Study of SPARC1103 in Subjects With Spasticity
Phase: PHASE2
Conditions: Spasticity
Sponsor: Sun Pharma Advanced Research Company Limited

 
 
 
 
 
 
 
 
 
 
~Sun Pharma Advanced Research Company, LTD~ 
 
 
 
A Double-Blind, Randomized, Placebo-Controlled, Parallel Group Trial to 
 
 
 
 
 
 
 
 
 
 in Subjects 
with Spasticity due to Multiple Sclerosis (MS) 
 
 
 
  
 
Statistical Analysis Plan 
 
Version 1.0 
 
Prepared by: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 

  
 
 
Approved by  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
 
 
 
  
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 

  
REVISION HISTORY 
 
Version No. 
Version Date 
Description of Modifications 
0.1 
22Jul2014 
 
  
0.2 
28Apr2017 
 
 
0.3 
 
22May2017 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
1.0 
31May2017 
 
 
 
 

  
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................... VI 
1. 
INTRODUCTION ............................................................................................................ 7 
2. 
OBJECTIVES ................................................................................................................... 7 
3. 
INVESTIGATIONAL PLAN .......................................................................................... 7 
3.1. OVERALL STUDY DESIGN AND PLAN .................................................................................. 7 
3.2. STUDY ENDPOINTS ............................................................................................................. 8 
3.2.1. 
Efficacy Endpoints ...................................................................................................... 8 
3.2.2. 
Safety Endpoints.......................................................................................................... 8 
4. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................... 9 
4.1. SAMPLE SIZE ...................................................................................................................... 9 
4.2. RANDOMIZATION, STRATIFICATION, AND BLINDING .......................................................... 9 
4.3. ANALYSIS SETS ................................................................................................................ 10 
5. 
SUBJECT DISPOSITION ............................................................................................. 10 
5.1. DISPOSITION ..................................................................................................................... 10 
5.2. PROTOCOL DEVIATIONS ................................................................................................... 11 
6. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .................................. 11 
6.1. DEMOGRAPHICS ................................................................................................................ 11 
6.2. MS MEDICAL HISTORY .................................................................................................... 11 
6.3. NON-MS MEDICAL HISTORY ............................................................................................ 11 
6.4. INCLUSION AND EXCLUSION CRITERIA ............................................................................. 11 
7. 
TREATMENTS AND MEDICATIONS ....................................................................... 12 
7.1. PRIOR AND CONCOMITANT MEDICATIONS ........................................................................ 12 
7.2. STUDY TREATMENTS ........................................................................................................ 12 
8. 
EFFICACY ANALYSIS................................................................................................. 13 
8.1. PRIMARY EFFICACY ANALYSIS ......................................................................................... 13 
8.2. SECONDARY EFFICACY ANALYSES ................................................................................... 14 
8.2.1. 
Spasm Frequency ...................................................................................................... 14 
8.2.2. 
Night Time Awakening Score .................................................................................... 15 
8.2.3. 
CGIC ......................................................................................................................... 15 
8.2.4. 
SGIS .......................................................................................................................... 15 
9. 
SAFETY ANALYSIS ..................................................................................................... 15 
9.1. ADVERSE EVENTS ............................................................................................................. 16 
9.2. CLINICAL LABORATORY EVALUATIONS ........................................................................... 18 
9.3. VITAL SIGN MEASUREMENTS ........................................................................................... 19 
9.4. PHYSICAL EXAMINATION ................................................................................................. 19 
9.5. ELECTROCARDIOGRAM ..................................................................................................... 19 
9.6. C-SSRS ASSESSMENTS .................................................................................................... 19 
9.7. PREGNANCY TEST............................................................................................................. 20 

  
9.8. COMMENTS ....................................................................................................................... 20 
10. 
REFERENCES ................................................................................................................ 20 
11. 
APPENDICES ................................................................................................................. 21 
11.1. 
LIST OF TABLES ............................................................................................................. 21 
11.2. 
LIST OF LISTINGS .......................................................................................................... 24 
11.3. 
LIST OF FIGURES ........................................................................................................... 26 
11.4. 
ALGORITHM FOR IMPUTATION OF PARTIAL AND MISSING DATES ................................. 27 
11.5. 
SCHEDULE OF STUDY PROCEDURES .............................................................................. 29 
 
 

  
List of Abbreviations 
 
AE 
Adverse event 
 
 
 
 
 
 
 
 
CI 
Confidence interval 
 
 
 
 
 
 
CS 
Clinically significant 
 
 
 
 
  
ECG 
Electrocardiogram 
 
 
 
ITT 
Intent-to-treat 
LS 
Least square 
MedDRA 
Medical Dictionary for Regulatory Activities 
 
 
 
NCS 
Not clinical significant 
NE 
Not estimable 
PT 
Preferred term 
 
 
 
