 
Labeling 
It will be listed on the labelling in 
accordance with the regulatory 
requirements in Japan.
It will be listed on the labelling in 
accordance with the regulatory 
requirements in Japan.
Manufacturer
Allergan (Ireland) 
Allergan (Ireland)
Dose
400 units
240 units
Dose
Dosing instructions
Part 1: 240 or 400 units of the product will be injected into the muscles that act on the 
finger (including thumb flexors), wrist and elbow flexors, in accordance with Table 2.
In and after Part 2: 400 units of the product will be injected into the muscles that 
act on the finger (including thumb flexors), wrist, elbow and shoulder flexors in 
accordance with Table 3. For the muscles that the investigator considers 
unnecessary to be treated, an injection may be skipped. Dose intervals should be at 
least 12 weeks.
For adjustment of the product, the product will be dissolved with 2 ml of normal 
saline per 1 vial (100 units). The details will be described on Table.4. 
In the blind phase

A total of 240 units of product will be injected into the muscles that act on finger (including 
thumb flexors) and wrist flexors, and a total of 160 units of the product or placebo for the 
muscles that act on the elbow flexors in divided doses in accordance with Table 2.

The muscles which are not listed on Table2 must not be used.

All of the muscles descried on Table 2 must be used. If the subject with no symptoms with 
thumb, the investigator does not have to inject to thumb. 

If the total dose for the muscles that act on the finger and writs flexors is ensured by 240 
units, and 160 units for the muscles that act on the elbow flexors, the dose can be adjusted at 
an investigator’s discretion based on the symptoms of a subject.
In the open-label phase

The investigator will decide the dose and the muscle to be injected based on the symptoms 
of patients, and a total of 400 units will be injected in divided doses. For the muscles that 
the investigator considers unnecessary to be treated, an injection may be skipped.

The muscles to be injected must be chosen from Table 3, and the muscles which are not 
listed on Table 3 must not be used. For dose and number of injection site (sites/muscles), 
refer to Table 3 and will be decided by investigator. 


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Table 2    Muscle Involvement and Dose in the Blind Phase
Number
Muscles
The 400 units 
group
Dose (units)
The 240 units 
group
Dose (units)
Number of 
injection site (site 
and muscles)3
Joint
A1
Biceps brachii 
701
Placebo
2
A.Elbow 
A2
Brachialis
451
1
A3
Brachioradialis
451
1
B1
Flexor carpi radialis 
502
502
1
B.Wrist  
B2
Flexor carpi ulnaris 
502
502
1
C1
Flexor digitorum profundus 
502
502
1
C.Finger 
C2
Flexor digitorum superficialis
502
502
1
D1
Flexor pollicis longus 
202
202
1
D.Thumb
D2
Adductor pollicis 
202
202
1
Total
4002
2402
1
-
1: Within the limits of the total of 160 units (the elbow flexors), the dose will be decided by an investigator depending on the patient’s 
symptoms.
2: Within the limits of the total of 240 units (the finger and wrist flexors), the dose will be decided by an investigator depending on 
the patient’s symptoms.
3: When the dose exceeds 50 U per muscle, take into account the divided-injection.
Table 3    Muscle Involvement and Reference Dose in the Open-Label Phase
(Modified partially of “Dosing, Administration, and a Treatment Algorithm for Use of 
Botulinum Toxin A for Adult-Onset Spasticity. [Brin, 1997]”)
Number
Muscles1
Dose (units)2
Number of 
injection site
(Sites/muscles) 2
Joint
A1
Biceps brachii 
50-200
4
A.Elbow
A2
Brachialis
25-75
2
A3
Brachioradialis
25-75
2
B1
Flexor carpi radialis
25-100
2
B.Wrist
B2
Flexor carpi ulnaris
10-50
2
C1
Flexor digitorum profundus
25-100
2
C.Finger
C2
Flexor digitorum superficialis
25-75
4
C3
Lumbricales interossei
10-50/hand
3
D1
Flexor pollicis longus
5-25
1
D.Thumb
D2
Adductor pollicis
5-25
1
D3
Opponens
5-25
1
E1
Pronator teres
25-75
1
E.Forearms
E2
Pronator quadratus
10-50
1
F1
Teres major 
25-75
1
F.Shoulder
F2
Latissimus dorsi
50-150
4
F3
Pectoralis major 
75-150
4
F4
Subscapularis
25-75
1
(Brin MF and the Spasticity Study Group, 1997)
1: The muscles which are not listed on Table 3 must not be used
2: For dose and number of injection site (sites/muscles), refer to Table 3 and will be decided by investigator.


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Table 4    Muscle Involvement and Reference Dose in the Open-Label Phase
Dose (units)
Injection Volume (ml)
100
2.0 
95
1.9 
90
1.8 
85
1.7 
80
1.6 
75
1.5 
70
1.4 
65
1.3 
60
1.2 
55
1.1 
50
1.0 
45
0.9 
40
0.8 
35
0.7 
30
0.6 
25
0.5 
20
0.4 
15
0.3 
10
0.2 
5
0.1 
7.2.
Dose Modification
Not applicable
7.3.
Method of Treatment Assignment
After completion of all evaluations at screening phase/initiation of the blind phase, the subjects who 
met the inclusion criteria and none of the exclusion criteria will be given their randomization number
at a case registry center and randomized to either the 240 or 400 units group. The assigned 
randomization number cannot be re-used. The table of the allocation will be prepared via a computer 
in GSK, using the RandAll systems. 
Based on the MAS score (3 or 4) in the elbow flexors, subjects will be stratified at the time of 
randomization. 
The subjects who meet the eligibility for the injections in the open-label phase can move forward to 
the open-label phase and be injected (Refer to section 5.1.3). In the open-label phase, 400 units of the 
product will be given to all subjects. Other detailed information will be described on SRM.
7.4.
Blinding
This study consists of the blind phase (Part 1), followed by the open-label phase (Part 2 and 
subsequent Parts), and in the blind phase, following processes are applied. 
A Role of the Person Responsible for Investigational Product Assignment  
The person who is responsible for investigational product assignment will prepare an operating 
procedure for the assignment. The operation will be conducted in accordance with the operating 
procedure. The person who is responsible for the investigational product assignment will display the 
drug number on a container of the investigational product (investigational product and control drug) 


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after checking of the investigational product (investigational product and control drug) and the 
indistinguishability of packaging appearance. The confirmation of the investigational product 
(investigational product and control drug) and the indistinguishability of packaging appearance will be 
also performed after completion of the study. In addition, an operating procedure for occasion where 
the emergency treatment disclosure is required will be prepared. In response to the request of 
disclosure, unblinding procedures are performed for the requested drug only.
The unblinded subjects by the investigator will discontinue participation in the study. In addition, 
the major reasons for discontinuation (the event(s) or condition led to unblinding) will be described on 
case report form (CRF). 
The Global Clinical Safety and Pharmacovigilance (GCSP) of the sponsor may disclose the 
assigned treatment in the subject, who experienced serious adverse events. For serious adverse events 
requiring emergency report to the regulatory authority, a copy of an emergency report on the assigned 
treatment of the subject may be sent to the study involving investigator in accordance with the 
regulations, policy of the sponsor, or both.  
7.5.
Preparation/Handling/Storage/Control
1.
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported and 
resolved before use of the study treatment. 
2.
Only participants enrolled in the study may receive study treatment and only authorized site staff 
may supply or administer study treatment. All study treatments must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the investigator and authorized site staff. 
3.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
4.
Further guidance and information for the final disposition of unused study treatment are provided in the 
Study Reference Manual
.
7.6.
Treatment Compliance
Subjects will be intramuscularly injected the product at a medical institution. The injection will be 
recorded in the source documents, and described in the case report form. 
7.7.
Concomitant Therapies
The medications that are used by subjects at the time of enrolment in the study or all medications 
and vaccines to be used during the study (over the counter drugs or prescribed drugs, vitamins, and/or 
herbal supplements) must be recoded with the following items: 

Reasons for use

Initial date of administration and administration dates, including completion day

Regarding the dose, including dosage and number of administration


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Contact the medical monitor if there are any questions about concomitant therapies or preceding 
drugs.
7.7.1.
Permitted Concomitant Drugs/Therapies
Following drugs and therapies are permissible only if a subject is already using them before 
initiation of the study. However, the dosage and administration will not be changed from the screening 
through completion of the blind phase. In and after open-label phase, dose reduction and 
discontinuation of the drugs will be allowed. However, once dose is decreased, re-increase will not be 
performed. If the drug(s) is/are discontinued, the drugs cannot be resumed. No new treatment will not 
be started after screening phase. 

Central muscle relaxants
(baclofen, tizanidine hydrochloride, eperisone hydrochloride, chlorphenesin carbamate, 
afloqualone, etc.)

Tetracycline antibiotics
(tetracycline hydrochloride, doxycycline hydrochloride, minocycline hydrochloride, etc.)

Anticholinergics
(butylscopolammonium bromide, trihexyphenidyl hydrochloride, etc.)

Benzodiazepines
(diazepam, etizolam, etc.)

Benzamides
(tiapride hydrochloride, sulpiride, etc.)

Antiepileptic drugs
(phenytoin, etc.)

Intrathecal baclofen therapy
Rehabilitation therapies such as physical therapy, occupational therapy, and static splint are 
permissible. However, in the blind phase, the frequency and regimens (description of the therapy and 
intensiveness) for the upper limb, which involves in the study will not be changed. In addition, in the 
open-label phase, changing rehabilitation therapy to another one that seems to be the most appropriate 
for a subject is permissible based on the degree of improvements in spasticity. In such cases, the 
information will be described on CRF. Rehabilitation therapy will not be given on the day of 
investigational product injection.
Appropriate rehabilitation therapies should be selected from among the following: task-specific 
training, muscle strengthening exercise, stretching/range of motion (ROM) exercise, splints and 
orthoses, taping, positioning aid, and others (specify). As for the frequnecy, the number of days per 
month, when rehabilitation therapies were performed, between V1 and V5 will be calculated, and the 
most appropriate frequency will be selected from among the following: not performed, 8 days per 
month, >8 and 16 days per month, >16 and 24 days per month, and >24 days per month. Details 
will be provided in the study reference manual (SRM).


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7.7.2.
Contraindicated Medications/Therapies 
Following drugs and therapies will be prohibited to use from screening phase through completion of 
the study:

Botulinum toxin preparations

Peripherally acting muscle relaxants

(dantrolene sodium, suxamethonium chloride, pancuronium bromide, vecuronium bromide, 
rocuronium bromide) 

Antibiotic agents with neuromuscular junction blocking effects

Aminoglycosides
(streptomycin sulfate, kanamycin sulfate, gentamicin sulfate, neomycin sulfate, 
spectinomycin hydrochloride, etc.)

Polypeptides
(polymyxin B sulfate)

Lincomycins 
(lincomycin hydrochloride, clindamycin)

Enviomycin sulfate

Nerve blocks such as phenol block, ethanol block and MAB for the upper limb

Surgical cast or a dynamic splint

A surgery for the upper limb

A surgical cast or a dynamic splint for the upper limb

Corticosteroid injection or an anesthetic agent for the upper limb

Ultrasound therapy, TENS (transcutaneous electrical nerve stimulation ), electrical 
stimulation therapy, or acupuncture therapy for the upper limb
Following drugs and therapies will be prohibited to use from screening phase through completion of 
the blinded-phase:

CIMT (constraint-induced movement therapy)
7.8.
Treatments after Completion of the Study
The investigator will take responsibility for subject’s medical care after completion of the study, 
whether the sponsor provides a certain treatment or not.
8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
The efficacy of the investigational product used in this study sustains for about 3 to 4 months 
following a single dose, and thus daily dosage is not required; accordingly, treatment discontinuation 
shall not be defined in this study, and will be considered to be identical to subject withdrawal from 
this study.
8.2.
Withdrawal from the Study


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
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, compliance 
or administrative reasons. 

If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 

If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must document this in the site study records. 

A subject discontinuing this study must visit the study site for study termination assessment 
promptly upon decision to discontinue the study.

Refer to the schedule of assessment (SoA), completion visit (FV), for the details of data to 
be collected at the study discontinuation, and additional assessment that must be completed.
8.2.1.
Liver Chemistry Stopping Criteria
A set of criteria for study discontinuation and follow-up investigation based on hepatic function 
test (in reference to FDA premarketing clinical liver safety guidance) is specified herein to ensure the 
safety of subjects and to evaluate the causes of hepatic events. The guidelines related to this protocol 
are based on the FDA premarketing clinical liver safety guidance: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM1
74090.pdf.
The investigator should consider discontinuing the study treatment upon discovery of liver function 
test abnormal, and if the subject is applicable to any of the symptoms presented in the algorithm, or 
such discontinuation is determined to be the best choice for the subject as judged by the investigator.
Algorithm A: Phase III-IV Liver Chemistry Stopping and Increased Monitoring Algorithm
Liver Safety Required Actions and Follow up Assessments Section can be found in Appendix 6.


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Algorithm B: Phase III-IV Liver Chemistry Increased Monitoring Algorithm with Continued 
Therapy for ALT ≥3xULN but <8xULN
Liver Safety Required Actions and Follow up Assessments Section can be found in Appendix 6.


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8.2.2.
QTc Stopping Criteria

For a decision on a subject's eligibility or study discontinuation, the same method for 
correction of QT interval must be used in the subject throughout the study, and must not be 
changed once the subject is enrolled. 

For instance, if a subject is enrolled based on QTcB, decisions on the subject's 
withdrawal must be made based on QTcB. 

The method used for correction of QT interval pertinent to the enrollment of a subject 
must be used for all QTc data to be collected throughout the study for the data analysis 
on the subject; provided that such rule is not applicable to ECG intended to ensure 
safety and also ECG not defined in the protocol. 

QTc should be determined based on a single measurement of ECG or the mean of ECG 
measured at 3 timepoints in a short period of time (e.g., 5 to 10 minutes). If abnormality is 
detected in a single measurement, ECG should be measured again, this time, at 3 timepoints. 

The lowest value of QTc cannot be used for a decision to withdraw a subject. 
Refer to the schedule of assessment (SoA), completion visit (FV), for the details of data to be 
collected at the discontinuation of study treatment. Discontinue this study if the mean ECG is 
applicable to any of the following conditions:

QTc >500 msec or uncorrected QT >600 msec

Change in QTc from baseline >60 msec
The following withdrawal criteria should be applied for subjects with bundle branch block: 
Baseline for subjects with bundle branch block
Withdrawal criteria for subjects with bundle 
branch block
<450 msec
>500 msec
450 to 480msec
IJYO530 msec
8.2.3.
Treatment discontinuation due to treatment-related SAE
A subject should be withdrawn from this study if treatment-related serious adverse event has 
occurred.
8.2.4.
Treatment discontinuation due to pregnancy
A female subject who become pregnant during this study must be withdrawn from the study.
8.2.5.
Withdrawal of subjects who start receiving prohibited medications or 
therapies
If a prohibited medication or therapy (See section 7.7.2.) needs to be started during the study, the 
subject must be withdrawn from this study; in which case, the subject must make the study completion 
visit (FV) before starting the prohibited medication or therapy.


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8.2.6.
Prohibition of treatment resumption
Study treatment must not be resumed in subjects who are once withdrawn from this study for a 
reason associated with hepatic function test, QTc, treatment-related serious adverse event, pregnancy, 
or commencement of a prohibited medication or therapy.
8.3.
Lost to follow up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 

The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in the 
study.

Before a participant is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
9.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA. 

Protocol waivers or exemptions are not allowed. 

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue study 
treatment. 

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 

Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and was performed 
within the time frame defined in the SoA. 


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9.1.
Efficacy assessments
9.1.1.
Evaluation methods
9.1.1.1.
Modified Ashworth Scale (MAS)
According to "2. SCHEDULE OF ACTIVITIES (SoA)" the investigator will use MAS (Table 5) to 
evaluate the level of spasticity. MAS should be measured and evaluated by the investigator, 
physiotherapist, or occupational therapist who has been given the training as an assessor. 
The test should be performed on sitting position throughout the study. The affected parts should be 
extended as fast as possible to grade the flexor muscle tones. The final assessment will be made by the 
investigator in consideration of the information from physiotherapist or occupational therapist. The 
assessor should in principle remain unchanged throughout the study period.
Table 5    Modified Ashworth Scale (MAS)
0
No increase in muscle tone
1
Slight increase in muscle tone, manifested by a catch and release or by minimal resistance at 
the end of the range of motion when the affected part(s) is moved in flexion or extension
1+
Slight increase in muscle tone, manifested by a catch, followed by minimal resistance 
throughout the reminder (less than half) of the ROM (range of movement)
2
More marked increase in muscle tone through most of the ROM, but affected part(s) easily 
moved
3
Considerable increase in muscle tone passive, movement difficult
4
Affected part(s) rigid in flexion or extension

MAS measurement as inclusion criteria (Screening and Day 1)
The subject's wrist or fingers and elbow should all be evaluated as inclusion criteria. Subjects 
meeting the eligibility and randomized should be evaluated for MAS at Visit 1 of Treatment Period 1
on the same day; provided that measurement may be performed only once if the affected part to be 
evaluated is the same. The detail of inclusion criteria are shown in 6.1.

MAS measurement during the blinded period
The subject's wrist, fingers, thumb and elbow should all be evaluated during the blinded period. 
Likewise, the subject's wrist, fingers, thumb and elbow should all be evaluated for MAS at Visit 5 and 
QRV of the blinded period. Subjects meeting the eligibility and transferred to the open-label period 
should be evaluated for MAS at Visit 1 of Treatment Period 2 on the same day; provided that 
measurement may be performed only once if the affected part to be evaluated is the same. Meanwhile, 
MAS needs to be evaluated again if the affected part to be evaluated is not the same. In subjects who 
have received no injection to any muscles affecting the thumb, MAS measurement on the thumb will 
not be performed.

MAS measurement during the open-label period
During the open-label period, MAS should be evaluated for the flexors at which the muscle given 
the study treatment functions (fingers, thumb, wrist, elbow, fore-arm) (Table 6). If the subject is 
determined to be eligible, the V5/QRV and V1 would be on the same day, and therefore, the MAS 


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measured at V5/QRV of the previous treatment period should not be measured again on V1; the 
measurement on V5/QRV should be used for the assessment (Figure 6). MAS on flexors to be newly 
assessed on V1 should be evaluated before dose on V1. The MAS on the shoulder should be evaluated 
comprehensively for the adductor and invertor. 
Table 6    Regions to be evaluated for MAS during the open-label period
Number
Muscles to be injected
Regions to be evaluated 
for MAS 
A1
Biceps brachii
Elbow flexors (flexion)
A2
Brachialis
A3
Brachioradialis
B1
Flexor carpi radialis
Wrist flexors (flexion)
B2
Flexor carpi ulnaris
C1
Flexor digitorum profundus
Fingers (flexion)
C2
Flexor digitorum superficialis
C3
Lumbricales interossei
D1
Flexor pollicis longus
Thumb (flexion, 
adduction)
D2
Adductor pollicis
D3
Opponens pollicis
E1
Pronator teres
Forearm (pronate)
E2
Pronator quadratus
F1
Teres major
Shoulder (flexion,
adduction, and internal 
rotation)
F2
Latissimus dorsi
F3
Pectoralis major
F4
Subscapularis
Visit
SV V1 V2 V3 V4 V 5 V1 V2 V3 V4 V5 V1 V2 V3 V4 V 5 V1 V2 V3 V4 V5
A.Elbow
●
●
●
●
●
●
(○) ●
●
●
●
(○) ●
●
●
●
(○) ●
●
●
●
B.Wrist
●
●
●
●
●
●
●
●
●
●
●
(○) ●
●
●
●
C .Finger
●
●
●
●
●
●
(○) ●
●
●
●
(○) ●
●
●
●
(○) ●
●
●
●
D .Thum b
●
●
●
●
●
E.Forearm
●
●
●
●
●
(○) ●
●
●
●
(○) ●
●
●
●
F.Shoulder
●
●
●
●
●
●
●
●
●
●
Part 1
Part 2
Part 3
Part 4
●: MAS measurement (before treatment)
（○）: Use V5 or QRV MAS measurement
Figure 6    Subjects to be evaluated for MAS
9.1.1.2.
Numeric Rating Scale (NRS) 
According to "2. SCHEDULE OF ACTIVITIES (SoA)" the investigator (or subinvestigator) will 
use NRS (Figure 7) to evaluate the severity of flexors pain.
The investigator will perform the interview on NRS following the assessment of MAS. Each subject 
will be interviewed on the severity of pain on the treated part when extended based on a scale with 0 


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being "no pain" and 10 being "the worst imaginable pain"; 1 response on the scale should be selected 
by the subject.
0
1
2
3
4
5
6
7
8
9
10
No pain
Pain as 
bad as 
you can 
imagine
Figure 7    Numeric Rating Scale (NRS) for pain

NRS measurement during the blinded period
During the blinded period, the severity of pain in the elbow flexors will be evaluated. 

NRS measurement during the open-label period
During the open-label period, a major part with pain [specify 1 part from among fingers, thumb, 
wrist, elbow, fore-arm (pronate), and shoulder] will be evaluated for the severity of pain on Visit 1. 
The part to be evaluated does not have to be the same within each treatment period, but should be the 
same part as that evaluated for MAS. 
9.1.1.3.
Disability Assessment Scale (DAS)
According to "2. SCHEDULE OF ACTIVITIES (SoA)" the investigator (or subinvestigator) will 
use the 4 disability assessment parameters presented in Table 7 and evaluate all of them based on the 
scale presented in Table 8. Before starting the study treatment, the investigator shall discuss with the 
subject, and select and evaluate 1 parameter agreed with the subject as the "main assessment 
parameter." The assessor should in principle remain unchanged throughout the study period. The main 
assessment parameter should also remain unchanged throughout the study period.
Table 7    Disability assessment parameters
Content of assessment
Hygiene
The extent of maceration/ulceration and/or palmar infection, palm/hand 
cleanliness, ease of cleanliness, ease of nail trimming, and interference with 
hygiene-related disability in the subject's daily life
Pain
The intensity of pain/discomfort, and the interference that upper-limb pain-
related disability has in the patient’s daily life.
Dressing
The difficulty or ease for the subject in putting on the relevant clothing (e.g., 
shirts, jackets, gloves, etc.) and the interference that upper-limb dressing-related 
disability has in the patient's daily life.
Limb posture
The psychological and/or social interference that the disfigured upper limb has 
in the patient's daily life.


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Table 8    Disability Assessment Scale
Description
0: No functional disability
No functional disability
1: Mild disability
Noticeable but does not interfere significantly with normal activities
2: Moderate disability
Normal activities require increased effort and/or assistance.
3: Severe disability
Normal activities limited.
9.1.1.4.
Clinical Global Impression of Change (CGI) assessed by an investigator
The investigator (or subinvestigator) will evaluate CGI according to "2. SCHEDULE OF 
ACTIVITIES (SoA)”; Changes in spasticity (Clinical Global Impression) from baseline (V1 in each 
treatment phase) will be evaluated by 9 grades as shown in Table 9.
The investigator shall also consider the subject's clinical symptoms and adverse events pertinent to 
the assessment of CGI. Also, the therapeutic effect of the product injected in the subject's fingers, 
wrist, and elbow should be taken into an account. The assessor should in principle remain unchanged 
throughout the study period.
Table 9    Clinical Global Impression of Change (CGI)
-4
Very much worsened
-3
Much worsened
-2
Moderately worsened
-1
Slightly worsened
0
Unchanged
+1
Slightly improved
+2
Moderately improved
+3
Much improved
+4
Very much improved
9.1.1.5.
Clinical Global Impression of Change (CGI) assessed by a patient
According to "2. SCHEDULE OF ACTIVITIES (SoA))" the investigator (or subinvestigator) will 
use Table 9 to record subject-reported CGI. The investigator shall interview each subject on changes 
in spasticity from predose, and the subject will evaluate it using Table 9.
9.1.1.6.
Time to patient-reported onset of spasticity symptom relief (Visit 2):
According to "2. SCHEDULE OF ACTIVITIES (SoA)" the investigator (or subinvestigator) will 
record the time to alleviation of spasticity reported by subjects. The investigator shall ask the subject 
whether the product was effective on the spasticity, and if the subject's response to the question is 
positive, ask him/her "how many days did it take for the therapeutic effect to appear after the current 
dose?" and record the number of days.
9.1.1.7.
Patient-reported benefit of injection (Visits 3, 4, and 5)
According to "2. SCHEDULE OF ACTIVITIES (SoA)" the investigator (or subinvestigator) will 
record the efficacy of treatment reported by subjects. The investigator shall ask, "Was the product
effective?" and the subject shall respond either by "Yes" or "No."


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9.2.
Adverse events
Definitions of adverse events and serious adverse events (SAE) are as specified in Appendix 4.
The investigator or a person assigned by the investigator is responsible for detecting, recording, and 
reporting events that match the definitions of adverse events and SAEs, and also, responsible for 
follow-up investigations on SAEs, as well as events related to the study drug or this study, and events 
that resulted in treatment discontinuation or subject withdrawal (See section 8). 
9.2.1.
Period subject to collection of data related to adverse events and SAEs, and 
the frequency of such data collection

All SAEs will be collected from the start of treatment until Final Visit at the time points 
specified in the SoA (Section 2). 

All AEs will be collected from the start of treatment until Final Visit at the time points 
specified in the SoA (Section 2). 

Medical occurrences that begin before the start of study treatment but after obtaining 
informed consent will be recorded on the Medical History/Current Medical Conditions 
section of the case report form (CRF) not the AE section. 

All SAEs will be recorded and reported to the sponsor or designee within 24 hours, as 
indicated in Appendix 4. The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available. 

Investigators are not obligated to actively seek AEs or SAEs in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a 
participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study treatment or study participation, the investigator must 
promptly notify the sponsor. 

The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 4.
9.2.2.
Method used to detect adverse events and SAEs
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and non-leading 
verbal questioning of the participant is the preferred method to inquire about AE occurrence.
9.2.3.
Follow up on adverse events and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each participant at 
subsequent visits/contacts. All SAEs will be followed until the event is resolved, stabilized, otherwise 
explained, or the participant is lost to follow-up (as defined in Section 8.3). Further information on 
follow-up procedures is given in Appendix 4.
9.2.4.
Regulatory requirements of SAE reporting

Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study treatment under clinical investigation are met. 


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
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, Institutional Review Boards (IRB)/Independent Ethics 
Committees (IEC), and investigators. 

Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary. 

An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAE) from the sponsor will review 
and then file it along with the Investigator’s Brochure and will notify the IRB/IEC, if 
appropriate according to local requirements. 
9.2.5.
Cardiovascular events and death
For any cardiovascular events detailed in Appendix 4 and all deaths, whether or not they are 
considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF will be required to be 
completed. These sections include questions regarding cardiovascular (including sudden cardiac 
death) and non-cardiovascular death. 
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA terms. The 
CV information should be recorded in the specific cardiovascular section of the CRF within one week 
of receipt of a CV Event data query prompting its completion. 
The Death CRF is provided immediately after the occurrence or outcome of death is reported. Initial 
and follow-up reports regarding death must be completed within one week of when the death is 
reported.
9.2.6.
Pregnancy

Details of all pregnancies in female partners of male participants will be collected after the 
start of study treatment and until Final Visit. 

If a pregnancy is reported, the investigator should inform GSK within 24 hours of learning 
of the pregnancy and should follow the procedures outlined in Appendix [X]. 

Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAE. 
9.3.
Management of overdosage
A dosage of the product exceeding 400 units within 24 hours shall be considered as overdosage in 
this study. Overdosage may cause excessive pharmacodynamic responses such as hyposthenia, 
muscular paralysis, and other localized adverse reactions. Symptoms and signs may not immediately 
appear following dose. Moreover, blepharoptosis, dysarthria, dysphagia, dyspnea, myasthenia, and 
other events suspected to be an effect on other muscles distal to the treated muscle have been reported 
overseas. If such a symptom appears, the subject should be carefully monitored, and given appropriate 
interventions, if necessary with hospitalization. Also, supportive therapies such as artificial breathing 
should be considered for respiratory symptoms.


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Upon confirmation of overdosage, the investigator should;
1.
Contact the Medical Monitor immediately.
Carefully monitor the adverse event/SAE, and laboratory abnormalities in the subject for at least 4 
weeks; and 
Document the quantity of the excess dose as well as the duration of the overdosing in the CRF.
The investigator shall discuss with the sponsor's medical monitor on the clinical assessment of the 
subject, and upon which, decide whether or not to discontinue the study treatment.
9.4.
Safety assessments
Assessment timepoints for all safety parameters are as shown in SoA.
9.4.1.
Physical examination
Physical examination (complete version): Only during screening

The head and neck, skin, lungs, cardiovascular system, abdominal region (liver and spleen), 
gastrointestinal system, lymph node, and nervous system should be examined, and the 
results thereof should be recorded; these organs should be examined for the 
presence/absence of pre-existing conditions and abnormal findings, and if there is any 
suspected abnormality, detailed examinations should be performed. 

The pulmonary function test should be conducted in details if any sign of pulmonary 
impairment is found. For the pulmonary function test, spirometry by pulmonologists is 
recommended. 
Physical examination (simplified version): To be conducted only if an eligibility criterion is not met 
during the open-label period. 

At least, the lungs, cardiovascular system, and abdominal region (liver and spleen) should 
be examined, and the results thereof should be recorded. 

The investigator should pay attention to clinical signs and symptoms related to a history of 
serious disease. 
The physical examinations should be performed by doctors in accordance with the standard clinical 
guidelines of each study site.
9.4.2.
Vital signs

For the vital signs, body temperatures (oral, intra-aural, or axillary fossa), systolic/diastolic 
blood pressures, and pulse rates should be measured in a semi-recumbent position after a 5-
minute rest. If measurement in a semi-recumbent position is difficult, measurement in 
another position (e.g., sitting) is acceptable. In this case, however, the measurement should 
be performed always in the same position during the study period.

If a temperature is to be measured orally, the subject must refrain from eating food or 
drinking beverage within 5 minutes before the measurement. The method for the 
measurement of body temperature must remain the same throughout the study. 


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
The blood pressures and pulse rates should be measured with an automated device. A 
manual method may be used only if there is no automated device available for use. 
9.4.3.
Height and weight
The standard clinical guidelines of each study site should be followed.
9.4.4.
Pulmonary test

Refer to SoA for the timepoints and frequency of testing.

If post-injection SpO2 is decreased by 3% or more from the baseline (pre-injection on Day 
1) or a SpO2 value is <95%, medical examination by pulmonologist is required. A subject 
with pulmonary dysfunction due to study treatment based on the investigator's opinion
will be referred to a pulmonologist as well.

If a medical institution has no pulmonologist, visit other hospitals for medical examination 
by specialists. For the pulmonary function test, spirometry by pulmonologists is 
recommended.

If a subject is referred to a pulmonologist and considered to have no concerns about 
pulmonary function, the investigator should carefully consider whether to start or continue 
study treatment.
9.4.5.
ECG

QTc should be determined based on a single measurement of ECG or the mean of ECG 
measured at 3 timepoints in a short period of time (e.g., 5 to 10 minutes). 

An automated measurement and manual re-interpretation in accordance with SoA should be 
used to collect data on the heart rates, PR, QRS, QT, and QTc interval. Refer to section 
8.2.2. for QTc-related treatment discontinuation standard, and additional QTc to be 
measured as required. 

Each interval between timepoints for the measurement of ECG should be minimized as 
much possible (within 2 minutes). The measurement of ECG should be performed 3 times 
consecutively and completed within 5 to 10 minutes. 
9.4.6.
Neutralizing antibody test
The investigator shall draw blood for neutralizing antibody samples in accordance with the study 
schedule. The neutralizing antibody will be measured collectively by central laboratories designated 
by GSK (Intertek Pharmaceutical Services Co. and Pacific BioLabs Co.). The screening samples will 
be retained temporarily by the central laboratories, and then, upon retrieval of samples from all 
subjects, will be collected and tested by Intertek for screening. Samples tested positive at Intertek will 
be separately sent to Pacific BioLabs for retest to finalize the results of neutralizing antibody test. The 
above procedures shall also be taken for samples collected for Week 12 visit during the blinded period, 
and upon completion of study treatment in all subjects.


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9.4.7.
Clinical Safety Laboratory Assessments

Refer to Appendix 2 for the list of clinical laboratory parameters that should be tested, and 
to SoA for the timepoints and frequency of testing. 

The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal during 
participation in the study should be repeated until the values return to normal or baseline or 
are no longer considered significantly

If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified.

All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted 
in accordance with the laboratory manual and the SoA.

If a result of clinical laboratory test not scheduled in the protocol is obtained by a study site, 
which requires a change in the patient management, or is determined to be clinically 
important by the investigator, that is SAE, adverse event, an event requiring dose 
modification, or any other relevant event, the record thereof must be documented in the 
CRF. 

Follow-up investigation may be performed at any time during the study as determined to be 
necessary by the investigator, or required by the Japanese regulation. 


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9.5.
Pharmacokinetics
PK parameters are not evaluated in this study.
9.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
9.7.
Genetics/Pharmacogenetics
Genetics and pharmacogenetics are not evaluated in this study.
9.8.
Biomarkers
Biomarkers are not evaluated in this study.
9.9.
Pharmacoeconomics
Pharmacoeconomic parameters are not evaluated in this study.


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10. STATISTICAL CONSIDERATIONS
10.1.
Sample Size Determination
This study is not intended to verify a statistical hypothesis, but is rather intended to verify that the 
responder rate in the 400 units group exceeds that in the 240 units group, and for which, about 120 
subjects (60 in each treatment group) are to be enrolled.
During Treatment Period 1 of this study, 160 units of the product will be administered in the muscle 
which affects the elbow; thus, the sample size was determined in reference to an overseas phase III 
study (Study 127) in which a similar dosage as this study (150 units) was administered in the muscle 
which affects the elbow. The responder rate in the elbow at Week 6 of the initial dose in Study 127 
was 72.2% and 47.1% in the product 300 units group (150 units in the muscle which affects the elbow 
flexors) and placebo group, respectively. The number of subjects in the intention-to-treat (ITT) 
population was small in both the product 300 units group and placebo group of Study 127, which was 
18 subjects each; thus, considering the uncertainty of the results of Study 127, the responder rates in 
the product 400 units and 240 units groups in this study were conservatively assumed to be 70.0% and 
50.0%, respectively. Assuming that the sample size is 60 subjects in each group, the power of test to 
detect an intergroup difference in the responder rates would be about 62% with a two- sided
significance level of 5% while the probability of the responder rate in the product 400 units group to 
exceed that in the product 240 units group as a point-estimate would be 98%.
With about 120 subjects enrolled, 100 subjects are expected to complete Week 48 of the initial dose.
10.2.
Populations for Analyses
Populations for statistical analyses in this study are defined as follows.
Population
Description
ITT
All subjects randomized in the study and had at least 1 post-baseline 
efficacy assessment: ITT is the primary efficacy analysis population, and 
the subjects will be analyzed in line with the randomized treatment group. 
Safety 
All subjects randomized in the study and received study treatment at least 
once: The subjects will be analyzed based on the treatment actually given. 
10.3.
Statistical Analyses
10.3.1.
Efficacy Analyses
This study is not intended to verify a statistical hypothesis; thus, there will be no statistical test.
All of the efficacy analyses will be performed on the ITT population separately for the blinded 
period and the open-label period.


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Endpoints
Statistical Analysis Methods
Primary
The primary endpoint is the proportion of subjects whose MAS score on the elbow at 
Week 6 of the initial dose decreased by at least 1 level from the baseline (responder rate). 
The primary endpoint will be calculated as the proportion of subjects whose MAS score 
decreased by at least 1 level from the baseline in the ITT population. Also, a 95% 
confidence interval of the intergroup difference in the responder rate will be computed. 
Subjects with no MAS score available at Week 6 will not be counted as subjects whose 
MAS score decreased by at least 1 level from the baseline (that is, counted in as non-
responder). 
The MAS scores, 0, 1, 1+, 2, 3, and 4 will be encoded to 0, 1, 2, 3, 4, and 5, respectively, 
for the analysis purpose. 
Secondary
Unless specified otherwise, the data up to Week 12 of treatment will be summarized for 
each repeated dose during the open-label period. 
During the blinded period, a mixed model for repeated measurement (MMRM) will be 
used for the analysis on the endpoints specified below, and the least-square mean and 95% 
confidence interval will be calculated. The details of the model will be described in the 
statistical analysis plan. For the open-label period, only a summary statistics will be 
performed for each treatment group. Missing values will not be imputed. 
Change in MAS score in the fingers, thumb, wrist, and elbow from the baseline
Change in Disability Assessment Scale (primary endpoint) from the baseline 
The proportion of subjects in whom MAS score in the fingers, thumb, wrist, and elbow 
decreased by at least 1 level from the baseline (responder rate) during the blinded period 
will be analyzed with the same method as that for the primary endpoint. For the open-
label period, the denominator to be used for the calculation of responder rate shall be the 
number of subjects in each subgroup stratified by the number of injections given, not the 
ITT population. Also, a 95% confidence interval of the intergroup difference in the 
responder rate will not be calculated. 
Exploratory
Time to patient-reported onset of spasticity symptom relief will be evaluated for subjects 
who reported alleviation of spasticity at in 2 weeks postdose. The number of days from 
dose to the alleviation of spasticity will be summarized for each treatment group. 
Clinical Global Impression of Change (CGI) assessed by an investigator, CGI assessed by 
a patient, and Patient-reported benefit of injection will be summarized for each treatment 
group. Missing values will not be complemented. 
Other details will be specified in the statistical analysis plan. 
10.3.2.
Safety Analysis
Safety analyses will all be performed on the safety population separately for the blinded and open-
label periods.