 
 
 
 
 
 
 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SD 
Standard deviation 
SE 
Standard error 
SGIS 
Subject’s Global Impression of Severity 
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 
WBC 
White blood cell 
WHODD 
World Health Organization Drug Dictionary 
 
 
 

  
1. Introduction 
 
The purpose of the Statistical Analysis Plan is to provide a framework that addresses the 
protocol objectives in a statistically rigorous fashion with minimized bias or analytical 
deficiencies. Specifically, this plan has the following purpose: 
 To prospectively (a priori) outline the types of analyses and data presentations that 
will address the study objectives outlined in the protocol. 
 To explain in detail how the data will be handled and analyzed, adhering to 
commonly accepted standards and practices of statistical analysis in the 
pharmaceutical industry. 
2. Objectives 
 
The objective of this trial is t
o
 
e
valuate the duration of act
i
o n
 
o
f
 
a single 30 or 60 mg dose
 
o
f
 
Baclofen ER Capsules (
Retentive S
 
)
 compared to placebo
 in 
alleviating spasticity 
o
v
e
r 24 hours following administration
. 
3. Investigational Plan 
3.1. Overall Study Design and Plan 
 
This is a double-blind, 
m
i
z
e
d
, placebo controlled, parallel group clinical trial
 
 a single 
2
4
 
hour pharmacodynamic evaluation period
, in subjects with spasticity 
due to MS.  
A
p
p
r
o
x i
m
a
tely 135 subjects will be enrolled in approximately 15 study sites
.  
Upon completion of informed consent, at the start of 
c
r eening (Visit 1, Days
 
21 to  1),
 
s
u
b
j
ects will be given appropriate wash
o
u
t , eligibility confirmed at endscreening
 
( V
i
s
i
t
 
2
,
 D
a
y
 
1), and eligible subjects will be randomized to one of three treatment groups:
 
o
f
e
n
 
E
R
 
C
a
p
s
u
l es (GRS) 30 mg, Baclofen ER Capsules (GRS) 60 mg, or placebo, in a  
1
:1
:
1  
r
a
t
i
o
.  Subjects randomized to Baclofen ER Capsules (GRS) will be up
t itrated in 10
 
m
g
 i
n
c
r e
m
e
n
t
s
 
e
v e r
y 3 days such that at the end of the 22 day period (Day 1 to Day 22),
 
s
u
b
j
e
c
t
s  
h a
v
e
 been receiving the target dose for at least 7 days. Subjects randomized to  
p
l
a
c
e
b
o
 
w
i
l
l
 
r
eceive placebo for the duration of the trial. On Day 23, subjects will be
 
h o u
sed in a research facility
 
f o
r a standardized meal
 
prior to  
. Safety and efficacy 
assessments will be performed according to the schedule of events in Section 11.5. 
 Day
 

  
 
o
r
 
2
5
,
 
subjects will be discharged from the study
 following the completion of exit 
assessments. 
3.2. Study Endpoints 
3.2.1. Efficacy Endpoints 
 
Primary Efficacy Endpoint:   
 
D
uration of effect
 
will be
 
a
s
sessed as improvement in  Total Modified Ashworth Score over 
time 
f
o
l
l
o
w
i
ng administration of Baclofen ER Capsules (GRS) or placebo
. The primary 
efficacy endpoint of the study is  
c
h
ange from baseline in  Total Modified Ashworth Scores 
o
f the six
 
l
o
w
er extremity muscle groups (
hip flex,
 
hip adduct
,
 knee flex
, knee
 ,
 
dorsi flex
 
a
nd plantar flex
 
o
f
 both lower limbs)
 assessed on Days 23 and 
24. 
Secondary Efficacy Endpoints:   
 
 
e
 from baseline
  spasm frequency   
 
C
h
ange from baseline in  nighttime awakening score 
 
g
r oup difference in post
 Clinical Global Impression of 
Change (CGIC) score on 
D
a
ys 23 and 24
 
 
g
r oup difference in post
 Subject’s Global Impression of 
Severity (SGIS) 
 
o
n
 
Days 23 and 24
 
3.2.2. Safety Endpoints 
 
 Adverse events (AEs)  
 Vital signs 
 12-lead electrocardiogram (ECG) 
 Laboratory tests 

  
 Columbia Suicide Severity Rating Scale (C-SSRS) 
4. General Statistical Considerations 
 