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Endpoints
Statistical Analysis Method
Primary
Not applicable
Secondary
Adverse events that occurred in the overall study period, blinded period, and open-label 
period will be summarized for each treatment group. For the blinded period, 2 patterns of 
analyses on adverse events will be performed; one is on adverse events that occurred 
between the initial dose and the first dose in the open-label period (or at the completion 
of study if no dose is given in the open-label period or at the study withdrawal), and 
another one is on adverse events that occurred within 84 days from the initial dose. 
Adverse events will be summarized separately for SOC (system organ class) and PT 
(preferred term). Also, adverse events related to study treatment, adverse events that 
resulted in discontinuation, adverse events by subgroups stratified by severity, and 
serious adverse events will be summarized. 
Laboratory findings and vital signs at each visit and their changes from baseline will be 
summarized for each treatment group. 
Exploratory
Will be specified in the statistical analysis plan. 
10.3.3.
Other analyses
Other analyses will be specified in the statistical analysis plan.
10.3.4.
Interim analyses
The details of the interim analysis plan will be specified in the statistical analysis plan.
When all subjects (except for early termination) complete the visit at Week 24 of the initial dose, 
the data on all of the subjects until Week 24 of the initial dose may be locked, unblinded, and analyzed 
for reporting to authorities.
11. Reference
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Brin MF, the Spasticity Study Group. Dosing, Administration, and a Treatment Algorithm for Use of 
Botulinum Toxin A for Adult-Onset Spasticity. Muscle & Nerve. 1997;20 (Supplement 6):S208-20.
Gracies JM, Hefter H, Simpson DM, et al. Handbook of Botulinum Toxin Treatment, 2nd ed. .Oxford, 
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Grazko MA, Polo KB, Jabbari B. Botulinum toxin A for spasticity, muscle spasm, and rigidity. 
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Gregson JM, Leathley MJ, Moore AP, , et al. Reliability of measurements of muscle tone and muscle 
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Jankovic J. Botulinum toxin therapy for cervical dystonia. Neurotox Res. 2006 Apr;9(2-3):145-8.
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Kinoshita Y. Spasticity and botulinum therapy. BRAIN NURSING. 2015; 31(2):191-4.
Klein AW. Complications and adverse reactions with the use of botulinum toxin. Dis Mon. 2002 
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Lance JW. Symposium synopsis. Spasticity, disordered motor control . Year Book Medical Publishers, 
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Marciniak CM, Harvey RL, Gagnon CM. Does botulinum toxin type A decrease pain and lessen 
disability in hemiplegic survivors of stroke with shoulder pain and spasticity?. Physical Medicine and 
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Mutlu A, Livanelioglu A, Gunel MK. Reliability of Ashworth and modified Ashworth scales in 
children with spastic cerebral palsy. BMC Musculoskeletal Disorders. 2008;9:44.
Nemto A. Therapeutic method for treatment of spasticity, and conditions indicated for treatment. 
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Ogawa, Idee, Katayama. Treatment Guideline for Cerebral Stroke 2015. 2015. 
Ohsawa, Mezaki, Miyagi. Standard Neurotherapy: Botulinum treatment. Neurotherapy. 2013; 
30(4):473-94.
Shinohara, Ogawa, Suzuki et al. Treatment Guideline for Cerebral Stroke 2009. 2009. 
Sloan RL, Sinclair E, Thompson J, Taylor S, et al. Inter-rater reliability of the modified Ashworth 
Scale for spasticity in hemiplegic patients. Int J Rehabil Res. 1992;15:158-61.
Yelnik AP, Colle FM, Bonan IV, et al. Treatment of shoulder pain in spastic hemiplegia by reducing 
spasticity of the subscapular muscle:a randomised, double blind, placebo controlled study of 
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12. Appendices
12.1.
Appendix 1: Abbreviations and trademarks
Trademark
Trademark of Glaxo SmithKline Group
Trademarks that do not belong to Glaxo 
SmithKline Group
Botox
―
12.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 10 will be performed by central laboratory. 

A test needs to be performed by study sites only if the result cannot be obtained from the 
central laboratory in time for study treatment and/or assessment. Even if measurement is 
performed at a study site, another sample at the same assessment timepoint is separately 
required for measurement at central laboratory. If a result of measurement at the study site 
is to be used for a decision of study treatment and/or assessment, the result should be 
recorded in the CRF. 

Protocol-specific inclusion/exclusion criteria are as specified in section 6 of the protocol. 

Protocol-specific inclusion/exclusion criteria are as specified in section 6 of the protocol. 


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Table 10    Protocol-Required Safety Laboratory Assessments
Clinical 
laboratory
Parameters
Hematological 
tests
Platelet count
Erythrocyte indices: 
Mean corpuscular volume 
(MCV)
Mean corpuscular 
hemoglobin (MCH)
Reticulocyte count (%)
Percentage of white blood 
cell:
Neutrophil
Lymphocyte
Monocyte
Eosinophil
Basophil
RBC
Hemoglobin
Hematocrit
White blood cell count
Chemistry1
Urea 
nitrogen 
(BUN)
Potassium
Aspartate aminotransferase (AST) /
Serum glutamic oxaloacetic 
transaminase (SGOT) 1
Total bilirubin and 
direct bilirubin
Creatinine
Sodium
Alanine aminotransferase (ALT) / 
Serum glutamic pyruvic 
transaminase (SGPT) 1
Total protein
Calcium
Alkaline 
phosphatase
Urinalysis
Specific gravity
PH with test paper, glucose, protein, occult blood, ketone, bilirubin, urobilinogen, 
nitrite, and white blood cell esterase
Microscopy (if occult blood or protein is deviated)
Other tests

Pregnancy test (if necessary in a woman of child-bearing potential): 
Serum or urine human chorionic gonadotropin (hCG) 2
The following parameters should be tested during the screening period. 

Serological verification: HIV antibody

The following parameters should be tested only for subjects with chronic 
hepatitis B or C that is stabilized at screening, and subjects currently 
receiving or expected to receive immunosuppressant. 

Serological verification: Hepatitis B virus surface antigen (HBsAg), 
and hepatitis C virus antibody

The following parameter should be tested for women of no child-bearing 
potential. 

Follicle stimulating hormone and estradiol
Caution: 
1. Details of the discontinuation criteria based on hepatic function test, and the interventions and follow up 
necessary after the occurrence of hepatic events are specified in section 8.1 and Appendix 6. SAEs must 
be reported for all events with ALT IJYO3 times the upper limit of normal range (ULN), and at the same 
time, bilirubin IJYO2 times the ULN (direct bilirubin >35%), or ALT IJYO3 times the ULN, and at the 
same time, the international normalized ratio (INR) >1.5 if measured [which suggests a possibility of 
severe liver injury (applicable to Hy's Law)]. 
2. Pregnancy tests should be performed with serum samples at screening, and with urine samples for 
routine tests after randomization. 


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12.3.
APPENDIX 3: Study Governance Considerations
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.

Any amendments to the protocol will require IEC/IRB approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as required by IRB/IEC 
procedures

Providing oversight of the conduct of the study at the site and adherence to requirements of 
21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial certification 
or disclosure statements to the appropriate regulatory authorities. Investigators are responsible for 
providing information on financial interests during the course of the study and for 1 year after 
completion of the study.
Process of obtaining consent

The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding 
the study.

Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed consent 
that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health 
Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, and 
the IRB/IEC or study center.


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
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.
Data protection

Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant names 
or any information which would make the participant identifiable will not be transferred.

The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.

The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
Composition of committee
No committee will be established.
Publication Policy

The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor before 
submission. This allows the sponsor to protect proprietary information and to provide 
comments.

The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating investigator will be designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.
Dissemination of Clinical Study Data

Disclosure of a Clinical Study Report (CSR) after the evaluation by the regulatory 
authority(ies).

GSK may post the study information and tabulated-form study results on the website 
(www.ClinTrials.gov) of the U.S. National Institution of Health (NIH) or other websites 
open to the public 

GSK may post the study results to scientific journals that conduct peer review in order to 
report the study results.


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Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the sponsor or designee electronically (eg, laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.

The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.

The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.

The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.

Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study 
is being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.

Records and documents, including signed ICF, pertaining to the conduct of this study must 
be retained by the investigator for 25 years from the issue of the final Clinical Study Report 
(CSR)/ equivalent summary unless local regulations or institutional policies require a longer 
retention period. No records may be destroyed during the retention period without the 
written approval of the sponsor. No records may be transferred to another location or party 
without written notification to the sponsor.
Source documents

Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available.

Definition of what constitutes source data can be found in the corresponding list of source 
documents.
Study and Site Closure
GSK or its designee reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of GSK. Study sites will be closed upon study completion. A study site is 
considered closed when all required documents and study supplies have been collected and a study-
site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are not 
limited to:


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
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study treatment development


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12.4.
APPENDIX 4: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study treatment, whether or not considered related to the study 
treatment.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other
safety assessments (eg, ECG, radiological scans, vital signs measurements), including those 
that worsen from baseline, considered clinically significant in the medical and scientific 
judgment of the investigator (ie, not related to progression of underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even though it may 
have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study treatment or 
a concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is an 
intentional overdose taken with possible suicidal/self-harming intent. Such overdoses should 
be reported regardless of sequelae.

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be reported 
as an AE or SAE. Such instances will be captured in the efficacy assessments. However, the 
signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be reported as 
AE or SAE if they fulfill the definition of an AE or SAE.

The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be reported 
as AE or SAE if they fulfill the definition of an AE or SAE. Also, "lack of efficacy" or 
"failure of expected pharmacological action" constitutes an AE or SAE.


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Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
Definition of an SAE
If an event does not correspond any of the above definitions of an AE, even if it is a serious condition, 
it will not be regarded as an SAE (e.g.; hospitalization due to the signs/symptoms of the disease being 
studied, death caused by exacerbation of the disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
results in death
b.
is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the subject was at 
risk of death at the time of the event. It does not refer to an event, which hypothetically might have 
caused death, if it were more severe.
c.
requires hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the subject has been detained (usually involving at least an 
overnight stay) at the hospital or emergency ward for observation and/or treatment that would not 
have been appropriate in the investigator’s office or out-patient setting. Complications that occur 
during hospitalization are AEs. If a complication prolongs hospitalization or fulfils any other serious 
criteria, the event is serious. When in doubt as to whether “hospitalization” occurred or was necessary, 
the AE should be considered serious. Hospitalization for elective treatment of a pre-existing condition 
that did not worsen from baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday life 
functions but do not constitute a substantial disruption.
e.
is congenital anomaly/birth defect


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f.
other important medical situations:

Medical or scientific judgement should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require medical or surgical intervention to prevent one of the other outcomes 
listed in the above definition. These should also be considered serious.
Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that 
do not result in hospitalization, or development of drug dependency or drug abuse.
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the following AEs 
and SAEs:

Myocardial infarction/angina unstable

Cardiac failure congestive

Arrhythmia

Valvular disease

Pulmonary hypertension

Cerebrovascular event/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep vein thrombosis/pulmonary embolism

Revascularisation
Recording of AEs and SAEs
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to GSK in lieu of completion of the GSK /AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are requested by 
GSK. In this case, all participant identifiers, with the exception of the participant number, 
will be redacted on the copies of the medical records before submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE.


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Assessment of intensity
The investigator will make an assessment of intensity for each AE and SAE reported during the study 
and classify it to one of the following categories:

Mild: An event that is easily tolerated by the subject, causing minimal discomfort and not 
interfering with everyday activities.

Moderate: An event that is sufficiently discomforting to interfere with normal everyday 
activities.

Severe: An event that prevents normal everyday activities - An AE that is assessed as severe 
will not be confused with an SAE. Severity is a category utilized for rating the intensity of 
an event; and both AEs and SAEs can be assessed as severe.
An event is defined as “serious”, not when it is assessed as severe but when it meets at least one of the 
pre-defined outcomes as described in the definition of an SAE.
Assessment of causality

The investigator is obligated to assess the relationship between investigational product and 
the occurrence of each AE/SAE.

A “reasonable possibility” is meant to convey that there are facts/evidence or arguments to 
suggest a causal relationship, rather than a relationship cannot be ruled out.

The investigator will use clinical judgement to determine the relationship.

Alternative causes, such as natural history of the underlying diseases, concomitant therapy, 
other risk factors, and the temporal relationship of the event to the investigational product 
will be considered and investigated.

The investigator will also consult the IB, for marketed products, in the determination of 
his/her assessment.

The investigator must record that he or she reviewed AEs and SAEs and assessed the 
causality in the medical record.

There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK. However, it is very important that the 
investigator always make an assessment of causality for every event prior to the initial 
transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up information, 
prepare and send the follow-up report of SAE by amending the assessment result of the 
causality accordingly.

The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.


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Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.

If a subject dies during participation in the study, the investigator will provide GSK with a
copy of any post-mortem findings, including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit all updated SAE data to GSK within 24 hours after obtaining 
the information.
Reporting of SAEs to GSK
SAE Reporting to GSK via Electronic Data Collection Tool

The primary mechanism for reporting SAE to GSK will be the electronic data collection 
tool.

If the electronic system is unavailable for more than 24 hours, then the site will use the 
paper SAE data collection tool (see next section).

The site will enter the SAE data into the electronic system as soon as it becomes available.

The investigator or medically-qualified sub-investigator must show evidence within the 
eCRF (e.g., check review box, signature, etc.) of review and verification of the relationship 
of each SAE to IP/study participation (causality) within 72 hours of SAE entry into the 
eCRF.

After the study is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated data on 
a previously reported SAE after the electronic data collection tool has been taken off-line, 
then the site can report this information on a paper SAE form (see next section) or to the 
SAE coordinator by telephone.

Contacts for SAE reporting can be found in ATTACHMENT.
SAE Reporting to GSK via Paper CRF

Facsimile transmission of the SAE page of the CRF is the preferred method to transmit the 
information on SAEs to GSK. 

In rare circumstances and in the absence of facsimile equipment, initial notification by 
telephone is acceptable followed by a copy of the SAE page of the CRF sent by overnight 
mail or by courier. 

Initial notification via the telephone does not replace the need for the investigator (or 
subinvestigator) to complete and sign the SAE page of the CRF within the designated 
reporting time frames.

The ATTACHMENT 1 shows a contact information to which the SAEs should be reported.


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12.5.
APPENDIX 5: Contraceptive Guidance and Collection of Pregnancy 
Information
Definition
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below)
Women in the following categories are not considered WOCBP
1.
Premenarchal
Premenopausal female with ONE of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s: review of participant’s medical records, 
medical examination, or medical history interview.
Postmenopausal women

A postmenopausal state is defined as no menses for 12 months without an alternative
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 12 
months of amenorrhea, a single FSH measurement is insufficient.

Females on HRT and whose menopausal status is in doubt will be required to use one of the 
non-hormonal highly effective contraception methods if they wish to continue their HRT 
during the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrollment.
Contraception Guidance
Male study subject

A male study subject who has a female partner of childbearing potential can participate in 
this study if he agrees to any of the following conditions: 

He must agree not to have a sex (sexual intercourse) with a person of the opposite sex as a 
normal favourable lifestyle (continuously having no sex for a long period of time) and also 
agree to keep that condition. 

If he has a sex with a woman of childbearing potential, he must agree to use a male condom
and use at least one of the contraception methods with an annual failure rate below 1% 
which are shown in Table 11.

A male study subject who has a pregnant or breastfeeding female partner must agree not to 
have a sex from the time during the study or use a male condom when having a sex. 

A male study subject must agree not to provide his sperm during the study. 


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Female study subject
A female study subject of childbearing potential can participate in this study if she agrees to use any 
of the extremely effective methods of contraception shown in Table 11continuously and accurately. 
Among the methods of contraception shown in Table 11, those deleted with strikethrough lines have 
neither been approved nor been accepted in Japan.
Table 11    Extremely effective methods of contraception
User-dependent extremely effective methods of contraception a
Their annual failure rates are below 1% if they are used continuously and accurately.
Contraception by mixed (estrogen and progestogen-containing) hormone preparation (inhibit 
ovulation)b

Oral

Intravaginal

Transdermal
Contraception by only progestogen-containing hormone preparation (inhibit ovulation)b

Injection
User-independent extremely effective methods of contraception

Contraception by only progestogen-containing implantable hormone preparation (inhibit 
ovulation)b

Intrauterine device (IUD)

Intrauterine system (IUS)

Bilateral tubal occlusion
Male partner’s vasectomy
(If her male partner has been vasectomised, it is an extremely effective method of contraception for a 
woman of childbearing potential if that partner is the only man with whom she has a sex and it has 
been confirmed that he is sterile. Otherwise, he/she must use other additional extremely effective 
method(s) of contraception.)
Having no sexual relations
(If the subjects decide to refrain himself or herself from having a sex of the opposite sex for the entire 
period when there is a risk of the investigational product, abstinence is deemed to be an extremely 
effective method of contraception. However, the credibility of abstinence needs to be evaluated during 
the study period and from the perspectives of the subject’s normal favourable lifestyle.)
Notes:
a.
The usual failure rate is different from the rate when contraception is used continuously and 
accurately. The subjects should use the methods of contraception that match with regulations 
concerning the methods of contraception for study subjects in each country.
b.
The efficacy of contraception by hormone preparations may decrease as a result of the interaction 
with the investigational product. In that case, the subject should use two extremely effective 
methods of contraception during the treatment period and at least for 3 months after the last dose 
of the investigational product.


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Pregnancy test

A woman of childbearing potential can be enrolled to this study only if it is confirmed that 
she is negative in a highly sensitive serum pregnancy test along with her menstrual period. 

Pregnancy test should be performed if no menstruation occurred or she is suspected to be 
pregnant.

Analysis should be performed according to the package insert using a testing kit provided 
by GSK.
Collection of pregnancy information
If a male study subject’s partner becomes pregnant

Investigator will attempt to collect pregnancy information on any male participant’s female 
partner of a male study participant who becomes pregnant while participating in this study. 
This applies only to participants who receive study treatment.

After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the investigator will record pregnancy information on the appropriate form and 
submit it to GSK within 2 weeks of learning of the partner’s pregnancy.

Partner will also be followed to determine the outcome of the pregnancy. Information on the 
status of the mother and child will be forwarded to GSK

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery 
date. Any termination of the pregnancy will be reported regardless of fetal status (presence 
or absence of anomalies) or indication for procedure.
Female Participants who become pregnant

Investigator will collect pregnancy information on any female participant, who becomes 
pregnant while participating in this study. 

Information will be recorded on the appropriate form and submitted to GSK within 24 hours 
of learning of a participant's pregnancy. 

Participant will be followed to determine the outcome of the pregnancy. The investigator 
will collect follow up information on participant and neonate, which will be forwarded to 
GSK Generally, follow-up will not be required for longer than 6 to 8 weeks beyond the 
estimated delivery date.

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
or elective termination of a pregnancy will be reported as an AE or SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as such.

Any SAE occurring as a result of a post-study pregnancy which is considered reasonably 
related to the study treatment by the investigator, will be reported to GSK as described in 
Appendix 4. While the investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous reporting.


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For a female study subject who discovers her pregnancy while participating in this study, 

The administration of the investigational product will be discontinued. 


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12.6.
APPENDIX 6: Liver Safety Required Actions and Follow up Assessments
In order to secure the subject’s safety and evaluate the causes of liver event, the criteria for 
discontinuation and follow-up based on the liver function test values in the phase III-IV studies
will be stipulated.
Criteria for discontinuation based on the liver function test values in the phase III-IV studies
and necessary follow-up
Criteria for discontinuation based on the liver function test values
ALT
ALT ≥ 8xULN
ALT increase ALT ≥ 5xULN but <8xULN persists for ≥2 weeks
ALT ≥ 3xULN but <5xULN persists for ≥4 weeks
Bilirubin1, 2
ALT ≥ 3xULN and bilirubin ≥ 2xULN (>35% direct bilirubin)
INR2
ALT ≥ 3xULN and INR>1.5, if INR measured
Cannot 
Monitor
ALT ≥ 5xULN but <8xULN and cannot be monitored weekly for ≥2 weeks
ALT ≥ 3xULN but <5xULN and cannot be monitored weekly for ≥4 weeks
Symptom 3
ALT ≥ 3xULN associated with symptoms (new or worsening) believed to be related 
to liver injury or hypersensitivity
Necessary measures and assessment items for liver event
Actions 
Follow Up Assessments 

Immediately discontinue the 
administration of the investigational 
product.

Report it to GSK within 24 hours.

Complete the liver event CRF and 
complete an SAE data collection tool if 
the event also meets the criteria for an 
SAE 2.

Perform liver event follow up 
assessments

Monitor the participant until liver 
chemistries resolve, stabilize, or return 
to within baseline (see MONITORING
below)

Do not restart/rechallenge participant 
with study treatment unless allowed per 
protocol and GSK Medical Governance 
approval is granted

If the resumption/re-administration of 
the investigational product is not 
stipulated in the protocol or approved
by GSK’s Medical Governance, the 
administration of the investigational 
product will be discontinued 

Viral hepatitis serology4

Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend

Only in those with underlying chronic 
Hepatitis B at study entry (identified by 
positive Hepatitis B surface antigen) 
quantitative Hepatitis B DNA and 
Hepatitis delta antibody5

Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin≥2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications 
on the concomitant medications report 
form including acetaminophen, herbal 
remedies, other over the counter 
medications.


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permanently and the follow-up 
prescribed in the protocol 8.1. will be 
conducted.
MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT,
AST, alkaline phosphatase, bilirubin) 
and perform liver event follow up 
assessments within 24 hrs

Monitor participants twice weekly until 
liver chemistries resolve, stabilize or 
return to within baseline

A specialist or hepatology consultation 
is recommended
For other criteria:

Repeat liver chemistries (include ALT, 
AST, alkaline phosphatase, bilirubin) 
and perform liver event follow up 
assessments within 24-72 hrs

Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

Record alcohol use on the liver event 
alcohol intake case report form (CRF) 
page
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG) or gamma globulins.

Liver imaging (ultrasound, magnetic 
resonance, or computerised 
tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver 
Imaging and/or Liver Biopsy CRF 
forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin 
fractionation is not immediately available, discontinue study treatment for that participant if ALT 
≥ 3xULN and bilirubin ≥ 2xULN. Additionally, if serum bilirubin fractionation testing is 
unavailable, record presence of detectable urinary bilirubin on dipstick, indicating direct bilirubin 
elevations and suggesting liver injury.
All events of ALT ≥ 3xULN and bilirubin ≥ 2xULN (>35% direct bilirubin) or ALT ≥ 3xULN and 
INR>1.5, if INR measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be 
reported as an SAE (excluding studies of hepatic impairment or cirrhosis); INR measurement is not 
required and the threshold value stated will not apply to participants receiving anticoagulants
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such 
as fever, rash or eosinophilia)
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen (HbsAg) and Hepatitis B Core 
Antibody (IgM); Hepatitis C RNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen 
IgM antibody (or if unavailable, obtain heterophile antibody or monospot testing); Hepatitis E IgM 
antibody
Criteria for follow-up with continued treatment based on the liver function test values in the 
phase III-IV studies


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Criteria for follow-up based on liver test function values – Liver events to be followed
Criteria
Actions
ALT ≥5xULN and <8xULN and bilirubin 
<2xULN without symptoms believed to be related 
to liver injury or hypersensitivity, and who can be 
monitored weekly for 2 weeks.
OR
ALT ≥3xULN and <5xULN and bilirubin 
<2xULN without symptoms believed to be related 
to liver injury or hypersensitivity, and who can be 
monitored weekly for 4 weeks. 

Notify the GSK medical monitor within 
24 hours of learning of the abnormality 
to discuss participant safety.

Participant can continue study treatment

Participant must return weekly for 
repeat liver chemistries (ALT, AST, 
alkaline phosphatase, bilirubin) until 
they resolve, stabilise or return to within 
baseline

If at any time participant meets the liver 
chemistry stopping criteria, proceed as 
described above

If ALT decreases from ALT ≥5xULN 
and <8xULN to ≥3xULN but <5xULN, 
continue to monitor liver chemistries 
weekly.

If, after 4 weeks of monitoring, ALT 
<3xULN and bilirubin <2xULN, 
monitor participants twice monthly until 
liver chemistries normalize or return to 
within baseline.


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12.7.
APPENDIX 7: COUNTRY SPECIFIC DESCRIPTIONS
12.7.1.
Regulatory and Ethical Considerations
This study will be conducted in compliance with the “Good Clinical Practice (GCP)” (MHW 
Ordinance No. 28, March 27, 1997) and the “Act on Securing Quality, Efficacy and Safety of 
Pharmaceuticals, Medical Devices, etc. (PMD Act)”. 
GSK will submit the CTN to the regulatory authorities in accordance with the PMD Act before 
concluding the study agreement with the medical institution
12.7.2.
Obtaining of Informed Consent
Prior to participation in the study, the investigator should fully inform the potential subject and/or 
his or her legally acceptable representative of the study using the information document. In doing so, 
the investigator should provide the subject sufficient time and opportunity to inquire about details of 
the study and obtain the subject and/or his or her legally acceptable representative’s signature or 
printed name and seal and date of consent on the consent form. The subject may take the informed 
consent form home to review it. The person who provided the explanation and the clinical research 
coordinator who provided the supplementary explanation should also sign or affix his or her printed 
name and seal on the consent form and enter the date of signature. If an impartial witness is needed, he 
or she should also sign or affix his or her printed name and seal on the consent form and enter the date 
of witness. The investigator should attach the original of the above signed or affixed with printed 
name/seal and dated consent form (and information document) to the original medical record such as 
medical chart (in accordance with the rules for records retention, if any, at each medical institution), 
retain it, and give a copy to the subject and/or his or her legally acceptable representative. 
12.7.3.
Study Implementation Period
July 2017 – February 2019
12.7.4.
Study Conduct Structure
The Attachment 1 shows the sponsor’s information. Also, the Attachment 2 shows a list of medical 
institutions and investigators. 
12.8.
APPENDIX 8: PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
The protocol amendment summary of changes table for the latest amendment is provided on the pages 
before the contents.
Amendment 1: 24-MAY-2017
Overall Rationale for the Amendment:01
The protocol was changed based on the regulatory inquires by the Pharmaceuticals and Medical 
Devices Agency (PMDA).
Overall Rationale for the Amendment: 01
Section # and Name 
Description of Change 
Brief Rationale 


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Section # and Name 
Description of Change 
Brief Rationale 
1. SYNOPSIS
Add pulmonary test and 
description adjustment
Requested by PMDA
2. SCHEDULE OF 
ACTIVITIES (SoA)
Add pulmonary test and 
description adjustment
Requested by PMDA
5.1.3.1. Eligibility 
Criteria for Injection in 
and after Part 2
Add pulmonary test 
Requested by PMDA
6.1.1. Screening Phase 
(Day -28 to Day -1)
Add pulmonary test 
Requested by PMDA
6.2.2. Day 1 (Prior to 
injection)
Description adjustment
Establish consistency with section 7.7.2
6.4. Screen Failures
Description adjustment
Not shown due to minor changes
7.7.2. Contraindicated 
Medications/Therapies
Description adjustment
Establish consistency with section 6.2.2
9.1.1.4. Clinical Global 
Impression of Change 
(CGI) assessed by an
investigator
Error correction
Not shown due to minor changes
9.4.4. Pulmonary test
Add pulmonary test 
Requested by PMDA
9.4.5.ECG
Description adjustment
Add manual re-interpretation
Amendment 2: 6-OCT-2017
Overall Rationale for the Amendment: 02
The protocol was revised for study procedure clarification, error correction, and description 
adjustment.
Section # and 
Name 
Description of Change 
Brief Rationale 
Cover
Change of address
Office relocation
1. SYNOPSIS, 
Delete laboratory data from the 
Eligibility Criteria for Injection in and 
after Part 2.
Add eligibility criteria regarding the 
pulmonary test.
GSK1358820 is unlikely to affect laboratory test
data.
Specify the acceptable range of SpO2 values.
2. SCHEDULE 
OF ACTIVITIES 
(SoA)
Add a footnote.
Clarify the procedure for V1 assessment in and 
after Part 2.
5.1.3.1. Eligibility 
Criteria for 
Injection in and 
Delete laboratory data from the 
Eligibility Criteria for Injection in and 
after Part 2.
GSK1358820 is unlikely to affect laboratory test
data.


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Section # and 
Name 
Description of Change 
Brief Rationale 
after Part 2
Add eligibility criteria regarding the 
pulmonary test.
Specify the acceptable range of SpO2 values.
6.2.2. Day 1 (Prior 
to injection)
Add eligibility criteria regarding the 
pulmonary test.
Specify the acceptable range of SpO2 values to 
ensure the safety.
7.1. Treatments 
Administered
Table 2. Muscle 
Involvement and 
Dose in the Blind 
Phase
Table 3. Muscle 
Involvement and 
Reference Dose in 
the Open-Label 
Phase
Description adjustment
Not shown due to minor changes.
7.7.1. Permitted 
Concomitant 
Drugs/Therapies
Description adjustment
Delete tolperisone hydrochloride, which has 
been withdrawn from the market.
7.7.1. Permitted 
Concomitant 
Drugs/Therapies
Add a description regarding 
rehabilitation therapies.
Specify acceptable rehabilitation therapies and 
the procedure for collecting rehabilitation 
therapy related information.
9.1.1.1. Modified 
Ashworth Scale 
(MAS)
Description adjustment
Add a description regarding MAS assessment on 
the thumb.
9.1.1.1. Modified 
Ashworth Scale 
(MAS)
Table 6. Regions 
to be evaluated for 
MAS during the 
open-label period
Description adjustment
Not shown due to minor changes
9.4.2. Vital signs
Add a description regarding 
measurement in a sitting position.
Add an instruction for vital sign measurement.
9.4.4. Pulmonary 
Test
Add a description regarding the 
pulmonary test.
Specify the acceptable range of SpO2 values to 
ensure the safety.

SAP_001.pdf: 
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Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for A phase III study (a placebo 
controlled, randomized, double-blind comparative study and 
an open-label, uncontrolled study) to evaluate the efficacy 
and safety of GSK1358820 in patients with post-stroke upper 
limb spasticity. 
Compound Number 
:
GSK1358820
Effective Date 
:
02-APR-2018
Description:

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 207660.

This RAP is intended to describe the efficacy and safety analyses required for the 
study. 

This RAP will be provided to the study team members to convey the content of the 
interim and final Statistical Analysis Complete (SAC) deliverable.
RAP Author(s):
Approver
Date
Approval Method
Lead Statistician (Biostatistics Group 2, 
Biomedical Data Sciences Dept., Japan)
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
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RAP Team Approvals:
Approver
Date
Approval Method
23-MAR-2018
eSignature
Japan Project Lead (Future Pipelines Discovery 
Office, Medicines Development, Japan)
23-MAR-2018
eSignature
Clinical Investigations Lead (Future Pipelines 
Discovery Office, Medicines Development, 
Japan)
23-MAR-2018
eSignature
Operations and Science Lead (6, Clinical 
Operations Dept., Japan)
28-MAR-2018
eSignature
Data Quality Lead (Data Practice Group, 
Biomedical Data Sciences Dept., Japan)
27-MAR-2018
eSignature
Medical Writer (2, Medical Writing Office, 
Medicines Development, Japan)
28-MAR-2018
eSignature
Lead Programmer (Statistical Programming & 
Reporting Group, Biomedical Data Sciences 
Dept., Japan)
Clinical Statistics and Clinical Programming Line Approvals:
Approver
Date
Approval Method
28-MAR-2018
eSignature
Manager (Biostatistics Group 2, Biomedical Data 
Sciences Dept., Japan)
02-APR-2018
eSignature
Department Manager (Biomedical Data Sciences 
Dept., Japan)
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TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................6
1.1.
Summary of Key Protocol Information...........................................................6
1.1.1.
Changes to the Protocol Defined Statistical Analysis Plan.............6
1.1.2.
Study Objective(s) and Endpoint(s)................................................6
1.1.3.
Study Design .................................................................................7
1.1.4.
Statistical Hypotheses / Statistical Analyses ..................................8
2.
PLANNED ANALYSES ............................................................................................8
2.1.
Interim Analyses ...........................................................................................8
2.2.
Final Analyses ..............................................................................................9
3.
ANALYSIS POPULATIONS .....................................................................................9
3.1.
Protocol Deviations.....................................................................................10
4.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................11
4.1.
Study Treatment & Sub-group Display Descriptors.....................................11
4.2.
Baseline Definitions ....................................................................................11
4.3.
Multicentre Studies .....................................................................................11
4.4.
Examination of Covariates, Other Strata and Subgroups............................11
4.4.1.
Covariates and Other Strata ........................................................11
4.4.2.
Examination of Subgroups...........................................................11
4.5.
Multiple Comparisons and Multiplicity .........................................................12
4.6.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................12
5.
STUDY POPULATION ANALYSES .......................................................................13
5.1.
Overview of Planned Study Population Analyses........................................13
5.2.
Participant Disposition and Population........................................................13
5.3.
Protocol Deviation.......................................................................................13
5.4.
Demographic and Baseline Characteristics.................................................13
5.5.
Prior and Concomitant Medications ............................................................14
5.6.
Rehabilitation..............................................................................................14
6.
EFFICACY ANALYSES..........................................................................................15
6.1.
Primary Efficacy Analyses ..........................................................................15
6.1.1.
Endpoint / Variables.....................................................................15
6.1.2.
Summary Measure ......................................................................15
6.1.3.
Population of Interest...................................................................15
6.1.4.
Strategy for Intercurrent (Post-Randomization) Events ................15
6.1.5.
Statistical Analyses / Methods .....................................................15
6.1.5.1.
Statistical Methodology Specification..........................16
6.2.
Secondary Efficacy Analyses......................................................................16
6.2.1.
Endpoint / Variables.....................................................................16
6.2.2.
Summary Measure ......................................................................17
6.2.3.
Population of Interest...................................................................17
6.2.4.
Strategy for Intercurrent (Post-Randomization) Events ................17
6.2.5.
Statistical Analyses / Methods .....................................................17
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6.2.5.1.
Statistical Methodology Specification..........................18
6.3.
Exploratory Efficacy Analyses.....................................................................18
6.3.1.
Modified Ashworth Scale (MAS) ..................................................18
6.3.2.
Numeric Rating Scale (NRS) for pain...........................................19
6.3.3.
Disability Assessment Scale (DAS)..............................................19
6.3.4.
Clinical Global Impression of Change (CGI) of functional 
disability.......................................................................................19
6.3.5.
Patient-Reported Benefit of Injection............................................19
6.3.6.
Time to Patient-Reported Onset of Spasticity Symptom 
Relief ...........................................................................................19
6.3.7.
Time to Qualification for Retreatment...........................................20
7.
SAFETY ANALYSES .............................................................................................20
7.1.
Adverse Events Analyses ...........................................................................20
7.2.
Adverse Events of Special Interest Analyses..............................................22
7.3.
Clinical Laboratory Analyses.......................................................................22
7.4.
Other Safety Analyses ................................................................................22
7.5.
Exposure ....................................................................................................23
8.
REFERENCES.......................................................................................................25
9.
APPENDICES........................................................................................................26
9.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................26
9.2.
Appendix 2: Schedule of Activities ..............................................................27
9.2.1.
Protocol Defined Schedule of Events...........................................27
9.3.
Appendix 3: Assessment Windows .............................................................30
9.4.
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................31
9.4.1.
Study Phases for Concomitant Medication...................................31
9.4.2.
Study Phases for Adverse Events................................................31
9.4.2.1.
Definition of Adverse Events of Special Interest .........31
9.5.
Appendix 5: Data Display Standards & Handling Conventions....................32
9.5.1.
Reporting Process .......................................................................32
9.5.2.
Reporting Standards....................................................................32
9.6.
Appendix 6: Derived and Transformed Data ...............................................34
9.6.1.
General........................................................................................34
9.6.2.
Study Population..........................................................................34
9.6.3.
Efficacy........................................................................................35
9.7.
Appendix 7: Reporting Standards for Missing Data.....................................36
9.7.1.
Premature Withdrawals................................................................36
9.7.2.
Handling of Missing Data.............................................................36
9.7.2.1.
Handling of Missing and Partial Dates ........................36
9.8.
Appendix 8: Values of Potential Clinical Importance ...................................37
9.9.
Appendix 9: Population Pharmacokinetic (PopPK) Analyses ......................38
9.10.
Appendix 10: Pharmacokinetic / Pharmacodynamic Analyses ....................39
9.11.
Appendix 11: Abbreviations & Trade Marks ................................................40
9.11.1.
Abbreviations...............................................................................40
9.11.2.
Trademarks .................................................................................41
9.12.
Appendix 12: List of Data Displays..............................................................42
9.12.1.
Data Display Numbering..............................................................42
9.12.2.
Mock Example Shell Referencing ................................................42
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9.12.3.
Deliverables.................................................................................42
9.12.4.
Study Population Tables..............................................................43
9.12.4.1.
Interim Analyses.........................................................43
9.12.4.2.
Final Analyses............................................................44
9.12.5.
Efficacy Tables ............................................................................45
9.12.5.1.
Interim Analyses.........................................................45
9.12.5.2.
Final Analyses............................................................49
9.12.6.
Efficacy Figures ...........................................................................53
9.12.6.1.
Interim Analyses.........................................................53
9.12.6.2.
Final Analyses............................................................57
9.12.7.
Safety Tables...............................................................................61
9.12.7.1.
Interim Analyses.........................................................61
9.12.7.2.
Final Analyses............................................................68
9.12.8.
Safety Figures .............................................................................79
9.12.8.1.
Interim Analyses.........................................................79
9.12.9.
ICH Listings .................................................................................80
9.12.9.1.
Interim Analyses.........................................................80
9.12.9.2.
Final Analyses............................................................83
9.13.
Appendix 13: List of Preferred Terms / System Organ Class of 
Adverse Events of Special Interest .............................................................87
9.13.1.
Convulsions and Seizures ...........................................................87
9.13.2.
Respiratory Adverse Events.........................................................87
9.13.3.
Possible Distant Spread of Toxin.................................................87
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1.
INTRODUCTION
1.1.
Summary of Key Protocol Information
1.1.1.
Changes to the Protocol Defined Statistical Analysis Plan
There were no changes or deviations to the originally planned statistical analysis 
specified in the protocol amendment 02 [(Dated: 06OCT2017)].
1.1.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To evaluate the efficacy of the 
injections of 400 units of the 
product at Week 6 (finger/ wrist 
flexors: 240 units, elbow flexors: 
160 units), comparing to that of 240 
units (finger/ wrist flexors: 240 
units, elbow flexors: placebo).

The responder rate: The rate of the participants that 
Modified Ashworth Scale (MAS) score was reduced 
at least 1 from baseline in the elbow flexors.
Secondary Objectives
Secondary Endpoints

To evaluate the efficacy of 400 
units of the product, comparing to 
240 units of the product

The responder rate of MAS score from baseline in the 
finger, thumb and wrist flexors

Changes in MAS score from baseline in the finger, 
thumb, wrist and elbow flexors

Changes in Disability Assessment Scale (DAS) from 
baseline

To evaluate the safety and 
tolerability of the product of 400 
units, comparing to 240 units of the 
product/ To evaluate the safety and 
tolerability of 400 units of the 
product

Adverse events

Physical examinations

Clinical laboratory tests (haematology, blood 
biochemistry, urinalysis)

Vital signs (heart rate, blood pressure, body 
temperature)
Exploratory Objectives
Exploratory Endpoints

To evaluate the efficacy of 400 
units of the product

Changes in MAS score from baseline in finger, 
thumb, wrist, elbow, pronation of the forearm and 
shoulder flexors

To evaluate the other efficacy of 
the product of 400 units, comparing 
to 240 units of the product/ To 
evaluate the other efficacy of 400 
units of the product

Changes in Numeric Rating Scale (NRS) for pain 
from baseline

Changes in other items of DAS from baseline

Clinical Global Impression of Change (CGI) of 
functional disability by an investigator

CGI of functional disability by a patient

Time to patient-reported onset of spasticity symptom 
relief

Patient-reported benefit of injection

Time to qualification for retreatment
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Objectives
Endpoints

To evaluate neutralizing antibody 
production

Testing for neutralizing antibody
1.1.3.
Study Design
Overview of Study Design and Key Features
Design 
Features
This study includes a Screening Phase, Blind Phase, and Open-label Phase. The 
study design of each treatment phase is shown below.

Blind Phase: Multicenter, randomized, double-blind, placebo-controlled, 
parallel-group comparison design

Open-Label Phase: Multicenter, uncontrolled, open-label design
Dosing

In the Blind Phase, participants will be randomly assigned 1:1 to either the 400 or 
the 240-unit group.

In the 400-unit group, 240 units of the product will be injected into the 
muscles that act on the finger (including thumb flexors) and wrist flexors, and 
160 units into the muscles that act on the elbow flexors. A total of 400 units 
of the product will be injected. 

In the 240-unit group, 240 units of the product will be injected into the 
muscles that act on the finger (including thumb flexors) and wrist flexors. 
Placebo will be injected into the muscles that act on the elbow flexors. A total 
of 240 units of the product will be injected. 

In the Open-label phase, a total of 400 units will be injected in both groups. 

The product can be injected up to 3 times after completion of Part 1 in the 
blind phase. Participants whom the investigator considers as eligible for the 
injections will be treated. The next injections cannot be performed until the 
eligibility of the participant has been confirmed by the investigator. 