In general, continuous variables will be summarized with descriptive statistics (number of 
observations, mean, standard deviation, median, minimum, maximum, and 95% CI) and 
categorical variables will be summarized with count and percentage, unless otherwise 
specified. If there is only one observation, the standard deviation will be displayed as NE 
(Not Estimable). The p-values will be two-sided and rounded to four decimal places, and a 
significance level of alpha (α) = 0.05 will be used to reject the null hypothesis. Baseline 
will be defined as the last pre-dose non-missing measurement, unless specified otherwise.  
4.1. Sample Size 
 
 
t
r
e
a
t
m
e
n
t difference of 1.0 point on the Modified Ashworth Score
 
 
chosen for
 the
 
p
u
rposes of sample size
 .
  A  
s
t
a
ndard deviation (SD) of 1.2
 points
 
was assumed
 
b
a s
e
d
 
on a small study by Meythaler JM
 et al
  
I
n
 this study, 11
 
 
with disabling
 
l
o
w
e
r
 
e x
t
r
e
m
ity spastic hypertonia for more than a year after brain injury were randomized
 
 a double
blind, placebo
c
o
ntrolled crossover study to  ive
 
bolus intrathecal
 
i
n
j
e
c
t
ion of normal saline or baclofen 50 mcg.
  
T
h
e
 observed standard deviation range
 
 
0 .6 to 0.8.
  
 a
 standard deviation
 
of 1.2
 will
 
c
o
ver values up to  
% larger
 than
 
w
h at’s observed in Meythaler
 study.
  
To detect
 a t
r
e
atment difference of 1.0
 
b
a sed on a two
sample t
t e
s
t at the 0.05 significance
 
level (two
 31 evaluable subjects in each treatment group is required to provide 90% 
power, assuming a common standard deviation 
of 1.2
.  To account for the drop-out rate of 
30%, approximately 135 subjects will be randomized in this trial.   
4.2. Randomization, Stratification, and Blinding 
 
Eligible subjects will be randomized to receive lacebo,
 
Baclofen ER
 capsules
 
 
 or
 
Baclofen ER
 capsules
 
 
. Randomizati
o
n
 
will be performed centrally
 
in a  
 
f
ashion without stratification
.  
T
h
e
 
r
a
n
d
omization and blinding codes will be maintained by the
 
p
o
nsor or its designee
 who
  
i
n
d
e
p
e
n
dent of the trial team. The independent statistician will
 
h
a ve access to the
 
n
d
ing code and will
 
u
nblind individual subjects
 as required for regulatory reporting 

  
purposes. 
U
n l e
s
s
 
there is a medical emergency, the blind will
 not
 
be broken
 
until final
 
database lock.
  
4.3. Analysis Sets 
 
Two analysis sets will be used in this study: 
 The Intent-to-Treat (ITT) population consists of all subjects who are 
 
randomized to a treatment, who receive a
t
 
l
e
a
st one dose of study drug, and
 
h a
v
e
 
a
 
M
o dified Ashworth Score assessment (including Not Testable) at predose,
 
a n
d
 
a
t least two post dose assessme
. Subjects in this population will be analyzed 
according to the treatment they were randomized to, regardless of any dosing error. 
T
h
e
 
I
T
T population will be used for the
 
primary and
 
 
efficacy endpoints.
   
 
The safety
 
p o
p
ulation is defined as all
 randomized
 
 
w
h o
 receive at least one
 
d
o
se of study drug.
 
 i
n
 
t
h
i
s  population will be analyzed according to the
 
a
c
tual treatment they received.
 
A
l
l
 
s
a
fety analyses will be performed using the
 
safety population
. 
5. Subject Disposition 
 
5.1. Disposition 
 
Subject disposition will be listed and summarized for all enrolled subjects, by dose group 
and overall. The number and percentage of subjects who were screened, were randomized, 
and who are in the ITT and Safety populations will be summarized. The number and 
percent of subjects who completed and who discontinued the study will be summarized. 
The reasons for study discontinuation will be summarized for the categories below: 
 Adverse Event  
 Major Protocol Violation   
 Lost to Follow-Up  
 Worsening of Condition 

  
 Other Reasons 
5.2. Protocol Deviations 
 
Protocol violations (i.e., divergences from the inclusion and exclusion criteria, received 
excluded concomitant medications, received wrong treatment or incorrect dose, and those 
who developed withdrawal criteria but were not withdrawn) and deviations (i.e., non-
adherence to trial procedures or schedule) will be recorded on the CRF and tracked in a 
deviation log. Protocol violations will be summarized in a table for the ITT population, by 
dose group and overall. Protocol violations and deviations will be displayed in a listing. 
6. Demographics and Baseline Characteristics 
6.1. Demographics 
 
Subject demographics, including age, 
a
g
e
 g
roup (<65 and ≥ 65 years),
 sex, race and 
ethnicity, will be summarized with descriptive statistics for the ITT and Safety populations, 
by dose group and overall. Listings of individual subjects’ data will also be produced. 
6.2. MS Medical History 
 
The MS medical history at screening will be summarized by 
M
S
 type, MS duration,
 
n
tensity of MS,
 
b
enign or ma
lignant status,
 
r
e
a
t
m
ents for MS, total duration of treatment,
 
t
o
t
a
l
 
d
a
i
l
y dose of Baclofen and time since last dose of Baclofen
 
for the
 ITT and Safety 
Populations, by dose group and overall. This information will also be presented in a data 
listing. 
 
 
 
 
 
 
The n
MS m
e
d i
c
a
l
 
h
istory at screening (prior conditions and present conditions) w
ill be
 summarized
 by
 
S
y
s
t
e
m
 O
r
g
an Class and Preferred Term according to the latest version of
 
t
h
e
 
M
edical Dictionary for Regulatory Activities (MedDRA®)
 
f
o
r the Safety Population,
 
b
y
 
dose group and overall
.  A by
subject listing
 
with non
 history will also be created.   
6.4. Inclusion and Exclusion Criteria 
 

  
All inclusion/exclusion information on enrolled subjects will be included in a by-patient 
listing.  The listing will include a flag indicating whether all criteria were satisfied.  For 
subjects who did not satisfy the criteria, the criteria number will be listed with the 
deviation 
7. Treatments and Medications 
7.1. Prior and Concomitant Medications 
 
A medication will be categorized as prior medication if the medication end date is before 
the first dose date.  A medication will be categorized as a concomitant medication if the 
medication end date is after the first dose date or is ongoing at study completion. If the 
start or end date of a medications is missing, it will be imputed as described in Appendix 
11.4. All prior and concomitant medications will be coded to Anatomical Therapeutic 
Chemical (ATC) Class 3 and Preferred Name according to the latest version of the World 
Health Organization Drug Dictionary (WHODD).  
The number and percentage of subjects in the Safety population taking prior or 
concomitant medications will be summarized by ATC class and Preferred Name in two 
separate tables, by dose group and overall. In addition, the prior medications for MS and 
spasticity, and the medications subjects washed out from in order to enter the study, as well 
as neurological and anti-spasticity concomitant medications, and concomitant medications 
present at Day 23 check-in will be summarized separately. Antispasticity and neurological 
medications will be identified via a Medial Monitor review of coded terms prior to 
database lock. Subject listings of prior and concomitant medications will be provided. The 
medications taken within 30 days prior to the screening visit will be listed in a separate 
listing. 
7.2. Study Treatments 
 
Duration of
 
e x
p
o
s
u
r
e
 i
s  
defined as the total number of days a subject is exposed to  the
 
study drug
.  
I
t
 will be calculated as
 
(
Last Dose Date
  
First Dose
 
D ate + 1)
, where
 
he first
 
d
ose date is  
a ssumed to be
 
Day 1  
(Visit 2)
  Duration of exposure will be summarized 
descriptively using number, mean, standard deviaion, median, minimum and maximum at 
Day 1
,
 
Day 23 check
i
n
,
 
and Day 23 supervised dosing
 
for t
h
e Safety population
, by 
dose group and overall.  Counts and percentages will be provided for subjects exposed for 
1
0 days, 1
2
2
 days, and 1
23 days.
 

  
Study treatment compliance rate will be calculated as the ratio of the total number of 
tablets taken to the total number of tablets assigned, where the total number of tablets 
taken is (
N
u
mber of Tablets Dispensed
  
N
u
mber of Tablets Returned
).  Percent
 
 
w
i
l
l be summarized descriptively for
 
 
 
 
,
 Days 1
22, at  
Day 23
,
 
a nd up to Day
 
 overall
 
).  T
i
m
e from the meal
 in minutes
 
o
n Day 23
 
will be
 
s
u
mmarized with descriptive statistics.
  The
 
n
u
m
ber and percentage of subjects
 
w
ho are compliant
 
a c
c
o
r
d
i n
g to the following categories: <75%, ≥75% to ≤125%, and 
 
>
1
25%, will be summarized
 
for Day
 
10, Day
 22,
 
Days 1
22, at  
Day 23
,
 
and up to  
Day 23
 
 
. A subject listing of study treatment compliance will be 
provided.  
8. Efficacy Analysis 
 
This is a pharmacodynamic study. Analysis of the primary pharmacodynamic endpoint, the 
Modified Ashworth Score, is described in Section 8.1. Analyses for the secondary 
endpoints, spasm frequency, nighttime awakening due to spasms, CGIC and SGIS are 
described in Sections 8.2. The primary and secondary efficacy analyses will be based on 
the ITT population. 
8.1. Primary Efficacy Analysis 
 