The muscle to be injected and the dose will be decided by the investigator 
based on the patient’s symptoms, and a total dose of 400 units of the product 
will be injected in a divided dose. For the muscles that the investigator 
considers as unnecessary to be treated, an injection may be skipped. The 
involving muscle and the dose do not have to be same each time always. 
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Overview of Study Design and Key Features
Treatment 
Assignment

Number of participants (randomized participants): 120 (60 per group)

GSK RandAll NG will be used to generate the randomization schedule.

The randomization will be stratified by the MAS score (3 or 4) in the elbow flexors 
at Day1
Interim 
Analysis

Interim analysis is planned in this study as described in 3.1.
1.1.4.
Statistical Hypotheses / Statistical Analyses
No formal hypothesis will not be tested. 
2.
PLANNED ANALYSES
2.1.
Interim Analyses
The interim planned primary analyses will be performed after the completion of the 
following sequential steps:
1.
All participants (except for early termination) complete the visit at Week 24 of the 
initial dose as defined in the protocol. The participants who complete that visit are 
defined as below.
The participant is re-treated at Week 12 visit in Blind Phase and completes the Week 12 
visit in Open-label Phase.
The participant is re-treated at Week 16 visit in Blind Phase and completes the Week 12 
visit in Open-label Phase.
The participant is re-treated at Week 20 visit in Blind Phase and completes the Week 4 
visit in Open-label Phase.
The participant completes the Week 24 visit in Blind Phase.
2.
All required database cleaning activities have been completed and interim database 
release and database freeze has been declared by Data Management.
3.
All criteria for unblinding the randomization codes have been met. 
4.
Randomization codes have been distributed according to RandAll NG procedures.
5.
Interim analyses will be performed. 
The interim analyses will be performed for regulatory submission. However subject level 
data will not be disclosed to people who work at the sites including investigators. 
All planned interim analyses (i.e. Study population, Efficacy and Safety analyses) will be 
performed using data up to Week 24 visit for all participants. 
For Adverse Events, Cardiovascular Events, Liver Events and Medication, the data up to 
Week 24 visit is defined by using the start date. If the start date of these data is earlier 
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than or same as the date of Week 24 visit defined above, these data will be included in 
the data up to Week 24 visit. Otherwise the data will not. 
2.2.
Final Analyses
The final planned primary analyses will be performed after the completion of the 
following sequential steps:
1.
All participants have completed the study as defined in the protocol.
2.
All required database cleaning activities have been completed and final database 
release and database freeze has been declared by Data Management.
3.
Final analyses will be performed. 
3.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
Screened

Comprise of all screened participants

Study Population
Enrolled

Comprise of all participants who meet the 
eligibility criteria at a screening and Day 1 visit. 

Study Population 
Intent-To-Treat 1 
(ITT1)

This population consists of all participants who 
are randomized in the study and who have at 
least 1 post-baseline efficacy assessment:

ITT is the primary efficacy analysis population, 
and the participants will be analyzed in line 
with the randomized treatment group

Any participant who receives a study treatment 
randomization number will be considered to 
have been randomized.

Study Population

Efficacy
ITT2

This population consists of all participants in 
ITT1 population, who have at least 2 study 
treatments and who have at least 1 efficacy 
assessment after the 2nd treatment. 

Study Population

Efficacy
ITT3

This population consists of all participants in 
ITT2 population, who have at least 3 study 
treatments and who have at least 1 efficacy 
assessment after the 3rd treatment.

Study Population

Efficacy
ITT4

This population consists of all participants in 
ITT3 population, who have 4 study treatments 
and who have at least 1 efficacy assessment 
after the 4th treatment.

Study Population

Efficacy
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Population
Definition / Criteria
Analyses Evaluated
Safety1

This population consists of all participants who 
are randomized in the study and who receive 
study treatment at least once

The participants will be analyzed based on the 
treatment actually given.

Safety
Safety2

This population consists of all participants in 
Safety1 population, who receive study 
treatment at least twice.

The participants will be analyzed based on the 
treatment actually given.

Safety
Safety3

This population consists of all participants who 
are randomized in the study and who receive 
study treatment at least three times

The participants will be analyzed based on the 
treatment actually given.

Safety
Safety4

This population consists of all participants in 
Safety1 population, who receive study 
treatment four times.

The participants will be analyzed based on the 
treatment actually given.

Safety
NOTES : 

Please refer to Appendix 12: List of Data Displays which details the population to be used for each displays being 
generated.
3.1.
Protocol Deviations
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarised and listed.
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan.
o Data will be reviewed prior to unblinding and freezing the database to ensure all 
important deviations are captured and categorised on the protocol deviations 
dataset. 
o This dataset will be the basis for the summaries and listings of protocol 
deviations.
A separate listing of all inclusion/exclusion criteria deviations will also be provided. This 
listing will be based on data as recorded on the inclusion/exclusion page of the eCRF.
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4.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
4.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
RandAll NG
Data Displays for Reporting 
Code
Description
Description
Order in TLF 
A
GSK1358820 240U
GSK1358820 240U
1
B
GSK1358820 400U
GSK1358820 400U
2
Treatment comparisons will be displayed as follows using the descriptors as specified:
1.
GSK1358820 400U vs GSK1358820 240U
4.2.
Baseline Definitions
For all endpoints (except as noted in baseline definitions) the baseline value will be the 
latest pre-dose assessment with a non-missing value, including those from unscheduled 
visits. If time is not collected, Day 1 assessments are assumed to be taken prior to first 
dose and used as baseline. These baseline values will be used for all analyses in both 
Blind Phase and Open Label Phase. 
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing.
4.3.
Multicentre Studies
No data will be analysed by center.
4.4.
Examination of Covariates, Other Strata and Subgroups
4.4.1.
Covariates and Other Strata
The list of covariates and other strata may be used in descriptive summaries and 
statistical analyses, some of which may also be used for subgroup analyses. Additional 
covariates and other strata of clinical interest may also be considered.
Category
Details
Strata and 
Covariates
Baseline MAS value (3 or 4)
4.4.2.
Examination of Subgroups
The list of subgroups may be used in descriptive summaries and statistical analyses.
Additional subgroups of clinical interest may also be considered.
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
If the percentage of participants is small within a particular subgroup, then the 
subgroup categories may be refined prior to unblinding the trial.

If the category cannot be refined further, then descriptive rather than statistical 
comparisons may be performed for the particular subgroup.
Subgroup
Categories 
Baseline MAS value
3 or 4 
Baseline Rehabilitation
Task-specific practice
Yes, or No
The subgroup analyses will be conducted by each rehabilitation use. 
Muscle strengthening exercise
Stretching/Range of motion 
exercise
Splinting/Orthoses
Taping
Positioning aids
4.5.
Multiple Comparisons and Multiplicity
No multiplicity adjustment is considered in this study because no statistical hypothesis 
will be tested.
4.6.
Other Considerations for Data Analyses and Data Handling 
Conventions
Other considerations for data analyses and data handling conventions are outlined in the 
appendices:
Section
Component
Section 9.3
Appendix 3: Assessment Windows
Section 9.4
Appendix 4: Study Phases and Treatment Emergent Adverse Events
Section 9.5
Appendix 5: Data Display Standards & Handling Conventions
Section 9.6
Appendix 6: Derived and Transformed Data
Section 9.7
Appendix 7: Reporting Standards for Missing Data
Section 9.8
Appendix 8: Values of Potential Clinical Importance
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5.
STUDY POPULATION ANALYSES
5.1.
Overview of Planned Study Population Analyses
The study population analyses will be based on the Screened, Enrolled and ITT
populations, unless otherwise specified.
Study population analyses including analyses of participant’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
and rehabilitations will be based on GSK Core Data Standards.  Details of the planned 
displays are presented in Appendix 12: List of Data Displays.
5.2.
Participant Disposition and Population
The number and percentage of those participants below will be presented by treatment 
group and total.

Participants who completed the Week 24 and who withdrew early from study by 
Week 24 (including the reasons for early withdrawal)

Participants who completed the study and who withdrew early from study 
(including the reasons for early withdrawal)

Participants who passed screening and who failed screening (including the 
reasons for screen failure)

Participants at each centre

Participants included in each population defined in the Section 3. 
These items below will be listed. 

The reasons for early withdrawal and screen failure. 

Participants who were rescreened. 

Participants for whom the treatment blind was broken. 

Planned and actual treatments

Participants excluded from any population defined in the Section 3.
5.3.
Protocol Deviation
The number and percentage of participants with important protocol deviation will be 
presented by treatment group. This summary will not include subcategories
Important protocol deviations and participants with inclusion/exclusion criteria deviation 
will be listed. 
5.4.
Demographic and Baseline Characteristics
These parameters as below will be summarized by treatment group and total.

Demographic data (age, sex, ethnicity, weight, height, body mass index(BMI), 
race and racial combinations)
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
Baseline Efficacy Parameter
o
Modified Ashworth Scales in finger, thumb, wrist, elbow, pronation of 
forearm and shoulder flexors.
o
Numeric Rating Scale for pain
o
Disability Assessment Scale (Main Assessment Parameter)
o
Disability Assessment Scale (Hygiene, Pain, Dressing and Limb posture)
o
The selected item as a Main Assessment Parameter of DAS out of the 4 
items

Hygiene

Pain

Dressing

Limb posture
5.5.
Prior and Concomitant Medications
All medication used in this study will be coded according to drug name as defined in the 
GSK Drug Dictionary. The relationship between the ATC level 1 and ingredient will be 
summarized for the all prior and concomitant medications, respectively. 
5.6.
Rehabilitation

Screening
The number and percentage of Rehabilitations will be presented.

Treatment phase
The category and frequency of Rehabilitations will be collected on eCRF. The number 
and percentage of each Rehabilitation will be presented in Blind Phase. The category and 
frequency of Rehabilitations in all treatment phase will be listed. 

Category and Frequency
The categories of Rehabilitation are as below: 

Task-specific practice

Muscle strengthening exercise

Stretching/Range of motion exercise

Splinting/Orthoses

Taping

Positioning aids
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
Other
The category of frequency which will be collected on CRF is defined as below:
o
No practice
o
> 8 days per month
o
> 8 and 16 days per month
o
> 16 and 24 days per month
o
> 24 days per month
6.
EFFICACY ANALYSES
6.1.
Primary Efficacy Analyses
6.1.1.
Endpoint / Variables
The primary endpoint is the responder rate of MAS score.
6.1.2.
Summary Measure
The summary measure is the difference in the responder rate of MAS score.
6.1.3.
Population of Interest
The primary efficacy analyses will be based on the Intent-To-Treat 1 population, unless 
otherwise specified.
6.1.4.
Strategy for Intercurrent (Post-Randomization) Events
Intercurrent event: early withdrawal from study
Strategy : if MAS score is missing because of an early withdrawal from the study, the 
participant will be regarded as a non-responder.
6.1.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 6.1.1 will be 
summarised using descriptive statistics and listed.
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6.1.5.1.
Statistical Methodology Specification
Endpoint / Variables

Responder Rate of MAS in the elbow flexors at Week 6 of the initial dose
Model Specification

To summarize the primary endpoint without statistical model
o
The primary endpoint will be calculated as the proportion of participants whose MAS score 
decreased by at least 1 level from the baseline in the ITT1 population.
o
The intergroup difference in the responder rate and its 95% confidence interval (Wald-
type) will be computed.
Data Convention

The MAS scores, 0, 1, 1+, 2, 3 and 4 will be encoded to 0, 1, 2, 3, 4 and 5, respectively, for the 
analyses.
Definition of Responder and Responder rate
“Responder” is defined as a participant whose MAS score decrease by at least 1 level from the 
baseline. 
Responder Rate will be calculated as below. 
Responder Rate (%) = (Number of Respondersparticipant) / (Number of participants in ITT1 
population) x 100

If MAS score of a given participant is missing at Week 6, then this participants will be regarded 
as a non-responder.
Model Results Presentation

The difference in the responder rate (400 units – 200 units) and its associated 95% CI will be 
presented.
Subgroup Analyses (Rehabilitation)

Subgroup analyses will be performed by baseline rehabilitation in the Section 4.4.

The difference (400 units – 200 units) and its 95% CI will be presented.
Subgroup Analyses (baseline MAS score)

Subgroup analyses will be performed by baseline MAS score (3 or 4).

The difference (400 units – 200 units) and its 95% CI will be presented.
Supportive Analyses

The difference in the responder rate will be estimated using Mantel-Haenszel method to 
consider a stratification factor, that is baseline MAS score (3 or 4).

Mantel-Haenszel rate difference (400 units – 200 units) and its 95% CI will be calculated.
6.2.
Secondary Efficacy Analyses
6.2.1.
Endpoint / Variables
Secondary Efficacy Endpoints are the following items:

MAS scores in the elbow, finger, thumb and wrist flexors.
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
Change from baseline in MAS scores

Responder rate of MAS in the elbow, finger, thumb and wrist flexors.

DAS score (Main Assessment Parameter)

Change from baseline in DAS score (Main Assessment Parameter)
6.2.2.
Summary Measure
Summary Measures are as below.

The differences in the responder rate of MAS scores

The differences in the least square means of changes from baseline in MAS scores

The differences in the least square means of changes from baseline in DAS scores
6.2.3.
Population of Interest
The secondary efficacy analyses will be based on the Intent-To-Treat 1 population, unless 
otherwise specified.
The secondary efficacy analyses will be performed for only double blind phase. All 
efficacy analyses for open -label phase and other endpoints for double blind phase will be 
done as exploratory.
Unless specified otherwise, the data up to Week 12 of treatment will be summarized 
during the double-blind period. This is because this study allows to re-treat. In other 
words, after 12 weeks, only participants who have a smaller MAS score would remain 
and the difference of the change from baseline in MAS between 240 units and 400 units 
would be attenuated. Therefore, the data up to Week 12 of initial treatment will be 
analysed as secondary statistical analyses. This is the case for exploratory analyses for 
open label period (i.e. the data up to week 12 of re-treatment will be summarized). 
Listing will include the data after week 12 of treatment/re-treatment.
6.2.4.
Strategy for Intercurrent (Post-Randomization) Events
Intercurrent event: early withdrawal from study.
Strategy for dichotomous data: the participant will be regarded as a non-responder.
Strategy for continuous data: the missing data will be removed from the analyses. 
6.2.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 6.2.1 will be 
summarised using descriptive statistics, graphically presented and listed.
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6.2.5.1.
Statistical Methodology Specification
Secondary Efficacy Analysis
Endpoint / Variables

Change from baseline in MAS and DAS scores
Model Specification

The endpoint will be analyzed using a mixed model for repeated measures (MMRM)

Terms fitted in the MMRM will include the items below as fixed and categorical effects.

Treatment

Visit

Treatment-by-visit interaction

Baseline value

Baseline-by-visit interaction

An unstructured variance structure will be used to model the within-participant errors, shared 
across treatments.

The empirical sandwich estimator will be used to estimate the standard errors.
Model Checking & Diagnostics

If the model will not converge with unstructured variance, AR(1) variance structure can be
used. 
Model Results Presentation

Adjusted means (least square means) and corresponding standard errors of means will be 
presented for each treatment by visit, together with estimated treatment differences (400 units 
– 240 units) and the corresponding 95% CI.
Data included in Model

The dataset including only data until week 12 after the first treatment will be used. 
Endpoint / Variables

Responder Rate of MAS score
Model Specification

See primary endpoint section.
Data Convention

See primary endpoint section. 
Supportive Statistical Analyses

See supportive statistical analyses for primary efficacy analyses section.
6.3.
Exploratory Efficacy Analyses
6.3.1.
Modified Ashworth Scale (MAS)
These analyses will be based on ITT 2, 3 and 4 populations.
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Values and changes from baseline in MAS scores in finger, thumb, wrist, elbow, 
pronation of the forearm and shoulder flexors will be summarised using descriptive 
statistics, graphically presented and listed by visit and treatment cycle. Data up to Week 
12 in each treatment cycle will be used for summary tables and Figures, whereas all data 
will be listed. 
6.3.2.
Numeric Rating Scale (NRS) for pain
These analyses will be based on ITT 1, 2, 3 and 4 populations. 
Values and changes from baseline in NRS for pain will be summarised using descriptive 
statistics, graphically presented and listed by visit and treatment cycle. 
6.3.3.
Disability Assessment Scale (DAS)
These analyses will be based on ITT 1, 2, 3 and 4 populations. 
Values and changes from baseline in all items of DAS will be summarised using 
descriptive statistics, graphically presented and listed by visit and treatment cycle. 
6.3.4.
Clinical Global Impression of Change (CGI) of functional 
disability
These analyses will be based on ITT 1, 2, 3 and 4 populations. 
Values of the variables below will be summarised using descriptive statistics, graphically 
presented and listed by visit and treatment cycle.
CGI of functional disability by an investigator
CGI of functional disability by a patient
6.3.5.
Patient-Reported Benefit of Injection
These analyses will be based on ITT 1, 2, 3 and 4 populations. 
The number and percentage of patient-reported benefit of injection will be presented and 
listed by visit and treatment cycle.
6.3.6.
Time to Patient-Reported Onset of Spasticity Symptom Relief
These analyses will be based on ITT 1, 2, 3 and 4 populations. 
Time to event data will be summarized using the descriptive statistics below and listed. 

The number of events and censored cases. 

Median survival time with the associated 95% CI. 

25% and 75% survival time. 
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Survival analyses will be conducted using a Kaplan-Meier method. To graphically 
compare the survival functions between 400 units and 240 units, the analysis will be 
conducted based on ITT 1 population whereas the analyses will be based on ITT 2, 3 and 
4 populations to assess the survival time by treatment cycle. Participants who are
withdrawn from this study before Visit 2 are censored at the withdrawal date. All other 
participants who do not experience the event and is not withdrawn from study are 
censored at the Visit 2. 
Survival function estimates will be summarized (survival probabilities and the number of 
participants at risk per time to event, and median in survival time) based on Kaplan Meier 
method. Kaplan Meier plots will be presented. 
6.3.7.
Time to Qualification for Retreatment
These analyses will be based on ITT 1, 2, 3 and 4 populations. 
The number and percentage of event of interest will be presented by visit. Time to event 
data will be summarized using the descriptive statistics below and listed. 

The number of events and censored cases. 

Median survival time with the associated 95% CI. 

25% and 75% survival time. 
Survival analyses will be conducted using a Kaplan-Meier method. To graphically 
compare the survival functions between 400 units and 240 units, the analysis will be 
conducted based on ITT 1 population whereas the analyses will be based on ITT 2, 3 and 
4 populations to assess the survival time by treatment cycle. Participants who are 
withdrawn from this study before the event are censored at the withdrawal date. All 
other participants who do not experience the event and is not withdrawn from study are 
censored at the Last Observed Visit at the interim analyses or the final analyses.
Survival function estimates will be summarized (survival probabilities and the number of 
participants at risk per time to event, and median in survival time) based on Kaplan Meier 
method. Kaplan Meier plots will be presented. 
Note that the retreatment is not allowed within 83 days from the previous treatment. 
Therefore, this event will not occur before 83 days later after the treatment/re-treatment. 
7.
SAFETY ANALYSES
The safety analyses will be based on the Safety 1, 2, 3 and 4 populations, unless 
otherwise specified.
7.1.
Adverse Events Analyses
Adverse events analyses including the analysis of adverse events (AEs), Serious (SAEs)
and other significant AEs will be based on GSK Core Data Standards. The details of the 
planned displays are provided in Appendix 12: List of Data Displays.
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Adverse events that occurred in the overall study period, blinded period and open-label 
period will be summarized for each treatment group. The treatment group is based on 
dose actually given in blind period. For the blinded period, 2 patterns of analyses on 
adverse events will be performed, one is on adverse events that occurred between the 
initial dose and the first dose in the open-label period (or at the completion of study if no 
dose is given in the open-label period or at the study withdrawal), and another one is on 
adverse events that occurred within 84 days from the initial dose. 
Overall study period (Treatment Emergent AEs)
Blind phase
1.
AEs occurred between the initial dose and the first dose in the open-label period 
(or at the completion of study if no dose is given in the open-label period or at 
the study withdrawal)
2.
AEs occurred within 84 days from the initial dose
Open-label phase
1. AEs occurred during 2nd treatment cycle.
2. AEs occurred during 3rd treatment cycle. 
3. AEs occurred during 4th treatment cycle. 
The number and percentages of participants who experience at least one AE will be 
presented for each category of AE listed as below by treatment group. 

All Treatment Emergent AEs (by SOC and PT, by SOC, PT and Maximum 
Intensity)

Common AEs (>= 3%) (by overall frequency)

Drug Related AEs (by SOC and PT, by SOC, PT and Maximum Intensity)

Non-Fatal Serious AEs

Drug Related Non-Fatal Serious AEs

AEs Leading to Permanent Discontinuation of Study Treatment or Withdrawal 
from Study (by SOC and PT)

Most Common Serious Drug Related AEs (by overall frequency)

Most Common Non-Serious Drug Related AEs (by overall frequency)

Common (>= 5%) Non-Serious AEs (by SOC and PT)
o
Number of Participant and Occurrences will be presented. 
“Common (>= 3%) AEs” is defined as the percentage of AEs is more than and equal to 
3% in either treatment group. 
In addition, the items below will be listed. 

All AEs

Participant Numbers for Individual AEs

Fatal Serious AEs

Non-Fatal Serious AEs

Reasons for Considering as a Serious AE
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
AEs Leading Withdrawal from Study/ Permanent Discontinuation of Study 
Treatment

Relationship between AE SOC, PT and Verbatim Text.
7.2.
Adverse Events of Special Interest Analyses
Adverse Events of Special Interest are defined as below. 

Convulsions and Seizures

Respiratory Adverse Events

Possible Distant Spread of Toxin
The number and percentage of AESI will be presented by treatment cycle and treatment 
group. The details of how to identify are described in the Appendix 13. 
7.3.
Clinical Laboratory Analyses
Laboratory evaluations including the analyses of Chemistry laboratory tests, Hematology 
laboratory tests, Urinalysis, and liver function tests will be based on GSK Core Data 
Standards. The details of the planned displays are in Appendix 12: List of Data Displays.
These data at Screening Visit, in Blind Phase and at Final Visit will be summarized by 
visit. Data at all visits will be listed. 
Values and change from baseline in Chemistry Laboratory tests and Hematology 
laboratory tests will be summarized by treatment group and visit. 
Worst case results relative to normal range from baseline will be presented for Chemistry, 
Hematology and Urinalysis. 
Shifts from baseline relative to normal range will be summarized by treatment group and 
visit for Chemistry and Hematology values. 
Scatter plot of Chemistry and Hematology at Week 12 versus baseline in Blind Phase will 
be presented. 
The outputs regarding liver events will not be presented unless at least one liver event is 
observed. See the details in the Appendix 12. 
7.4.
Other Safety Analyses
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified. The details of the 
planned displays are presented in Appendix 12: List of Data Displays.
These above data at Screening Visit, in Blind Phase and at Final Visit will be summarized 
by visit. Data at all visits will be listed. 
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ECG findings (Normal, Abnormal – not clinically significant, Abnormal -clinically 
significant) will be summarized by visit. 
Values and changes from baseline in ECG and vital sign data will be summarized by visit. 
Values and changes from baseline in SpO2 will be summarized and listed by visit. Data 
at Screening visit, Visit 1 and 5 in Blind Phase and Final Visit will be summarized and 
those at all visits will be listed. 
7.5.
Exposure

Blind Phase
The number and percentage of participants treated will be presented and the dosage will 
be summarized by muscle region below, Joint and total. The dosage will be listed by 
muscle region, subtotal and total. 
Joint
Each muscle region
Elbow
Biceps brachii
Brachialis
Brachioradialis
Wrist
Flexor carpi radialis
Flexor carpi ulnaris
Finger
Flexor digitorum profundus
Flexor digitorum superficialis
Thumb
Flexor pollicis longus
Adductor pollicis

Open Label Phase
The number and percentage of participants treated will be presented and the dosage will 
be summarized by treatment phase (2nd, 3rd and 4th treatment), muscle region below, 
Joint and total. The dosage will be listed by treatment phase and muscle region, Joint and 
total.
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Joint
Each muscle region
Elbow
Biceps brachii 
Brachialis
Brachioradialis
Wrist
Flexor carpi radialis
Flexor carpi ulnaris
Finger
Flexor digitorum profundus
Flexor digitorum superficialis
Lumbricales interossei
Thumb
Flexor pollicis longus
Adductor pollicis
Opponens
Forearms
Pronator teres
Pronator quadratus
Shoulder
Teres major 
Latissimus dorsi
Pectoralis major 
Subscapularis
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8.
REFERENCES
GlaxoSmithKline Document Number 2017N315029_02 Study ID 207660. A phase III 
study (a placebo controlled, randomized, double-blind comparative study and an open-
label, uncontrolled study) to evaluate the efficacy and safety of GSK1358820 in patients 
with post-stroke upper limb spasticity. Report Date 06-Oct-2017. 
Study Reference Manual, Study ID 207660. A phase III study (a placebo controlled, 
randomized, double-blind comparative study and an open-label, uncontrolled study) to 
evaluate the efficacy and safety of GSK1358820 in patients with post-stroke upper limb 
spasticity. Effective Date 29-Jun-2017
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9.
APPENDICES
9.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
Per Protocol Population is not defined in this study.
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9.2.
Appendix 2: Schedule of Activities
9.2.1.
Protocol Defined Schedule of Events
Screeninga
Blind phase
1)
If a participant meets the eligibility at V5/ QRV, 
the participant will move forward to the open-label phase
Open-label phase
If a participant meets the eligibility at V5/QRV, the participant will 
move forward to the next treatment phase
Completion 
visit
Part 1
Eligibility 
evaluation b
Part 2/Part 3/ Part 4
Eligibility 
evaluation b
Visit
SV
V1
(Day 1)
V2
V3
V4
V5 c
(Eligibility 
evaluation)
QRV
V1
V2
V3
V4
V5 d
(Eligibility 
evaluation)
QRV
Final
Visit
Time from initial injection 
(Day 1) (Weeks)
―
0
2
4
6
12 
Allowable Week 16 
to 36e
―
―
―
―
―
Allowable Week 24 to 
36 e
48/
Withdrawal
Time from injection day in each 
treatment phase (Weeks)
―
0
2
4
6
12
16/ 20/ 24/ 28/ 32/ 
36
0
2
4
6
12
16/ 20/ 24
-
Acceptable visit windows 
(days) 
―
4
4
4
+4 f
14 g
(+4)v
4
4
4
+4 f
14 g
4
Written informed consent
X h
Randomization
X i
Injections
X
X
Evaluation of eligibility
X
X
X
X
Inclusion/exclusion criteria j
X
X i
Participant demography
X
MAS k
X
X i
X
X
X
X
X
X i,t
X
X
X
X
X
X
NRS l
X i
X
X
X
X
X i,t
X
X
X
X
(X) r
DAS 
X i
X
X
X
X
X i,t
X
X
X
X
(X) r
CGI by a investigator
X
X
X
X
X
X
X
X
(X) r
CGI by a patient
X
X
X
X
X
X
X
X
(X) r
Time to patient-reported onset 
of spasticity symptom relief
X
X
Patient-reported benefit of 
injection
X
X
X
X
X
X
(X) r
Physical examination (complete 
version)
X
Physical examination 
(simplified version)
X i
X
X i,t
X
X
Medical history
X
X i
Vital signs m
X
X i
X
X i,t
X
X
Height
X
Body weight
X
X u
X u
X u
X u
Pulmonary function test
X
X
X
X u
X
X u
X
Electrocardiogram
X
X u
X u
X u
X u
Pregnancy test n
X
X i
X u
X u
Xs, u
X u
X
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Screeninga
Blind phase
1)
If a participant meets the eligibility at V5/ QRV, 
the participant will move forward to the open-label phase
Open-label phase
If a participant meets the eligibility at V5/QRV, the participant will 
move forward to the next treatment phase
Completion 
visit
Part 1
Eligibility 
evaluation b
Part 2/Part 3/ Part 4
Eligibility 
evaluation b
Visit
SV
V1
(Day 1)
V2
V3
V4
V5 c
(Eligibility 
evaluation)
QRV
V1
V2
V3
V4
V5 d
(Eligibility 
evaluation)
QRV
Final
Visit
Laboratory test o
X
X
X
X
Adverse events p
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medications/therapies
X
X i
X
X
X
X
X
X
X
X
X
X
X
X
Testing for neutralising 
antibodies q
X
X
X
a.
Test items for screening must be performed from 4 weeks to 1 weeks before Day 1 visit (±3 days).
b.
Eligibility evaluation (Qualification for Retreatment Visit: QRV) will be performed at V5 as a starting point if a participant does not meet the criteria only. 
The evaluation is performed at a 4-week interval, V5 as a starting point, The QRV when a participant meets the criteria will be a same day as the injection in 
the next treatment period.
c.
If a participant is evaluated to meet the eligibility for the injection in the blind phase at V5, the participant will move forward to Part 2 in the open-label 
phase (Namely, V5 in Part 1 and V1 in Part 2 is a same day). If the participant does not meet the eligibility, QRV will be performed 4 weeks later, at V5 as s 
starting point. 
d.
If a participant is evaluated to meet the eligibility at V5 in the open-label phase, the participant will move forward to the next treatment phase (V5 and V1 in 
the next treatment phase is a same day). If the participant does not meet the eligibility, QRV is performed 4 weeks later, V5 as a starting point. If V5 in each 
treatment phase is at Week 48 after initial injection, V5 will be considered to be completion visit (FV). However, for the testing items, pre-scheduled tests at 
V5 and neutralizing antibody tests will be performed. If V5 in Parts 2 and 3 is performed at Week 36 or later, after completion of V5, completion visit will 
be performed at Week 48.
e.
QRV is allowable to perform from initial injection to Week 36. Eligibility evaluation (QRV) will not be performed after Week 36.  
f.
V5 must be performed at least 84 days after V1. 
g.
The acceptable visit windows will be -14 to +4 days if QRV is performed at Week 36.
h.
Must be performed earlier than any other procedures
i.
Must be performed before injection of the product
j.
For inclusion/exclusion criteria, the items to be observed are different between screening phase and Day 1. For details, refer to Protocol Section 6.1 and 
Section 6.2.
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k.
For MAS evaluation, the items to be evaluated differ depending on the treatment phase. For details, refer to Protocol Section 9.1.1.1.
l.
MAS evaluation will be followed by NRS evaluation. For NRS evaluation, items to be evaluated differ. For details, refer to Protocol Section 9.1.1.2.
m. Body temperature, heart rate, and blood pressure will be measured as vital signs. 
n.
Women of childbearing potential will be only performed. Serum hCG pregnancy test must be performed at screening, and urine hCG pregnancy test after 
randomization. The tests can be performed beyond the protocol specifications if an investigator considers to be necessary.  
o.
For laboratory test items, refer to Protocol Section 12.2. Attachment 2. Fasting is not required for blood collection. 
p.
Adverse events and serious adverse events collection period will be from the initial injection day (Day 1) to completion visit (FV).
q.
Neutralizing antibody testing is performed 3 times in each participant. The first test will be performed in screening phase, the second is at V5 in the blind 
phase, and the third is at completion visit.
r.
A participant who withdraws the study before 12 weeks after last injection will be performed. 
s.
Perform if V5 in each treatment phase is at Week 48 after initial injection
t.
Not necessary to perform doubly as V1 assessment if the same assessment is performed at V5 or QRV. If V1 assessment or retreatment cannot be performed 
on the same day as V5 or QRV, MAS assessment should be performed again on the day of visit for the V1 assessment.
u.
Evaluation of retreatment is performed only when the dosing conditions (1 to 5) of retreatment evaluation are met. If V1 assessment or retreatment cannot be 
performed on the same day as V5 or QRV, body weight, pulmonary function test, electrocardiogram, and pregnancy test should not be performed again on 
the day of visit for V1 assessment.
v.
V1 assessment in Part 2 or subsequent parts should be performed as a rule on the same day as V5 or QRS (when eligibility was confirmed) of the previous 
part. If this is not possible, the V1 assessment may be performed on another day but within the acceptable visit window. 
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9.3.
Appendix 3: Assessment Windows
This study does not define Assessment Windows. 
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9.4.
Appendix 4: Study Phases and Treatment Emergent 
Adverse Events
9.4.1.
Study Phases for Concomitant Medication
Study Phase
Definition
Prior
If medication end date is not missing and is prior to the date of first treatment
Concomitant
Any medication that is not a prior
NOTES: 

Please refer to Appendix 7: Reporting Standards for Missing Data for handling of missing and partial dates for 
concomitant medication. Use the rules in this table if concomitant medication date is completely missing.
9.4.2.
Study Phases for Adverse Events
Flag
Definition
Treatment 
Emergent

First Study Treatment Date ≤ AE Start Date ≤ Final Visit Date/Early Withdrawal 
Date
Blind phase (until 
second dose)

First Study Treatment Date AE Start Date Second Study Treatment Date AND
AE Start Time < Second Study Treatment Time IF AE Start Time is collected

First Study Treatment Date AE Start Date < Second Study Treatment Date IF
AE Start Time is not collect. 
Blind phase 
(within 84 days)

First Study Treatment Date AE Start Date First Study Treatment Date + 84 
days AND AE Start Time < Second Study Treatment Time
Open-Label 
Phase (2nd 
Treatment)

Second Study Treatment Date AE Start Date Third Study Treatment Date 
AND Second Study Treatment Time AE Start Time < Third Study Treatment 
Time IF AE Start Time is collected

Second Study Treatment Date AE Start Date < Third Study Treatment Date IF
AE Start Time is not collected
Open-Label 
Phase (3rd 
Treatment)

Third Study Treatment Date AE Start Date Fourth Study Treatment Date AND
Third Study Time AE Start Time < Fourth Study Treatment Time IF AE Start 
Time is collected

Third Study Treatment Date AE Start Date < Fourth Study Treatment Date IF AE 
Start Time is not collected
Open-Label 
Phase (4th 
Treatment)

Fourth Study Treatment Date AE Start Date Final Visit Date AND Fourth 
Study Time AE Start Time IF AE Start Time is collected

Fourth Study Treatment Date AE Start Date Final Visit Date IF AE Start Time 
is not collected
Drug related

If relationship to Study treatment(GSK1358820/Placebo) is marked ‘YES’ on CRF 
OR value is missing. 
9.4.2.1.
Definition of Adverse Events of Special Interest
AEs of Special Interest are defined in the Appendix 13. If a Preferred Term of AE is 
included in the list of PTs of the specific AESI, that AE will be considered as AESI. See 
the details in the Appendix 13. 
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9.5.
Appendix 5: Data Display Standards & Handling 
Conventions
9.5.1.
Reporting Process
Software

The currently supported versions of SAS software will be used.
Reporting Area
HARP Server
: US1SALX00259.corpnet2.com
HARP Compound
: arenv\arprod\gsk1358820\mid207660
Analysis Datasets 

Analysis datasets will be created according to Legacy GSK A&R dataset standards.
Generation of RTF Files

RTF files will not be generated.
9.5.2.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: 
https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx):

4.03 to 4.23: General Principles

5.01 to 5.08: Principles Related to Data Listings

6.01 to 6.11: Principles Related to Summary Tables

7.01 to 7.13: Principles Related to Graphics 

Do not include participant level listings in the main body of the GSK Clinical Study Report. All 
participant level listings should be located in the modular appendices as ICH listings
Formats

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for reporting of 
data based on the raw data collected, unless otherwise stated.

Numeric data will be reported at the precision collected on the eCRF.

The reported precision from non eCRF sources will follow the IDSL statistical principles but may be
adjusted to a clinically interpretable number of DP’s. 
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses:

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled visit days 
on the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the participant’s listings. 
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Unscheduled Visits

Unscheduled visits will not be included in summary tables and/or figures.

All unscheduled visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Time to event data

The number of events and censored case.

25th and 75th percentiles survival time. 

Median survival time with the associated 95% CIs.
95%CIs will be calculated based on Brookmeyer and Crowley method using log-log 
function as a g-transformation. (This method can be performed using Proc 
LIFETEST with no special statement or option (SAS 9.4))
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.
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9.6.
Appendix 6: Derived and Transformed Data
9.6.1.
General
Study Day

Calculated as the number of days from First Dose Date:

Ref Date = Missing              → Study Day = Missing 

Ref Date < First Dose Date → Study Day = Ref Date – First Dose Date

Ref Data ≥ First Dose Date → Study Day = Ref Date – (First Dose Date) + 1    
9.6.2.
Study Population
Age

GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed as 
follow:
o
Any participant with a missing date and month will have this imputed as ‘30th June’.

Birth date will be presented in listings as ‘YYYY’. 

Age will be calculated based on year of the Screening visit as an Age reference date. 
Age Group

The following category will be used for Summary of Demography.
o
Age 18 (years)
o
19 < Age < 64
o
65 Age
Age Category

The following category will be used for Summary of Age Ranges.
o
Age < 17 (years)
o
18 Age 64
o
65 Age 84
o
85 Age
Extent of Exposure

The total of dosage per treatment cycle will be calculated based on the formula:
Total of Dosage per treatment cycle = Sum of (Dosage in each Muscle Region)

The subtotal of dosage in each joint per treatment cycle will be calculated based on the formula:
Subtotal of Dosage in the joint per treatment cycle = Sum of (Dosage in each Muscle Region of 
the Joint)

Example
Subtotal of Dosage in Elbow = Sum of (Dosage in Biceps brachii, Brachalis and Brachioradialis)
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9.6.3.
Efficacy
Time to Event Data
Time to Qualification for Retreatment

This time to event data will be derived based on the following formula:
Time to Event (Days) = Date When a Participant Meets the Criteria for Retreatment – Study 
Treatment Start Date (Days)

If a participant is withdrawn from this study, the participant will be regarded as censoring and censored 
date will be a withdrawal date. 
Time to Patient Reported Onset of Spasticity Symptom Relief

This time to event data will be derived based on the following formula:
Time to Event (Days) = Onset Date of the Spasticity Symptom Relief – Study Treatment Start 
Date (Days)
If a participant is withdrawn from this study, the participant will be regarded as censoring and censored date 
will be a withdrawal date.
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9.7.
Appendix 7: Reporting Standards for Missing Data
9.7.1.
Premature Withdrawals
Element
Reporting Detail
General

Participant study completion (i.e. as specified in the protocol) was defined as those who 
completed all the study procedures, including a completion visit. . 

Withdrawn participants were not replaced in the study.

All available data from participants who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, unless 
otherwise specified.

Withdrawal visits will be slotted as per Appendix 3: Assessment Windows or will be 
summarised as withdrawal visits.
9.7.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank fields on 
the collection instrument:
o
These data will be indicated by the use of a “blank” in participant listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such.
Responder 
of MAS

If MAS score is missing at the corresponding visit, the participant will be regarded as 
those who are a non-responder (i.e. non-responder imputation). 
9.7.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in participant listing displays.
Concomitant 
Medications

Partial dates for any concomitant medications recorded in the CRF will be imputed 
using the following convention:
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' will be 
used for the month
o
If the partial date is a stop date, a '28/29/30/31' will be used for the day (dependent 
on the month and year) and 'Dec' will be used for the month.