E
a
c
h
 
B
a
c
l
o f
e
n ER Capsules (GRS) treatment group will be compared to placebo. As the
 
p
u
r
p o se of the trial is to determine
 the duration of effect, p-values will be used as a guide; 
a hierarchical approach to the analysis of time points will be used as described below. For 
these reasons, the p-values will not be adjusted for the multiple comparisons performed. 
The baseline total Modified Ashworth Score is defined as the total score at 
Day 1  
(Visit 2)
. 
Statistical significance of 
group (
p
l
acebo versus each Baclofen
 
ER Capsules
 
[GRS] group
), time
m
atched differences in  the
 mean
 
c
h
ange from baseline in  total 
Modified Ashworth Score will be assessed. At each time point, the change from baseline 
will be computed. A hierarchical testing procedure will be used to assess duration of effect 
separately for each dose level. 
F
i
r
s
t
,
 
an analysis of covariance (ANCOVA) model will be
 
 
w
i
t
h  
c
h
a
n
g
e
 from baseline to hour 24 as the dependent variable, treatment group
 
as a  
factor, baseline
 total Modified Ashworth Score as a covariate, and the interaction between 
treatment group and baseline Modified Ashworth Score. I
f
 
the difference between active
 
a
n d
 
p l
acebo is statistically significant at hour 24,
 
f
i
r
st for the 60 mg
 
d
o
s
e, then for the 30
 

  
mg dose,
 
t
h
e
n
 
t
h
e  
d
u
r a
t
i
on of effect will be concluded to be 24 hours. If not, the same type
 
o
f
 
m
o
d
e
l
 
w i
l
l
 
b
e fit using the change from baseline to hour 22 as the dependent variable
. 
This procedure will be continued until reaching a time point at which the difference 
between active and placebo is statistically significant.  
F
or calculation of
 
the Modified
 
A
s
h
w
o
r
t
h score, the following scores will be assigned to  
e
a
ch category of the
 
odified Ashworth
 cale:
 
Not Testable=NA,
 0  = 0 units,
 
1 = 1 unit,
 
1 +
=
 2
 
u n
i
t s, 2= 3 units, 3= 4 units, 4= 5 units
  
T
h
e  
t
o
t
al score is the sum of the score
 o f 
t h
e
 
6
 
l
o
w
e
r extremity muscle groups on both left and right sides
 
( range = 0.
  
In the
 
p
rimary analysis, i f  
3
 
o
r
 
l
ess of the 12 scores are missing
 
(
i
.
e., not testable), then the
 
missing score
 
w
ill be imputed
 
 
t
h
e
 
average of the remaining non
missing scores.
  I f 
m
ore than 3  
m
u
scle group scores are
 missing,
 then
 
t
h
e total score will
 
b
e set to  missing.
  
A s
 a sensitivity check
 
o
n the results,
 a supp
l
e
m
e
ntal analysis will be performed with
 the
 
t
o
t a
l  
s
c
o
r
e
 
s et to missing if any of the 12 muscle group scores is missing
. The
 observed
 
s
c
o
r
e
 
and change from baseline will be summarized
 
with descriptive
 
statistics for
 
e
a
c
h
 
timepoint. From the ANCOVA model, t
h
e
 
e
stimate of the Least Square
 
(
LS) mean difference
 
b
e
t
ween active and placebo in  
c
hange from baseline
, the 
corresponding standard error (SE), 95% Confidence Interval (CI), and the p-value 
representing the significance of treatment effect will be displayed for each timepoint in a 
separate table. The observed score and change from baseline will be displayed in separate 
boxplots by time points. 
8.2. Secondary Efficacy Analyses 
 All
 
s
econdary efficacy analyss
 
will be
 
p
e
r
f
ormed based on the ITT population
. For the 
spasm frequency and nighttime awakening score, baseline is the measurement taken at the 
screening visit.  
8.2.1. Spasm Frequency 
 
The 
o
b
served and change from
 baseline spasm 
 will be summarized by visit.  
Statistical significance of treatment difference (placebo
 versus
 
 
 
ER Capsules
 
 )
  
c
h
a n
g
e
 
from baseline to Day 23 evening and 24
hour post
d
o
se on Day 24
 
w
ill be assessed.
 
ANCOVA model
 
w
ill be fit
 
w
i
t
h  
c
hange from baseline to Day 23 and
 
D
a
y
 
2
4 as the dependent variables, t
r
e
a t
m
e
nt group as a factor, baseline spasm frequenc
 

  
a s a covariate
,
 
a
n
d
 
t
h
e
 interaction between treatment group and baseline spasm frequency
. 
T
h
e
 
e
stimate of the LS mean difference
 
b
e
t
w
een each Baclofen group and placebo
, the
 corresponding
 
, 95% CI, and the p-value representing the significance of treatment 
effect will be displayed in a table. The change from baseline in spasm frequency will be 
displayed in histograms for each treatment group by visit. The actual score will be listed in 
a data listing. 
8.2.2. Night Time Awakening Score 
 
The nighttime awakening score will be summarized in the same way as spasm frequency. 
A
n
 
A
NCOVA model will be fit
 
h
 
c
h a
n
g
e
 from baseline to Day 24 as the dependent
 
,
 
t
r e
atment group as a factor, baseline
 
nighttime aw
akening score
 
a s a covariate,
 
a
n
d
 
t
h
e
 
interaction between treatment group and baseline awakening score
. The observed 
scores will be listed in a data listing. The change from baseline in nighttime awakening 
score will be displayed in histograms for each treatment group by visit.  
8.2.3. CGIC 
 
The CGIC at 
D
a
y
 23 and Day 24
 
will be
 summarized
 
b
y treatment group
 
i
ng counts and
 
p
ercentage for t
h
e categorical outcomes
 
(
1
=
Very Much Improved, 2=Much Improved,
 
3
=
M
i
n
imally Improved, 4=No Change, 5=Minimally Worse, 6=Much
 
Worse, 7=Very
 
Much Worse).
 
Treatment difference
 
p
l
acebo versus each Baclofen
 
E
R Capsules [GRS]
 
 i
n
 
CGIC will be tested
 using
 
two separate
 exact
 
square exact
 .
 
The CGIC
 
s
c
o
r
e will also be shown in  
h
i
s
tograms by treatment and visit
. 
8.2.4. SGIS 
 
The SGIS will be summarized in the same way as the CGIC for the categorical outcomes 
1
=
N
o
r
m
al, No Spasticity, 2=Borderline Spasticity, 3=Mild Spasticity, 4=Moderate
 
S
p
a
s
t
i
city, 5=Marked Spasticity, 6=Severe Spasticity, 7=Worst Spasticity Imaginable
. The
 
 
s
c
o
r
e  also will be shown in histograms
. 
 
9. Safety Analysis 
 

  
Safety evaluations will be based on the incidence, severity, and causality of AEs, vital 
signs, Columbia-Suicide Severity Rating Scale C-SSRS, electrocardiogram (ECG), and 
clinical laboratory results. The safety analysis for female subjects will also include urine 
pregnancy results. All safety analyses will be conducted on the Safety population. 
9.1. Adverse Events 
 
Treatment-emergent adverse events (TEAEs) will be used for summary and analysis 
purposes.  A TEAE is defined as: any new event that occurred 
 
 
, a condition that existed before drug administration but increased in 
severity, or a condition that existed prior to drug treatment but increased in frequency of 
occurrence.  A treatment-emergent serious adverse event (SAE) is defined as any 
treatment-emergent event that results in death, is immediately life threatening, requires 
inpatient hospitalization or prolongation of existing hospitalization, results in persistent or 
significant disability/incapacity, is a congenital anomaly/birth defect, or is an important 
medical event.  TEAEs will be recorded 
b
y
 the clinical site
 
u p
 
t
o
 
30 days after the end o f 
treatment and
 will be coded to System Organ Class (SOC) and Preferred Terms (PTs) using 
the latest version of of MedDRA®.  
A treatment-related AE is an event that is considered possibly or probably related to study 
drug, in the judgment of the investigator.  If the AE start date is missing, it will be imputed 
as described in Appendix 11.4.  
The following summaries of AEs by SOC and PT will be provided: 
 Overall TEAE summary, including: 
o Incidence of subjects with one or more TEAE 
o Incidence of TEAEs by highest relationship 
o Incidence of TEAEs by highest severity 
o Incidence of TEAEs by action taken 
o Incidence of TEAEs by outcome 
o Incidence of treatment-emergent SAEs 

  
 TEAEs by SOC and PT 
 TEAEs by descending order of frequency of PTs 
 TEAEs by SOC and PT and highest relationship to treatment 
 Treatment-related TEAEs by SOC and PT 
 TEAEs by SOC and PT and highest severity 
 Treatment-related TEAEs by SOC and PT and highest severity 
 TEAEs by SOC and PT and sex 
 TEAEs by SOC and PT and age group 
 TEAEs by SOC and PT and race 
 TEAEs by SOC and PT and frequently used concomitant medications (i.e., 
medications used by 20% or more of the subjects overall) 
 TEAEs by SOC and PT and concomitant medications present on 
Day 23
 
 TEAEs leading to treatment discontinuation by SOC and PT 
 SAEs by SOC and PT 
 Fatal SAEs by SOC and PT 
 Treatment-related SAEs by SOC and PT 
At each level of summarization, a subject will be counted only once for each AE he/she 
experiences within that level. For the summary by relationship, if a subject has more than 
one AE on different levels, the most related AE will be counted. For the summary by 
severity, if a subject has more than one AE on different levels, the most severe AE will be 
summarized in the table. All summaries by SOC/PT will be presented in the descending 
order of frequency in the total column (i.e., all treatment groups combined). Data listings 
will be provided for all AEs, SAEs, and AEs leading to study drug discontinuation. 