The recorded partial date will be displayed in listings.
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9.8.
Appendix 8: Values of Potential Clinical Importance
This is not applicable to this study. 
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9.9.
Appendix 9: Population Pharmacokinetic (PopPK) Analyses
This is not applicable to this study. 
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9.10.
Appendix 10: Pharmacokinetic / Pharmacodynamic 
Analyses
This is not applicable to this study. 
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9.11.
Appendix 11: Abbreviations & Trade Marks
9.11.1.
Abbreviations
Abbreviation
Description
ADaM
Analysis Data Model
AE
Adverse Event
AIC
Akaike's Information Criteria
A&R
Analysis and Reporting 
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CPMS
Clinical Pharmacology Modelling & Simulation
CS
Clinical Statistics
CSR
Clinical Study Report
CTR
Clinical Trial Register
CVb / CVw
Coefficient of Variation (Between) / Coefficient of Variation (Within)
DBF
Database Freeze
DBR
Database Release
DOB
Date of Birth
DP
Decimal Places
eCRF
Electronic Case Record Form
EMA
European Medicines Agency
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Clinical Results Disclosure Requirements
GSK
GlaxoSmithKline
IA
Interim Analysis
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee 
IDSL
Integrated Data Standards Library
IMMS
International Modules Management System
IP
Investigational Product
ITT
Intent-To-Treat
MMRM
Mixed Model Repeated Measures
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PK
Pharmacokinetic
PP
Per Protocol
PopPK
Population PK
QC
Quality Control
QTcF
Frederica’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RAP
Reporting & Analysis Plan
RAMOS
Randomization & Medication Ordering System 
SAC
Statistical Analysis Complete
SDSP
Study Data Standardization Plan
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Abbreviation
Description
SDTM
Study Data Tabulation Model
SOP
Standard Operation Procedure
TA
Therapeutic Area
TFL
Tables, Figures & Listings 
9.11.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
NONE
SAS
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9.12.
Appendix 12: List of Data Displays
9.12.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.18
Efficacy
2.1 to 2.49
2.1 to 2.56
Safety
3.1 to 3.132
3.1 to 3.2
Section
Listings
ICH Listings
1 to 61
9.12.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated
Section
Figure
Table
Listing
Study Population
POP_Tn
POP_Ln
Efficacy
EFF_Fn
EFF_Tn
EFF_Ln
Safety
SAFE_Fn
SAFE_Tn
NOTES: 

Non-Standard displays are indicated in the ‘IDSL / Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’
9.12.3.
Deliverables
Delivery
Description
IA SAC
Interim Analysis Statistical Analysis Complete
SAC
Final Statistical Analysis Complete
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9.12.4.
Study Population Tables
9.12.4.1.
Interim Analyses
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Participant Disposition
1.1.
ITT1
ES1
Summary of Participant Disposition for the Participant
Conclusion Record (Week 24)
ICH E3, FDAAA, EudraCT
Participant disposition at Week 24. 
IA SAC
1.2.
Screened
ES6
Summary of Screening Status and Reasons for Screen Failure
Journal Requirements
IA SAC
1.3.
Enrolled
NS1
Summary of Number of Participant by Site ID
EudraCT/Clinical Operations
IA SAC
Protocol Deviation
1.4.
ITT1
DV1
Summary of Important Protocol Deviations
ICH E3
IA SAC
Population Analysed
1.5.
Screened
SP1
Summary of Study Populations 
IDSL
IA SAC
Demographic and Baseline Characteristics
1.6.
ITT1
DM1
Summary of Demographic Characteristics
ICH E3, FDAAA, EudraCT
Include total arm (240 U + 400 U)
IA SAC
1.7.
Enrolled
DM11
Summary of Age Ranges
EudraCT
IA SAC
1.8.
Enrolled
DM5
Summary of Race and Racial Combinations
ICH E3, FDA, FDAAA, EudraCT
IA SAC
1.9.
ITT1
POP_T1
Summary of Baseline Efficacy Parameters

MAS scores in finger, thumb, 
wrist, elbow, pronation of forearm 
and shoulder flexors

Numeric Rating Scale for pain

Disability Assessment Scale

Include total arm (240 U + 400 U)
IA SAC
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Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Prior and Concomitant Medications
1.10.
ITT1
CM1
Summary of Prior Medications
IA SAC
1.11.
ITT1
CM1
Summary of Concomitant Medications
ICH E3
IA SAC
1.12.
ITT1
POP_T2
Summary of Rehabilitation
IA SAC
9.12.4.2.
Final Analyses
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Participant Disposition
1.13.
ITT1
ES1
Summary of Participant Disposition for the Participant 
Conclusion Record
ICH E3, FDAAA, EudraCT
SAC
Protocol Deviation
1.14.
ITT1
DV1
Summary of Important Protocol Deviations
ICH E3
SAC
Population Analysed
1.15.
Screened
SP1
Summary of Study Populations 
IDSL
SAC
Prior and Concomitant Medications
1.16.
ITT1
CM1
Summary of Prior Medications
SAC
1.17.
ITT1
CM1
Summary of Concomitant Medications
ICH E3
SAC
1.18.
ITT1
POP_T2
Summary of Rehabilitation
SAC
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9.12.5.
Efficacy Tables
9.12.5.1.
Interim Analyses
Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
MAS
2.1.
ITT1
EFF_T1
Summary of MAS score in Blind Phase

Values and change from 
baseline

Summarize data up to Visit 5
IA SAC
2.2.
ITT1
EFF_T2
Summary of the Results of Mixed Models for Repeated 
Measures of Change from Baseline in MAS scores in Blind 
Phase
Analyse data up to Visit 5
IA SAC
2.3.
ITT1
EFF_T3
Summary of Responder rate of MAS score at Week 6 in Blind 
Phase
Including subgroup analyses
IA SAC
2.4.
ITT1
EFF_T4
Summary of Responder rate of MAS score in Blind Phase
Summarize data up to Visit 5
Include Mantel Haenszel estimators
IA SAC
2.5.
ITT2
EFF_T1
Summary of MAS score in Open Label Phase (2nd Treatment)

Values and change from 
baseline

Summarize data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
IA SAC
2.6.
ITT2
EFF_T5
Summary of Responder rate of MAS score in Open Label Phase 
(2nd Treatment)

Summarize data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
IA SAC
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
DAS
2.7.
ITT1
EFF_T1
Summary of Main Assessment Parameter and All Items of DAS 
in Blind Phase

Values and change from 
baseline

Summarize data up to Visit 5
IA SAC
2.8.
ITT1
EFF_T2
Summary of the Results of Mixed Models for Repeated 
Measures of Main Assessment Parameter of DAS in Blind 
Phase
Analyse data up to Visit 5
IA SAC
2.9.
ITT2
EFF_T1
Summary of Main Assessment Parameter and All Items of DAS 
in Open Label Phase (2nd Treatment)

Values and change from 
baseline

Summarize data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
IA SAC
NRS for pain
2.10.
ITT1
EFF_T1
Summary of NRS for pain in Blind Phase

Values and change from 
baseline

Summarize data up to Visit 5
IA SAC
2.11.
ITT2
EFF_T1
Summary of NRS for pain in Open Label Phase (2nd Treatment)

Values and change from 
baseline

Summarize data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
IA SAC
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
CGI of functional disability
2.12.
ITT1
EFF_T1
Summary of CGI of functional disability by an investigator in 
Blind Phase

Values and change from 
baseline

Summarize data up to Visit 5
IA SAC
2.13.
ITT2
EFF_T1
Summary of CGI of functional disability by an investigator in 
Open Label Phase (2nd Treatment)

Values and change from 
baseline

Summarize data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
IA SAC
2.14.
ITT1
EFF_T1
Summary of CGI of functional disability by a patient in Blind 
Phase

Values and change from 
baseline

Summarize data up to Visit 5
IA SAC
2.15.
ITT2
EFF_T1
Summary of CGI of functional disability by a patient in Open 
Label Phase (2nd Treatment)

Values and change from 
baseline

Summarize data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
IA SAC
Patient-Reported Benefit of Injection
2.16.
ITT1
EFF_T5
Summary of Patient-Reported Benefit of Injection in Blind Phase

Values and change from 
baseline

Summarize data up to Visit 5
IA SAC
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
2.17.
ITT2
EFF_T5
Summary of Patient-Reported Benefit of Injection in Open Label 
Phase (2nd Treatment)

Values and change from 
baseline

Summarize data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
IA SAC
Time to Patient-Reported Onset of Spasticity Symptom Relief
2.18.
ITT1
EFF_T6
Summary of Time to Patient-Reported Onset of Spasticity 
Symptom Relief
IA SAC
2.19.
ITT1
EFF_T7
Summary of Survival Analyses Results of Time to Patient-
Reported Onset of Spasticity Symptom Relief in Blind Phase

Survival function estimates will 
be summarized
IA SAC
2.20.
ITT2
EFF_T7
Summary of Survival Analyses Results of Time to Patient-
Reported Onset of Spasticity Symptom Relief in Open Label 
Phase (2nd Treatment)

Survival function estimates will 
be summarized

Three treatment arms (240, 
400 and 240 + 400U)
IA SAC
Time to Qualification for Retreatment
2.21.
ITT1
EFF_T8
Summary of Events in Which a Participant Meets the Criteria for 
Retreatment
IA SAC
2.22.
ITT1
EFF_T6
Summary of Time to Qualification for Retreatment
IA SAC
2.23.
ITT1
EFF_T7
Summary of Survival Analyses Results of Time to Qualification
for Retreatment in Blind Phase

Survival function estimates will 
be summarized

Two treatment arms (240 and 
400U)
IA SAC
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
2.24.
ITT2
EFF_T7
Summary of Survival Analyses Results of Time to Qualification
for Retreatment in Open Label Phase (2nd Treatment)

Survival function estimates will 
be summarized

Three treatment arms (240, 
400 and 240 + 400U)
IA SAC
9.12.5.2.
Final Analyses
Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable
MAS
2.25.
ITT3
EFF_T1
Summary of MAS score in Open Label Phase (3rd Treatment)

Values and change from 
baseline

Summarize data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
SAC
2.26.
ITT4
EFF_T1
Summary of MAS score in Open Label Phase (4th Treatment)
SAC
2.27.
ITT3
EFF_T5
Summary of Responder rate of MAS score in Open Label Phase 
(3rd Treatment)

Summarize data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
SAC
2.28.
ITT4
EFF_T5
Summary of Responder rate of Mas Score in Open Label Phase 
(4th Treatment)
SAC
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Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable
DAS
2.29.
ITT3
EFF_T1
Summary of Main Assessment Parameter and All Items of DAS 
in Open Label Phase (3rd Treatment)

Values and change from 
baseline

Summarize data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
SAC
2.30.
ITT4
EFF_T1
Summary of Main Assessment Parameter and All Items of DAS 
in Open Label Phase (4th Treatment)
SAC
NRS for pain
2.31.
ITT3
EFF_T1
Summary of NRS for pain in Open Label Phase (3rd Treatment)

Values and change from 
baseline

Summarize data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
SAC
2.32.
ITT4
EFF_T1
Summary of NRS for pain in Open Label Phase (4th Treatment)
SAC
CGI of functional disability
2.33.
ITT3
EFF_T1
Summary of CGI of functional disability by an investigator in 
Open Label Phase (3rd Treatment)

Values and change from 
baseline

Summarize data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
SAC
2.34.
ITT4
EFF_T1
Summary of CGI of functional disability by an investigator in 
Open Label Phase (4th Treatment)
SAC
2.35.
ITT3
EFF_T1
Summary of CGI of functional disability by a patient in Open 
Label Phase (3rd Treatment)

Values and change from 
baseline

Summarize data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
SAC
2.36.
ITT4
EFF_T1
Summary of CGI of functional disability by a patient in Open 
Label Phase (4th Treatment)
SAC
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Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable
Patient-Reported Benefit of Injection
2.37.
ITT3
EFF_T5
Summary of Patient-Reported Benefit of Injection in Open Label 
Phase (3rd Treatment)

Values and change from 
baseline

Summarize data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
SAC
2.38.
ITT4
EFF_T5
Summary of Patient-Reported Benefit of Injection in Open Label 
Phase (4th Treatment)
SAC
Time to Patient-Reported Onset of Spasticity Symptom Relief
2.39.
ITT1
EFF_T6
Summary of Time to Patient-Reported Onset of Spasticity 
Symptom Relief
SAC
2.40.
ITT1
EFF_T7
Summary of Survival Analyses Results of Time to Patient-
Reported Onset of Spasticity Symptom Relief in Blind Phase

Survival function estimates will 
be summarized
SAC
2.41.
ITT2
EFF_T7
Summary of Survival Analyses Results of Time to Patient-
Reported Onset of Spasticity Symptom Relief in Open Label 
Phase (2nd Treatment)

Survival function estimates will 
be summarized

Three treatment arms (240, 
400 and 240 + 400U)
SAC
2.42.
ITT3
EFF_T7
Summary of Survival Analyses Results of Time to Patient-
Reported Onset of Spasticity Symptom Relief in Open Label 
Phase (3rd Treatment)
SAC
2.43.
ITT4
EFF_T7
Summary of Survival Analyses Results of Time to Patient-
Reported Onset of Spasticity Symptom Relief in Open Label 
Phase (4th Treatment)
SAC
Time to Qualification for Retreatment
2.44.
ITT1
EFF_T8
Summary of Events in Which a Participant Meets the Criteria for 
Retreatment
SAC
2.45.
ITT1
EFF_T6
Summary of Time to Qualification for Retreatment
SAC
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Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable
2.46.
ITT1
EFF_T7
Summary of Survival Analyses Results of Time to Qualification 
for Retreatment in Blind Phase

Survival function estimates will 
be summarized

Two treatment arms (240 and 
400U)
SAC
2.47.
ITT2
EFF_T7
Summary of Survival Analyses Results of Time to Qualification 
for Retreatment in Open Label Phase (2nd Treatment)

Survival function estimates will 
be summarized

Three treatment arms (240, 
400 and 240 + 400U)
SAC
2.48.
ITT3
EFF_T7
Summary of Survival Analyses Results of Time to Qualification 
for Retreatment in Open Label Phase (3rd Treatment)
SAC
2.49.
ITT4
EFF_T7
Summary of Survival Analyses Results of Time to Qualification 
for Retreatment in Open Label Phase (4th Treatment)
SAC
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9.12.6.
Efficacy Figures
9.12.6.1.
Interim Analyses
Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
MAS
2.50.
ITT1
EFF_F1
Plot of Mean (95%CI) MAS score Profiles in Blind Phase

Plot data up to Visit 5

Two treatment arms (240 and 
400U)
IA SAC
2.51.
ITT2
EFF_F1
Plot of Mean (95%CI) MAS score Profiles in Open Label Phase 
(2nd Treatment)

Plot data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
IA SAC
2.52.
ITT1
EFF_F1
Plot of Mean (95%CI) Change from Baseline in MAS score 
Profiles in Blind Phase

Plot data up to Visit 5

Two treatment arms (240 and 
400U)
IA SAC
2.53.
ITT2
EFF_F1
Plot of Mean (95%CI) Change from Baseline in MAS score 
Profiles in Open Label Phase (2nd Treatment)

Plot data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
IA SAC
2.54.
ITT1
EFF_F2
Plot of Responder rate of MAS score by Visit in Blind Phase

Plot data up to Visit 5

Two treatment arms (240 and 
400U)
IA SAC
2.55.
ITT2
EFF_F2
Plot of Responder rate of MAS score by Visit in Open Label 
Phase (2nd Treatment)

Plot data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
IA SAC
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Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
DAS
2.56.
ITT1
EFF_F1
Plot of Mean (95%CI) DAS score (Main Assessment Parameter) 
Profiles in Blind Phase

Plot data up to Visit 5

Two treatment arms (240 and 
400U)
IA SAC
2.57.
ITT2
EFF_F1
Plot of Mean (95%CI) DAS score (Main Assessment Parameter) 
Profiles in Open Label Phase (2nd Treatment)

Plot data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
IA SAC
2.58.
ITT1
EFF_F1
Plot of Mean (95%CI) Change from Baseline in DAS score (Main 
Assessment Parameter) Profiles in Blind Phase

Plot data up to Visit 5

Two treatment arms (240 and 
400U)
IA SAC
2.59.
ITT2
EFF_F1
Plot of Mean (95%CI) Change from Baseline in DAS score (Main 
Assessment Parameter) Profiles in Open Label Phase (2nd 
Treatment)

Plot data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
IA SAC
2.60.
ITT1
EFF_F1
Plot of Mean (95%CI) DAS score Profiles in Blind Phase

Plot data up to Visit 5

Create plots by component of 
DAS score

Two treatment arms (240 and 
400U)
IA SAC
2.61.
ITT2
EFF_F1
Plot of Mean (95%CI) DAS score Profiles in Open Label Phase 
(2nd Treatment)

Plot data up to Visit 5

Create plots by component of 
DAS score

Three treatment arms (240 and 
400U)
IA SAC
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Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
2.62.
ITT1
EFF_F1
Plot of Mean (95%CI) Change from Baseline in DAS score 
Profiles in Blind Phase

Plot data up to Visit 5

Create plots by component of 
DAS score

Two treatment arms (240 and 
400U)
IA SAC
2.63.
ITT2
EFF_F1
Plot of Mean (95%CI) Change from Baseline in DAS score 
Profiles in Open Label Phase (2nd Treatment)

Plot data up to Visit 5

Create plots by component of 
DAS score

Three treatment arms (240 and 
400U)
IA SAC
Numeric Rating Scale for pain
2.64.
ITT1
EFF_F1
Plot of Mean (95%CI) NRS for pain Profiles in Blind Phase

Plot data up to Visit 5

Two treatment arms (240 U 
and 400U)
IA SAC
2.65.
ITT2
EFF_F1
Plot of Mean (95%CI) NRS for pain Profiles in Open Label 
Phase (2nd Treatment)

Plot data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
IA SAC
2.66.
ITT1
EFF_F1
Plot of Mean (95%CI) Change from Baseline in NRS for pain 
Profiles in Blind Phase

Plot data up to Visit 5

Two treatment arms (240 U 
and 400U)
IA SAC
2.67.
ITT2
EFF_F1
Plot of Mean (95%CI) Change from Baseline in NRS for pain 
Profiles in Open Label Phase (2nd Treatment)

Plot data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
IA SAC
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Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Clinical Global Impression of Change of functional disability
2.68.
ITT1
EFF_F1
Plot of Mean (95%CI) CGI of functional disability Profiles in Blind 
Phase

Plot data up to Visit 5

Two treatment arms (240 and 
400 U)
IA SAC
2.69.
ITT2
EFF_F1
Plot of Mean (95%CI) CGI of functional disability Profiles in 
Open Label Phase (2nd Treatment)

Plot data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400 U)
IA SAC
Time to Patient-Reported Onset of Spasticity Symptom Relief
2.70.
ITT1
EFF_F3
Kaplan Meier Plot of Time to Patient-Reported Onset of 
Spasticity Symptom Relief in Blind Phase
Two treatment arm (240 U and 
400U)
IA SAC
2.71.
ITT2
EFF_F3
Kaplan Meier Plot of Time to Patient-Reported Onset of 
Spasticity Symptom Relief in Open Label Phase (2nd 
Treatment)
Three treatment arms (240, 400, 
240 + 400U)
IA SAC
2.72.
ITT3
EFF_F3
Kaplan Meier Plot of Time to Patient-Reported Onset of 
Spasticity Symptom Relief in Open Label Phase (3rd Treatment)
IA SAC
2.73.
ITT4
EFF_F3
Kaplan Meier Plot of Time to Patient-Reported Onset of 
Spasticity Symptom Relief in Open Label Phase (4th Treatment)
IA SAC
Time to Qualification for Retreatment
2.74.
ITT1
EFF_F3
Kaplan Meier Plot of Survival Function Estimates of Time to 
Qualification for Retreatment in Blind Phase
Two treatment arm (240 U, 400U)
IA SAC
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Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
2.75.
ITT2
EFF_F3
Kaplan Meier Plot of Survival Function Estimates of Time to 
Qualification for Retreatment in Open Label Phase (2nd 
Treatment)
Three treatment arm (240, 400, 240 
+ 400U)
IA SAC
2.76.
ITT3
EFF_F3
Kaplan Meier Plot of Survival Function Estimates of Time to 
Qualification for Retreatment in Open Label Phase (3rd 
Treatment)
IA SAC
2.77.
ITT4
EFF_F3
Kaplan Meier Plot of Survival Function Estimates of Time to 
Qualification for Retreatment in Open Label Phase (4th 
Treatment)
IA SAC
9.12.6.2.
Final Analyses
Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
MAS
2.78.
ITT3
EFF_F1
Plot of Mean (95%CI) MAS score Profiles in Open Label Phase 
(3rd Treatment)

Plot data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
SAC
2.79.
ITT4
EFF_F1
Plot of Mean (95%CI) MAS score Profiles in Open Label Phase 
(4th Treatment)
SAC
2.80.
ITT3
EFF_F1
Plot of Mean (95%CI) Change from Baseline in MAS score 
Profiles in Open Label Phase (3rd Treatment)

Plot data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
SAC
2.81.
ITT4
EFF_F1
Plot of Mean (95%CI) Change from Baseline in MAS score 
Profiles in Open Label Phase (4th Treatment)
SAC
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Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
2.82.
ITT3
EFF_F2
Plot of Responder rate of MAS score by Visit in Open Label 
Phase (3rd Treatment)

Plot data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
SAC
2.83.
ITT4
EFF_F2
Plot of Responder rate of MAS score by Visit in Open Label 
Phase (4th Treatment)
SAC
DAS
2.84.
ITT3
EFF_F1
Plot of Mean (95%CI) DAS score (Main Assessment Parameter) 
Profiles in Open Label Phase (3rd Treatment)

Plot data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
SAC
2.85.
ITT4
EFF_F1
Plot of Mean (95%CI) DAS score (Main Assessment Parameter) 
Profiles in Open Label Phase (4th Treatment)
SAC
2.86.
ITT3
EFF_F1
Plot of Mean (95%CI) Change from Baseline in DAS score (Main 
Assessment Parameter) Profiles in Open Label Phase (3rd 
Treatment)

Plot data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
SAC
2.87.
ITT4
EFF_F1
Plot of Mean (95%CI) Change from Baseline in DAS score (Main 
Assessment Parameter) Profiles in Open Label Phase (4th 
Treatment)
SAC
2.88.
ITT3
EFF_F1
Plot of Mean (95%CI) DAS score Profiles in Open Label Phase 
(3rd Treatment)

Plot data up to Visit 5

Create plots by component of 
DAS score

Three treatment arms (240 and 
400U)
SAC
2.89.
ITT4
EFF_F1
Plot of Mean (95%CI) DAS score Profiles in Open Label Phase 
(4th Treatment)
SAC
2.90.
ITT3
EFF_F1
Plot of Mean (95%CI) Change from Baseline in DAS score 
Profiles in Open Label Phase (3rd Treatment)

Plot data up to Visit 5

Create plots by component of 
DAS score

Three treatment arms (240 and 
400U)
SAC
2.91.
ITT4
EFF_F1
Plot of Mean (95%CI) Change from Baseline in DAS score 
Profiles in Open Label Phase (4th Treatment)
SAC
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Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Numeric Rating Scale for pain
2.92.
ITT3
EFF_F1
Plot of Mean (95%CI) NRS for pain Profiles in Open Label 
Phase (3rd Treatment)

Plot data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
SAC
2.93.
ITT4
EFF_F1
Plot of Mean (95%CI) NRS for pain Profiles in Open Label 
Phase (4th Treatment)
SAC
2.94.
ITT3
EFF_F1
Plot of Mean (95%CI) Change from Baseline in NRS for pain 
Profiles in Open Label Phase (3rd Treatment)

Plot data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
SAC
2.95.
ITT4
EFF_F1
Plot of Mean (95%CI) Change from Baseline in NRS for pain 
Profiles in Open Label Phase (4th Treatment)
SAC
Clinical Global Impression of Change of functional disability
2.96.
ITT3
EFF_F1
Plot of Mean (95%CI) CGI of functional disability Profiles in 
Open Label Phase (3rd Treatment)