  
9.2. Clinical Laboratory Evaluations 
 
Clinical laboratory tests performed at screening and Day 24 include the following:  
 
Hematology:  
 
 Red blood cell indices, including RBC count and hemoglobin  
 
 Total WBC count  
 
 Differential WBC count  
 
 Platelet count  
 
Serum chemistry:  
 
 Sodium  
 
 Potassium  
 
 Chloride  
 
 BUN  
 
 Creatinine 
  
A central laboratory will be used for chemistry and hematology testing. Values outside the 
laboratory normal ranges (see Appendix 11.6) as well as those considered clinically 
significant by the investigator are to be flagged as L (low) or H (high). Chemistry and 
hematology results will be displayed in separate data listings with abnormal values flagged. 
The numerical results of laboratory tests will be summarized separately for Chemistry and 
Hematology, including observed values, change from baseline, and shift from baseline for 
the L/H/Normal flags. For change from baseline summaries at 
Day 24,
 only subjects with 
data present at both screening 
a
nd Day 24
 will be summarized. Due to subject dropout, this 
will generally reflect a smaller sample than at screening. Therefore, at 
Day 24
 an additional 
baseline mean and standard deviation summary will be provided for those subjects present. 
The investigators will assign a rating of not clinically significant (NCS) or clinically 
significant (CS) to all laboratory values. The CS clarification requires reporting of the 
laboratory event as an AE. Clinically significant results will be flagged in data listings. 

  
9.3. Vital Sign Measurements 
 
Seated diastolic and systolic blood pressures and resting pulse measurements at baseline 
and each post-baseline timepoint will be summarized using descriptive statistics. Similarly, 
change from baseline to 
Day 1,  
D
ay 23 pre
dose, 3
h
ours and 24
h
ours post dose
 will also 
be summarized. Change from baseline summaries will use subjects who have both a 
baseline and a post-baseline value present and will include an additional baseline mean and 
standard deviation summary for those subjects present. The change from baseline for vital 
sign measurements will be shown in a boxplot. The investigators will assign a rating of 
NCS or CS to all vital sign values. The CS clarification requires reporting of the vital sign 
value as an AE. Vital sign values will be displayed in a data listing with CS results flagged. 
9.4. Physical Examination 
 
Physical examinations will be performed at screening, the beginning of 
Day 23
 and the end 
of 
ay 24
. The results will be displayed in a data listing. 
9.5. Electrocardiogram 
 
ECG recordings will be collected at screening, 
Day 1 , 
w i
thin 2 hours pre
d
o
se on Day 23
, 
3
 
h
o
u
r
s
 
p
ost dose on Day 23, and 24 hours post
d
o
se on Day 24
. ECG measurements will 
be collected in triplicate, 2
 
m
i
n
u
t es apart, and the average of 3 readings
 will be calculated 
for ECG intervals (QT, PR, RR QRS, ventricular rate). The QT interval will be corrected 
for heart rate using Fridericia’s correction (QTcF) and Bazett’s correction (QTcB). ECG 
intervals will be summarized using descriptive statistics. In addition, change from baseline 
in ECG intervals and shift from baseline in overall ECG interpretation (Normal, Abnormal 
– NCS, Abnormal – CS) will be provided. Change from baseline summaries will use 
subjects who have both a baseline and a post-baseline value present and will include an 
additional baseline mean and standard deviation summary for those subjects present. All 
ECG results will be displayed in a data listing and the ECG abnormalities will be flagged 
out. 
 
9.6. C-SSRS Assessments 
 

  
The C-SSRS is assessed at screening and 
Day 24
 and results will be summarized for the 
Safety Population. The suicidal ideation and suicidal behavior results will be displayed in a 
listing. The number and percentage of subjects who answered yes to each of the five 
categories in suicidal ideation and suicidal behavior will be summarized.  
Suicidal ideation score is defined as the maximum suicidal ideation category present for 
the assessment.  A
 
s
core of zero wi
l
l
 b
e
 assigned if no ideation is present.
  
Serious suicidal
 
i d
e
a t
i
o
n
 i
s defined as a suicidal ideation score of 4 or 5 .  The number and percentage of 
subjects with any decrease in suicidal ideation score 
from baseline
 
(i.e., improvement)
, any
 
increase in  
a
l
 
ideation score from baseline
 
(i.e., treatment
e
mergent suicidal ideation),
 
 
r
e
a
se from score of 0
3  
t
o score of 4
 
(i.e., treatment
e
mergent serious suicidal
 
,
 
a
n
d
 
a n y
 
increase from score of 0 to score of 45
 
(
i
.e., emergence of serious
 
suicidal ideation)
 will be summarized.  
Similarly, suicidal behavior score i
s
 
d
e
f
ined as the maximum suicidal behavior category
 
p
r
esent for the assessment.
  