Plot data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400 U)
SAC
2.97.
ITT4
EFF_F1
Plot of Mean (95%CI) CGI of functional disability Profiles in 
Open Label Phase (4th Treatment)
SAC
Time to Patient-Reported Onset of Spasticity Symptom Relief
2.98.
ITT1
EFF_F3
Kaplan Meier Plot of Time to Patient-Reported Onset of 
Spasticity Symptom Relief in Blind Phase
Two treatment arm (240 U and 
400U)
SAC
2.99.
ITT2
EFF_F3
Kaplan Meier Plot of Time to Patient-Reported Onset of 
Spasticity Symptom Relief in Open Label Phase (2nd 
Treatment)
Three treatment arms (240, 400, 
240 + 400U)
SAC
2.100.
ITT3
EFF_F3
Kaplan Meier Plot of Time to Patient-Reported Onset of 
Spasticity Symptom Relief in Open Label Phase (3rd Treatment)
SAC
2.101.
ITT4
EFF_F3
Kaplan Meier Plot of Time to Patient-Reported Onset of 
Spasticity Symptom Relief in Open Label Phase (4th Treatment)
SAC
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Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Time to Qualification for Retreatment
2.102.
ITT1
EFF_F3
Kaplan Meier Plot of Survival Function Estimates of Time to 
Qualification for Retreatment in Blind Phase
Two treatment arm (240 U, 400U)
SAC
2.103.
ITT2
EFF_F3
Kaplan Meier Plot of Survival Function Estimates of Time to 
Qualification for Retreatment in Open Label Phase (2nd 
Treatment)
Three treatment arm (240, 400, 240 
+ 400U)
SAC
2.104.
ITT3
EFF_F3
Kaplan Meier Plot of Survival Function Estimates of Time to 
Qualification for Retreatment in Open Label Phase (3rd 
Treatment)
SAC
2.105.
ITT4
EFF_F3
Kaplan Meier Plot of Survival Function Estimates of Time to 
Qualification for Retreatment in Open Label Phase (4th 
Treatment)
SAC
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9.12.7.
Safety Tables
9.12.7.1.
Interim Analyses
Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
Adverse Events (AEs)
3.1.
Safety 1
AE1
Summary of All Adverse Events by System Organ Class and 
Preferred Term
ICH E3
Treatment Emergent
IA SAC
3.2.
Safety 1
AE1
Summary of All Adverse Events by System Organ Class and 
Preferred Term in Blind Phase
Blind Phase (until second dose)
See the Section 9.4.2.
Two treatment arm (240 and 400U)
IA SAC
3.3.
Safety 1
AE1
Summary of All Adverse Events within 84 days from the initial 
dose by System Organ Class and Preferred Term
Blind Phase (within 84 days)
See the Section 9.4.2.
Two treatment arm (240 and 400U)
IA SAC
3.4.
Safety 2
AE1
Summary of All Adverse Events by System Organ Class and 
Preferred Term in Open Label Phase (2nd Treatment)
Open Label Phase (2nd Treatment)
See the Section 9.4.2.
Three treatment arms (240, 400 and 
240 + 400U)
IA SAC
3.5.
Safety 1
AE5A
Summary of All Adverse Events by Maximum Intensity by 
System Organ Class and Preferred Term
ICH E3
Treatment Emergent
Use AE1 or AE1CP if 
Grade/Intensity not used; otherwise 
use AE5A/B (with a Total column 
across all grades/severities, which 
provides same detail as AE1)
IA SAC
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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
3.6.
Safety 1
AE5A
Summary of All Adverse Events by Maximum Intensity by 
System Organ Class and Preferred Term in Blind Phase
Blind Phase (until second dose)
See the Section 9.4.2. 
Two treatment arm (240 and 400U)
IA SAC
3.7.
Safety 1
AE5A
Summary of All Adverse Events within 84 days from the initial 
dose by Maximum Intensity by System Organ Class and 
Preferred Term
Blind Phase (within 84 days)
See the Section 9.4.2. 
Two treatment arm (240 and 400U)
IA SAC
3.8.
Safety 2
AE5A
Summary of All Adverse Events by Maximum Intensity by 
System Organ Class and Preferred Term in Open Label Phase 
(2nd Treatment)
Open Label Phase (2nd Treatment)
See the Section 9.4.2.
Three treatment arms (240, 400 and 
240 + 400U)
IA SAC
3.9.
Safety 1
AE3
Summary of Common (>=3%) Adverse Events by Overall 
Frequency
ICH E3
Treatment Emergent
IA SAC
3.10.
Safety 1
AE3
Summary of Common (>=3%) Adverse Events by Overall 
Frequency in Blind Phase
Blind Phase (until second dose)
See the Section 9.4.2. 
Two treatment arm (240 and 400U)
IA SAC
3.11.
Safety 1
AE3
Summary of Common (>=3%) Adverse Events within 84 days 
from the initial dose by Overall Frequency
Blind Phase (within 84 days)
See the Section 9.4.2. 
Two treatment arm (240 and 400U)
IA SAC
3.12.
Safety 2
AE3
Summary of Common (>=3%) Adverse Events by Overall 
Frequency in Open Label Phase (2nd Treatment)
Open Label Phase (2nd Treatment)
See the Section 9.4.2.
Three treatment arms (240, 400 and 
240 + 400U)
IA SAC
3.13.
Safety 1
AE1
Summary All Drug-Related Adverse Events by System Organ 
Class and Preferred Term
ICH E3
Treatment Emergent
IA SAC
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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
3.14.
Safety 1
AE1
Summary of All Drug-Related Adverse Events by System Organ 
Class and Preferred Term in Blind Phase
Blind Phase (until second dose)
See the Section 9.4.2. 
Two treatment arm (240 and 400U)
IA SAC
3.15.
Safety 1
AE1
Summary of All Drug-Related Adverse Events within 84 days 
from the initial dose by System Organ Class and Preferred Term
Blind Phase (within 84 days)
See the Section 9.4.2. 
Two treatment arm (240 and 400U)
IA SAC
3.16.
Safety 2
AE1
Summary of All Drug-Related Adverse Events by System Organ 
Class and Preferred Term in Open Label Phase in Open Label 
Phase (2nd Treatment)
Open Label Phase (2nd Treatment)
See the Section 9.4.2.
Three treatment arms (240, 400 and 
240 + 400U)
IA SAC
3.17.
Safety 1
AE5A
Summary of All Drug-Related Adverse Events by System Organ 
Class and Preferred Term and Maximum Intensity
ICH E3
Treatment Emergent AE
See the Section 9.4.2
IA SAC
3.18.
Safety 1
AE5A
Summary of All Drug-Related Adverse Events by System Organ 
Class and Preferred Term and Maximum Intensity in Blind 
Phase
Blind Phase (until second dose)
See the Section 9.4.2. 
Two treatment arm (240 and 400U)
IA SAC
3.19.
Safety 1
AE5A
Summary of All Drug-Related Adverse Events within 84 days 
from the initial dose by System Organ Class and Preferred Term 
and Maximum Intensity
Blind Phase (within 84 days)
See the Section 9.4.2. 
Two treatment arm (240 and 400U)
IA SAC
3.20.
Safety 2
AE5A
Summary of All Drug-Related Adverse Events by System Organ 
Class and Preferred Term and Maximum Intensity in Open Label 
Phase (2nd Treatment)
Open Label Phase (2nd Treatment)
See the Section 9.4.2.
Three treatment arms (240, 400 and 
240 + 400U)
IA SAC
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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
3.21.
Safety 1
AE15
Summary of Common (>=5%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of Participant 
and Occurrences)
FDAAA, EudraCT
Treatment Emergent AE
See the Section 9.4.2
IA SAC
Serious and Other Significant Adverse Events
3.22.
Safety 1
SAFE_T1
Summary of Adverse Events of Special Interest
Treatment Emergent AE
See the Section 9.4.2
IA SAC
3.23.
Safety 1
SAFE_T1
Summary of Adverse Events of Special Interest in Blind Phase
Blind Phase (until second dose)
See the Section 9.4.2. 
Two treatment arm (240 and 400U)
IA SAC
3.24.
Safety 1
SAFE_T1
Summary of Adverse Events of Special Interest within 84 days 
from the initial dose
Blind Phase (within 84 days)
See the Section 9.4.2. 
Two treatment arm (240 and 400U)
IA SAC
3.25.
Safety 2
SAFE_T1
Summary of Adverse Events of Special Interest in Open Label 
Phase (2nd Treatment)
Open Label Phase (2nd Treatment)
See the Section 9.4.2
Three treatment arms (240, 400 and 
240 + 400U)
IA SAC
3.26.
Safety 1
AE1
Summary of Non-Fatal Serious Adverse Events
Treatment Emergent AE
See the Section 9.4.2
IA SAC
3.27.
Safety 1
AE1
Summary of Non-Fatal Serious Adverse Events in Blind Phase
Blind Phase (until second dose)
See the Section 9.4.2. 
Two treatment arm (240 and 400U)
IA SAC
3.28.
Safety 1
AE1
Summary of Non-Fatal Serious Adverse Events within 84 days 
from the initial dose
Blind Phase (within 84 days)
See the Section 9.4.2. 
Two treatment arm (240 and 400U)
IA SAC
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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
3.29.
Safety 2
AE1
Summary of Non-Fatal Serious Adverse Events in Open Label 
Phase (2nd Treatment)
Open Label Phase (2nd Treatment)
See the Section 9.4.2
Three treatment arms (240, 400 and 
240 + 400U)
IA SAC
3.30.
Safety 1
AE1
Summary of Drug-Related Non-Fatal Serious Adverse Events
Treatment Emergent AE
See the Section 9.4.2
IA SAC
3.31.
Safety 1
AE1
Summary of Drug-Related Non-Fatal Serious Adverse Events in 
Blind Phase
Blind Phase (until second dose)
See the Section 9.4.2. 
Two treatment arm (240 and 400U)
IA SAC
3.32.
Safety 1
AE1
Summary of Drug-Related Non-Fatal Serious Adverse Events 
within 84 days from the initial dose
Blind Phase (within 84 days)
See the Section 9.4.2. 
Two treatment arm (240 and 400U)
IA SAC
3.33.
Safety 2
AE1
Summary of Drug-Related Non-Fatal Serious Adverse Events in 
Open Label Phase (2nd Treatment)
Open Label Phase (2nd Treatment)
See the Section 9.4.2
Three treatment arms (240, 400 and 
240 + 400U)
IA SAC
3.34.
Safety 1
AE16
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Participants and Occurrences)
FDAAA, EudraCT
Treatment Emergent AE
See the Section 9.4.2
IA SAC
3.35.
Safety 1
AE1
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study by 
System Organ Class and Preferred Term
IDSL
Treatment Emergent AE
See the Section 9.4.2
IA SAC
3.36.
Safety 1
AE1
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study by 
System Organ Class and Preferred Term in Blind Phase
Blind Phase (until second dose)
See the Section 9.4.2. 
Two treatment arm (240 and 400U)
IA SAC
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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
3.37.
Safety 1
AE1
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study 
within 84 days from the initial dose by System Organ Class and 
Preferred Term
Blind Phase (within 84 days)
See the Section 9.4.2. 
Two treatment arm (240 and 400U)
IA SAC
3.38.
Safety 2
AE1
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study by 
System Organ Class and Preferred Term in Open Label Phase 
(2nd Treatment)
Open Label Phase (2nd Treatment)
See the Section 9.4.2.
Three treatment arms (240, 400 and 
240 + 400U)
IA SAC
Laboratory: Chemistry 
3.39.
Safety 1
LB1
Summary of Chemistry by Visit
Summarize data at Screening Visit, 
in Blind Phase and at Final Visit. 
IA SAC
3.40.
Safety 1
LB1
Summary of Chemistry Changes from Baseline by Visit
Summarize data at Screening Visit, 
in Blind Phase and at Final Visit. 
ICH E3
IA SAC
3.41.
Safety 1
LB3
Summary of Chemistry Shifts from Baseline Relative to Normal 
Range
IA SAC
3.42.
Safety 1
LB15
Summary of Worst Case Chemistry Results Relative to Normal 
Range Post-Baseline Relative to Baseline
ICH E3
IA SAC
Laboratory: Hematology
3.43.
Safety 1
LB1
Summary of Haematology by Visit
Summarize data at Screening Visit, 
in Blind Phase and at Final Visit. 
IA SAC
3.44.
Safety 1
LB1
Summary of Hematology Changes from Baseline
Summarize data at Screening Visit, 
in Blind Phase and at Final Visit. 
ICH E3
IA SAC
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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
3.45.
Safety 1
LB3
Summary of Hematology Shifts from Baseline Relative to 
Normal Range
IA SAC
3.46.
Safety 1
LB15
Summary of Worst Case Hematology Results Relative to Normal 
Range Post-Baseline Relative to Baseline
ICH E3
IA SAC
Laboratory: Urinalysis
3.47.
Safety 1
UR1
Summary of Worst Case Urinalysis Results (Discrete or 
Character Values) Post-Baseline Relative to Baseline
ICH E3
IA SAC
Laboratory: Hepatobiliary (Liver)
3.48.
Safety 1
LIVER1
Summary of Liver Monitoring/Stopping Event Reporting
This display will be presented if liver 
events occur. 
IA SAC
3.49.
Safety 1
LIVER10
Summary of Hepatobiliary Laboratory Abnormalities
IDSL
IA SAC
ECG
3.50.
Safety 1
EG1
Summary of ECG Findings 
Summarize data at Screening Visit, 
in Blind Phase and at Final Visit. 
IDSL
IA SAC
3.51.
Safety 1
EG2
Summary of Change from Baseline in ECG Values by Visit
Summarize data at Screening Visit, 
in Blind Phase and at Final Visit. 
IDSL
IA SAC
Vital Signs
3.52.
Safety 1
VS1
Summary of Change from Baseline in Vital Signs
Summarize data at Screening Visit, 
in Blind Phase and at Final Visit. 
ICH E3
IA SAC
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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
SpO2
3.53.
Safety 1
SAFE_T2
Summary of Value and Change from Baseline in SpO2
SAC
Exposure and Treatment Compliance
3.54.
Safety 1
SAFE_T3
Summary of Exposure to Study Treatment
ICH E3
IA SAC
3.55.
Safety 1
SAFE_T4
Summary of Extent of Exposure to Study Treatment by 
Treatment Cycle and Muscle Region
IA SAC
3.56.
Safety 1
SAFE_T4
Summary of Extent of Exposure to Study Treatment by 
Treatment Cycle and Joint
IA SAC
9.12.7.2.
Final Analyses
Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Adverse Events (AEs)
3.57.
Safety 1
AE1
Summary of All Adverse Events by System Organ Class and 
Preferred Term
ICH E3
Treatment Emergent
SAC
3.58.
Safety 1
AE1
Summary of All Adverse Events by System Organ Class and 
Preferred Term in Blind Phase
Blind Phase (until second dose)
See the Section 9.4.2.
Two treatment arm (240 and 400U)
SAC
3.59.
Safety 1
AE1
Summary of All Adverse Events within 84 days from the initial 
dose by System Organ Class and Preferred Term
Blind Phase (within 84 days)
See the Section 9.4.2. 
Two treatment arm (240 and 400U)
SAC
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Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
3.60.
Safety 2
AE1
Summary of All Adverse Events by System Organ Class and 
Preferred Term in Open Label Phase (2nd Treatment)
Open Label Phase (2nd Treatment)
See the Section 9.4.2.
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.61.
Safety 3
AE1
Summary of All Adverse Events by System Organ Class and 
Preferred Term in Open Label Phase (3rd Treatment)
Open Label Phase (3rd Treatment)
See the Section 9.4.2.
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.62.
Safety 4
AE1
Summary of All Adverse Events by System Organ Class and 
Preferred Term in Open Label Phase (4th Treatment)
Open Label Phase (4th Treatment)
See the Section 9.4.2.
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.63.
Safety 1
AE5A
Summary of All Adverse Events by Maximum Intensity by 
System Organ Class and Preferred Term
ICH E3
Treatment Emergent
SAC
3.64.
Safety 1
AE5A
Summary of All Adverse Events by Maximum Intensity by 
System Organ Class and Preferred Term in Blind Phase
Blind Phase (until second dose)
See the Section 9.4.2. 
Two treatment arm (240 and 400U)
SAC
3.65.
Safety 1
AE5A
Summary of All Adverse Events within 84 days from the initial 
dose by Maximum Intensity by System Organ Class and 
Preferred Term
Blind Phase (within 84 days)
See the Section 9.4.2. 
Two treatment arm (240 and 400U)
SAC
3.66.
Safety 2
AE5A
Summary of All Adverse Events by Maximum Intensity by 
System Organ Class and Preferred Term in Open Label Phase 
(2nd Treatment)
Open Label Phase (2nd Treatment)
See the Section 9.4.2.
Three treatment arms (240, 400 and 
240 + 400U)
SAC
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Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
3.67.
Safety 3
AE5A
Summary of All Adverse Events by Maximum Intensity by 
System Organ Class and Preferred Term in Open Label Phase 
(3rd Treatment)
Open Label Phase (3rd Treatment)
See the Section 9.4.2.
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.68.
Safety 4
AE5A
Summary of All Adverse Events by Maximum Intensity by 
System Organ Class and Preferred Term in Open Label Phase 
(4th Treatment)
Open Label Phase (4th Treatment)
See the Section 9.4.2.
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.69.
Safety 1
AE3
Summary of Common (>=3%) Adverse Events by Overall 
Frequency
ICH E3
Treatment Emergent
SAC
3.70.
Safety 1
AE3
Summary of Common (>=3%) Adverse Events by Overall 
Frequency in Blind Phase
Blind Phase (until second dose)
See the Section 9.4.2. 
Two treatment arm (240 and 400U)
SAC
3.71.
Safety 1
AE3
Summary of Common (>=3%) Adverse Events within 84 days 
from the initial dose by Overall Frequency
Blind Phase (within 84 days)
See the Section 9.4.2. 
Two treatment arm (240 and 400U)
SAC
3.72.
Safety 2
AE3
Summary of Common (>=3%) Adverse Events by Overall 
Frequency in Open Label Phase (2nd Treatment)
Open Label Phase (2nd Treatment)
See the Section 9.4.2.
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.73.
Safety 3
AE3
Summary of Common (>=3%) Adverse Events by Overall 
Frequency in Open Label Phase (3rd Treatment)
Open Label Phase (3rd Treatment)
See the Section 9.4.2.
Three treatment arms (240, 400 and 
240 + 400U)
SAC
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Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
3.74.
Safety 4
AE3
Summary of Common (>=3%) Adverse Events by Overall 
Frequency in Open Label Phase (4th Treatment)
Open Label Phase (4th Treatment)
See the Section 9.4.2.
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.75.
Safety 1
AE1
Summary All Drug-Related Adverse Events by System Organ 
Class and Preferred Term
ICH E3
Treatment Emergent
SAC
3.76.
Safety 1
AE1
Summary of All Drug-Related Adverse Events by System Organ 
Class and Preferred Term in Blind Phase
Blind Phase (until second dose)
See the Section 9.4.2. 
Two treatment arm (240 and 400U)
SAC
3.77.
Safety 1
AE1
Summary of All Drug-Related Adverse Events within 84 days 
from the initial dose by System Organ Class and Preferred Term
Blind Phase (within 84 days)
See the Section 9.4.2. 
Two treatment arm (240 and 400U)
SAC
3.78.
Safety 2
AE1
Summary of All Drug-Related Adverse Events by System Organ 
Class and Preferred Term in Open Label Phase in Open Label 
Phase (2nd Treatment)
Open Label Phase (2nd Treatment)
See the Section 9.4.2.
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.79.
Safety 2
AE1
Summary of All Drug-Related Adverse Events by System Organ 
Class and Preferred Term in Open Label Phase in Open Label 
Phase (3rd Treatment)
Open Label Phase (3rd Treatment)
See the Section 9.4.2.
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.80.
Safety 2
AE1
Summary of All Drug-Related Adverse Events by System Organ 
Class and Preferred Term in Open Label Phase in Open Label 
Phase (4th Treatment)
Open Label Phase (4th Treatment)
See the Section 9.4.2.
Three treatment arms (240, 400 and 
240 + 400U)
SAC
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Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
3.81.
Safety 1
AE5A
Summary of All Drug-Related Adverse Events by System Organ 
Class and Preferred Term and Maximum Intensity
ICH E3
Treatment Emergent AE
See the Section 9.4.2
SAC
3.82.
Safety 1
AE5A
Summary of All Drug-Related Adverse Events by System Organ 
Class and Preferred Term and Maximum Intensity in Blind 
Phase
Blind Phase (until second dose)
See the Section 9.4.2. 
Two treatment arm (240 and 400U)
SAC
3.83.
Safety 1
AE5A
Summary of All Drug-Related Adverse Events within 84 days 
from the initial dose by System Organ Class and Preferred Term 
and Maximum Intensity
Blind Phase (within 84 days)
See the Section 9.4.2. 
Two treatment arm (240 and 400U)
SAC
3.84.
Safety 2
AE5A
Summary of All Drug-Related Adverse Events by System Organ 
Class and Preferred Term and Maximum Intensity in Open Label 
Phase (2nd Treatment)
Open Label Phase (2nd Treatment)
See the Section 9.4.2.
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.85.
Safety 2
AE5A
Summary of All Drug-Related Adverse Events by System Organ 
Class and Preferred Term and Maximum Intensity in Open Label 
Phase (3rd Treatment)
Open Label Phase (3rd Treatment)
See the Section 9.4.2.
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.86.
Safety 2
AE5A
Summary of All Drug-Related Adverse Events by System Organ 
Class and Preferred Term and Maximum Intensity in Open Label 
Phase (4th Treatment)
Open Label Phase (4th Treatment)
See the Section 9.4.2
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.87.
Safety 1
AE3
Summary of Most Common Serious Drug Related Adverse 
Events by Overall Frequency
SAC
3.88.
Safety 1
AE2
Summary of Most Common Non-Serious Drug Related Adverse 
Events by Overall Frequency
SAC
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Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
3.89.
Safety 1
AE15
Summary of Common (>=5%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of Participant 
and Occurrences)
FDAAA, EudraCT
Treatment Emergent AE
See the Section 9.4.2
SAC
Serious and Other Significant Adverse Events
3.90.
Safety 1
SAFE_T1
Summary of Adverse Events of Special Interest
Treatment Emergent AE
See the Section 9.4.2
SAC
3.91.
Safety 1
SAFE_T1
Summary of Adverse Events of Special Interest in Blind Phase
Blind Phase (until second dose)
See the Section 9.4.2. 
Two treatment arm (240 and 400U)
SAC
3.92.
Safety 1
SAFE_T1
Summary of Adverse Events of Special Interest within 84 days 
from the initial dose
Blind Phase (within 84 days)
See the Section 9.4.2. 
Two treatment arm (240 and 400U)
SAC
3.93.
Safety 2
SAFE_T1
Summary of Adverse Events of Special Interest in Open Label 
Phase (2nd Treatment)
Open Label Phase (2nd Treatment)
See the Section 9.4.2
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.94.
Safety 3
SAFE_T1
Summary of Adverse Events of Special Interest in Open Label 
Phase (3rd Treatment)
Open Label Phase (3rd Treatment)
See the Section 9.4.2
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.95.
Safety 4
SAFE_T1
Summary of Adverse Events of Special Interest in Open Label 
Phase (4th Treatment)
Open Label Phase (4th Treatment)
See the Section 9.4.2
Three treatment arms (240, 400 and 
240 + 400U)
SAC
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Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
3.96.
Safety 1
AE1
Summary of Non-Fatal Serious Adverse Events
Treatment Emergent AE
See the Section 9.4.2
SAC
3.97.
Safety 1
AE1
Summary of Non-Fatal Serious Adverse Events in Blind Phase
Blind Phase (until second dose)
See the Section 9.4.2. 
Two treatment arm (240 and 400U)
SAC
3.98.
Safety 1
AE1
Summary of Non-Fatal Serious Adverse Events within 84 days 
from the initial dose
Blind Phase (within 84 days)
See the Section 9.4.2. 
Two treatment arm (240 and 400U)
SAC
3.99.
Safety 2
AE1
Summary of Non-Fatal Serious Adverse Events in Open Label 
Phase (2nd Treatment)
Open Label Phase (2nd Treatment)
See the Section 9.4.2
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.100.
Safety 3
AE1
Summary of Non-Fatal Serious Adverse Events in Open Label 
Phase (3rd Treatment)
Open Label Phase (3rd Treatment)
See the Section 9.4.2
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.101.
Safety 4
AE1
Summary of Non-Fatal Serious Adverse Events in Open Label 
Phase (4th Treatment)
Open Label Phase (4th Treatment)
See the Section 9.4.2
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.102.
Safety 1
AE1
Summary of Drug-Related Non-Fatal Serious Adverse Events
Treatment Emergent AE
See the Section 9.4.2
SAC
3.103.
Safety 1
AE1
Summary of Drug-Related Non-Fatal Serious Adverse Events in 
Blind Phase
Blind Phase (until second dose)
See the Section 9.4.2. 
Two treatment arm (240 and 400U)
SAC
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Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
3.104.
Safety 1
AE1
Summary of Drug-Related Non-Fatal Serious Adverse Events 
within 84 days from the initial dose
Blind Phase (within 84 days)
See the Section 9.4.2. 
Two treatment arm (240 and 400U)
SAC
3.105.
Safety 2
AE1
Summary of Drug-Related Non-Fatal Serious Adverse Events in 
Open Label Phase (2nd Treatment)
Open Label Phase (2nd Treatment)
See the Section 9.4.2
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.106.
Safety 3
AE1
Summary of Drug-Related Non-Fatal Serious Adverse Events in 
Open Label Phase (3rd Treatment)
Open Label Phase (3rd Treatment)
See the Section 9.4.2
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.107.
Safety 4
AE1
Summary of Drug-Related Non-Fatal Serious Adverse Events in 
Open Label Phase (4th Treatment)
Open Label Phase (4th Treatment)
See the Section 9.4.2
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.108.
Safety 1
AE16
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Participants and Occurrences)
FDAAA, EudraCT
Treatment Emergent AE
See the Section 9.4.2
SAC
3.109.
Safety 1
AE1
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study by 
System Organ Class and Preferred Term
IDSL
Treatment Emergent AE
See the Section 9.4.2
SAC
3.110.
Safety 1
AE1
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study by 
System Organ Class and Preferred Term in Blind Phase
Blind Phase (until second dose)
See the Section 9.4.2. 
Two treatment arm (240 and 400U)
SAC
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Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
3.111.
Safety 1
AE1
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study 
within 84 days from the initial dose by System Organ Class and 
Preferred Term
Blind Phase (within 84 days)
See the Section 9.4.2. 
Two treatment arm (240 and 400U)
SAC
3.112.
Safety 2
AE1
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study by 
System Organ Class and Preferred Term in Open Label Phase 
(2nd Treatment)
Open Label Phase (2nd Treatment)
See the Section 9.4.2.
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.113.
Safety 3
AE1
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study by 
System Organ Class and Preferred Term in Open Label Phase 
(3rd Treatment)
Open Label Phase (3rd Treatment)
See the Section 9.4.2.
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.114.
Safety 4
AE1
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study by 
System Organ Class and Preferred Term in Open Label Phase 
(4th Treatment)
Open Label Phase (4th Treatment)
See the Section 9.4.2.
Three treatment arms (240, 400 and 
240 + 400U)
SAC
Laboratory: Chemistry 
3.115.
Safety 1
LB1
Summary of Chemistry by Visit
Summarize data at Screening Visit, 
in Blind Phase and at Final Visit. 
SAC
3.116.
Safety 1
LB1
Summary of Chemistry Changes from Baseline by Visit
Summarize data at Screening Visit, 
in Blind Phase and at Final Visit. 
ICH E3
SAC
3.117.
Safety 1
LB3
Summary of Chemistry Shifts from Baseline Relative to Normal 
Range
SAC
3.118.
Safety 1
LB15
Summary of Worst Case Chemistry Results Relative to Normal 
Range Post-Baseline Relative to Baseline
ICH E3
SAC
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Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Laboratory: Hematology
3.119.
Safety 1
LB1
Summary of Haematology by Visit
Summarize data at Screening Visit, 
in Blind Phase and at Final Visit. 
SAC
3.120.
Safety 1
LB1
Summary of Hematology Changes from Baseline
Summarize data at Screening Visit, 
in Blind Phase and at Final Visit. 
ICH E3
SAC
3.121.
Safety 1
LB3
Summary of Hematology Shifts from Baseline Relative to 
Normal Range
SAC
3.122.
Safety 1
LB15
Summary of Worst Case Hematology Results Relative to Normal 
Range Post-Baseline Relative to Baseline
ICH E3
SAC
Laboratory: Urinalysis
3.123.
Safety 1
UR1
Summary of Worst Case Urinalysis Results (Discrete or 
Character Values) Post-Baseline Relative to Baseline
ICH E3
SAC
Laboratory: Hepatobiliary (Liver)
3.124.
Safety 1
LIVER1
Summary of Liver Monitoring/Stopping Event Reporting
This display will be presented if liver 
events occur. 
SAC
3.125.
Safety 1
LIVER10
Summary of Hepatobiliary Laboratory Abnormalities
IDSL
SAC
ECG
3.126.
Safety 1
EG1
Summary of ECG Findings 
Summarize data at Screening Visit, 
in Blind Phase and at Final Visit. 
IDSL
SAC
3.127.
Safety 1
EG2
Summary of Change from Baseline in ECG Values by Visit
Summarize data at Screening Visit, 
in Blind Phase and at Final Visit. 
IDSL
SAC
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Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Vital Signs
3.128.
Safety 1
VS1
Summary of Change from Baseline in Vital Signs
Summarize data at Screening Visit, 
in Blind Phase and at Final Visit. 
ICH E3
SAC
SpO2
3.129.
Safety 1
SAFE_T1
Summary of Value and Change from Baseline in SpO2
SAC
Exposure and Treatment Compliance
3.130.
Safety 1
SAFE_T3
Summary of Exposure to Study Treatment
ICH E3
SAC
3.131.
Safety 1
SAFE_T4
Summary of Extent of Exposure to Study Treatment by 
Treatment Cycle and Muscle Region
SAC
3.132.
Safety 1
SAFE_T4
Summary of Extent of Exposure to Study Treatment by 
Treatment Cycle and Joint
SAC
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9.12.8.
Safety Figures
9.12.8.1.
Interim Analyses
Safety Figures
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable
Chemistry
3.1.
Safety1
SAFE_F1
Scatter plot of Chemistry at Week 12 versus Baseline in Blind 
Phase
IA SAC
Hematology
3.2.
Safety1
SAFE_F1
Scatter plot of Hematology at Week 12 versus Baseline in Blind 
Phase
IA SAC
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9.12.9.
ICH Listings
9.12.9.1.
Interim Analyses
ICH: Listings
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable
Participant Disposition
1.
Screened
ES7
Listing of Reasons for Screen Failure
Journal Guidelines
IA SAC
2.
ITT1
ES2
Listing of Reasons for Study Withdrawal
ICH E3
IA SAC
3.
Screened
ES9
Listing of Participants Who Were Rescreened
IA SAC
4.
ITT1
BL1
Listing of Participants for Whom the Treatment Blind was 
Broken
ICH E3
IA SAC
5.
ITT1
TA1
Listing of Planned and Actual Treatments
IDSL
IA SAC
Protocol Deviations
6.
ITT1
DV2
Listing of Important Protocol Deviations 
ICH E3
IA SAC
7.
ITT1
IE3
Listing of Participants with Inclusion/Exclusion Criteria 
Deviations
ICH E3
IA SAC
Populations Analysed
8.
Screened
SP3
Listing of Participants Excluded from Any Population
ICH E3
IA SAC
Demographic and Baseline Characteristics
9.
ITT1
DM2
Listing of Demographic Characteristics
ICH E3
IA SAC
10.
ITT1
DM9
Listing of Race
ICH E3
IA SAC
Prior and Concomitant Medications
11.
ITT1
CP_CM3
Listing of Medications
IDSL
IA SAC
12.
ITT1
POP_L1
Listing of Rehabilitation
IA SAC
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ICH: Listings
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable
Exposure and Treatment Compliance
13.
ITT1
POP_L2
Listing of Exposure Data
ICH E3
IA SAC
Efficacy Endpoints
14.
ITT1
EFF_L1
Listing of Modified Ashworth Scales

Values

Changes from baseline

Responders
IA SAC
15.
ITT1
EFF_L1
Listing of Disability Assessment Scales

Values

Changes from baseline

Main Assessment Parameter
IA SAC
16.
ITT1
EFF_L1
Listing of Numeric Rating Scale for pain

Values

Changes from baseline
IA SAC
17.
ITT1
EFF_L1
Listing of Clinical Global Impression of Change

CGI by an investigator and a 
patient

Values
IA SAC
18.
ITT1
EFF_L2
Listing of Patient-Reported Benefit of Injection
IA SAC
19.
ITT1
EFF_L3
Listing of Time to Patient Reported Onset of Spasticity 
Symptom Relief
IA SAC
20.
ITT1
EFF_L3
Listing of Time to Qualification for Retreatment
IA SAC
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ICH: Listings
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable
Adverse Events
21.
Safety 1
AE8
Listing of All Adverse Events
ICH E3
Including Maximum Intensities,
Study Phases for Adverse Events
and AESI, SAE flag
IA SAC
22.
Safety 1
AE7
Listing of Participant Numbers for Individual Adverse Events
ICH E3
IA SAC
23.
Safety 1
AE2
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text
IDSL
IA SAC
Serious and Other Significant Adverse Events
24.
Safety 1
AE8
Listing of Fatal Serious Adverse Events
ICH E3
Including Study Phases for 
Adverse Events
IA SAC
25.
Safety 1
AE8
Listing of Non-Fatal Serious Adverse Events
ICH E3
Including Study Phases for 
Adverse Events
IA SAC
26.
Safety 1
AE14
Listing of Reasons for Considering as a Serious Adverse Event
ICH E3
IA SAC
27.
Safety 1
AE8
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment
ICH E3
Including Study Phases for 
Adverse Events
IA SAC
Hepatobiliary (Liver)
28.
Safety 1
MH2
Listing of Medical Conditions for Participants with Liver 
Stopping Events
This display will be presented if 
liver events occur.
IA SAC
29.
Safety 1
SU2
Listing of Substance Use for Participants with Liver Stopping 
Events
This display will be presented if 
liver events occur. 
IA SAC
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ICH: Listings
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable
All Laboratory
30.
Safety 1
LB5
Listing of All Laboratory Data for Participants with Any Value 
Outside Normal Range
ICH E3
IA SAC
31.
Safety 1
LB14
Listing of Laboratory Data with Character Results
ICH E3
IA SAC
32.
Safety 1
UR2A
Listing of Urinalysis Data for Participants
ICH E3
IA SAC
9.12.9.2.
Final Analyses
ICH: Listings
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable
Participant Disposition
33.
ITT1
ES2
Listing of Reasons for Study Withdrawal
ICH E3
SAC
34.
Screened
ES9
Listing of Participants Who Were Rescreened
SAC
35.
ITT1
BL1
Listing of Participants for Whom the Treatment Blind was 
Broken
ICH E3
SAC
Protocol Deviations
36.
ITT1
DV2
Listing of Important Protocol Deviations 
ICH E3
SAC
Populations Analysed
37.
Screened
SP3
Listing of Participants Excluded from Any Population
ICH E3
SAC
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ICH: Listings
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable
Demographic and Baseline Characteristics
38.
ITT1
DM2
Listing of Demographic Characteristics
ICH E3
SAC
39.
ITT1
DM9
Listing of Race
ICH E3
SAC
Prior and Concomitant Medications
40.
ITT1
CP_CM3
Listing of Medications
IDSL
SAC
41.
ITT1
POP_L1
Listing of Rehabilitation
SAC
Exposure and Treatment Compliance
42.
ITT1
POP_L2
Listing of Exposure Data
ICH E3
SAC
Efficacy Endpoints
43.
ITT1
EFF_L1
Listing of Modified Ashworth Scales

Values

Changes from baseline

Responders
SAC
44.
ITT1
EFF_L1
Listing of Disability Assessment Scales

Values

Changes from baseline

Main Assessment Parameter
SAC
45.
ITT1
EFF_L1
Listing of Numeric Rating Scale for pain

Values

Changes from baseline
SAC
46.
ITT1
EFF_L1
Listing of Clinical Global Impression of Change

CGI by an investigator and a 
patient

Values
SAC
47.
ITT1
EFF_L2
Listing of Patient-Reported Benefit of Injection
SAC
48.
ITT1
EFF_L3
Listing of Time to Patient Reported Onset of Spasticity 
Symptom Relief
SAC
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ICH: Listings
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable
49.
ITT1
EFF_L3
Listing of Time to Qualification for Retreatment
SAC
Adverse Events
50.
Safety 1
AE8
Listing of All Adverse Events
ICH E3
Including Maximum Intensities,
Study Phases for Adverse Events
and AESI, SAE flag
SAC
51.
Safety 1
AE7
Listing of Participant Numbers for Individual Adverse Events
ICH E3
SAC
52.
Safety 1
AE2
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text
IDSL
SAC
Serious and Other Significant Adverse Events
53.
Safety 1
AE8
Listing of Fatal Serious Adverse Events
ICH E3
Including Study Phases for 
Adverse Events
SAC
54.
Safety 1
AE8
Listing of Non-Fatal Serious Adverse Events
ICH E3
Including Study Phases for 
Adverse Events
SAC
55.
Safety 1
AE14
Listing of Reasons for Considering as a Serious Adverse Event
ICH E3
SAC
56.
Safety 1
AE8
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment
ICH E3
Including Study Phases for 
Adverse Events
SAC
Hepatobiliary (Liver)
57.
Safety 1
MH2
Listing of Medical Conditions for Participants with Liver 
Stopping Events
This display will be presented if 
liver events occur. 
SAC
58.
Safety 1
SU2
Listing of Substance Use for Participants with Liver Stopping 
Events
This display will be presented if 
liver events occur. 
SAC
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ICH: Listings
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable
All Laboratory
59.
Safety 1
LB5
Listing of All Laboratory Data for Participants with Any Value 
Outside Normal Range
ICH E3
SAC
60.
Safety 1
LB14
Listing of Laboratory Data with Character Results
ICH E3
SAC
61.
Safety 1
UR2A
Listing of Urinalysis Data for Participants
ICH E3
SAC
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9.13.
Appendix 13: List of Preferred Terms / System Organ Class 
of Adverse Events of Special Interest
Adverse Events of Special Interest will be identified based on MedDRA version 20.1. 
9.13.1.
Convulsions and Seizures
This AESI will be identified using Convulsion (SMQ) with narrow scope. 
9.13.2.
Respiratory Adverse Events
This AESI will be identified using the System Organ Class and High Level Term as 
below. 
SOC: “Respiratory, thoracic and mediastinal disorders”
HLT: “Respiratory and pulmonary function diagnostic procedures”
9.13.3.
Possible Distant Spread of Toxin
This AESI will be identified using the Preferred Term as below. 
Accommodation disorder
Aspiration
Bradycardia
Botulism
Bulbar palsy
Constipation
Cranial nerve palsies multiple
Cranial nerve paralysis
Diaphragmatic paralysis
Diplopia
Dry mouth
Dysarthria
Dysphagia
Dysphonia
Dyspnoea
Extraocular muscle paresis
Eyelid function disorder
Eyelid ptosis
Facial paresis
Facial paralysis
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Hyporeflexia
Hypotonia
Illeus paralytic
Muscular weakness
Paralysis
Paralysis flaccid
Paresis cranial nerve
Pelvic floor muscle weakness
Peripheral nerve palsy
Peripheral paralysis
Pneumonia aspiration
Pupillary reflex impaired
Respiratory arrest
Respiratory depression
Respiratory failure
Speech disorder
Urinary retention
VIIth nerve paralysis
Vision blurred
Vocal cord paralysis
Vocal cord paresis
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The GlaxoSmithKline group of companies
207660
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for A phase III study (a placebo 
controlled, randomized, double-blind comparative study and 
an open-label, uncontrolled study) to evaluate the efficacy 
and safety of GSK1358820 in patients with post-stroke upper 
limb spasticity. 
Compound Number 
:
GSK1358820
Effective Date 
:
20-AUG-2018
Description:

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 207660.

This RAP is intended to describe the efficacy and safety analyses required for the 
study. 

This RAP will be provided to the study team members to convey the content of the 
interim and final Statistical Analysis Complete (SAC) deliverable.
RAP Author(s):
Approver
Date
Approval Method
NA
NA
Lead Statistician (Biostatistics Group 2, 
Biomedical Data Sciences Dept., Japan)
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
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RAP Team Approvals:
Approver
Date
Approval Method
17-Aug-2018
eSignature
Japan Project Lead (Future Pipelines Discovery 
Office, Medicines Development, Japan)
17-Aug-2018
eSignature
Clinical Investigations Lead (Immuno-
Inflammation/Oncology TA office, Medicines 
Development, Japan)
17-Aug-2018
eSignature
Operations and Science Lead (6, Clinical 
Operations Dept., Japan)
17-Aug-2018
eSignature
Data Quality Lead (Data Practice Group, 
Biomedical Data Sciences Dept., Japan)
17-Aug-2018
eSignature
Medical Writer (2, Medical Writing Office, 
Medicines Development, Japan)
17-Aug-2018
eSignature
Lead Programmer (Statistical Programming & 
Reporting Group, Biomedical Data Sciences 
Dept., Japan)
Clinical Statistics and Clinical Programming Line Approvals:
Approver
Date
Approval Method
20-Aug-2018
eSignature
Manager (Biostatistics Group 2, Biomedical Data 
Sciences Dept., Japan)
20-Aug-2018
eSignature
Department Manager (Biomedical Data Sciences 
Dept., Japan)
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TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................6
1.1.
RAP Amendments ........................................................................................6
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................8
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................8
2.2.
Study Objective(s) and Endpoint(s)...............................................................8
2.3.
Study Design ................................................................................................9
2.4.
Statistical Hypotheses / Statistical Analyses ...............................................10
3.
PLANNED ANALYSES ..........................................................................................10
3.1.
Interim Analyses .........................................................................................10
3.2.
Final Analyses ............................................................................................11
4.
ANALYSIS POPULATIONS ...................................................................................12
4.1.
Protocol Deviations.....................................................................................13
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................13
5.1.
Study Treatment & Sub-group Display Descriptors.....................................13
5.2.
Baseline Definitions ....................................................................................14
5.3.
Multicentre Studies .....................................................................................14
5.4.
Examination of Covariates, Other Strata and Subgroups............................14
5.4.1.
Covariates and Other Strata ........................................................14
5.4.2.
Examination of Subgroups...........................................................14
5.5.
Multiple Comparisons and Multiplicity .........................................................15
5.6.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................15
6.
STUDY POPULATION ANALYSES .......................................................................15
6.1.
Overview of Planned Study Population Analyses........................................15
6.2.
Participant Disposition and Population........................................................15
6.3.
Protocol Deviation.......................................................................................16
6.4.
Demographic and Baseline Characteristics.................................................16
6.5.
Prior and Concomitant Medications ............................................................17
6.6.
Rehabilitation..............................................................................................17
6.7.
Other Surgical Procedure ...........................................................................17
6.8.
Actual dose.................................................................................................18
7.
EFFICACY ANALYSES..........................................................................................19
7.1.
Primary Efficacy Analyses ..........................................................................19
7.1.1.
Endpoint / Variables.....................................................................19
7.1.2.
Summary Measure ......................................................................19
7.1.3.
Population of Interest...................................................................20
7.1.4.
Strategy for Intercurrent (Post-Randomization) Events ................20
7.1.5.
Statistical Analyses / Methods .....................................................20
7.1.5.1.
Statistical Methodology Specification..........................20
7.2.
Secondary Efficacy Analyses......................................................................21
7.2.1.
Endpoint / Variables.....................................................................21
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7.2.2.
Summary Measure ......................................................................21
7.2.3.
Population of Interest...................................................................21
7.2.4.
Strategy for Intercurrent (Post-Randomization) Events ................22
7.2.5.
Statistical Analyses / Methods .....................................................22
7.2.5.1.
Statistical Methodology Specification..........................22
7.3.
Exploratory Efficacy Analyses.....................................................................23
7.3.1.
Modified Ashworth Scale (MAS) ..................................................23
7.3.2.
Numeric Rating Scale (NRS) for pain...........................................24
7.3.3.
Disability Assessment Scale (DAS)..............................................24
7.3.4.
Clinical Global Impression of Change (CGI) of functional 
disability.......................................................................................24
7.3.5.
Patient-Reported Benefit of Injection............................................24
7.3.6.
Time to Patient-Reported Onset of Spasticity Symptom 
Relief ...........................................................................................25
7.3.7.
Time to Qualification for Retreatment...........................................25
8.
SAFETY ANALYSES .............................................................................................26
8.1.
Adverse Events Analyses ...........................................................................26
8.2.
Adverse Events of Special Interest Analyses..............................................27
8.3.
Clinical Laboratory Analyses.......................................................................27
8.4.
Other Safety Analyses ................................................................................28
8.5.
Patient Profiles ...........................................................................................28
8.6.
Exposure ....................................................................................................29
9.
REFERENCES.......................................................................................................31
10. APPENDICES........................................................................................................32
10.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................32
10.2.
Appendix 2: Schedule of Activities ..............................................................33
10.2.1.
Protocol Defined Schedule of Events...........................................33
10.3.
Appendix 3: Assessment Windows .............................................................36
10.3.1.
Definitions of Assessment Windows for Efficacy Analyses 
(only Final Visit and Withdraw Visit, and only Final 
Analyses).....................................................................................36
10.4.
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................37
10.4.1.
Study Phases for Concomitant Medication...................................37
10.4.2.
Study Phases for Adverse Events................................................37
10.4.2.1.
Definition of Adverse Events of Special Interest .........38
10.5.
Appendix 5: Data Display Standards & Handling Conventions....................39
10.5.1.
Reporting Process .......................................................................39
10.5.2.
Reporting Standards....................................................................39
10.6.
Appendix 6: Derived and Transformed Data ...............................................41
10.6.1.
General........................................................................................41
10.6.2.
Study Population..........................................................................41
10.6.3.
Efficacy........................................................................................42
10.7.
Appendix 7: Reporting Standards for Missing Data.....................................43
10.7.1.
Premature Withdrawals................................................................43
10.7.2.
Handling of Missing Data.............................................................43
10.7.2.1.
Handling of Missing and Partial Dates ........................43
10.8.
Appendix 8: Values of Potential Clinical Importance ...................................44
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10.9.
Appendix 9: Population Pharmacokinetic (PopPK) Analyses ......................45
10.10. Appendix 10: Pharmacokinetic / Pharmacodynamic Analyses ....................46
10.11. Appendix 11: Abbreviations & Trade Marks ................................................47
10.11.1. Abbreviations...............................................................................47
10.11.2. Trademarks .................................................................................48
10.12. Appendix 12: List of Data Displays..............................................................49
10.12.1. Data Display Numbering..............................................................49
10.12.2. Mock Example Shell Referencing ................................................49
10.12.3. Deliverables.................................................................................49
10.12.4. Study Population Tables..............................................................50
10.12.4.1. Interim Analyses.........................................................50
10.12.4.2. Final Analyses............................................................52
10.12.5. Efficacy Tables ............................................................................53
10.12.5.1. Interim Analyses.........................................................53
10.12.5.2. Final Analyses............................................................56
10.12.6. Efficacy Figures ...........................................................................61
10.12.6.1. Interim Analyses.........................................................61
10.12.6.2. Final Analyses............................................................65
10.12.7. Safety Tables...............................................................................69
10.12.7.1. Interim Analyses.........................................................69
10.12.7.2. Final Analyses............................................................77
10.12.8. Safety Figures .............................................................................90
10.12.8.1. Interim Analyses.........................................................90
10.12.9. ICH Listings .................................................................................91
10.12.9.1. Interim Analyses.........................................................91
10.12.9.2. Final Analyses............................................................94
10.12.10.Patient Profiles ............................................................................98
10.12.10.1.
Final Analyses ........................................98
10.13. Appendix 13: List of Preferred Terms / System Organ Class of 
Adverse Events of Special Interest .............................................................99
10.13.1. Convulsions and Seizures ...........................................................99
10.13.2. Respiratory Adverse Events.........................................................99
10.13.3. Possible Distant Spread of Toxin.................................................99
10.14. Appendix 14: Decision Tree to determine Data cutoff visit and date..........102
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1.
INTRODUCTION
1.1.
RAP Amendments
Revision chronology: 
RAP Section
Amendment Details
Reporting and Analysis Plan_Study207660_Final_V1 02-Apr-2018
Reporting and Analysis Plan_Study207660_Amendment_Final_V1 20-Aug-2018
Section 2.1.

Added Changes to the Protocol Defined Statistical Analysis Plan
Section 3.1.
Interim analyses

Added the definition of the Rehabilitation data used for the interim 
analysis

Changed that Cardiovascular event will not be output in the interim 
analysis. 
Section 5.4.1.

Clarified that a randomization stratum is Baseline MAS value “of the 
elbow” in this study. 
Section 6.4.
“Summary of Baseline 
Efficacy Parameter”

Removed the MAS in the pronation of forearm and shoulder flexors 
from the summary table since the associated baseline value was not 
planned to be collected. 

Clarified a joint location of NRS used for the summary table. 

Added Baseline MAS score of the elbow as randomization strata in 
the item list of this summary table.

Clarified whether these items are continuous or categorical. 
Section 6.7.Section 6.8. 

Added the plans for listing of Other Surgical Procedure and displays 
about actual dose by muscle region and joint. 
Section 6.6.
Category of Frequency

Corrected the category from “>8 days per month” to “>0 and 8 days 
per month”
Section 7.1.1.

Clarified which visit the endpoint is. 
Section 7.2.5.1.
Secondary Efficacy Analyses

Clarified that the Main Assessment Parameter of DAS is used for the 
secondary efficacy analysis. 

Clarified whether the fixed effects are categorial or continuous. 

Clarified the secondary efficacy analysis for the Responder Rate of 
MAS score.

Changed the definition of Responder of MAS in the thumb to that of 
which denominator does not include the unevaluable thumb. 
Section 7.3.1. 
Modified Ashworth Scale

Removed change from baseline in MAS scores of the pronation of the 
forearm and should flexors since the corresponding baseline values 
were not collected. 
Section 7.3.2.
Numeric Rating Scale for Pain

Removed change from baseline in NRS except for that of the elbow 
since the corresponding baseline values were not collected. 
Section 7.3.3.
Disability Assessment Scale
Section 7.3.4.
Clinical Global Impression of 

Clarified the data used for the summary tables and figures. 
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RAP Section
Amendment Details
Change of functional disability
Section 7.3.6. 
Time to Patient-Reported 
Onset of Spasticity Symptom 
Relief

Added the derivation of time to event data in case that the participant 
does not complete Visit 2 and is withdrawn from study later than the 
planned date of Visit2. 
Section 7.3.7. 
Time to Qualification for 
retreatment

Removed ITT4 population from the time to qualification for retreatment 
analysis since participants who were treated 4 times were not 
assessed to be retreated. 
Section 8.1.

Added the plan for summary of AE within 84 days by sex and age 
group. 
Section 8.3.

Added the details of Worst case urinalysis. 
Section 8.5.

Added Patient Profiles analysis
Section 10.3 
Assessment Windows

Added the definition of assessment windows for efficacy analyses. 
The rationale was also added in the section. 
Section 10.4.1.

Changed the definition of study phases for concomitant medication. 
Section 10.4.2.

Corrected the definition of Study Phase for AE to that for which AE 
start time is not used since the previous definition was not that of AE 
which occurred within 84days. 
Section 10.5.2.

Added the plan for 95% confidence interval in summary tables for 
continuous efficacy endpoints. 
Section 10.6.2
Age Category

Changed the definition of Age Category to that of EudraCT 
requirement.
Section 10.12.4.

Corrected the analysis population of “Summary of Race and Racial 
Combinations” from Enrolled to ITT1 because of baseline 
characteristics evaluation. 
Section 10.12.5.2.

Added the summary tables of efficacy endpoints in Open Label Phase 
(2nd treatment)
Section 10.14.

Added the decision tree to determine data cutoff visit and date.
Section 10.13.

Removed the two following PT to identify AESI since these were
included in the list by mistake. 
o
Paralysis flaccid
o
Vllth nerve paralysis
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2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
There was one change to the originally planned statistical analysis specified in the 
protocol amendment 02 [(Dated: 06OCT2017)] as the following Table shows: 
Protocol
Reporting & Analysis Plan
Objectives and endpoints
Statistical Analysis Plan
Rationale for Changes

Exploratory endpoints

Changes in MAS score from 
baseline in finger, thumb, 
wrist, elbow, pronation of the 
forearm and shoulder flexors

Change from baseline in MAS 
scores of the finger, thumb, 
wrist and elbow only will be 
calculated, whereas those of 
the pronation of the forearm 
and shoulder will not. 

MAS scores in the pronation 
of the forearm and shoulder 
flexors were not collected in 
Blind Phase. 

Since baseline value is 
defined as the latest value 
prior to the initial treatment, 
the baseline value would be 
usually the data at Visit1 in 
Blind Phase.  

Therefore, there were not the 
data of the baseline value in 
the pronation of the forearm 
and shoulder
flexors, and 
changes from baseline 
cannot be calculated. 
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To evaluate the efficacy of the 
injections of 400 units of the 
product at Week 6 (finger/ wrist 
flexors: 240 units, elbow flexors: 
160 units), comparing to that of 
240 units (finger/ wrist flexors: 240 
units, elbow flexors: placebo).

The responder rate: The rate of the participants that 
Modified Ashworth Scale (MAS) score was reduced 
at least 1 from baseline in the elbow flexors.
Secondary Objectives
Secondary Endpoints

To evaluate the efficacy of 400 
units of the product, comparing to 
240 units of the product

The responder rate of MAS score from baseline in 
the finger, thumb and wrist flexors

Changes in MAS score from baseline in the finger, 
thumb, wrist and elbow flexors

Changes in Disability Assessment Scale (DAS) from 
baseline

To evaluate the safety and 
tolerability of the product of 400 
units, comparing to 240 units of the 
product/ To evaluate the safety 

Adverse events

Physical examinations

Clinical laboratory tests (haematology, blood 
biochemistry, urinalysis)
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Objectives
Endpoints
and tolerability of 400 units of the 
product

Vital signs (heart rate, blood pressure, body 
temperature)
Exploratory Objectives
Exploratory Endpoints

To evaluate the efficacy of 400 
units of the product

Changes in MAS score from baseline in finger, 
thumb, wrist, elbow, pronation of the forearm and 
shoulder flexors

To evaluate the other efficacy of 
the product of 400 units, 
comparing to 240 units of the 
product/ To evaluate the other 
efficacy of 400 units of the product

Changes in Numeric Rating Scale (NRS) for pain 
from baseline

Changes in other items of DAS from baseline

Clinical Global Impression of Change (CGI) of 
functional disability by an investigator

CGI of functional disability by a patient

Time to patient-reported onset of spasticity symptom 
relief

Patient-reported benefit of injection

Time to qualification for retreatment

To evaluate neutralizing antibody 
production

Testing for neutralizing antibody
2.3.
Study Design
Overview of Study Design and Key Features
Design 
Features
This study includes a Screening Phase, Blind Phase, and Open-label Phase. The 
study design of each treatment phase is shown below.

Blind Phase: Multicenter, randomized, double-blind, placebo-controlled, 
parallel-group comparison design

Open-Label Phase: Multicenter, uncontrolled, open-label design
Dosing

In the Blind Phase, participants will be randomly assigned 1:1 to either the 400 
or the 240-unit group.

In the 400-unit group, 240 units of the product will be injected into the 
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Overview of Study Design and Key Features
muscles that act on the finger (including thumb flexors) and wrist flexors, 
and 160 units into the muscles that act on the elbow flexors. A total of 400 
units of the product will be injected. 

In the 240-unit group, 240 units of the product will be injected into the 
muscles that act on the finger (including thumb flexors) and wrist flexors. 
Placebo will be injected into the muscles that act on the elbow flexors. A 
total of 240 units of the product will be injected. 

In the Open-label phase, a total of 400 units will be injected in both groups. 

The product can be injected up to 3 times after completion of Part 1 in the 
blind phase. Participants whom the investigator considers as eligible for 
the injections will be treated. The next injections cannot be performed until 
the eligibility of the participant has been confirmed by the investigator. 

The muscle to be injected and the dose will be decided by the investigator 
based on the patient’s symptoms, and a total dose of 400 units of the 
product will be injected in a divided dose. For the muscles that the 
investigator considers as unnecessary to be treated, an injection may be 
skipped. The involving muscle and the dose do not have to be same each 
time always. 
Treatment 
Assignment

Number of participants (randomized participants): 120 (60 per group)

GSK RandAll NG will be used to generate the randomization schedule.

The randomization will be stratified by the MAS score (3 or 4) in the elbow 
flexors at Day1
Interim 
Analysis

Interim analysis is planned in this study as described in 3.1.
2.4.
Statistical Hypotheses / Statistical Analyses
No formal hypothesis will not be tested. 
3.
PLANNED ANALYSES
3.1.
Interim Analyses
The interim planned primary analyses will be performed after the completion of the 
following sequential steps:
1.
All participants (except for early termination) complete the visit at Week 24 of the 
initial dose as defined in the protocol. The participants who complete that visit are 
defined as below.
The participant is re-treated at Week 12 visit in Blind Phase and completes the Week 12 
visit in Open-label Phase.
The participant is re-treated at Week 16 visit in Blind Phase and completes the Week 12 
visit in Open-label Phase.
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The participant is re-treated at Week 20 visit in Blind Phase and completes the Week 4 
visit in Open-label Phase.
The participant completes the Week 24 visit in Blind Phase.
2.
All required database cleaning activities have been completed and interim database 
release and database freeze has been declared by Data Management.
3.
All criteria for unblinding the randomization codes have been met. 
4.
Randomization codes have been distributed according to RandAll NG procedures.
5.
Interim analyses will be performed. 
The interim analyses will be performed for regulatory submission. However subject level 
data will not be disclosed to people who work at the sites including investigators. 
All planned interim analyses (i.e. Study population, Efficacy and Safety analyses) will be 
performed using data up to Week 24 visit for all participants. 
For Rehabilitations, the data at Screening visit and Week 12 visit will be used for the 
interim analysis. 
For Adverse Events, Liver Events and Medication, the data up to Week 24 visit is defined 
by using the start date. If the start date of these data is earlier than or same as the date of 
Week 24 visit defined above, these data will be included in the data up to Week 24 visit. 
Otherwise the data will not. See the decision tree (Appendix 14) to determine the Week 
24 visit and date of the participant. 
Cardiovascular Events will not be output in the interim analysis. 
3.2.
Final Analyses
The final planned primary analyses will be performed after the completion of the 
following sequential steps:
1.
All participants have completed the study as defined in the protocol.
2.
All required database cleaning activities have been completed and final database 
release and database freeze has been declared by Data Management.
3.
Final analyses will be performed. 
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4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
Screened

Comprise of all screened participants

Study Population
Enrolled

Comprise of all participants who meet the 
eligibility criteria at a screening and Day 1 visit. 

Study Population 
Intent-To-Treat 1 
(ITT1)

This population consists of all participants who 
are randomized in the study and who have at 
least 1 post-baseline efficacy assessment:

ITT is the primary efficacy analysis population, 
and the participants will be analyzed in line 
with the randomized treatment group

Any participant who receives a study treatment 
randomization number will be considered to 
have been randomized.

Study Population

Efficacy
ITT2

This population consists of all participants in 
ITT1 population, who have at least 2 study 
treatments and who have at least 1 efficacy 
assessment after the 2nd treatment. 

Study Population

Efficacy
ITT3

This population consists of all participants in 
ITT2 population, who have at least 3 study 
treatments and who have at least 1 efficacy 
assessment after the 3rd treatment.

Study Population

Efficacy
ITT4

This population consists of all participants in 
ITT3 population, who have 4 study treatments 
and who have at least 1 efficacy assessment 
after the 4th treatment.

Study Population

Efficacy
Safety1

This population consists of all participants who 
are randomized in the study and who receive 
study treatment at least once

The participants will be analyzed based on the
treatment actually given.

Safety
Safety2

This population consists of all participants in 
Safety1 population, who receive study 
treatment at least twice.

The participants will be analyzed based on the 
treatment actually given.

Safety
Safety3

This population consists of all participants who 
are randomized in the study and who receive 
study treatment at least three times

The participants will be analyzed based on the 

Safety
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Population
Definition / Criteria
Analyses Evaluated
treatment actually given.
Safety4

This population consists of all participants in 
Safety1 population, who receive study 
treatment four times.

The participants will be analyzed based on the 
treatment actually given.

Safety
NOTES : 

Please refer to Appendix 12: List of Data Displays which details the population to be used for each displays being 
generated.
4.1.
Protocol Deviations
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarised and listed.
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan.
o Data will be reviewed prior to unblinding and freezing the database to ensure all 
important deviations are captured and categorised on the protocol deviations 
dataset. 
o This dataset will be the basis for the summaries and listings of protocol 
deviations.
A separate listing of all inclusion/exclusion criteria deviations will also be provided. This 
listing will be based on data as recorded on the inclusion/exclusion page of the eCRF.
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
RandAll NG
Data Displays for Reporting 
Code
Description
Description
Order in TLF 
A
GSK1358820 240U
GSK1358820 240U
1
B
GSK1358820 400U
GSK1358820 400U
2
Treatment comparisons will be displayed as follows using the descriptors as specified:
1.
GSK1358820 400U vs GSK1358820 240U
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5.2.
Baseline Definitions
For all endpoints (except as noted in baseline definitions) the baseline value will be the 
latest pre-dose assessment with a non-missing value, including those from unscheduled 
visits. If time is not collected, Day 1 assessments are assumed to be taken prior to first 
dose and used as baseline. These baseline values will be used for all analyses in both 
Blind Phase and Open Label Phase. 
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing.
5.3.
Multicentre Studies
No data will be analysed by center.
5.4.
Examination of Covariates, Other Strata and Subgroups
5.4.1.
Covariates and Other Strata
The list of covariates and other strata may be used in descriptive summaries and 
statistical analyses, some of which may also be used for subgroup analyses. Additional 
covariates and other strata of clinical interest may also be considered.
Category
Details
Strata
Baseline MAS value of the elbow (3 or 4)
5.4.2.
Examination of Subgroups
The list of subgroups may be used in descriptive summaries and statistical analyses.
Additional subgroups of clinical interest may also be considered.

If the percentage of participants is small within a particular subgroup, then the 
subgroup categories may be refined prior to unblinding the trial.

If the category cannot be refined further, then descriptive rather than statistical 
comparisons may be performed for the particular subgroup.
Subgroup
Categories 
Baseline MAS value of the elbow
3 or 4 
Baseline Rehabilitation
Task-specific practice
Yes, or No
The subgroup analyses will be conducted by each rehabilitation use. 
Muscle strengthening exercise
Stretching/Range of motion 
exercise
Splinting/Orthoses
Taping
Positioning aids
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5.5.
Multiple Comparisons and Multiplicity
No multiplicity adjustment is considered in this study because no statistical hypothesis 
will be tested.
5.6.
Other Considerations for Data Analyses and Data Handling 
Conventions
Other considerations for data analyses and data handling conventions are outlined in the 
appendices:
Section
Component
Section 10.3
Appendix 3: Assessment Windows
Section 10.4
Appendix 4: Study Phases and Treatment Emergent Adverse Events
Section 10.5
Appendix 5: Data Display Standards & Handling Conventions
Section 10.6
Appendix 6: Derived and Transformed Data
Section 10.7
Appendix 7: Reporting Standards for Missing Data
Section 10.8
Appendix 8: Values of Potential Clinical Importance
6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
The study population analyses will be based on the Screened, Enrolled and ITT
populations, unless otherwise specified.
Study population analyses including analyses of participant’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
and rehabilitations will be based on GSK Core Data Standards.  Details of the planned 
displays are presented in Appendix 12: List of Data Displays.
6.2.
Participant Disposition and Population
The number and percentage of those participants below will be presented by treatment 
group and total.

Participants who completed the Week 24 and who withdrew early from study by 
Week 24 (including the reasons for early withdrawal)

Participants who completed the study and who withdrew early from study 
(including the reasons for early withdrawal)

Participants who passed screening and who failed screening (including the 
reasons for screen failure)

Participants at each centre

Participants included in each population defined in the Section 4. 
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These items below will be listed. 

The reasons for early withdrawal and screen failure. 

Participants who were rescreened. 

Participants for whom the treatment blind was broken. 

Planned and actual treatments

Participants excluded from any population defined in the Section 4.
6.3.
Protocol Deviation
The number and percentage of participants with important protocol deviation will be 
presented by treatment group. This summary will not include subcategories
Important protocol deviations and participants with inclusion/exclusion criteria deviation 
will be listed. 
6.4.
Demographic and Baseline Characteristics
These parameters as below will be summarized by treatment group and total.

Demographic data (age, sex, ethnicity, weight, height, body mass index(BMI), 
race and racial combinations)

Baseline Efficacy Parameter
o
Continuous variable

Modified Ashworth Scales in finger, thumb, wrist and elbow

Numeric Rating Scale for pain in elbow

Disability Assessment Scale (Main Assessment Parameter)

Disability Assessment Scale (Hygiene, Pain, Dressing and Limb 
posture)
o
Categorical variable

Baseline MAS score of the elbow (3 or 4, original values) as 
randomization strata

The selected item as a Main Assessment Parameter of DAS out of 
the 4 items

Hygiene

Pain

Dressing

Limb posture
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6.5.
Prior and Concomitant Medications
All medication used in this study will be coded according to drug name as defined in the 
GSK Drug Dictionary. The relationship between the ATC level 1 and ingredient will be 
summarized for the all prior and concomitant medications, respectively. 
6.6.
Rehabilitation

Screening
The number and percentage of Rehabilitations will be presented.

Treatment phase
The category and frequency of Rehabilitations will be collected on eCRF. The number 
and percentage of each Rehabilitation will be presented in Blind Phase. The category and 
frequency of Rehabilitations in all treatment phase will be listed. 

Category and Frequency
The categories of Rehabilitation are as below: 

Task-specific practice

Muscle strengthening exercise

Stretching/Range of motion exercise

Splinting/Orthoses

Taping

Positioning aids
The category of frequency which will be collected on CRF is defined as below:
o
No practice
o
> 0 and 8 days per month
o
> 8 and 16 days per month
o
> 16 and 24 days per month
o
> 24 days per month
6.7.
Other Surgical Procedure
The other surgical procedure except for Rehabilitation will be listed by treatment group. 
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6.8.
Actual dose
The dosage in each muscle and joint to which more than 0 unit of GSK1358820 is 
administered will be summarized by treatment group and treatment cycle. The 
Relationship between Muscle Region and Joint is shown below in each treatment phase. 

Muscle Region
If a muscle region of a participant is not treated, the muscle will not be included when 
calculating the summary statistics. 
Example
Dosage of Biceps brachii (unit)
Mean
Subject
0
(40 + 80 + 120) / 3 = 80 units
Subject
40
Subject
80
Subject
120

Joint
If no muscle region of a Joint of a Participant is treated, the corresponding joint will 
not be included when calculating the summary statistics. 
Example
Muscle Region
Dosage of 
each Muscle 
(unit)
Dosage of 
Elbow (unit)
Mean
Subject
Biceps brachii
0
0
(100 + 110 + 
180) / 3 = 130 
units
Brachialis
0
Brachioradialis
0
Subject
Biceps brachii
0
100
Brachialis
20
Brachioradialis
80
Subject
Biceps brachii
10
110
Brachialis
40
Brachioradialis
60
Subject
Biceps brachii
40
180
Brachialis
60
Brachioradialis
80

Blind Phase
Joint
Each muscle region
Elbow
Biceps brachii
Brachialis
Brachioradialis
Wrist
Flexor carpi radialis
Flexor carpi ulnaris
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Joint
Each muscle region
Finger
Flexor digitorum profundus
Flexor digitorum superficialis
Thumb
Flexor pollicis longus
Adductor pollicis

Open Label Phase
Joint
Each muscle region
Elbow
Biceps brachii 
Brachialis
Brachioradialis
Wrist
Flexor carpi radialis
Flexor carpi ulnaris
Finger
Flexor digitorum profundus
Flexor digitorum superficialis
Lumbricales interossei
Thumb
Flexor pollicis longus
Adductor pollicis
Opponens
Forearms
Pronator teres
Pronator quadratus
Shoulder
Teres major 
Latissimus dorsi
Pectoralis major 
Subscapularis
7.
EFFICACY ANALYSES
7.1.
Primary Efficacy Analyses
7.1.1.
Endpoint / Variables
The primary endpoint is the responder rate of MAS score in the elbow flexors at Week 6 
of the initial dose.
7.1.2.
Summary Measure
The summary measure is the difference in the responder rate of MAS score in the elbow 
flexors.
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7.1.3.
Population of Interest
The primary efficacy analyses will be based on the Intent-To-Treat 1 population, unless 
otherwise specified.
7.1.4.
Strategy for Intercurrent (Post-Randomization) Events
Intercurrent event: early withdrawal from study
Strategy : if MAS score is missing because of an early withdrawal from the study, the 
participant will be regarded as a non-responder.
7.1.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 7.1.1 will be 
summarised using descriptive statistics and listed.
7.1.5.1.
Statistical Methodology Specification
Endpoint / Variables

Responder Rate of MAS in the elbow flexors at Week 6 of the initial dose
Model Specification

To summarize the primary endpoint without statistical model
o
The primary endpoint will be calculated as the proportion of participants whose MAS score 
decreased by at least 1 level from the baseline in the ITT1 population.
o
The intergroup difference in the responder rate and its 95% confidence interval (Wald-
type) will be computed.
Data Convention

The MAS scores, 0, 1, 1+, 2, 3 and 4 will be encoded to 0, 1, 2, 3, 4 and 5, respectively, for the 
analyses.
Definition of Responder and Responder rate
“Responder” is defined as a participant whose MAS score decrease by at least 1 level from the 
baseline. 
Responder Rate will be calculated as below. 
Responder Rate (%) = (Number of Responders) / (Number of participants in ITT1 population) x 100

If MAS score of a given participant is missing at Week 6, then this participant will be regarded 
as a non-responder.
Model Results Presentation

The difference in the responder rate (400 units – 240 units) and its associated 95% CI will be 
presented.
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Subgroup Analyses (Rehabilitation)

Subgroup analyses will be performed by baseline rehabilitation in the Section 5.4.

The difference (400 units – 240 units) and its 95% CI will be presented.
Subgroup Analyses (baseline MAS score)

Subgroup analyses will be performed by baseline MAS score of the elbow (3 or 4) used as
randomization strata.

The difference (400 units – 240 units) and its 95% CI will be presented.
Supportive Analyses

The difference in the responder rate will be estimated using Mantel-Haenszel method to 
consider a stratification factor, that is baseline MAS score of the elbow (3 or 4).

Mantel-Haenszel rate difference (400 units – 240 units) and its 95% CI will be calculated.
7.2.
Secondary Efficacy Analyses
7.2.1.
Endpoint / Variables
Secondary Efficacy Endpoints are the following items in Blind Phase:

MAS scores in the elbow, finger, thumb and wrist flexors.

Change from baseline in MAS scores

Responder rate of MAS in the elbow, finger, thumb and wrist flexors.

DAS score (Main Assessment Parameter)

Change from baseline in DAS score (Main Assessment Parameter)
7.2.2.
Summary Measure
Summary Measures are as below.

The differences in the responder rate of MAS scores

The differences in the least square means of changes from baseline in MAS scores

The differences in the least square means of changes from baseline in DAS scores
7.2.3.
Population of Interest
The secondary efficacy analyses will be based on the Intent-To-Treat 1 population, unless 
otherwise specified.
The secondary efficacy analyses will be performed for only double blind phase. All 
efficacy analyses for open -label phase and other endpoints for double blind phase will be 
done as exploratory.
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Unless specified otherwise, the data up to Week 12 of treatment will be summarized 
during the double-blind period. This is because this study allows to re-treat. In other 
words, after 12 weeks, only participants who have a smaller MAS score would remain 
and the difference of the change from baseline in MAS between 240 units and 400 units 
would be attenuated. Therefore, the data up to Week 12 of initial treatment will be 
analysed as secondary statistical analyses. This is the case for exploratory analyses for 
open label period (i.e. the data up to week 12 of re-treatment will be summarized). 
Listing will include the data after week 12 of treatment/re-treatment.
7.2.4.
Strategy for Intercurrent (Post-Randomization) Events
Intercurrent event: early withdrawal from study.
Strategy for dichotomous data: the participant will be regarded as a non-responder.
Strategy for continuous data: the missing data will be removed from the analyses. 
7.2.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 7.2.1 will be 
summarised using descriptive statistics, graphically presented and listed.
7.2.5.1.
Statistical Methodology Specification
Secondary Efficacy Analysis
Endpoint / Variables

Change from baseline in MAS in each joint and DAS (Main Assessment Parameter) scores
Model Specification

The endpoint will be analyzed using a mixed model for repeated measures (MMRM)

Terms fitted in the MMRM will include the items below as fixed effects.

Categorical effect
o
Treatment
o
Visit
o
Treatment-by-visit interaction

Continuous effect
o
Baseline value in MAS of each joint or in DAS (Main Assessment Parameter)
o
Baseline-by-visit interaction

An unstructured variance structure will be used to model the within-participant errors, shared 
across treatments.

The empirical sandwich estimator will be used to estimate the standard errors.
Model Checking & Diagnostics

If the model will not converge with unstructured variance, AR(1) variance structure can be 
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Secondary Efficacy Analysis
used. 
Model Results Presentation

Adjusted means (least square means) and corresponding standard errors of means will be 
presented for each treatment by visit, together with estimated treatment differences (400 units 
– 240 units) and the corresponding 95% CI.
Data included in Model

The dataset including only data until week 12 after the first treatment will be used. 
Secondary Efficacy Analysis
Endpoint / Variables

Responder Rate of MAS score in each joint at all visit

Responder is defined as well as primary endpoint. 

For the elbow, finger and wrist flexors.
o
Responder rate (%) = (Number of Responders) / (Number of participants in ITT1 
population) x 100

For the thumb flexors
o
Responder rate (%) = (Number of Responders) / (Number of Participants in ITT1 
population, except for the participants of which thumb was not evaluable, x 100. 
o
In case that the thumb was not evaluable, MAS score data will be entered as “Not 
Applicable”. 
Model Specification

See primary endpoint section.
Data Convention

See primary endpoint section. 
Supportive Statistical Analyses

See supportive statistical analyses for primary efficacy analyses section. 

Baseline MAS score of the elbow as a stratification factor will be used for the Mantel Haenszel 
Estimator, regardless of the Responder rate of MAS score in the other joint. 
7.3.
Exploratory Efficacy Analyses
7.3.1.
Modified Ashworth Scale (MAS)
These analyses will be based on ITT 2, 3 and 4 populations.
Values and changes from baseline in MAS scores in finger, thumb, wrist and elbow will 
be summarised using descriptive statistics, graphically presented and listed by visit and 
treatment cycle. In addition, the number and percentage of Responder in MAS score of 
each joint will be presented by visit and treatment cycle including graphically. The 
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Responder rate will be the proportion of the responder in the corresponding population, 
except for the participant of which joint was not evaluable. MAS score values in 
pronation of the forearm and shoulder flexors will be summarised using descriptive 
statistics, graphically presented and listed by visit and treatment cycle. Data up to Week 
12 in each treatment cycle will be used for summary tables and Figures, whereas all data 
will be listed. 
7.3.2.
Numeric Rating Scale (NRS) for pain
These analyses will be based on ITT 1, 2, 3 and 4 populations. 
Values and changes from baseline in NRS of the elbow for pain will be summarised 
using descriptive statistics, graphically presented and listed by visit, treatment cycle and 
evaluated part. NRS values except for that of elbow flexors will be summarised using 
descriptive statistics, graphically presented and listed by visit and treatment cycle. Data 
up to Week 12 in each treatment cycle will be used for summary tables and Figures, 
whereas all data will be listed.
7.3.3.
Disability Assessment Scale (DAS)
These analyses will be based on ITT 1, 2, 3 and 4 populations. 
Values and changes from baseline in all items of DAS will be summarised using 
descriptive statistics, graphically presented and listed by visit and treatment cycle. Data 
up to Week 12 in each treatment cycle will be used for summary tables and Figures, 
whereas all data will be listed.
7.3.4.
Clinical Global Impression of Change (CGI) of functional 
disability
These analyses will be based on ITT 1, 2, 3 and 4 populations. 
Values of the variables below will be summarised using descriptive statistics, graphically 
presented and listed by visit and treatment cycle. Data up to Week 12 in each treatment 
cycle will be used for summary tables and Figures, whereas all data will be listed.
CGI of functional disability by an investigator
CGI of functional disability by a patient
7.3.5.
Patient-Reported Benefit of Injection
These analyses will be based on ITT 1, 2, 3 and 4 populations. 
The number and percentage of patient-reported benefit of injection will be presented and 
listed by visit and treatment cycle.
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7.3.6.
Time to Patient-Reported Onset of Spasticity Symptom Relief
These analyses will be based on ITT 1, 2, 3 and 4 populations. 
Time to event data will be summarized using the descriptive statistics below and listed. 

The number of events and censored cases. 

Median survival time with the associated 95% CI. 

25% and 75% survival time. 
Survival analyses will be conducted using a Kaplan-Meier method. To graphically 
compare the survival functions between 400 units and 240 units, the analysis will be 
conducted based on ITT 1 population whereas the analyses will be based on ITT 2, 3 and 
4 populations to assess the survival time by treatment cycle. Participants who are
withdrawn from this study before Visit 2 are censored at the withdrawal date. All other 
participants who do not experience the event and is not withdrawn from study or of 
whom the date of Visit 2 is missing and is not withdrawn from study before the planned 
date of Visit 2 are censored at the Visit 2. 
Survival function estimates will be summarized (survival probabilities and the number of 
participants at risk per time to event, and median in survival time) based on Kaplan Meier 
method. Kaplan Meier plots will be presented. 
7.3.7.
Time to Qualification for Retreatment
These analyses will be based on ITT 1, 2 and 3 populations. 
The number and percentage of event of interest will be presented by visit. Time to event 
data will be summarized using the descriptive statistics below and listed. 

The number of events and censored cases. 

Median survival time with the associated 95% CI. 

25% and 75% survival time. 
Survival analyses will be conducted using a Kaplan-Meier method. To graphically 
compare the survival functions between 400 units and 240 units, the analysis will be 
conducted based on ITT 1 population whereas the analyses will be based on ITT 2 and 3
populations to assess the survival time by treatment cycle. Participants who are 
withdrawn from this study before the events are censored at the withdrawal date. All 
other participants who do not experience the event and is not withdrawn from study are 
censored at the Last Observed Visit at the interim analyses or the final analyses.
Survival function estimates will be summarized (survival probabilities and the number of 
participants at risk per time to event, and median in survival time) based on Kaplan Meier 
method. Kaplan Meier plots will be presented. 
Note that the retreatment is not allowed within 83 days from the previous treatment. 
Therefore, this event will not occur before 83 days later after the treatment/re-treatment. 
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8.
SAFETY ANALYSES
The safety analyses will be based on the Safety 1, 2, 3 and 4 populations, unless 
otherwise specified.
8.1.
Adverse Events Analyses
Adverse events analyses including the analysis of adverse events (AEs), Serious (SAEs)
and other significant AEs will be based on GSK Core Data Standards. The details of the 
planned displays are provided in Appendix 12: List of Data Displays.
Adverse events that occurred in the overall study period, blinded period and open-label 
period will be summarized for each treatment group. The treatment group is based on 
dose actually given in blind period. For the blinded period, 2 patterns of analyses on 
adverse events will be performed, one is on adverse events that occurred between the 
initial dose and the first dose in the open-label period (or at the completion of study if no 
dose is given in the open-label period or at the study withdrawal), and another one is on 
adverse events that occurred within 84 days from the initial dose. 
Overall study period (Treatment Emergent AEs)
Blind phase
1.
AEs occurred between the initial dose and the first dose in the open-label period 
(or at the completion of study if no dose is given in the open-label period or at 
the study withdrawal)
2.
AEs occurred within 84 days from the initial dose
Open-label phase
3.01.
AEs occurred during 2nd treatment cycle.
3.02.
AEs occurred during 3rd treatment cycle. 
3.03.
AEs occurred during 4th treatment cycle. 
The number and percentages of participants who experience at least one AE will be 
presented for each category of AE listed as below by treatment group. 

All Treatment Emergent AEs (by SOC and PT, by SOC, PT and Maximum 
Intensity)

Common AEs (>= 3%) (by overall frequency)

Drug Related AEs (by SOC and PT, by SOC, PT and Maximum Intensity)

Non-Fatal Serious AEs

Drug Related Non-Fatal Serious AEs

AEs Leading to Withdrawal from Study (by SOC and PT)

Most Common Serious Drug Related AEs (by overall frequency)

Most Common Non-Serious Drug Related AEs (by overall frequency)

Common (>= 5%) Non-Serious AEs (by SOC and PT)
o
Number of Participant and Occurrences will be presented. 
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The number and percentages of participants wo experience at least one AE 
will be presented for AEs below. This summary will include only AE occurred within 84 
days in Blind Phase. 

Common AEs (>= 3%) within 84 days in Blind Phase by Sex (by overall 
frequency)

Common AEs (>= 3%) within 84 days in Blind Phase by Age group (Age < 65, 
Age >= 65) (by overall frequency)
“Common (>= 3%) AEs” is defined as the percentage of AEs is more than and equal to 
3% in either treatment group. 
In addition, the items below will be listed. 

All AEs

Participant Numbers for Individual AEs

Fatal Serious AEs

Non-Fatal Serious AEs

Reasons for Considering as a Serious AE

AEs Leading to Withdrawal from Study

Relationship between AE SOC, PT and Verbatim Text.
8.2.
Adverse Events of Special Interest Analyses
Adverse Events of Special Interest are defined as below. 

Convulsions and Seizures

Respiratory Adverse Events

Possible Distant Spread of Toxin
The number and percentage of AESI will be presented by treatment cycle and treatment 
group. The details of how to identify are described in the Appendix 13. 
8.3.
Clinical Laboratory Analyses
Laboratory evaluations including the analyses of Chemistry laboratory tests, Hematology 
laboratory tests, Urinalysis, and liver function tests will be based on GSK Core Data 
Standards. The details of the planned displays are in Appendix 12: List of Data Displays.
These data at Screening Visit, in Blind Phase and at Final Visit will be summarized by 
visit. Data at all visits for participants with any value outside normal range will be listed. 
Values and change from baseline in Chemistry Laboratory tests and Hematology 
laboratory tests will be summarized by treatment group and visit. 
Worst case results relative to normal range from baseline will be presented for Chemistry, 
Hematology and Urinalysis. Worst case urinalysis results relative to baseline for protein 
(category: NEG, TRA, 1+, 2+, 3+, 4+) and occult blood (category: NEG, TRA, 1+, 2+, 
3+) urinalysis only will be summarized by treatment group. The categories for worst case 
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are: No Change/Decreased, Any Increase, Increase to TRA, Increase to 1+, Increase to 
2+, Increase to 3+, Increase to 4+. The categorization is determined by comparing the 
baseline category to the worst case post-baseline category.  The determination of the 
worst case post-baseline takes into account both planned and unscheduled assessments.  
The percentages are based on the number of subjects in the treatment group with data for 
the test post-baseline. Subjects with missing baseline value are to be assumed to have 
normal/within range baseline value.
Shifts from baseline relative to normal range will be summarized by treatment group and 
visit for Chemistry and Hematology values. 
Scatter plot of Chemistry and Hematology at Week 12 versus baseline in Blind Phase will 
be presented. 
The outputs regarding liver events will not be presented unless at least one liver event is 
observed. See the details in the Appendix 12. 
8.4.
Other Safety Analyses
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified. The details of the 
planned displays are presented in Appendix 12: List of Data Displays.
These above data at Screening Visit, in Blind Phase and at Final Visit will be summarized 
by visit. These analyses will not include the data at QRV, in Open Label Phase and at 
Early Withdrawal, whereas all the data at all visit will be listed for final analyses. 
ECG findings (Normal, Abnormal – not clinically significant, Abnormal -clinically 
significant) will be summarized by visit. 
Values and changes from baseline in ECG and vital sign data will be summarized by visit. 
Values and changes from baseline in SpO2 will be summarized and listed by visit. Data 
at Screening visit, Visit 1 and 5 in Blind Phase and Final Visit will be summarized and 
those at all visits will be listed including values and changes from baseline. 
8.5.
Patient Profiles
Listing for patient profiles will be produced at only Final Analyses if at least one event is 
reported below. 
CV event (
Arrhythmias, 
Congestive Heart Failure, 
Cerebrovascular Events/Stroke and Transient Ischemic Attack, 
Deep Vein Thrombosis (DVT)/ Pulmonary Embolism (PE), 
Myocardial Infarction (MI)/ Unstable Angina (UA), 
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Peripheral Arterial Thromboembolism, 
Pulmonary Hypertension, 
Revascularization, 
Valvulopathy)
And Death. 
8.6.
Exposure
The number and percentage of participants treated will be presented by the number 
of injection. 

Blind Phase
The dosage will be summarized by muscle region below, Joint and total. The dosage will 
be listed by muscle region, joint and total. 
Joint
Each muscle region
Elbow
Biceps brachii
Brachialis
Brachioradialis
Wrist
Flexor carpi radialis
Flexor carpi ulnaris
Finger
Flexor digitorum profundus
Flexor digitorum superficialis
Thumb
Flexor pollicis longus
Adductor pollicis

Open Label Phase
The dosage will be summarized by treatment phase (2nd, 3rd and 4th treatment), muscle 
region below, Joint and total. The dosage will be listed by treatment phase and muscle 
region, Joint and total.
Joint
Each muscle region
Elbow
Biceps brachii 
Brachialis
Brachioradialis
Wrist
Flexor carpi radialis
Flexor carpi ulnaris
Finger
Flexor digitorum profundus
Flexor digitorum superficialis
Lumbricales interossei
Thumb
Flexor pollicis longus
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Joint
Each muscle region
Adductor pollicis
Opponens
Forearms
Pronator teres
Pronator quadratus
Shoulder
Teres major 
Latissimus dorsi
Pectoralis major 
Subscapularis
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9.
REFERENCES
GlaxoSmithKline Document Number 2017N315029_02 Study ID 207660. A phase III 
study (a placebo controlled, randomized, double-blind comparative study and an open-
label, uncontrolled study) to evaluate the efficacy and safety of GSK1358820 in patients 
with post-stroke upper limb spasticity. Report Date 06-Oct-2017. 
Study Reference Manual, Study ID 207660. A phase III study (a placebo controlled, 
randomized, double-blind comparative study and an open-label, uncontrolled study) to 
evaluate the efficacy and safety of GSK1358820 in patients with post-stroke upper limb 
spasticity. Effective Date 01-Jun-2018
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10.
APPENDICES
10.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
Per Protocol Population is not defined in this study.
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10.2.
Appendix 2: Schedule of Activities
10.2.1.
Protocol Defined Schedule of Events
Screeninga
Blind phase
1)
If a participant meets the eligibility at V5/ 
QRV, the participant will move forward to the open-
label phase
Open-label phase
If a participant meets the eligibility at V5/QRV, the 
participant will move forward to the next treatment phase
Completion 
visit
Part 1
Eligibility 
evaluation b
Part 2/Part 3/ Part 4
Eligibility 
evaluation b
Visit
SV
V1
(Day 
1)
V2 V3 V4
V5 c
(Eligibility 
evaluation)
QRV
V1
V2
V3
V4
V5 d
(Eligibility 
evaluation)
QRV
Final
Visit
Time from initial 
injection (Day 1) 
(Weeks)
―
0
2
4
6
12 
Allowable Week 
16 to 36e
―
―
―
―
―
Allowable Week 
24 to 36 e
48/
Withdrawal
Time from injection day 
in each treatment phase 
(Weeks)
―
0
2
4
6
12
16/ 20/ 24/ 28/ 
32/ 36
0
2
4
6
12
16/ 20/ 24
-
Acceptable visit 
windows (days) 
―
4
4
4
+4 f
14 g
(+4)v
4
4
4
+4 f
14 g
4
Written informed 
consent
X h
Randomization
X i
Injections
X
X
Evaluation of eligibility
X
X
X
X
Inclusion/exclusion 
criteria j
X
X i
Participant demography
X
MAS k
X
X i
X
X
X
X
X
X i,t
X
X
X
X
X
X
NRS l
X i
X
X
X
X
X i,t
X
X
X
X
(X) r
DAS 
X i
X
X
X
X
X i,t
X
X
X
X
(X) r
CGI by a investigator
X
X
X
X
X
X
X
X
(X) r
CGI by a patient
X
X
X
X
X
X
X
X
(X) r
Time to patient-reported 
onset of spasticity 
symptom relief
X
X
Patient-reported benefit 
of injection
X
X
X
X
X
X
(X) r
Physical examination 
X
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Screeninga
Blind phase
1)
If a participant meets the eligibility at V5/ 
QRV, the participant will move forward to the open-
label phase
Open-label phase
If a participant meets the eligibility at V5/QRV, the 
participant will move forward to the next treatment phase
Completion 
visit
Part 1
Eligibility 
evaluation b
Part 2/Part 3/ Part 4
Eligibility 
evaluation b
Visit
SV
V1
(Day 
1)
V2 V3 V4
V5 c
(Eligibility 
evaluation)
QRV
V1
V2
V3
V4
V5 d
(Eligibility 
evaluation)
QRV
Final
Visit
(complete version)
Physical examination 
(simplified version)
X i
X
X i,t
X
X
Medical history
X
X i
Vital signs m
X
X i
X
X i,t
X
X
Height
X
Body weight
X
X u
X u
X u
X u
Pulmonary function test
X
X
X
X u
X
X u
X
Electrocardiogram
X
X u
X u
X u
X u
Pregnancy test n
X
X i
X u
X u
Xs, u
X u
X
Laboratory test o
X
X
X
X
Adverse events p
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medications/therapies
X
X i
X
X
X
X
X
X
X
X
X
X
X
X
Testing for neutralising 
antibodies q
X
X
X
a.
Test items for screening must be performed from 4 weeks to 1 weeks before Day 1 visit (±3 days).
b.
Eligibility evaluation (Qualification for Retreatment Visit: QRV) will be performed at V5 as a starting point if a participant does not meet the criteria only. 
The evaluation is performed at a 4-week interval, V5 as a starting point, The QRV when a participant meets the criteria will be a same day as the injection in 
the next treatment period.
c.
If a participant is evaluated to meet the eligibility for the injection in the blind phase at V5, the participant will move forward to Part 2 in the open-label 
phase (Namely, V5 in Part 1 and V1 in Part 2 is a same day). If the participant does not meet the eligibility, QRV will be performed 4 weeks later, at V5 as s 
starting point. 
d.
If a participant is evaluated to meet the eligibility at V5 in the open-label phase, the participant will move forward to the next treatment phase (V5 and V1 in 
the next treatment phase is a same day). If the participant does not meet the eligibility, QRV is performed 4 weeks later, V5 as a starting point. If V5 in each 
treatment phase is at Week 48 after initial injection, V5 will be considered to be completion visit (FV). However, for the testing items, pre-scheduled tests at 
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V5 and neutralizing antibody tests will be performed. If V5 in Parts 2 and 3 is performed at Week 36 or later, after completion of V5, completion visit will 
be performed at Week 48.
e.
QRV is allowable to perform from initial injection to Week 36. Eligibility evaluation (QRV) will not be performed after Week 36.  
f.
V5 must be performed at least 84 days after V1. 
g.
The acceptable visit windows will be -14 to +4 days if QRV is performed at Week 36.
h.
Must be performed earlier than any other procedures
i.
Must be performed before injection of the product
j.
For inclusion/exclusion criteria, the items to be observed are different between screening phase and Day 1. For details, refer to Protocol Section 6.1 and 
Section 6.2.
k.
For MAS evaluation, the items to be evaluated differ depending on the treatment phase. For details, refer to Protocol Section 9.1.1.1.
l.
MAS evaluation will be followed by NRS evaluation. For NRS evaluation, items to be evaluated differ. For details, refer to Protocol Section 9.1.1.2.
m. Body temperature, heart rate, and blood pressure will be measured as vital signs. 
n.
Women of childbearing potential will be only performed. Serum hCG pregnancy test must be performed at screening, and urine hCG pregnancy test after 
randomization. The tests can be performed beyond the protocol specifications if an investigator considers to be necessary.  
o.
For laboratory test items, refer to Protocol Section 12.2. Attachment 2. Fasting is not required for blood collection. 
p.
Adverse events and serious adverse events collection period will be from the initial injection day (Day 1) to completion visit (FV).
q.
Neutralizing antibody testing is performed 3 times in each participant. The first test will be performed in screening phase, the second is at V5 in the blind 
phase, and the third is at completion visit.
r.
A participant who withdraws the study before 12 weeks after last injection will be performed. 
s.
Perform if V5 in each treatment phase is at Week 48 after initial injection
t.
Not necessary to perform doubly as V1 assessment if the same assessment is performed at V5 or QRV. If V1 assessment or retreatment cannot be performed 
on the same day as V5 or QRV, MAS assessment should be performed again on the day of visit for the V1 assessment.
u.
Evaluation of retreatment is performed only when the dosing conditions (1 to 5) of retreatment evaluation are met. If V1 assessment or retreatment cannot be 
performed on the same day as V5 or QRV, body weight, pulmonary function test, electrocardiogram, and pregnancy test should not be performed again on 
the day of visit for V1 assessment.
v.
V1 assessment in Part 2 or subsequent parts should be performed as a rule on the same day as V5 or QRS (when eligibility was confirmed) of the previous 
part. If this is not possible, the V1 assessment may be performed on another day but within the acceptable visit window. 
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10.3.
Appendix 3: Assessment Windows
10.3.1.
Definitions of Assessment Windows for Efficacy Analyses (only 
Final Visit and Withdraw Visit, and only Final Analyses)
If the Visit 5 in last treatment cycle coincides with Final Visit (e.g., Visit 5 in 3rd 
treatment cycle is achieved on Week 48 from the initial dose), the efficacy data will be 
entered as Final Visit, not the last visit in the treatment cycle. However, actually the data 
at the last visit is not missing. Therefore, in the following cases, the Final Visit data will 
be treated as the Visit 5 in the last treatment cycle for the efficacy analyses. 
Where the participant (except for the withdrawn from study) who was qualified for re-
treatment:

At Week 12 in Blind Phase, 2nd and 3rd Open Label Phase

At Week 12 in Blind Phase and at Week 24 in 2nd Open Label Phase. 