E
m
e
r g
e
n
c
e of suicidal behavior is defined as the occurrence o f 
suicidal behavior
 
 
f
r
o
m not having suicidal behavior
 at baseline.
 
The number
 percentage
 
of patients
 
w
ith emergence of
 
suicidal behavior
 will be summarized.  
 displaying
 
s
uicidal ideation score
 
a
nd suicidal behavior
 score
 for
 
Visit 1  
 
Day 24
 will be constructed.  
9.7. Pregnancy Test 
 
Urine pregnancy test results for female subjects will be displayed in a listing. 
9.8. Comments 
 
Comments will be listed with the eCRF section they are associated with noted. 
 
10. References 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
. 

  
11. Appendices 
 
11.1. 
List of Tables 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
   
 
 
 
 
 
   
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
   
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
   
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 

  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
   
 
 
 
 
 
  
 
   
 
 
 
 
 
 
  
 
   
 
 
 
 
 
 
  
 
   
 
 
 
 
  
 
   
 
 
 
 
  
 
   
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 f 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 

  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 

  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
11.2. 
List of Listings 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
   
 
 

  
 
 
 
 
 
 
 
 
  
 
  
 
 
 
   
 
 
 
 
 
 
 
 
 
  
   
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
   
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
   
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 

  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
11.3. 
 List of Figures 
 
Number 
Title 
Figure 
14.2.1.1.1 
 
 
 
 
 
 
 
 
 
Figure 
14.2.1.1.2 
 
 
 
 
 
 
 
 
 
  
 
 
Figure 
14.2.2.1.1 
 
 
 
 
 
  
 
   
Figure 
14.2.3.1.1 
 
 
 
 
 
 
  
 
   
Figure 
14.2.4.1.1 
 
 
  
 
   
Figure 
14.2.5.1.1 
 
 
  
 
   
Figure 
14.3.4.3.1 
 
 
 
 
 
 
  
 
 
Figure 
14.3.4.5.1.1 
 
 
 
  
 
   
 

  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 

  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 

  
 
 
11.5. 
Schedule of Study Procedures 
 
Activities   /   Visit 
Days 
   
  
 
 
 
 
 
   
 
 
 
  
 
   
 
 
 
 
 
 
  
 
 
 
 
 
 
 
Phone  call  
10
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Washout2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and 
medication history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Urine pregnancy test 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Physical examination 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Clinical laboratory 
tests3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
12-lead ECG 
X 
X 
 
X4 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X
5 
 
 
Vital sign 
measurements6 
X 
X 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study medication 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dosing under 
supervision 
 
 
 
 
 
 
 
 
X
7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Modified Ashworth 
score 
 
X 
 
X8 
 
 
X 
 
 
 
X 
 
X 
 
X X 
 
X 
 
X 
 
Clinical Global 
Impression of Change 
(CGIC) 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Subject Global 
Impression of Severity 
(SGIS) 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
AE evaluation 
 
 
 
X 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Record spasm 
frequency9 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Record nighttime 
awakening due to 
spasm score 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Record concomitant 
medication 
X 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Meals10 
 
 
 
 
X
11a 
 
 
X
11
 
X
11
 
X
11
 
X
11
 
 
X1
1f 
 
X
11
 
 

  
Activities   /   Visit 
Days 
   
  
 
 
 
 
 
   
 
 
 
  
 
   
 
 
 
 
 
 
  
 
 
 
 
 
 
 
Phone  call  
10
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
b 
c 
d 
e 
g 
 
1Subject will check-out of the clinic following the 
 
 
 
 
. 
2Subjects will be required to be currently receiving 
 
 
 prior to enrollment, and 
 
 
  
 
  
 
  
 
 
 
 
  
 
 
 
 
 
 
k
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
f
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
p
 
  
 
  
 
 
 
 
   
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
3Hematology: red blood cell (RBC) count, hemoglobin, total white blood cell (WBC) count, differential WBC count, 
platelet count; serum chemistry: sodium, potassium, chloride, blood urea nitrogen (BUN), creatinine. 
4Within 2 hours p
 
 
 
 
523 or 24 hours post-dose 
6Within 10 minutes of 12-lead ECG 
7Dosing at time “0  
 
 
 
 
 
 
 
8Within 2 hours pre-dose 
9Spasm frequency assessment 
 
 
   
  
 
 
 
 
 
 
 
 
h
 
 
 
 
 
 
  
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
  
 
   
 
 
  
p
 
 

  
 
11.6  Lab Normal Ranges 
 
 
 
 
  
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
p  
 
 
 
 
 
 
 
 
 
f  
 
 
 
 
 
 
f  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
f