At Week 16 in Blind Phase and at Week 20 in 2nd Open Label Phase.

At Week 20 in Blind Phase and at Week 16 in 2nd Open Label Phase.

At Week 24 in Blind Phase and at Week 12 in 2nd Open Label Phase.

At Week 36 in Blind Phase. 
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10.4.
Appendix 4: Study Phases and Treatment Emergent 
Adverse Events
10.4.1.
Study Phases for Concomitant Medication
Study Phase
Definition
Prior
“Taken prior to study?” is marked “Yes” on eCRF OR
Medication Start Date < First Study Treatment Date OR
Medication Start Date is missing. 
Concomitant
“Ongoing medication?” is marked “Yes” or missing on eCRF OR
Medication End Date First Study Treatment Date OR
Medication End Date is missing
NOTES: 

Please refer to Appendix 7: Reporting Standards for Missing Data for handling of missing and partial dates for 
concomitant medication. Use the rules in this table if concomitant medication date is completely missing.
10.4.2.
Study Phases for Adverse Events
Flag
Definition
Treatment 
Emergent

First Study Treatment Date ≤ AE Start Date ≤ Final Visit Date/Early Withdrawal 
Date
Blind phase (until 
second dose)

First Study Treatment Date AE Start Date Second Study Treatment Date AND
AE Start Time < Second Study Treatment Time IF AE Start Time is collected

First Study Treatment Date AE Start Date < Second Study Treatment Date IF
AE Start Time is not collect. 
Blind phase 
(within 84 days)

First Study Treatment Date AE Start Date First Study Treatment Date + 83
days
Open-Label 
Phase (2nd 
Treatment)

Second Study Treatment Date AE Start Date Third Study Treatment Date 
AND Second Study Treatment Time AE Start Time < Third Study Treatment 
Time IF AE Start Time is collected

Second Study Treatment Date AE Start Date < Third Study Treatment Date IF
AE Start Time is not collected
Open-Label 
Phase (3rd 
Treatment)

Third Study Treatment Date AE Start Date Fourth Study Treatment Date AND
Third Study Time AE Start Time < Fourth Study Treatment Time IF AE Start 
Time is collected

Third Study Treatment Date AE Start Date < Fourth Study Treatment Date IF AE 
Start Time is not collected
Open-Label 
Phase (4th 
Treatment)

Fourth Study Treatment Date AE Start Date Final Visit Date AND Fourth 
Study Time AE Start Time IF AE Start Time is collected

Fourth Study Treatment Date AE Start Date Final Visit Date IF AE Start Time 
is not collected
Drug related

If relationship to Study treatment(GSK1358820/Placebo) is marked ‘YES’ on CRF 
OR value is missing. 
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10.4.2.1.
Definition of Adverse Events of Special Interest
AEs of Special Interest are defined in the Appendix 13. If a Preferred Term of AE is 
included in the list of PTs of the specific AESI, that AE will be considered as AESI. See 
the details in the Appendix 13. 
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10.5.
Appendix 5: Data Display Standards & Handling 
Conventions
10.5.1.
Reporting Process
Software

The currently supported versions of SAS software will be used.
Reporting Area
HARP Server
: US1SALX00259.corpnet2.com
HARP Compound
: arenv\arprod\gsk1358820\mid207660
Analysis Datasets 

Analysis datasets will be created according to Legacy GSK A&R dataset standards.
Generation of RTF Files

RTF files will not be generated.
10.5.2.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: 
https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx):

4.03 to 4.23: General Principles

5.01 to 5.08: Principles Related to Data Listings

6.01 to 6.11: Principles Related to Summary Tables

7.01 to 7.13: Principles Related to Graphics 

Do not include participant level listings in the main body of the GSK Clinical Study Report. All 
participant level listings should be located in the modular appendices as ICH listings
Formats

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for reporting of 
data based on the raw data collected, unless otherwise stated.

Numeric data will be reported at the precision collected on the eCRF.

The reported precision from non eCRF sources will follow the IDSL statistical principles but may be
adjusted to a clinically interpretable number of DP’s. 
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses:

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled visit days 
on the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the participant’s listings. 
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Unscheduled Visits

Unscheduled visits will not be included in summary tables and/or figures.

All unscheduled visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
For continuous efficacy endpoints, 95%Confidence Interval will be calculated based 
on t-distribution. 
Categorical Data
N, n, frequency, %
Time to event data

The number of events and censored case.

25th and 75th percentiles survival time. 

Median survival time with the associated 95% CIs.
95%CIs will be calculated based on Brookmeyer and Crowley method using log-log 
function as a g-transformation. (This method can be performed using Proc 
LIFETEST with no special statement or option (SAS 9.4))
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.
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10.6.
Appendix 6: Derived and Transformed Data
10.6.1.
General
Study Day

Calculated as the number of days from First Dose Date:

Ref Date = Missing              → Study Day = Missing 

Ref Date < First Dose Date → Study Day = Ref Date – First Dose Date

Ref Data ≥ First Dose Date → Study Day = Ref Date – (First Dose Date) + 1    
10.6.2.
Study Population
Age

GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed as 
follow:
o
Any participant with a missing date and month will have this imputed as ‘30th June’.

Birth date will be presented in listings as ‘YYYY’. 

Age will be calculated based on year of the Screening visit as an Age reference date. 
Age Group

The following category will be used for Summary of Demography.
o
Age 18 (years)
o
19 < Age < 65
o
65 Age
Age Category

The following category will be used for Summary of Age Ranges.
o
In utero               
o
Preterm newborn infants (gestational age <37 weeks)
o
Newborns (0-27 days)
o
Infants and toddlers (28 days-23 months)
o
Children (2-11 years)
o
Adolescents (12-17 years)
o
Adult (18-64 years)     
o
>=65-84 years       
o
>=85 years      
Extent of Exposure

The total of dosage per treatment cycle will be calculated based on the formula:
Total of Dosage per treatment cycle = Sum of (Dosage in each Muscle Region)

The subtotal of dosage in each joint per treatment cycle will be calculated based on the formula:
Subtotal of Dosage in the joint per treatment cycle = Sum of (Dosage in each Muscle Region of 
the Joint)

Example
Subtotal of Dosage in Elbow = Sum of (Dosage in Biceps brachii, Brachalis and Brachioradialis)
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10.6.3.
Efficacy
Time to Event Data
Time to Qualification for Retreatment

This time to event data will be derived based on the following formula:
Time to Event (Days) = Date When a Participant Meets the Criteria for Retreatment – Study 
Treatment Start Date (Days)

If a participant is withdrawn from this study, the participant will be regarded as censoring and censored 
date will be a withdrawal date. 
Time to Patient Reported Onset of Spasticity Symptom Relief

This time to event data will be derived based on the following formula:
Time to Event (Days) = Onset Date of the Spasticity Symptom Relief – Study Treatment Start 
Date (Days)
If a participant is withdrawn from this study, the participant will be regarded as censoring and censored date 
will be a withdrawal date.
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10.7.
Appendix 7: Reporting Standards for Missing Data
10.7.1.
Premature Withdrawals
Element
Reporting Detail
General

Participant study completion (i.e. as specified in the protocol) was defined as those who 
completed all the study procedures, including a completion visit. . 

Withdrawn participants were not replaced in the study.

All available data from participants who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, unless 
otherwise specified.

Withdrawal visits will be slotted as per Appendix 3: Assessment Windows or will be 
summarised as withdrawal visits.
10.7.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank fields on 
the collection instrument:
o
These data will be indicated by the use of a “blank” in participant listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such.
Responder 
of MAS

If MAS score is missing at the corresponding visit, the participant will be regarded as 
those who are a non-responder (i.e. non-responder imputation). 
10.7.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in participant listing displays.
Concomitant 
Medications
and Surgery

Partial dates for any concomitant medications recorded in the CRF will be imputed 
using the following convention:
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' will be 
used for the month
o
If the partial date is a stop date, a '28/29/30/31' will be used for the day (dependent 
on the month and year) and 'Dec' will be used for the month.

The recorded partial date will be displayed in listings.
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10.8.
Appendix 8: Values of Potential Clinical Importance
This is not applicable to this study. 
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10.9.
Appendix 9: Population Pharmacokinetic (PopPK) Analyses
This is not applicable to this study. 
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10.10.
Appendix 10: Pharmacokinetic / Pharmacodynamic 
Analyses
This is not applicable to this study. 
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10.11.
Appendix 11: Abbreviations & Trade Marks
10.11.1.
Abbreviations
Abbreviation
Description
ADaM
Analysis Data Model
AE
Adverse Event
AIC
Akaike's Information Criteria
A&R
Analysis and Reporting 
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CPMS
Clinical Pharmacology Modelling & Simulation
CS
Clinical Statistics
CSR
Clinical Study Report
CTR
Clinical Trial Register
CVb / CVw
Coefficient of Variation (Between) / Coefficient of Variation (Within)
DBF
Database Freeze
DBR
Database Release
DOB
Date of Birth
DP
Decimal Places
eCRF
Electronic Case Record Form
EMA
European Medicines Agency
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Clinical Results Disclosure Requirements
GSK
GlaxoSmithKline
IA
Interim Analysis
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee 
IDSL
Integrated Data Standards Library
IMMS
International Modules Management System
IP
Investigational Product
ITT
Intent-To-Treat
MMRM
Mixed Model for Repeated Measures
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PK
Pharmacokinetic
PP
Per Protocol
PopPK
Population PK
QC
Quality Control
QTcF
Frederica’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RAP
Reporting & Analysis Plan
RAMOS
Randomization & Medication Ordering System 
SAC
Statistical Analysis Complete
SDSP
Study Data Standardization Plan
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Abbreviation
Description
SDTM
Study Data Tabulation Model
SOP
Standard Operation Procedure
TA
Therapeutic Area
TFL
Tables, Figures & Listings 
10.11.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
NONE
SAS
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10.12.
Appendix 12: List of Data Displays
10.12.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.22
Efficacy
2.1 to 2.53
2.1 to 2.55
Safety
3.1 to 3.138
3.1 to 3.2
Section
Listings
ICH Listings
1 to 78
10.12.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated
Section
Figure
Table
Listing
Study Population
POP_Tn
POP_Ln
Efficacy
EFF_Fn
EFF_Tn
EFF_Ln
Safety
SAFE_Fn
SAFE_Tn
NOTES: 

Non-Standard displays are indicated in the ‘IDSL / Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’
10.12.3.
Deliverables
Delivery
Description
IA SAC
Interim Analysis Statistical Analysis Complete
SAC
Final Statistical Analysis Complete
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10.12.4.
Study Population Tables
10.12.4.1. Interim Analyses
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Participant Disposition
1.01.
ITT1
ES1
Summary of Participant Disposition for the Participant
Conclusion Record (Week 24)
ICH E3, FDAAA, EudraCT
Participant disposition at Week 24.
Include total arm (240 U + 400 U)
IA SAC
1.02.
Screened
ES6
Summary of Screening Status and Reasons for Screen Failure
Journal Requirements
IA SAC
1.03.
Enrolled
NS1
Summary of Number of Participant by Site ID
EudraCT/Clinical Operations
IA SAC
Protocol Deviation
1.04.
ITT1
DV1
Summary of Important Protocol Deviations
ICH E3
Include total arm (240 U + 400 U)
IA SAC
Population Analysed
1.05.
Screened
SP1
Summary of Study Populations 
IDSL
IA SAC
Demographic and Baseline Characteristics
1.06.
ITT1
DM1
Summary of Demographic Characteristics
ICH E3, FDAAA, EudraCT
Include total arm (240 U + 400 U)
IA SAC
1.07.
Enrolled
DM11
Summary of Age Ranges
EudraCT
IA SAC
1.08.
ITT1
DM5
Summary of Race and Racial Combinations
ICH E3, FDA, FDAAA, EudraCT
IA SAC
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Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
1.09.
ITT1
POP_T1
Summary of Baseline Efficacy Parameters

MAS scores in finger, thumb, 
wrist and elbow

Randomization Strata

Numeric Rating Scale for pain

Disability Assessment Scale

Include total arm (240 U + 400 U)
IA SAC
Prior and Concomitant Medications
1.10.
ITT1
CM1
Summary of Prior Medications
Include total arm (240 U + 400 U)
IA SAC
1.11.
ITT1
CM1
Summary of Concomitant Medications
ICH E3
Include total arm (240 U + 400 U)
IA SAC
1.12.
ITT1
POP_T2
Summary of Rehabilitation
Include total arm (240 U + 400 U)
IA SAC
1.13.
ITT1
SAFE_T4
Summary of Actual Dosage in Exposed Muscle Region by 
Treatment Cycle and Muscle Region. 
IA SAC
1.14.
ITT1
SAFE_T4
Summary of Actual Dosage in Exposed Joint by Treatment 
Cycle and Joint
IA SAC
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10.12.4.2. Final Analyses
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Participant Disposition
1.15.
ITT1
ES1
Summary of Participant Disposition for the Participant 
Conclusion Record
ICH E3, FDAAA, EudraCT
Include total arm (240 U + 400 U)
SAC
Protocol Deviation
1.16.
ITT1
DV1
Summary of Important Protocol Deviations
ICH E3
Include total arm (240 U + 400 U)
SAC
Population Analysed
1.17.
Screened
SP1
Summary of Study Populations 
IDSL
SAC
Prior and Concomitant Medications
1.18.
ITT1
CM1
Summary of Prior Medications
Include total arm (240 U + 400 U)
SAC
1.19.
ITT1
CM1
Summary of Concomitant Medications
ICH E3
Include total arm (240 U + 400 U)
SAC
1.20.
ITT1
POP_T2
Summary of Rehabilitation
Include total arm (240 U + 400 U)
SAC
Actual dose
1.21.
ITT1
SAFE_T4
Summary of Actual Dosage in Exposed Muscle Region by 
Treatment Cycle and Muscle Region. 
SAC
1.22.
ITT1
SAFE_T4
Summary of Actual Dosage in Exposed Joint by Treatment 
Cycle and Joint
SAC
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10.12.5.
Efficacy Tables
10.12.5.1. Interim Analyses
Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
MAS
2.01.
ITT1
EFF_T1
Summary of MAS score in Blind Phase

Values and change from 
baseline

Summarize data up to Visit 5
IA SAC
2.02.
ITT1
EFF_T2
Summary of the Results of Mixed Models for Repeated 
Measures of Change from Baseline in MAS scores in Blind 
Phase
Analyse data up to Visit 5
IA SAC
2.03.
ITT1
EFF_T3
Summary of Responder rate of MAS score at Week 6 in Blind 
Phase
Including subgroup analyses
IA SAC
2.04.
ITT1
EFF_T4
Summary of Responder rate of MAS score in Blind Phase
Summarize data up to Visit 5
Include Mantel Haenszel estimators
IA SAC
2.05.
ITT2
EFF_T1
Summary of MAS score in Open Label Phase (2nd Treatment)

Values and change from 
baseline

Summarize data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
IA SAC
2.06.
ITT2
EFF_T5
Summary of Responder rate of MAS score in Open Label Phase 
(2nd Treatment)

Summarize data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
IA SAC
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
DAS
2.07.
ITT1
EFF_T1
Summary of Main Assessment Parameter and All Items of DAS 
in Blind Phase

Values and change from 
baseline

Summarize data up to Visit 5
IA SAC
2.08.
ITT1
EFF_T2
Summary of the Results of Mixed Models for Repeated 
Measures of Change from Baseline in Main Assessment 
Parameter of DAS in Blind Phase
Analyse data up to Visit 5
IA SAC
2.09.
ITT2
EFF_T1
Summary of Main Assessment Parameter and All Items of DAS 
in Open Label Phase (2nd Treatment)

Values and change from 
baseline

Summarize data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
IA SAC
NRS for pain
2.10.
ITT1
EFF_T1
Summary of NRS for pain in Blind Phase

Values and change from 
baseline

Summarize data up to Visit 5
IA SAC
2.11.
ITT2
EFF_T1
Summary of NRS for pain in Open Label Phase (2nd Treatment)

Values in each joint and 
change from baseline in only 
elbow. 

Summarize data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
IA SAC
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
CGI of functional disability
2.12.
ITT1
EFF_T1
Summary of CGI of functional disability by an investigator in 
Blind Phase

Values only

Summarize data up to Visit 5
IA SAC
2.13.
ITT2
EFF_T1
Summary of CGI of functional disability by an investigator in 
Open Label Phase (2nd Treatment)

Values only

Summarize data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
IA SAC
2.14.
ITT1
EFF_T1
Summary of CGI of functional disability by a patient in Blind 
Phase

Values only

Summarize data up to Visit 5
IA SAC
2.15.
ITT2
EFF_T1
Summary of CGI of functional disability by a patient in Open 
Label Phase (2nd Treatment)

Values only

Summarize data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
IA SAC
Patient-Reported Benefit of Injection
2.16.
ITT1
EFF_T5
Summary of Patient-Reported Benefit of Injection in Blind Phase

Summarize data up to Visit 5
IA SAC
2.17.
ITT2
EFF_T5
Summary of Patient-Reported Benefit of Injection in Open Label 
Phase (2nd Treatment)

Summarize data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
IA SAC
Time to Patient-Reported Onset of Spasticity Symptom Relief
2.18.
ITT1
EFF_T6
Summary of Time to Patient-Reported Onset of Spasticity 
Symptom Relief
IA SAC
2.19.
ITT1
EFF_T7
Summary of Survival Analyses Results of Time to Patient-
Reported Onset of Spasticity Symptom Relief in Blind Phase

Survival function estimates will 
be summarized
IA SAC
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
2.20.
ITT2
EFF_T7
Summary of Survival Analyses Results of Time to Patient-
Reported Onset of Spasticity Symptom Relief in Open Label 
Phase (2nd Treatment)

Survival function estimates will 
be summarized

Three treatment arms (240, 
400 and 240 + 400U)
IA SAC
Time to Qualification for Retreatment
2.21.
ITT1
EFF_T8
Summary of Events in Which a Participant Meets the Criteria for 
Retreatment
IA SAC
2.22.
ITT1
EFF_T6
Summary of Time to Qualification for Retreatment
IA SAC
2.23.
ITT1
EFF_T7
Summary of Survival Analyses Results of Time to Qualification
for Retreatment in Blind Phase

Survival function estimates will 
be summarized

Two treatment arms (240 and 
400U)
IA SAC
10.12.5.2. Final Analyses
Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable
MAS
2.24.
ITT2
EFF_T1
Summary of MAS score in Open Label Phase (2nd Treatment)

Values and change from 
baseline

Summarize data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
SAC
2.25.
ITT3
EFF_T1
Summary of MAS score in Open Label Phase (3rd Treatment)
SAC
2.26.
ITT4
EFF_T1
Summary of MAS score in Open Label Phase (4th Treatment)
SAC
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Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable
2.27.
ITT2
EFF_T5
Summary of Responder rate of MAS score in Open Label Phase 
(2nd Treatment)

Summarize data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
SAC
2.28.
ITT3
EFF_T5
Summary of Responder rate of MAS score in Open Label Phase 
(3rd Treatment)
SAC
2.29.
ITT4
EFF_T5
Summary of Responder rate of Mas Score in Open Label Phase 
(4th Treatment)
SAC
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Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable
DAS
2.30.
ITT2
EFF_T1
Summary of Main Assessment Parameter and All Items of DAS 
in Open Label Phase (2nd Treatment)

Values and change from 
baseline

Summarize data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
SAC
2.31.
ITT3
EFF_T1
Summary of Main Assessment Parameter and All Items of DAS 
in Open Label Phase (3rd Treatment)
SAC
2.32.
ITT4
EFF_T1
Summary of Main Assessment Parameter and All Items of DAS 
in Open Label Phase (4th Treatment)
SAC
NRS for pain
2.33.
ITT2
EFF_T1
Summary of NRS for pain in Open Label Phase (2nd Treatment)

Values in each joint and 
change from baseline in only 
elbow. 

Summarize data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
SAC
2.34.
ITT3
EFF_T1
Summary of NRS for pain in Open Label Phase (3rd Treatment)
SAC
2.35.
ITT4
EFF_T1
Summary of NRS for pain in Open Label Phase (4th Treatment)
SAC
CGI of functional disability
2.36.
ITT2
EFF_T1
Summary of CGI of functional disability by an investigator in 
Open Label Phase (2nd Treatment)

Values only

Summarize data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
SAC
2.37.
ITT3
EFF_T1
Summary of CGI of functional disability by an investigator in 
Open Label Phase (3rd Treatment)
SAC
2.38.
ITT4
EFF_T1
Summary of CGI of functional disability by an investigator in 
Open Label Phase (4th Treatment)
SAC
2.39.
ITT2
EFF_T1
Summary of CGI of functional disability by a patient in Open 
Label Phase (2nd Treatment)

Values only

Summarize data up to Visit 5

Three treatment arms (240, 
SAC
2.40.
ITT3
EFF_T1
Summary of CGI of functional disability by a patient in Open 
Label Phase (3rd Treatment)
SAC
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Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable
2.41.
ITT4
EFF_T1
Summary of CGI of functional disability by a patient in Open 
Label Phase (4th Treatment)
400 and 240 + 400U)
SAC
Patient-Reported Benefit of Injection
2.42.
ITT2
EFF_T5
Summary of Patient-Reported Benefit of Injection in Open Label 
Phase (2nd Treatment)

Summarize data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
SAC
2.43.
ITT3
EFF_T5
Summary of Patient-Reported Benefit of Injection in Open Label 
Phase (3rd Treatment)
SAC
2.44.
ITT4
EFF_T5
Summary of Patient-Reported Benefit of Injection in Open Label 
Phase (4th Treatment)
SAC
Time to Patient-Reported Onset of Spasticity Symptom Relief
2.45.
ITT1
EFF_T6
Summary of Time to Patient-Reported Onset of Spasticity 
Symptom Relief
SAC
2.46.
ITT2
EFF_T7
Summary of Survival Analyses Results of Time to Patient-
Reported Onset of Spasticity Symptom Relief in Open Label 
Phase (2nd Treatment)

Survival function estimates will 
be summarized

Three treatment arms (240, 
400 and 240 + 400U)
SAC
2.47.
ITT3
EFF_T7
Summary of Survival Analyses Results of Time to Patient-
Reported Onset of Spasticity Symptom Relief in Open Label 
Phase (3rd Treatment)
SAC
2.48.
ITT4
EFF_T7
Summary of Survival Analyses Results of Time to Patient-
Reported Onset of Spasticity Symptom Relief in Open Label 
Phase (4th Treatment)
SAC
Time to Qualification for Retreatment
2.49.
ITT1
EFF_T8
Summary of Events in Which a Participant Meets the Criteria for 
Retreatment
SAC
2.50.
ITT1
EFF_T6
Summary of Time to Qualification for Retreatment
SAC
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Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable
2.51.
ITT1
EFF_T7
Summary of Survival Analyses Results of Time to Qualification 
for Retreatment in Blind Phase

Survival function estimates will 
be summarized

Two treatment arms (240 and 
400U)
SAC
2.52.
ITT2
EFF_T7
Summary of Survival Analyses Results of Time to Qualification 
for Retreatment in Open Label Phase (2nd Treatment)

Survival function estimates will 
be summarized

Three treatment arms (240, 
400 and 240 + 400U)
SAC
2.53.
ITT3
EFF_T7
Summary of Survival Analyses Results of Time to Qualification 
for Retreatment in Open Label Phase (3rd Treatment)
SAC
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10.12.6.
Efficacy Figures
10.12.6.1. Interim Analyses
Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
MAS
2.01.
ITT1
EFF_F1
Plot of Mean (95%CI) MAS score Profiles in Blind Phase

Plot data up to Visit 5

Two treatment arms (240 and 
400U)
IA SAC
2.02.
ITT2
EFF_F1
Plot of Mean (95%CI) MAS score Profiles in Open Label Phase 
(2nd Treatment)

Plot data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
IA SAC
2.03.
ITT1
EFF_F1
Plot of Mean (95%CI) Change from Baseline in MAS score 
Profiles in Blind Phase

Plot data up to Visit 5

Two treatment arms (240 and 
400U)
IA SAC
2.04.
ITT2
EFF_F1
Plot of Mean (95%CI) Change from Baseline in MAS score 
Profiles in Open Label Phase (2nd Treatment)

Plot data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
IA SAC
2.05.
ITT1
EFF_F2
Plot of Responder rate of MAS score by Visit in Blind Phase

Plot data up to Visit 5

Two treatment arms (240 and 
400U)
IA SAC
2.06.
ITT2
EFF_F2
Plot of Responder rate of MAS score by Visit in Open Label 
Phase (2nd Treatment)

Plot data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
IA SAC
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Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
DAS
2.07.
ITT1
EFF_F1
Plot of Mean (95%CI) DAS score (Main Assessment Parameter) 
Profiles in Blind Phase

Plot data up to Visit 5

Two treatment arms (240 and 
400U)
IA SAC
2.08.
ITT2
EFF_F1
Plot of Mean (95%CI) DAS score (Main Assessment Parameter) 
Profiles in Open Label Phase (2nd Treatment)

Plot data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
IA SAC
2.09.
ITT1
EFF_F1
Plot of Mean (95%CI) Change from Baseline in DAS score (Main 
Assessment Parameter) Profiles in Blind Phase

Plot data up to Visit 5

Two treatment arms (240 and 
400U)
IA SAC
2.10.
ITT2
EFF_F1
Plot of Mean (95%CI) Change from Baseline in DAS score (Main 
Assessment Parameter) Profiles in Open Label Phase (2nd 
Treatment)

Plot data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
IA SAC
2.11.
ITT1
EFF_F1
Plot of Mean (95%CI) DAS score Profiles in Blind Phase

Plot data up to Visit 5

Create plots by component of 
DAS score

Two treatment arms (240 and 
400U)
IA SAC
2.12.
ITT2
EFF_F1
Plot of Mean (95%CI) DAS score Profiles in Open Label Phase 
(2nd Treatment)

Plot data up to Visit 5

Create plots by component of 
DAS score

Three treatment arms (240 and 
400U)
IA SAC
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Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
2.13.
ITT1
EFF_F1
Plot of Mean (95%CI) Change from Baseline in DAS score 
Profiles in Blind Phase

Plot data up to Visit 5

Create plots by component of 
DAS score

Two treatment arms (240 and 
400U)
IA SAC
2.14.
ITT2
EFF_F1
Plot of Mean (95%CI) Change from Baseline in DAS score 
Profiles in Open Label Phase (2nd Treatment)

Plot data up to Visit 5

Create plots by component of 
DAS score

Three treatment arms (240 and 
400U)
IA SAC
Numeric Rating Scale for pain
2.15.
ITT1
EFF_F1
Plot of Mean (95%CI) NRS for pain Profiles in Blind Phase

Plot data up to Visit 5

Two treatment arms (240 U 
and 400U)
IA SAC
2.16.
ITT2
EFF_F1
Plot of Mean (95%CI) NRS for pain Profiles in Open Label 
Phase (2nd Treatment)

Plot data of the elbow only up 
to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
IA SAC
2.17.
ITT1
EFF_F1
Plot of Mean (95%CI) Change from Baseline in NRS for pain 
Profiles in Blind Phase

Plot data up to Visit 5

Two treatment arms (240 U 
and 400U)
IA SAC
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Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Clinical Global Impression of Change of functional disability
2.18.
ITT1
EFF_F1
Plot of Mean (95%CI) CGI of functional disability Profiles in Blind 
Phase

Plot data up to Visit 5

Two treatment arms (240 and 
400 U)
IA SAC
2.19.
ITT2
EFF_F1
Plot of Mean (95%CI) CGI of functional disability Profiles in 
Open Label Phase (2nd Treatment)

Plot data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400 U)
IA SAC
Time to Patient-Reported Onset of Spasticity Symptom Relief
2.20.
ITT1
EFF_F3
Kaplan Meier Plot of Time to Patient-Reported Onset of 
Spasticity Symptom Relief in Blind Phase
Two treatment arm (240 U and 
400U)
IA SAC
2.21.
ITT2
EFF_F3
Kaplan Meier Plot of Time to Patient-Reported Onset of 
Spasticity Symptom Relief in Open Label Phase (2nd 
Treatment)
Three treatment arms (240, 400, 
240 + 400U)
IA SAC
Time to Qualification for Retreatment
2.22.
ITT1
EFF_F3
Kaplan Meier Plot of Survival Function Estimates of Time to 
Qualification for Retreatment in Blind Phase
Two treatment arm (240 U, 400U)
IA SAC
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10.12.6.2. Final Analyses
Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
MAS
2.23.
ITT2
EFF_F1
Plot of Mean (95%CI) MAS score Profiles in Open Label Phase 
(2nd Treatment)

Plot data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
SAC
2.24.
ITT3
EFF_F1
Plot of Mean (95%CI) MAS score Profiles in Open Label Phase 
(3rd Treatment)
SAC
2.25.
ITT4
EFF_F1
Plot of Mean (95%CI) MAS score Profiles in Open Label Phase 
(4th Treatment)
SAC
2.26.
ITT2
EFF_F1
Plot of Mean (95%CI) Change from Baseline in MAS score 
Profiles in Open Label Phase (2nd Treatment)

Plot data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
SAC
2.27.
ITT3
EFF_F1
Plot of Mean (95%CI) Change from Baseline in MAS score 
Profiles in Open Label Phase (3rd Treatment)
SAC
2.28.
ITT4
EFF_F1
Plot of Mean (95%CI) Change from Baseline in MAS score 
Profiles in Open Label Phase (4th Treatment)
SAC
2.29.
ITT2
EFF_F2
Plot of Responder rate of MAS score by Visit in Open Label 
Phase (2nd Treatment)

Plot data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
SAC
2.30.
ITT3
EFF_F2
Plot of Responder rate of MAS score by Visit in Open Label 
Phase (3rd Treatment)
SAC
2.31.
ITT4
EFF_F2
Plot of Responder rate of MAS score by Visit in Open Label 
Phase (4th Treatment)
SAC
DAS
2.32.
ITT2
EFF_F1
Plot of Mean (95%CI) DAS score (Main Assessment Parameter) 
Profiles in Open Label Phase (2nd Treatment)

Plot data up to Visit 5
SAC
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Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
2.33.
ITT3
EFF_F1
Plot of Mean (95%CI) DAS score (Main Assessment Parameter) 
Profiles in Open Label Phase (3rd Treatment)

Three treatment arms (240, 
400 and 240 + 400U)
SAC
2.34.
ITT4
EFF_F1
Plot of Mean (95%CI) DAS score (Main Assessment Parameter) 
Profiles in Open Label Phase (4th Treatment)
SAC
2.35.
ITT2
EFF_F1
Plot of Mean (95%CI) Change from Baseline in DAS score (Main 
Assessment Parameter) Profiles in Open Label Phase (2nd 
Treatment)

Plot data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
SAC
2.36.
ITT3
EFF_F1
Plot of Mean (95%CI) Change from Baseline in DAS score (Main 
Assessment Parameter) Profiles in Open Label Phase (3rd 
Treatment)
SAC
2.37.
ITT4
EFF_F1
Plot of Mean (95%CI) Change from Baseline in DAS score (Main 
Assessment Parameter) Profiles in Open Label Phase (4th 
Treatment)
SAC
2.38.
ITT2
EFF_F1
Plot of Mean (95%CI) DAS score Profiles in Open Label Phase 
(2nd Treatment)

Plot data up to Visit 5

Create plots by component of 
DAS score

Three treatment arms (240 and 
400U)
SAC
2.39.
ITT3
EFF_F1
Plot of Mean (95%CI) DAS score Profiles in Open Label Phase 
(3rd Treatment)
SAC
2.40.
ITT4
EFF_F1
Plot of Mean (95%CI) DAS score Profiles in Open Label Phase 
(4th Treatment)
SAC
2.41.
ITT2
EFF_F1
Plot of Mean (95%CI) Change from Baseline in DAS score 
Profiles in Open Label Phase (2nd Treatment)

Plot data up to Visit 5

Create plots by component of 
DAS score

Three treatment arms (240 and 
400U)
SAC
2.42.
ITT3
EFF_F1
Plot of Mean (95%CI) Change from Baseline in DAS score 
Profiles in Open Label Phase (3rd Treatment)
SAC
2.43.
ITT4
EFF_F1
Plot of Mean (95%CI) Change from Baseline in DAS score 
Profiles in Open Label Phase (4th Treatment)
SAC
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Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Numeric Rating Scale for pain
2.44.
ITT2
EFF_F1
Plot of Mean (95%CI) NRS for pain Profiles in Open Label 
Phase (2nd Treatment)

Plot data of the elbow only up 
to Visit 5

Three treatment arms (240, 
400 and 240 + 400U)
SAC
2.45.
ITT3
EFF_F1
Plot of Mean (95%CI) NRS for pain Profiles in Open Label 
Phase (3rd Treatment)
SAC
2.46.
ITT4
EFF_F1
Plot of Mean (95%CI) NRS for pain Profiles in Open Label 
Phase (4th Treatment)
SAC
Clinical Global Impression of Change of functional disability
2.47.
ITT2
EFF_F1
Plot of Mean (95%CI) CGI of functional disability Profiles in 
Open Label Phase (2nd Treatment)

Plot data up to Visit 5

Three treatment arms (240, 
400 and 240 + 400 U)
SAC
2.48.
ITT3
EFF_F1
Plot of Mean (95%CI) CGI of functional disability Profiles in 
Open Label Phase (3rd Treatment)
SAC
2.49.
ITT4
EFF_F1
Plot of Mean (95%CI) CGI of functional disability Profiles in 
Open Label Phase (4th Treatment)
SAC
Time to Patient-Reported Onset of Spasticity Symptom Relief
2.50.
ITT2
EFF_F3
Kaplan Meier Plot of Time to Patient-Reported Onset of 
Spasticity Symptom Relief in Open Label Phase (2nd 
Treatment)
Three treatment arms (240, 400, 
240 + 400U)
SAC
2.51.
ITT3
EFF_F3
Kaplan Meier Plot of Time to Patient-Reported Onset of 
Spasticity Symptom Relief in Open Label Phase (3rd Treatment)
SAC
2.52.
ITT4
EFF_F3
Kaplan Meier Plot of Time to Patient-Reported Onset of 
Spasticity Symptom Relief in Open Label Phase (4th Treatment)
SAC
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Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Time to Qualification for Retreatment
2.53.
ITT1
EFF_F3
Kaplan Meier Plot of Survival Function Estimates of Time to 
Qualification for Retreatment in Blind Phase
Two treatment arm (240 U, 400U)
SAC
2.54.
ITT2
EFF_F3
Kaplan Meier Plot of Survival Function Estimates of Time to 
Qualification for Retreatment in Open Label Phase (2nd 
Treatment)
Three treatment arm (240, 400, 240 
+ 400U)
SAC
2.55.
ITT3
EFF_F3
Kaplan Meier Plot of Survival Function Estimates of Time to 
Qualification for Retreatment in Open Label Phase (3rd 
Treatment)
SAC
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10.12.7.
Safety Tables
10.12.7.1. Interim Analyses
Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
Adverse Events (AEs)
3.01.
Safety 1
AE1
Summary of All Adverse Events until Week 24 visit by System 
Organ Class and Preferred Term
ICH E3
Treatment Emergent
Three treatment arms (240, 400 and 
240 + 400U)
IA SAC
3.02.
Safety 1
AE1
Summary of All Adverse Events until Week 24 visit by System 
Organ Class and Preferred Term in Blind Phase
Blind Phase (until second dose)
See the Section 10.4.2.
Two treatment arm (240 and 400U)
IA SAC
3.03.
Safety 1
AE1
Summary of All Adverse Events within 84 days from the initial 
dose by System Organ Class and Preferred Term in Blind Phase
Blind Phase (within 84 days)
See the Section 10.4.2.
Two treatment arm (240 and 400U)
IA SAC
3.04.
Safety 2
AE1
Summary of All Adverse Events until Week 24 visit by System 
Organ Class and Preferred Term in Open Label Phase (2nd 
Treatment)
Open Label Phase (2nd Treatment)
See the Section 10.4.2.
Three treatment arms (240, 400 and 
240 + 400U)
IA SAC
3.05.
Safety 1
AE5A
Summary of All Adverse Events until Week 24 visit by Maximum 
Intensity by System Organ Class and Preferred Term
ICH E3
Treatment Emergent
Use AE1 or AE1CP if 
Grade/Intensity not used; otherwise 
use AE5A/B (with a Total column 
across all grades/severities, which 
provides same detail as AE1)
IA SAC
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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
3.06.
Safety 1
AE5A
Summary of All Adverse Events until Week 24 visit by Maximum 
Intensity by System Organ Class and Preferred Term in Blind 
Phase
Blind Phase (until second dose)
See the Section 10.4.2. 
Two treatment arm (240 and 400U)
IA SAC
3.07.
Safety 1
AE5A
Summary of All Adverse Events within 84 days from the initial 
dose by Maximum Intensity by System Organ Class and 
Preferred Term in Blind Phase
Blind Phase (within 84 days)
See the Section 10.4.2. 
Two treatment arm (240 and 400U)
IA SAC
3.08.
Safety 2
AE5A
Summary of All Adverse Events until Week 24 visit by Maximum 
Intensity by System Organ Class and Preferred Term in Open 
Label Phase (2nd Treatment)
Open Label Phase (2nd Treatment)
See the Section 10.4.2.
Three treatment arms (240, 400 and 
240 + 400U)
IA SAC
3.09.
Safety 1
AE3
Summary of Common (>=3%) Adverse Events until Week 24 
visit by Overall Frequency
ICH E3
Treatment Emergent
Three treatment arms (240, 400 and 
240 + 400U)
IA SAC
3.10.
Safety 1
AE3
Summary of Common (>= 3%) Adverse Events within 84 days 
from the initial dose by Overall Frequency in Blind Phase (by 
Sex)
Three treatment arms (240, 400 and 
total)
IA SAC
3.11.
Safety 1
AE3
Summary of Common (>= 3%) Adverse Events within 84 days 
from the initial dose by Overall Frequency in Blind Phase (by 
Age Group)
Three treatment arms (240, 400 and 
total)
Age group (Age < 65 or Age >= 65)
IA SAC
3.12.
Safety 1
AE3
Summary of Common (>=3%) Adverse Events until Week 24 
visit by Overall Frequency in Blind Phase
Blind Phase (until second dose)
See the Section 10.4.2. 
Two treatment arm (240 and 400U)
IA SAC
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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
3.13.
Safety 1
AE3
Summary of Common (>=3%) Adverse Events within 84 days 
from the initial dose by Overall Frequency in Blind Phase
Blind Phase (within 84 days)
See the Section 10.4.2. 
Two treatment arm (240 and 400U)
IA SAC
3.14.
Safety 2
AE3
Summary of Common (>=3%) Adverse Events until Week 24 
visit by Overall Frequency in Open Label Phase (2nd Treatment)
Open Label Phase (2nd Treatment)
See the Section 10.4.2.
Three treatment arms (240, 400 and 
240 + 400U)
IA SAC
3.15.
Safety 1
AE1
Summary of All Drug-Related Adverse Events until Week 24 visit
by System Organ Class and Preferred Term
ICH E3
Treatment Emergent
Three treatment arms (240, 400 and 
240 + 400U)
IA SAC
3.16.
Safety 1
AE1
Summary of All Drug-Related Adverse Events until Week 24 visit
by System Organ Class and Preferred Term in Blind Phase
Blind Phase (until second dose)
See the Section 10.4.2. 
Two treatment arm (240 and 400U)
IA SAC
3.17.
Safety 1
AE1
Summary of All Drug-Related Adverse Events within 84 days 
from the initial dose by System Organ Class and Preferred Term
in Blind Phase
Blind Phase (within 84 days)
See the Section 10.4.2. 
Two treatment arm (240 and 400U)
IA SAC
3.18.
Safety 2
AE1
Summary of All Drug-Related Adverse Events until Week 24 visit
by System Organ Class and Preferred Term in Open Label 
Phase (2nd Treatment)
Open Label Phase (2nd Treatment)
See the Section 10.4.2.
Three treatment arms (240, 400 and 
240 + 400U)
IA SAC
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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
3.19.
Safety 1
AE5A
Summary of All Drug-Related Adverse Events until Week 24 visit
by System Organ Class and Preferred Term and Maximum 
Intensity
ICH E3
Treatment Emergent AE
See the Section 10.4.2
Three treatment arms (240, 400 and 
240 + 400U)
IA SAC
3.20.
Safety 1
AE5A
Summary of All Drug-Related Adverse Events until Week 24 visit
by System Organ Class and Preferred Term and Maximum 
Intensity in Blind Phase
Blind Phase (until second dose)
See the Section 10.4.2. 
Two treatment arm (240 and 400U)
IA SAC
3.21.
Safety 1
AE5A
Summary of All Drug-Related Adverse Events within 84 days 
from the initial dose by System Organ Class and Preferred Term 
and Maximum Intensity in Blind Phase
Blind Phase (within 84 days)
See the Section 10.4.2. 
Two treatment arm (240 and 400U)
IA SAC
3.22.
Safety 2
AE5A
Summary of All Drug-Related Adverse Events until Week 24 visit
by System Organ Class and Preferred Term and Maximum 
Intensity in Open Label Phase (2nd Treatment)
Open Label Phase (2nd Treatment)
See the Section 10.4.2.
Three treatment arms (240, 400 and 
240 + 400U)
IA SAC
3.23.
Safety 1
AE15
Summary of Common (>=5%) Non-serious Adverse Events until 
Week 24 visit by System Organ Class and Preferred Term 
(Number of Participant and Occurrences)
FDAAA, EudraCT
Treatment Emergent AE
See the Section 10.4.2
IA SAC
Serious and Other Significant Adverse Events
3.24.
Safety 1
SAFE_T1
Summary of Adverse Events of Special Interest until Week 24 
visit
Treatment Emergent AE
See the Section 10.4.2
Three treatment arms (240, 400 and 
240 + 400U)
IA SAC
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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
3.25.
Safety 1
SAFE_T1
Summary of Adverse Events of Special Interest until Week 24 
visit in Blind Phase
Blind Phase (until second dose)
See the Section 10.4.2. 
Two treatment arm (240 and 400U)
IA SAC
3.26.
Safety 1
SAFE_T1
Summary of Adverse Events of Special Interest within 84 days 
from the initial dose in Blind Phase
Blind Phase (within 84 days)
See the Section 10.4.2. 
Two treatment arm (240 and 400U)
IA SAC
3.27.
Safety 2
SAFE_T1
Summary of Adverse Events of Special Interest until Week 24 
visit in Open Label Phase (2nd Treatment)
Open Label Phase (2nd Treatment)
See the Section 10.4.2
Three treatment arms (240, 400 and 
240 + 400U)
IA SAC
3.28.
Safety 1
AE1
Summary of Non-Fatal Serious Adverse Events until Week 24 
visit
Treatment Emergent AE
See the Section 10.4.2
Three treatment arms (240, 400 and 
240 + 400U)
IA SAC
3.29.
Safety 1
AE1
Summary of Non-Fatal Serious Adverse Events until Week 24 
visit in Blind Phase
Blind Phase (until second dose)
See the Section 10.4.2. 
Two treatment arm (240 and 400U)
IA SAC
3.30.
Safety 1
AE1
Summary of Non-Fatal Serious Adverse Events within 84 days 
from the initial dose in Blind Phase
Blind Phase (within 84 days)
See the Section 10.4.2. 
Two treatment arm (240 and 400U)
IA SAC
3.31.
Safety 2
AE1
Summary of Non-Fatal Serious Adverse Events until Week 24 
visit in Open Label Phase (2nd Treatment)
Open Label Phase (2nd Treatment)
See the Section 10.4.2
Three treatment arms (240, 400 and 
240 + 400U)
IA SAC
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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
3.32.
Safety 1
AE1
Summary of Drug-Related Non-Fatal Serious Adverse Events 
until Week 24 visit
Treatment Emergent AE
See the Section 10.4.2
Three treatment arms (240, 400 and 
240 + 400U)
IA SAC
3.33.
Safety 1
AE1
Summary of Drug-Related Non-Fatal Serious Adverse Events 
until Week 24 visit in Blind Phase
Blind Phase (until second dose)
See the Section 10.4.2. 
Two treatment arm (240 and 400U)
IA SAC
3.34.
Safety 1
AE1
Summary of Drug-Related Non-Fatal Serious Adverse Events 
within 84 days from the initial dose in Blind Phase
Blind Phase (within 84 days)
See the Section 10.4.2. 
Two treatment arm (240 and 400U)
IA SAC
3.35.
Safety 2
AE1
Summary of Drug-Related Non-Fatal Serious Adverse Events 
until Week 24 visit in Open Label Phase (2nd Treatment)
Open Label Phase (2nd Treatment)
See the Section 10.4.2
Three treatment arms (240, 400 and 
240 + 400U)
IA SAC
3.36.
Safety 1
AE16
Summary of Serious Adverse Events until Week 24 visit by 
System Organ Class and Preferred Term (Number of 
Participants and Occurrences)
FDAAA, EudraCT
Treatment Emergent AE
See the Section 10.4.2
Three treatment arms (240, 400 and 
240 + 400U)
IA SAC
3.37.
Safety 1
AE1
Summary of Adverse Events until Week 24 visit Leading to 
Withdrawal from Study by System Organ Class and Preferred 
Term
IDSL
Treatment Emergent AE
See the Section 10.4.2
Three treatment arms (240, 400 and 
240 + 400U)
IA SAC
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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
3.38.
Safety 1
AE1
Summary of Adverse Events until Week 24 visit Leading to 
Withdrawal from Study by System Organ Class and Preferred 
Term in Blind Phase
Blind Phase (until second dose)
See the Section 10.4.2. 
Two treatment arm (240 and 400U)
IA SAC
3.39.
Safety 1
AE1
Summary of Adverse Events Leading to Withdrawal from Study 
within 84 days from the initial dose by System Organ Class and 
Preferred Term
Blind Phase (within 84 days)
See the Section 10.4.2. 
Two treatment arm (240 and 400U)
IA SAC
3.40.
Safety 2
AE1
Summary of Adverse Events until Week 24 visit Leading to 
Withdrawal from Study by System Organ Class and Preferred 
Term in Open Label Phase (2nd Treatment)
Open Label Phase (2nd Treatment)
See the Section 10.4.2.
Three treatment arms (240, 400 and 
240 + 400U)
IA SAC
Laboratory: Chemistry 
3.41.
Safety 1
LB1
Summary of Chemistry by Visit
Summarize data at Screening Visit
and in Blind Phase. 
IA SAC
3.42.
Safety 1
LB1
Summary of Chemistry Changes from Baseline by Visit
Summarize data in Blind Phase. 
ICH E3
IA SAC
3.43.
Safety 1
LB3
Summary of Chemistry Shifts from Baseline Relative to Normal 
Range
IA SAC
3.44.
Safety 1
LB15
Summary of Worst Case Chemistry Results Relative to Normal 
Range Post-Baseline Relative to Baseline
ICH E3
IA SAC
Laboratory: Hematology
3.45.
Safety 1
LB1
Summary of Haematology by Visit
Summarize data at Screening Visit
and in Blind Phase. 
IA SAC
3.46.
Safety 1
LB1
Summary of Hematology Changes from Baseline
Summarize data in Blind Phase. 
ICH E3
IA SAC
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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
3.47.
Safety 1
LB3
Summary of Hematology Shifts from Baseline Relative to 
Normal Range
IA SAC
3.48.
Safety 1
LB15
Summary of Worst Case Hematology Results Relative to Normal 
Range Post-Baseline Relative to Baseline
ICH E3
IA SAC
Laboratory: Urinalysis
3.49.
Safety 1
UR1
Summary of Worst Case Urinalysis Results (Discrete or 
Character Values) Post-Baseline Relative to Baseline
ICH E3
IA SAC
Laboratory: Hepatobiliary (Liver)
3.50.
Safety 1
LIVER1
Summary of Liver Monitoring/Stopping Event Reporting
This display will be presented if liver 
events occur. 
IA SAC
3.51.
Safety 1
LIVER10
Summary of Hepatobiliary Laboratory Abnormalities
IDSL
IA SAC
ECG
3.52.
Safety 1
EG1
Summary of ECG Findings 
Summarize data at Screening Visit 
and in Blind Phase. 
IDSL
IA SAC
3.53.
Safety 1
EG2
Summary of ECG Values
Summarize data at Screening Visit, 
in Blind Phase and at Final Visit.
IA SAC
3.54.
Safety 1
EG2
Summary of Change from Baseline in ECG Values by Visit
Summarize data in Blind Phase. 
IDSL
IA SAC
Vital Signs
3.55.
Safety 1
VS1
Summary of Vital Signs
Summarize data at Screening Visit 
and in Blind Phase. 
IA SAC
3.56.
Safety 1
VS1
Summary of Change from Baseline in Vital Signs
Summarize data in Blind Phase. 
ICH E3
IA SAC
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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
SpO2
3.57.
Safety 1
SAFE_T2
Summary of Value and Change from Baseline in SpO2
IA SAC
Exposure and Treatment Compliance
3.58.
Safety 1
SAFE_T3
Summary of Exposure to Study Treatment
ICH E3
IA SAC
3.59.
Safety 1
SAFE_T4
Summary of Extent of Exposure to Study Treatment by 
Treatment Cycle and Muscle Region
Include total arm in Open label 
phase only
IA SAC
3.60.
Safety 1
SAFE_T4
Summary of Extent of Exposure to Study Treatment by 
Treatment Cycle and Joint
Include total arm in Open label 
phase only
IA SAC
10.12.7.2. Final Analyses
Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Adverse Events (AEs)
3.61.
Safety 1
AE1
Summary of All Adverse Events by System Organ Class and 
Preferred Term in Overall Study Period
ICH E3
Treatment Emergent
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.62.
Safety 1
AE1
Summary of All Adverse Events by System Organ Class and 
Preferred Term in Blind Phase
Blind Phase (until second dose)
See the Section 10.4.2.
Two treatment arm (240 and 400U)
SAC
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Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
3.63.
Safety 1
AE1
Summary of All Adverse Events within 84 days from the initial 
dose by System Organ Class and Preferred Term in Blind Phase
Blind Phase (within 84 days)
See the Section 10.4.2. 
Two treatment arm (240 and 400U)
SAC
3.64.
Safety 2
AE1
Summary of All Adverse Events by System Organ Class and 
Preferred Term in Open Label Phase (2nd Treatment)
Open Label Phase (2nd Treatment)
See the Section 10.4.2.
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.65.
Safety 3
AE1
Summary of All Adverse Events by System Organ Class and 
Preferred Term in Open Label Phase (3rd Treatment)
Open Label Phase (3rd Treatment)
See the Section 10.4.2.
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.66.
Safety 4
AE1
Summary of All Adverse Events by System Organ Class and 
Preferred Term in Open Label Phase (4th Treatment)
Open Label Phase (4th Treatment)
See the Section 10.4.2.
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.67.
Safety 1
AE5A
Summary of All Adverse Events by Maximum Intensity by 
System Organ Class and Preferred Term in Overall Study 
Period
ICH E3
Treatment Emergent
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.68.
Safety 1
AE5A
Summary of All Adverse Events by Maximum Intensity by 
System Organ Class and Preferred Term in Blind Phase
Blind Phase (until second dose)
See the Section 10.4.2. 
Two treatment arm (240 and 400U)
SAC
3.69.
Safety 1
AE5A
Summary of All Adverse Events within 84 days from the initial 
dose by Maximum Intensity by System Organ Class and 
Preferred Term in Blind Phase
Blind Phase (within 84 days)
See the Section 10.4.2. 
Two treatment arm (240 and 400U)
SAC
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Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
3.70.
Safety 2
AE5A
Summary of All Adverse Events by Maximum Intensity by 
System Organ Class and Preferred Term in Open Label Phase 
(2nd Treatment)
Open Label Phase (2nd Treatment)
See the Section 10.4.2.
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.71.
Safety 3
AE5A
Summary of All Adverse Events by Maximum Intensity by 
System Organ Class and Preferred Term in Open Label Phase 
(3rd Treatment)
Open Label Phase (3rd Treatment)
See the Section 10.4.2.
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.72.
Safety 4
AE5A
Summary of All Adverse Events by Maximum Intensity by 
System Organ Class and Preferred Term in Open Label Phase 
(4th Treatment)
Open Label Phase (4th Treatment)
See the Section 10.4.2.
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.73.
Safety 1
AE3
Summary of Common (>=3%) Adverse Events by Overall 
Frequency in Overall Study Period
ICH E3
Treatment Emergent
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.74.
Safety 1
AE3
Summary of Common (>=3%) Adverse Events by Overall 
Frequency in Blind Phase
Blind Phase (until second dose)
See the Section 10.4.2. 
Two treatment arm (240 and 400U)
SAC
3.75.
Safety 1
AE3
Summary of Common (>=3%) Adverse Events within 84 days 
from the initial dose by Overall Frequency in Blind Phase
Blind Phase (within 84 days)
See the Section 10.4.2. 
Two treatment arm (240 and 400U)
SAC
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Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
3.76.
Safety 2
AE3
Summary of Common (>=3%) Adverse Events by Overall 
Frequency in Open Label Phase (2nd Treatment)
Open Label Phase (2nd Treatment)
See the Section 10.4.2.
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.77.
Safety 3
AE3
Summary of Common (>=3%) Adverse Events by Overall 
Frequency in Open Label Phase (3rd Treatment)
Open Label Phase (3rd Treatment)
See the Section 10.4.2.
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.78.
Safety 4
AE3
Summary of Common (>=3%) Adverse Events by Overall 
Frequency in Open Label Phase (4th Treatment)
Open Label Phase (4th Treatment)
See the Section 10.4.2.
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.79.
Safety 1
AE1
Summary of All Drug-Related Adverse Events by System Organ 
Class and Preferred Term in Overall Study Period
ICH E3
Treatment Emergent
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.80.
Safety 1
AE1
Summary of All Drug-Related Adverse Events by System Organ 
Class and Preferred Term in Blind Phase
Blind Phase (until second dose)
See the Section 10.4.2. 
Two treatment arm (240 and 400U)
SAC
3.81.
Safety 1
AE1
Summary of All Drug-Related Adverse Events within 84 days 
from the initial dose by System Organ Class and Preferred Term
in Blind Phase
Blind Phase (within 84 days)
See the Section 10.4.2. 
Two treatment arm (240 and 400U)
SAC
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Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
3.82.
Safety 2
AE1
Summary of All Drug-Related Adverse Events by System Organ 
Class and Preferred Term in Open Label Phase (2nd Treatment)
Open Label Phase (2nd Treatment)
See the Section 10.4.2.
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.83.
Safety 2
AE1
Summary of All Drug-Related Adverse Events by System Organ 
Class and Preferred Term in Open Label Phase (3rd Treatment)
Open Label Phase (3rd Treatment)
See the Section 10.4.2.
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.84.
Safety 2
AE1
Summary of All Drug-Related Adverse Events by System Organ 
Class and Preferred Term in Open Label Phase (4th Treatment)
Open Label Phase (4th Treatment)
See the Section 10.4.2.
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.85.
Safety 1
AE5A
Summary of All Drug-Related Adverse Events by System Organ 
Class and Preferred Term and Maximum Intensity in Overall 
Study Period
ICH E3
Treatment Emergent AE
See the Section 10.4.2
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.86.
Safety 1
AE5A
Summary of All Drug-Related Adverse Events by System Organ 
Class and Preferred Term and Maximum Intensity in Blind 
Phase
Blind Phase (until second dose)
See the Section 10.4.2. 
Two treatment arm (240 and 400U)
SAC
3.87.
Safety 1
AE5A
Summary of All Drug-Related Adverse Events within 84 days 
from the initial dose by System Organ Class and Preferred Term 
and Maximum Intensity in Blind Phase
Blind Phase (within 84 days)
See the Section 10.4.2. 
Two treatment arm (240 and 400U)
SAC
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Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
3.88.
Safety 2
AE5A
Summary of All Drug-Related Adverse Events by System Organ 
Class and Preferred Term and Maximum Intensity in Open Label 
Phase (2nd Treatment)
Open Label Phase (2nd Treatment)
See the Section 10.4.2.
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.89.
Safety 2
AE5A
Summary of All Drug-Related Adverse Events by System Organ 
Class and Preferred Term and Maximum Intensity in Open Label 
Phase (3rd Treatment)
Open Label Phase (3rd Treatment)
See the Section 10.4.2.
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.90.
Safety 2
AE5A
Summary of All Drug-Related Adverse Events by System Organ 
Class and Preferred Term and Maximum Intensity in Open Label 
Phase (4th Treatment)
Open Label Phase (4th Treatment)
See the Section 10.4.2
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.91.
Safety 1
AE3
Summary of Most Common Serious Drug Related Adverse 
Events by Overall Frequency in Overall Study Period
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.92.
Safety 1
AE2
Summary of Most Common Non-Serious Drug Related Adverse 
Events by Overall Frequency in Overall Study Period
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.93.
Safety 1
AE15
Summary of Common (>=5%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of Participant 
and Occurrences) in Overall Study Period
FDAAA, EudraCT
Treatment Emergent AE
See the Section 10.4.2
Three treatment arms (240, 400 and 
240 + 400U)
SAC
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Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Serious and Other Significant Adverse Events
3.94.
Safety 1
SAFE_T1
Summary of Adverse Events of Special Interest in Overall Study 
Period
Treatment Emergent AE
See the Section 10.4.2
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.95.
Safety 1
SAFE_T1
Summary of Adverse Events of Special Interest in Blind Phase
Blind Phase (until second dose)
See the Section 10.4.2. 
Two treatment arm (240 and 400U)
SAC
3.96.
Safety 1
SAFE_T1
Summary of Adverse Events of Special Interest within 84 days 
from the initial dose in Blind Phase
Blind Phase (within 84 days)
See the Section 10.4.2. 
Two treatment arm (240 and 400U)
SAC
3.97.
Safety 2
SAFE_T1
Summary of Adverse Events of Special Interest in Open Label 
Phase (2nd Treatment)
Open Label Phase (2nd Treatment)
See the Section 10.4.2
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.98.
Safety 3
SAFE_T1
Summary of Adverse Events of Special Interest in Open Label 
Phase (3rd Treatment)
Open Label Phase (3rd Treatment)
See the Section 10.4.2
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.99.
Safety 4
SAFE_T1
Summary of Adverse Events of Special Interest in Open Label 
Phase (4th Treatment)
Open Label Phase (4th Treatment)
See the Section 10.4.2
Three treatment arms (240, 400 and 
240 + 400U)
SAC
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Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
3.100.
Safety 1
AE1
Summary of Non-Fatal Serious Adverse Events in Overall Study 
Period
Treatment Emergent AE
See the Section 10.4.2
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.101.
Safety 1
AE1
Summary of Non-Fatal Serious Adverse Events in Blind Phase
Blind Phase (until second dose)
See the Section 10.4.2. 
Two treatment arm (240 and 400U)
SAC
3.102.
Safety 1
AE1
Summary of Non-Fatal Serious Adverse Events within 84 days 
from the initial dose in Blind Phase
Blind Phase (within 84 days)
See the Section 10.4.2. 
Two treatment arm (240 and 400U)
SAC
3.103.
Safety 2
AE1
Summary of Non-Fatal Serious Adverse Events in Open Label 
Phase (2nd Treatment)
Open Label Phase (2nd Treatment)
See the Section 10.4.2
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.104.
Safety 3
AE1
Summary of Non-Fatal Serious Adverse Events in Open Label 
Phase (3rd Treatment)
Open Label Phase (3rd Treatment)
See the Section 10.4.2
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.105.
Safety 4
AE1
Summary of Non-Fatal Serious Adverse Events in Open Label 
Phase (4th Treatment)
Open Label Phase (4th Treatment)
See the Section 10.4.2
Three treatment arms (240, 400 and 
240 + 400U)
SAC
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Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
3.106.
Safety 1
AE1
Summary of Drug-Related Non-Fatal Serious Adverse Events in 
Overall Study Period
Treatment Emergent AE
See the Section 10.4.2
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.107.
Safety 1
AE1
Summary of Drug-Related Non-Fatal Serious Adverse Events in 
Blind Phase
Blind Phase (until second dose)
See the Section 10.4.2. 
Two treatment arm (240 and 400U)
SAC
3.108.
Safety 1
AE1
Summary of Drug-Related Non-Fatal Serious Adverse Events 
within 84 days from the initial dose in Blind Phase
Blind Phase (within 84 days)
See the Section 10.4.2. 
Two treatment arm (240 and 400U)
SAC
3.109.
Safety 2
AE1
Summary of Drug-Related Non-Fatal Serious Adverse Events in 
Open Label Phase (2nd Treatment)
Open Label Phase (2nd Treatment)
See the Section 10.4.2
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.110.
Safety 3
AE1
Summary of Drug-Related Non-Fatal Serious Adverse Events in 
Open Label Phase (3rd Treatment)
Open Label Phase (3rd Treatment)
See the Section 10.4.2
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.111.
Safety 4
AE1
Summary of Drug-Related Non-Fatal Serious Adverse Events in 
Open Label Phase (4th Treatment)
Open Label Phase (4th Treatment)
See the Section 10.4.2
Three treatment arms (240, 400 and 
240 + 400U)
SAC
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Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
3.112.
Safety 1
AE16
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Participants and Occurrences) 
in Overall Study Period
FDAAA, EudraCT
Treatment Emergent AE
See the Section 10.4.2
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.113.
Safety 1
AE1
Summary of Adverse Events Leading to Withdrawal from Study
by System Organ Class and Preferred Term in Overall Study 
Period
IDSL
Treatment Emergent AE
See the Section 10.4.2
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.114.
Safety 1
AE1
Summary of Adverse Events Leading to Withdrawal from Study 
by System Organ Class and Preferred Term in Blind Phase
Blind Phase (until second dose)
See the Section 10.4.2. 
Two treatment arm (240 and 400U)
SAC
3.115.
Safety 1
AE1
Summary of Adverse Events Leading to Withdrawal from Study 
within 84 days from the initial dose by System Organ Class and 
Preferred Term in Blind Phase
Blind Phase (within 84 days)
See the Section 10.4.2. 
Two treatment arm (240 and 400U)
SAC
3.116.
Safety 2
AE1
Summary of Adverse Events Leading to Withdrawal from Study 
by System Organ Class and Preferred Term in Open Label 
Phase (2nd Treatment)
Open Label Phase (2nd Treatment)
See the Section 10.4.2.
Three treatment arms (240, 400 and 
240 + 400U)
SAC
3.117.
Safety 3
AE1
Summary of Adverse Events Leading to Withdrawal from Study 
by System Organ Class and Preferred Term in Open Label 
Phase (3rd Treatment)
Open Label Phase (3rd Treatment)
See the Section 10.4.2.
Three treatment arms (240, 400 and 
240 + 400U)
SAC
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Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
3.118.
Safety 4
AE1
Summary of Adverse Events Leading to Withdrawal from Study 
by System Organ Class and Preferred Term in Open Label 
Phase (4th Treatment)
Open Label Phase (4th Treatment)
See the Section 10.4.2.
Three treatment arms (240, 400 and 
240 + 400U)
SAC
Laboratory: Chemistry 
3.119.
Safety 1
LB1
Summary of Chemistry by Visit
Summarize data at Screening Visit, 
in Blind Phase and at Final Visit. 
SAC
3.120.
Safety 1
LB1
Summary of Chemistry Changes from Baseline by Visit
Summarize data in Blind Phase and 
at Final Visit. 
ICH E3
SAC
3.121.
Safety 1
LB3
Summary of Chemistry Shifts from Baseline Relative to Normal 
Range
SAC
3.122.
Safety 1
LB15
Summary of Worst Case Chemistry Results Relative to Normal 
Range Post-Baseline Relative to Baseline
ICH E3
SAC
Laboratory: Hematology
3.123.
Safety 1
LB1
Summary of Hematology by Visit
Summarize data at Screening Visit, 
in Blind Phase and at Final Visit. 
SAC
3.124.
Safety 1
LB1
Summary of Hematology Changes from Baseline
Summarize data in Blind Phase and 
at Final Visit. 
ICH E3
SAC
3.125.
Safety 1
LB3
Summary of Hematology Shifts from Baseline Relative to 
Normal Range
SAC
3.126.
Safety 1
LB15
Summary of Worst Case Hematology Results Relative to Normal 
Range Post-Baseline Relative to Baseline
ICH E3
SAC
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Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Laboratory: Urinalysis
3.127.
Safety 1
UR1
Summary of Worst Case Urinalysis Results (Discrete or 
Character Values) Post-Baseline Relative to Baseline
ICH E3
SAC
Laboratory: Hepatobiliary (Liver)
3.128.
Safety 1
LIVER1
Summary of Liver Monitoring/Stopping Event Reporting
This display will be presented if liver 
events occur. 
SAC
3.129.
Safety 1
LIVER10
Summary of Hepatobiliary Laboratory Abnormalities
IDSL
SAC
ECG
3.130.
Safety 1
EG1
Summary of ECG Findings 
Summarize data at Screening Visit, 
in Blind Phase and at Final Visit. 
IDSL
SAC
3.131.
Safety 1
EG2
Summary of ECG Values
Summarize data at Screening Visit, 
in Blind Phase and at Final Visit.
SAC
3.132.
Safety 1
EG2
Summary of Change from Baseline in ECG Values by Visit
Summarize data in Blind Phase and 
at Final Visit. 
IDSL
SAC
Vital Signs
3.133.
Safety 1
VS1
Summary of Vital Signs
Summarize data at Screening Visit, 
in Blind Phase and at Final Visit.
SAC
3.134.
Safety 1
VS1
Summary of Change from Baseline in Vital Signs
Summarize data in Blind Phase and 
at Final Visit. 
ICH E3
SAC
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Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
SpO2
3.135.
Safety 1
SAFE_T1
Summary of Value and Change from Baseline in SpO2
SAC
Exposure and Treatment Compliance
3.136.
Safety 1
SAFE_T3
Summary of Exposure to Study Treatment
ICH E3
SAC
3.137.
Safety 1
SAFE_T4
Summary of Extent of Exposure to Study Treatment by 
Treatment Cycle and Muscle Region
Include total arm in Open label 
phase only
SAC
3.138.
Safety 1
SAFE_T4
Summary of Extent of Exposure to Study Treatment by 
Treatment Cycle and Joint
Include total arm in Open label 
phase only
SAC
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10.12.8.
Safety Figures
10.12.8.1. Interim Analyses
Safety Figures
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable
Chemistry
3.1.
Safety1
SAFE_F1
Scatter plot of Chemistry at Week 12 versus Baseline in Blind 
Phase
IA SAC
Hematology
3.2.
Safety1
SAFE_F1
Scatter plot of Hematology at Week 12 versus Baseline in Blind 
Phase
IA SAC
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10.12.9.
ICH Listings
10.12.9.1. Interim Analyses
ICH: Listings
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable
Participant Disposition
1.
Screened
ES7
Listing of Reasons for Screen Failure
Journal Guidelines
IA SAC
2.
ITT1
ES2
Listing of Reasons for Study Withdrawal
ICH E3
IA SAC
3.
Screened
ES9
Listing of Participants Who Were Rescreened
IA SAC
4.
ITT1
BL1
Listing of Participants for Whom the Treatment Blind was 
Broken
ICH E3
IA SAC
5.
ITT1
TA1
Listing of Planned and Actual Treatments
IDSL
IA SAC
Protocol Deviations
6.
ITT1
DV2
Listing of Important Protocol Deviations 
ICH E3
IA SAC
7.
ITT1
IE3
Listing of Participants with Inclusion/Exclusion Criteria 
Deviations
ICH E3
IA SAC
Populations Analysed
8.
Enrolled
SP3
Listing of Participants Excluded from Any Population
ICH E3
IA SAC
Demographic and Baseline Characteristics
9.
ITT1
DM2
Listing of Demographic Characteristics
ICH E3
IA SAC
10.
ITT1
DM9
Listing of Race
ICH E3
IA SAC
Prior and Concomitant Medications
11.
ITT1
CM3
Listing of Medications
IDSL
IA SAC
12.
ITT1
POP_L1
Listing of Rehabilitation
IA SAC
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ICH: Listings
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable
13.
ITT1
Study Specific
Listing of Other Surgical Procedure
IA SAC
Exposure and Treatment Compliance
14.
ITT1
POP_L2
Listing of Exposure Data
ICH E3
IA SAC
Efficacy Endpoints
15.
ITT1
EFF_L1
Listing of Modified Ashworth Scales

Values

Changes from baseline

Responders
IA SAC
16.
ITT1
EFF_L1
Listing of Disability Assessment Scales

Values

Changes from baseline

Main Assessment Parameter
IA SAC
17.
ITT1
EFF_L1
Listing of Numeric Rating Scale for pain

Values in each joint 

Changes from baseline in only 
elbow joint
IA SAC
18.
ITT1
EFF_L1
Listing of Clinical Global Impression of Change

CGI by an investigator and a 
patient

Values
IA SAC
19.
ITT1
EFF_L2
Listing of Patient-Reported Benefit of Injection
IA SAC
20.
ITT1
EFF_L3
Listing of Time to Patient Reported Onset of Spasticity 
Symptom Relief
IA SAC
21.
ITT1
EFF_L3
Listing of Time to Qualification for Retreatment
IA SAC
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ICH: Listings
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable
Adverse Events
22.
Safety 1
AE8
Listing of All Adverse Events until Week 24 visit
ICH E3
Including Maximum Intensities,
Study Phases for Adverse Events
and AESI, SAE flag
IA SAC
23.
Safety 1
AE7
Listing of Participant Numbers for Individual Adverse Events
until Week 24 visit
ICH E3
IA SAC
24.
Safety 1
AE2
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text
IDSL
IA SAC
Serious and Other Significant Adverse Events
25.
Safety 1
AE8
Listing of Fatal Serious Adverse Events until Week 24 visit
ICH E3
Including Study Phases for 
Adverse Events
IA SAC
26.
Safety 1
AE8
Listing of Non-Fatal Serious Adverse Events until Week 24 visit
ICH E3
Including Study Phases for 
Adverse Events
IA SAC
27.
Safety 1
AE14
Listing of Reasons for Considering as a Serious Adverse Event
ICH E3
IA SAC
28.
Safety 1
AE8
Listing of Adverse Events Leading to Withdrawal from Study 
until Week 24 visit
ICH E3
Including Study Phases for 
Adverse Events
IA SAC
Hepatobiliary (Liver)
29.
Safety 1
MH2
Listing of Medical Conditions for Participants with Liver 
Stopping Events
This display will be presented if 
liver events occur. 
IA SAC
30.
Safety 1
SU2
Listing of Substance Use for Participants with Liver Stopping 
Events
This display will be presented if 
liver events occur. 
IA SAC
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ICH: Listings
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable
All Laboratory
31.
Safety 1
LB5
Listing of All Laboratory Data for Participants with Any Value 
Outside Normal Range
ICH E3
IA SAC
32.
Safety 1
LB14
Listing of Laboratory Data with Character Results
ICH E3
Except for urinalysis data
IA SAC
33.
Safety 1
UR2A
Listing of Urinalysis Data for Participants
ICH E3
IA SAC
SpO2
34.
Safety 1
VS4
Listing of SpO2
IA SAC
10.12.9.2. Final Analyses
ICH: Listings
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable
Participant Disposition
35.
ITT1
ES2
Listing of Reasons for Study Withdrawal
ICH E3
SAC
36.
Screened
ES9
Listing of Participants Who Were Rescreened
SAC
37.
ITT1
BL1
Listing of Participants for Whom the Treatment Blind was 
Broken
ICH E3
SAC
Protocol Deviations
38.
ITT1
DV2
Listing of Important Protocol Deviations 
ICH E3
SAC
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ICH: Listings
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable
Populations Analysed
39.
Enrolled
SP3
Listing of Participants Excluded from Any Population
ICH E3
SAC
Demographic and Baseline Characteristics
40.
ITT1
DM2
Listing of Demographic Characteristics
ICH E3
SAC
41.
ITT1
DM9
Listing of Race
ICH E3
SAC
Prior and Concomitant Medications
42.
ITT1
CM3
Listing of Medications
IDSL
SAC
43.
ITT1
POP_L1
Listing of Rehabilitation
SAC
44.
ITT1
Study Specific
Listing of Other Surgical Procedure
SAC
Exposure and Treatment Compliance
45.
ITT1
POP_L2
Listing of Exposure Data
ICH E3
SAC
Efficacy Endpoints
46.
ITT1
EFF_L1
Listing of Modified Ashworth Scales

Values

Changes from baseline

Responders
SAC
47.
ITT1
EFF_L1
Listing of Disability Assessment Scales

Values

Changes from baseline

Main Assessment Parameter
SAC
48.
ITT1
EFF_L1
Listing of Numeric Rating Scale for pain

Values in each joint

Changes from baseline in only 
elbow joint
SAC
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ICH: Listings
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable
49.
ITT1
EFF_L1
Listing of Clinical Global Impression of Change

CGI by an investigator and a 
patient

Values
SAC
50.
ITT1
EFF_L2
Listing of Patient-Reported Benefit of Injection
SAC
51.
ITT1
EFF_L3
Listing of Time to Patient Reported Onset of Spasticity 
Symptom Relief
SAC
52.
ITT1
EFF_L3
Listing of Time to Qualification for Retreatment
SAC
Adverse Events
53.
Safety 1
AE8
Listing of All Adverse Events
ICH E3
Including Maximum Intensities,
Study Phases for Adverse Events
and AESI, SAE flag
SAC
54.
Safety 1
AE7
Listing of Participant Numbers for Individual Adverse Events
ICH E3
SAC
55.
Safety 1
AE2
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text
IDSL
SAC
Serious and Other Significant Adverse Events
56.
Safety 1
AE8
Listing of Fatal Serious Adverse Events
ICH E3
Including Study Phases for 
Adverse Events
SAC
57.
Safety 1
AE8
Listing of Non-Fatal Serious Adverse Events
ICH E3
Including Study Phases for 
Adverse Events
SAC
58.
Safety 1
AE14
Listing of Reasons for Considering as a Serious Adverse Event
ICH E3
SAC
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ICH: Listings
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable
59.
Safety 1
AE8
Listing of Adverse Events Leading to Withdrawal from Study 
ICH E3
Including Study Phases for 
Adverse Events
SAC
Hepatobiliary (Liver)
60.
Safety 1
MH2
Listing of Medical Conditions for Participants with Liver 
Stopping Events
This display will be presented if 
liver events occur. 
SAC
61.
Safety 1
SU2
Listing of Substance Use for Participants with Liver Stopping 
Events
This display will be presented if 
liver events occur. 
SAC
All Laboratory
62.
Safety 1
LB5
Listing of All Laboratory Data for Participants with Any Value 
Outside Normal Range
ICH E3
SAC
63.
Safety 1
LB14
Listing of Laboratory Data with Character Results
ICH E3
Except for urinalysis data
SAC
64.
Safety 1
UR2A
Listing of Urinalysis Data for Participants
ICH E3
SAC
Other Safety
65.
Safety 1
EG3
Listing of All ECG values
SAC
66.
Safety 1
EG5
Listing of All ECG Findings
SAC
67.
Safety 1
VS4
Listing of Vital Signs
SAC
SpO2
68.
Safety 1
VS4
Listing of SpO2
SAC
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10.12.10. Patient Profiles
10.12.10.1. Final Analyses
Patient Profiles Listing
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable
69.
Safety1
IDSL standard
Listing of Investigator Reported Cardiovascular Events: 
Arrhythmias
This display will be presented if at 
least one event occurs.
SAC
70.
Safety1
IDSL standard
Listing of Investigator Reported Cardiovascular Events: 
Congestive Heart Failure
This display will be presented if at 
least one event occurs
SAC
71.
Safety1
IDSL standard
Listing of Investigator Reported Cardiovascular Events: 
Cerebrovascular Events/ Stroke and Transient Ischemic Attack
This display will be presented if at 
least one event occurs
SAC
72.
Safety1
IDSL standard
Listing of Investigator Reported Cardiovascular Events: Deep 
Vein Thrombosis/ Pulmonary Embolism
This display will be presented if at 
least one event occurs
SAC
73.
Safety1
IDSL standard
Listing of Investigator Reported Cardiovascular Events: 
Myocardial Infarction/ Unstable Angina
This display will be presented if at 
least one event occurs
SAC
74.
Safety1
IDSL standard
Listing of Investigator Reported Cardiovascular Events: 
Peripheral Arterial Thromboembolism
This display will be presented if at 
least one event occurs
SAC
75.
Safety1
IDSL standard
Listing of Investigator Reported Cardiovascular Events: 
Pulmonary Hypertension
This display will be presented if at 
least one event occurs
SAC
76.
Safety1
IDSL standard
Listing of Investigator Reported Cardiovascular Events: 
Revascularization
This display will be presented if at 
least one event occurs
SAC
77.
Safety1
IDSL standard
Listing of Investigator Reported Cardiovascular Events: 
Valvulopathy
This display will be presented if at 
least one event occurs
SAC
78.
Safety1
IDSL standard
Listing of Investigator Reported Events: Deaths
This display will be presented if at 
least one event occurs
SAC
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10.13.
Appendix 13: List of Preferred Terms / System Organ Class 
of Adverse Events of Special Interest
Adverse Events of Special Interest will be identified based on MedDRA version 20.1. 
10.13.1.
Convulsions and Seizures
This AESI will be identified using Convulsions (SMQ) with narrow scope. 
10.13.2.
Respiratory Adverse Events
This AESI will be identified using the System Organ Class and High Level Term as 
below. 
SOC: “Respiratory, thoracic and mediastinal disorders”
HLT: “Respiratory and pulmonary function diagnostic procedures”
10.13.3.
Possible Distant Spread of Toxin
This AESI will be identified using the Preferred Term as below. 
Accommodation disorder
Aspiration
Bradycardia
Botulism
Bulbar palsy
Constipation
Cranial nerve palsies multiple
Cranial nerve paralysis
Diaphragmatic paralysis
Diplopia
Dry mouth
Dysarthria
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Dysphagia
Dysphonia
Dyspnoea
Extraocular muscle paresis
Eyelid function disorder
Eyelid ptosis
Facial paresis
Facial paralysis
Hyporeflexia
Hypotonia
Illeus paralytic
Muscular weakness
Paralysis
Paresis cranial nerve
Pelvic floor muscle weakness
Peripheral nerve palsy
Peripheral paralysis
Pneumonia aspiration
Pupillary reflex impaired
Respiratory arrest
Respiratory depression
Respiratory failure
Speech disorder
Urinary retention
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Vision blurred
Vocal cord paralysis
Vocal cord paresis
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10.14.
Appendix 14: Decision Tree to determine Data cutoff visit and date
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